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Authorship：Lead author   Language：English   Publisher：Journal of the American College of Cardiology  

Background: Conventional time-to-first-event analyses cannot incorporate recurrent hospitalizations and patient well-being in a single outcome. Objectives: To overcome this limitation, we tested an integrated measure that includes days lost from death and hospitalization, and additional days of full health lost through diminished well-being. Methods: The effect of dapagliflozin on this integrated measure was assessed in the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) trial, which examined the efficacy of dapagliflozin, compared with placebo, in patients with NYHA functional class II to IV heart failure and a left ventricular ejection fraction ≤40%. Results: Over 360 days, patients in the dapagliflozin group (n = 2,127) lost 10.6 ± 1.0 (2.9%) of potential follow-up days through cardiovascular death and heart failure hospitalization, compared with 14.4 ± 1.0 days (4.0%) in the placebo group (n = 2,108), and this component of all measures of days lost accounted for the greatest between-treatment difference (−3.8 days [95% CI: −6.6 to −1.0 days]). Patients receiving dapagliflozin also had fewer days lost to death and hospitalization from all causes vs placebo (15.5 ± 1.1 days [4.3%] vs 20.3 ± 1.1 days [5.6%]). When additional days of full health lost (ie, adjusted for Kansas City Cardiomyopathy Questionnaire–overall summary score) were added, total days lost were 110.6 ± 1.6 days (30.7%) with dapagliflozin vs 116.9 ± 1.6 days (32.5%) with placebo. The difference in all measures between the 2 groups increased over time (ie, days lost by death and hospitalization −0.9 days [−0.7%] at 120 days, −2.3 days [−1.0%] at 240 days, and −4.8 days [−1.3%] at 360 days). Conclusions: Dapagliflozin reduced the total days of potential full health lost due to death, hospitalizations, and impaired well-being, and this benefit increased over time during the first year. (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure; NCT03036124)

DOI： 10.1016/j.jacc.2024.03.385

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Authorship：Lead author   Language：English   Publisher：Nature Medicine  

Win statistics offer a new approach to the analysis of outcomes in clinical trials, allowing the combination of time-to-event and longitudinal measurements and taking into account the clinical importance of the components of composite outcomes, as well as their relative timing. We examined this approach in a post hoc analysis of two trials that compared dapagliflozin to placebo in patients with heart failure and reduced ejection fraction (DAPA-HF) and mildly reduced or preserved ejection fraction (DELIVER). The effect of dapagliflozin on a hierarchical composite kidney outcome was assessed, including the following: (1) all-cause mortality; (2) end-stage kidney disease; (3) a decline in estimated glomerular filtration rate (eGFR) of ≥57%; (4) a decline in eGFR of ≥50%; (5) a decline in eGFR of ≥40%; and (6) participant-level eGFR slope. For this outcome, the win ratio was 1.10 (95% confidence interval (CI) = 1.06–1.15) in the combined dataset, 1.08 (95% CI = 1.01–1.16) in the DAPA-HF trial and 1.12 (95% CI = 1.05–1.18) in the DELIVER trial; that is, dapagliflozin was superior to placebo in both trials. The benefits of treatment were consistent in participants with and without baseline kidney disease, and with and without type 2 diabetes. In heart failure trials, win statistics may provide the statistical power to evaluate the effect of treatments on kidney as well as cardiovascular outcomes.

DOI： 10.1038/s41591-024-02941-8

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DOI： 10.1056/EVIDoa2300042

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Authorship：Lead author   Language：English   Publisher：Circulation  

BACKGROUND: Recent guidelines proposed a classification for heart failure (HF) on the basis of left ventricular ejection fraction (LVEF), although it remains unclear whether the divisions chosen were biologically rational. Using patients spanning the full range of LVEF, we examined whether there was evidence of LVEF thresholds in patient characteristics or inflection points in clinical outcomes. METHODS: Using patient-level information, we created a merged dataset of 33 699 participants who had been enrolled in 6 randomized controlled HF trials including patients with reduced and preserved ejection fraction. The relationship between the incidence of all-cause death (and specific causes of death) and HF hospitalization, and LVEF, was evaluated using Poisson regression models. RESULTS: As LVEF increased, age, the proportion of women, body mass index, systolic blood pressure, and prevalence of atrial fibrillation and diabetes increased, whereas ischemic pathogenesis, estimated glomerular filtration rate, and NT-proBNP (N-terminal pro-B-type natriuretic peptide) decreased. As LVEF increased >50%, age and the proportion of women continued to increase, and ischemic pathogenesis and NT-proBNP decreased, but other characteristics did not change meaningfully. The incidence of most clinical outcomes (except noncardiovascular death) decreased as LVEF increased, with a LVEF inflection point of around 50% for all-cause death and cardiovascular death, around 40% for pump failure death, and around 35% for HF hospitalization. Higher than those thresholds, there was little further decline in the incidence rate. There was no evidence of a J-shaped relationship between LVEF and death; no evidence of worse outcomes in patients with high-normal ("supranormal") LVEF. Similarly, in a subset of patients with echocardiographic data, there were no structural differences in patients with a high-normal LVEF suggestive of amyloidosis, and NT-proBNP levels were consistent with this conclusion. CONCLUSIONS: In patients with HF, there was a LVEF threshold of around 40% to 50% where the pattern of patient characteristics changed, and event rates began to increase compared with higher LVEF values. Our findings provide evidence to support current upper LVEF thresholds defining HF with mildly reduced ejection fraction on the basis of prognosis. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT00634309, NCT00634400, NCT00634712, NCT00095238, NCT01035255, NCT00094302, NCT00853658, and NCT01920711.

DOI： 10.1161/CIRCULATIONAHA.122.063642

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Authorship：Corresponding author   Language：English   Publisher：American Heart Journal  

Background: We examined the relationship between annual case volume at each hospital and outcome in cardiogenic shock (CS) patients receiving mechanical circulatory support (MCS) devices. Methods: This cross-sectional study used the Japanese nationwide database to identify patients receiving short-term MCS for CS between April 2012 and March 2020. Of 65,837 patients, 3 subcohorts were created; the intra-aortic balloon pump (IABP) alone (n = 48,643), the extracorporeal membrane oxygenation (ECMO) (n = 16,871), and the Impella cohorts (n = 696). Results: The median annual case volume was 13.5 (7.4-22.1) in the IABP alone cohort, 6.4 (3.4-11.0) in the ECMO cohort, and 7.5 (4.0-10.7) in the Impella cohort. The highest quintile for the volume of cases in the IABP alone and ECMO had the lowest in-hospital mortality (IABP alone, 25.1% in quintile 1 vs 15.2% in quintile 5; ECMO, 73.7% in quintile 1 in 67.4% in quintile 5). Adjusted ORs for in-hospital mortality decreased as case volume increased (IABP alone, 0.63 [0.58-0.68] in quintile 5; ECMO, 0.73 [0.65-0.82] in quintile 5, with the lowest quintile as reference) but did not decrease significantly in the Impella (0.90 [0.58-1.39] in tertile 3, with the lowest tertile as reference). In the continuous models with the case volume as a continuous variable, adjusted ORs for in-hospital mortality decreased to 28 IABP cases/year and 12 ECMO cases/year. They did not decrease or became almost flat above that. Conclusions: Higher volumes of IABP and ECMO are associated with a lower mortality. There is an upper limit to the decline. Centralizing patients with refractory CS in a particular hospital might improve patient outcomes in each region.

DOI： 10.1016/j.ahj.2023.03.017

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Authorship：Lead author   Language：English   Publisher：European Heart Journal  

Aims: Because an increased risk of amputation with canagliflozin was reported in the CANVAS trials, there has been a concern about the safety of sodium-glucose cotransporter 2 inhibitors in patients with peripheral artery disease (PAD) who are at higher risk of amputation. Methods and results: A patient-level pooled analysis of the DAPA-HF and DELIVER trials, which evaluated the efficacy and safety of dapagliflozin in patients with heart failure (HF) with reduced, mildly reduced/preserved ejection fraction, respectively, was conducted. In both trials, the primary outcome was the composite of worsening HF or cardiovascular death, and amputation was a prespecified safety outcome. Peripheral artery disease history was available for 11 005 of the total 11 007 patients. Peripheral artery disease was reported in 809 of the 11 005 patients (7.4%). Median follow-up was 22 months (interquartile range 17-30). The rate of the primary outcome (per 100 person-years) was higher in PAD patients than that in non-PAD patients: 15.1 [95% confidence interval (CI) 13.1-17.3) vs. 10.6 (10.2-11.1]; adjusted hazard ratio 1.23 (95% CI 1.06-1.43). The benefit of dapagliflozin on the primary outcome was consistent in patients with [hazard ratio 0.71 (95% CI 0.54-0.94)] and without PAD [0.80 (95% CI 0.73-0.88)] (Pinteraction = 0.39). Amputations, while more frequent in PAD patients, were not more common with dapagliflozin, compared with placebo, irrespective of PAD status (PAD, placebo 4.2% vs. dapagliflozin 3.7%; no PAD, placebo 0.4% vs. dapagliflozin 0.4%) (Pinteraction = 1.00). Infection rather than ischaemia was the main trigger for amputation, even in patients with PAD. Conclusion: The risk of worsening HF or cardiovascular death was higher in patients with PAD, as was the risk of amputation. The benefits of dapagliflozin were consistent in patients with and without PAD, and dapagliflozin did not increase the risk of amputation.

DOI： 10.1093/eurheartj/ehad276

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Authorship：Lead author,　Corresponding author   Language：English   Publisher：Journal of the American Heart Association  

BACKGROUND: Guideline-recommended therapies that improve prognosis remain underused in clinical practice. Physical frailty may lead to underprescription of life-saving therapy. We aimed to investigate the association between physical frailty and the use of evidence-based pharmacological therapy for heart failure with reduced ejection fraction and the impact of this on prognosis. METHODS AND RESULTS: The FLAGSHIP (Multicentre Prospective Cohort Study to Develop Frailty-Based Prognostic Criteria for Heart Failure Patients) included patients hospitalized for acute heart failure, and data on physical frailty were collected prospectively. We analyzed 1041 patients with heart failure with reduced ejection fraction (aged 70 years; 73% male) and divided them by physical frailty categories using grip strength, walking speed, Self-Efficacy for Walking–7 score, and Performance Measures for Activities of Daily Living–8 score: categories I (n=371; least frail), II (n=275), III (n=224), and IV (n=171). Overall prescription rates of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, β-blockers, and mineralocorticoid receptor antagonists were 69.7%, 87.8%, and 51.9%, respectively. The proportion of patients receiving all 3 drugs decreased as physical frailty increased (in category I patients, 40.2%; IV patients, 23.4%; P for trend<0.001). In adjusted analyses, the severity of physical frailty was an independent predictor for nonuse of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (odds ratio [OR], 1.23 [95% CI, 1.05–1.43] per 1 category increase) and β-blockers (OR, 1.32 [95% CI, 1.06–1.64]), but not mineralocorticoid receptor antagonists (OR, 0.97 [95% CI, 0.84–1.12]). Patients receiving 0 to 1 drug had a higher risk of the composite outcome of all-cause death or heart failure rehospitalization than those treated with 3 drugs in physical frailty categories I and II (hazard ratio [HR], 1.80 [95% CI, 1.08–2.98]) and III and IV (HR, 1.53 [95% CI, 1.01–2.32]) in the multivariate Cox proportional hazard model. CONCLUSIONS: Prescription of guideline-recommended therapy decreased as severity of physical frailty increased in heart failure with reduced ejection fraction. Underprescription of guideline-recommended therapy may contribute to the poor prognosis associated with physical frailty.

DOI： 10.1161/JAHA.122.026844

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Authorship：Lead author   Language：English   Publisher：Circulation  

Background: How patient characteristics and outcomes vary according to the duration of heart failure (HF) is unknown in individuals with mildly reduced or preserved ejection fraction. We compared these, and the efficacy and safety of dapagliflozin, according to the time from diagnosis of HF in a prespecified analysis of the DELIVER trial (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure). Methods: HF duration was categorized as ≤6 months, >6 to 12 months, >1 to 2 years, >2 to 5 years, or >5 years. The primary outcome was the composite of worsening HF or cardiovascular death. The effect of treatment was examined by HF duration category. Results: The number of patients in each category was as follows: 1160 (≤6 months), 842 (>6 to 12 months), 995 (>1 to 2 years), 1569 (>2 to 5 years), and 1692 (>5 years). Patients with longer-duration HF were older and had more comorbidities with worse symptoms. The rate of the primary outcome (per 100 person-years) increased with HF duration: ≤6 months, 7.3 (95% CI, 6.3 to 8.4); >6 to 12 months, 7.1 (6.0 to 8.5); >1 to 2 years, 8.4 (7.2 to 9.7); >2 to 5 years, 8.9 (7.9 to 9.9); and >5 years, 10.6 (9.5 to 11.7). Similar trends were seen for other outcomes. The benefit of dapagliflozin was consistent across HF duration category: the hazard ratio for the primary outcome in the ≤6-month group was 0.67 (95% CI, 0.50 to 0.91); >6 to 12 months, 0.78 (0.55 to 1.12); >1 to 2 years, 0.81 (0.60 to 1.09); >2 to 5 years, 0.97 (0.77 to 1.22); and >5 years, 0.78 (0.64 to 0.96; Pinteraction=0.41). The absolute benefit was greatest in longest-duration HF; the number needed to treat for HF >5 years was 24 versus 32 for ≤6 months. Conclusions: Patients with longer-duration HF were older, had more comorbidities and symptoms, and had higher rates of worsening HF and death. The benefits of dapagliflozin were consistent across HF duration. Even patients with long-standing HF and generally mild symptoms are not stable, and it is not too late for such patients to benefit from a sodium-glucose cotransporter 2 inhibitor. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03619213.

DOI： 10.1161/CIRCULATIONAHA.122.062918

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Authorship：Lead author,　Corresponding author   Language：English   Publisher：JACC: Asia  

Background: Temporary mechanical circulatory support (MCS) is often used in patients with cardiogenic shock (CS), and the type of MCS may vary by cause of CS. Objectives: This study sought to describe the causes of CS in patients receiving temporary MCS, the types of MCS used, and associated mortality. Methods: This study used a nationwide Japanese database to identify patients receiving temporary MCS for CS between April 1, 2012, and March 31, 2020. Results: Of 65,837 patients, the cause of CS was acute myocardial infarction (AMI) in 77.4%, heart failure (HF) in 10.9%, valvular disease in 2.7%, fulminant myocarditis (FM) in 2.5%, arrhythmia in 4.5%, and pulmonary embolism (PE) in 2.0% of cases. The most commonly used MCS was an intra-aortic balloon pump alone in AMI (79.2%) and in HF (79.0%) and in valvular disease (66.0%), extracorporeal membrane oxygenation with intra-aortic balloon pump in FM (56.2%) and arrhythmia (43.3%), and extracorporeal membrane oxygenation alone in PE (71.5%). Overall in-hospital mortality was 32.4%; 30.0% in AMI, 32.6% in HF, 33.1% in valvular disease, 34.2% in FM, 60.9% in arrhythmia, and 59.2% in PE. Overall in-hospital mortality increased from 30.4% in 2012 to 34.1% in 2019. After adjustment, valvular disease, FM, and PE had lower in-hospital mortality than AMI: valvular disease, OR: 0.56 (95% CI: 0.50-0.64); FM: OR: 0.58 (95% CI: 0.52-0.66); PE: OR: 0.49 (95% CI: 0.43-0.56); whereas HF had similar in-hospital mortality (OR: 0.99; 95% CI: 0.92-1.05) and arrhythmia had higher in-hospital mortality (OR: 1.14; 95% CI: 1.04-1.26). Conclusions: In a Japanese national registry of patients with CS, different causes of CS were associated with different types of MCS and differences in survival.

DOI： 10.1016/j.jacasi.2022.10.004

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Authorship：Lead author   Language：English   Publisher：European Heart Journal  

Aims: Patients with heart failure with reduced ejection fraction (HFrEF) are at significant risk of stroke. Anticoagulation reduces this risk in patients with and without atrial fibrillation (AF), but the risk-to-benefit balance in the latter group, overall, is not favourable. Identification of patients with HFrEF, without AF, at the highest risk of stroke may allow targeted and safer use of prophylactic anticoagulant therapy. Methods and results: In a pooled patient-level cohort of the PARADIGM-HF, ATMOSPHERE, and DAPA-HF trials, a previously derived simple risk model for stroke, consisting of three variables (history of prior stroke, insulin-treated diabetes, and plasma N-terminal pro-B-type natriuretic peptide level), was validated. Of the 20 159 patients included, 12 751 patients did not have AF at baseline. Among patients without AF, 346 (2.7%) experienced a stroke over a median follow up of 2.0 years (rate 11.7 per 1000 patient-years). The risk for stroke increased with increasing risk score: fourth quintile hazard ratio (HR) 2.35 [95% confidence interval (CI) 1.60-3.45]; fifth quintile HR 3.73 (95% CI 2.58-5.38), with the first quintile as reference. For patients in the top quintile, the rate of stroke was 21.2 per 1000 patient-years, similar to participants with AF not receiving anticoagulation (20.1 per 1000 patient-years). Model discrimination was good with a C-index of 0.84 (0.75-0.91). Conclusion: It is possible to identify a subset of HFrEF patients without AF with a stroke-risk equivalent to that of patients with AF who are not anticoagulated. In these patients, the risk-to-benefit balance might justify the use of prophylactic anticoagulation, but this hypothesis needs to be tested prospectively.

DOI： 10.1093/eurheartj/ehac487

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Language：English   Publisher：European Heart Journal  

Aims: Obesity is common and associated with unique phenotypic features in heart failure with preserved ejection fraction (HFpEF). Therefore, understanding the efficacy and safety of new therapies in HFpEF patients with obesity is important. The effects of dapagliflozin were examined according to body mass index (BMI) among patients in the Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure trial. Methods and results: Body mass index was analysed by World Health Organization (WHO) categories and as a continuous variable using restricted cubic splines. Body mass index ranged from 15.2 to 50 kg/m2 with a mean value of 29.8 (standard deviation ± 6.1) kg/m2. The proportions, by WHO category, were: normal weight 1343 (21.5%); overweight 2073 (33.1%); Class I obesity 1574 (25.2%); Class II obesity 798 (12.8%); and Class III obesity 415 (6.6%). Compared with placebo, dapagliflozin reduced the risk of the primary outcome to a similar extent across these categories: hazard ratio (95% confidence interval): 0.89 (0.69-1.15), 0.87 (0.70-1.08), 0.74 (0.58-0.93), 0.78 (0.57-1.08), and 0.72 (0.47-1.08), respectively (P-interaction = 0.82). The placebo-corrected change in Kansas City Cardiomyopathy Questionnaire total symptom score with dapagliflozin at 8 months was: 0.9 (-1.1, 2.8), 2.5 (0.8, 4.1), 1.9 (-0.1, 3.8), 2.7 (-0.5, 5.8), and 8.6 (4.0, 13.2) points, respectively (P-interaction = 0.03). The placebo-corrected change in weight at 12 months was: -0.88 (-1.28, -0.47), -0.65 (-1.04, -0.26), -1.42 (-1.89, -0.94), -1.17 (-1.94, -0.40), and -2.50 (-4.4, -0.64) kg (P-interaction = 0.002). Conclusions: Obesity is common in patients with HFpEF and is associated with higher rates of heart failure hospitalization and worse health status. Treatment with dapagliflozin improves cardiovascular outcomes across the spectrum of BMI, leads to greater symptom improvement in patients with obesity, compared with those without, and has the additional benefit of causing modest weight loss.

DOI： 10.1093/eurheartj/ehac481

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DOI： 10.1016/j.jacc.2022.08.718

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DOI： doi: 10.1038/s41591-022-01971-4

DOI： doi: 10.1038/s41591-022-01971-4

Authorship：Lead author   Language：English   Publisher：European Journal of Heart Failure  

New guidelines have emphasized the primacy of starting the four key life-saving therapies for patients with heart failure and reduced ejection fraction as quickly as possible, with titration to ‘target dose’ of these, as secondary consideration. In this article, we examine the reasons for this change in emphasis and revisit the evidence regarding the dosing of pharmacological therapy in heart failure. We demonstrate the early benefits obtained with even low doses of most of the foundational therapies for heart failure and reduced ejection fraction. We also clarify that the ‘target dose’ of those therapies requiring titration was a goal based on tolerability and often not reached in trials, i.e. the proven benefits of our foundational therapies were demonstrated with an average dose that was less than target and many patients in these trials were treated with sub-target doses.

DOI： 10.1002/ejhf.2447

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Authorship：Lead author,　Corresponding author   Language：English   Publisher：Journal of the American Heart Association  

BACKGROUND: Prognoses and long-term cardiac function of patients with fulminant myocarditis have not been fully elucidated. Therefore, we clarified the prognoses and long-term cardiac function according to required percutaneous mechanical circulatory support and histological findings among patients with fulminant myocarditis. METHODS AND RESULTS: We conducted a multicenter retrospective medical record review of 216 patients with fulminant my-ocarditis requiring percutaneous mechanical circulatory support. Sixty-one patients were treated with intra-aortic balloon pump or Impella alone, and 155 patients received veno-arterial extracorporeal membrane oxygenation and were treated with or without intra-aortic balloon pump or Impella. Histologically, 107 patients had lymphocytic myocarditis; 34, eosinophilic myocarditis; and 4, giant cell myocarditis. Freedom from composite end point (death, durable left ventricular assist device implantation, and heart transplantation) was 66% at 90 days, 62% at 1 year, and 57% at 6 years. Veno-arterial extracorporeal membrane oxygenation use was associated with poor prognosis in the multivariable analysis (hazard ratio [HR], 5.27; 95% CI, 1.60–17.36). The eosinophilic myocarditis subgroup showed better prognosis (HR, 0.28; 95% CI, 0.10– 0.80) compared with the lymphocytic myocarditis subgroup but not in the multivariable analysis. Ventricular tachycardia/ventricular fibrillation rhythm at admission, high C-reactive protein level, and no endomyocardial biopsy were also associated with poor prognosis. The left ventricular ejection fraction at 1 year was ≤50% in 16% of patients and was lower in patients with eosinophilic myocar-ditis (median: 57.9% [48.8– 65.0%]) than in those with lymphocytic myocarditis (65.0% [58.6– 68.7%]) (P=0.036). CONCLUSIONS: Patients with fulminant myocarditis who received veno-arterial extracorporeal membrane oxygenation had a poor prognosis. Long-term cardiac function was impaired in some patients, especially those with eosinophilic myocarditis.

DOI： 10.1161/JAHA.121.023719

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Authorship：Lead author   Language：English   Publisher：European Heart Journal  

DOI： 10.1093/eurheartj/ehab828

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Language：English   Publisher：Critical Care Medicine  

Objectives: To evaluate the impact of hospital-level median door-to-extracorporeal cardiopulmonary resuscitation (ECPR) time on survival and neurologic outcomes in patients with out-of-hospital cardiac arrest (OHCA) requiring ECPR. Design: Secondary analysis of the Japanese Association for Acute Medicine OHCA registry, a nationwide Japanese database of OHCA patients. Setting: Fifty-three hospitals across Japan. Patients: Adult patients who underwent ECPR between 2014 and 2021 were included. Hospitals were categorized into "rapid"or "delayed"groups based on their median door-to-ECPR times. Interventions: None. Measurements and Main Results: The primary outcome was 30-day survival. Secondary outcomes included 30-day and 90-day survival with favorable neurologic outcomes. Propensity score weighting was applied to adjust for confounders. In total, 2136 patients treated at 53 hospitals were included. Hospitals with shorter median door-to-ECPR times had higher 30-day survival rates (odds ratio [OR], 1.36; 95% CI, 1.21-1.53). Neurologic outcomes were better in the rapid hospital group at both 30 days (OR, 1.47; 95% CI, 1.24-1.73) and 90 days (OR, 1.47; 95% CI, 1.25-1.73) follow-ups. Conclusions: Hospital-level median door-to-ECPR time is a crucial predictor of survival and neurologic outcomes in OHCA patients requiring ECPR. Shorter door-to-ECPR times should be considered a key quality metric for ECPR processes.

DOI： 10.1097/CCM.0000000000006808

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Publisher：Jacc Asia  

DOI： 10.1016/j.jacasi.2025.07.017

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DOI： 10.1016/j.jchf.2025.102630

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DOI： 10.1186/s40560-025-00791-1

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Language：English   Publisher：The Japanese Circulation Society  

<p><b><i>Background:</i></b> The optimal device for mechanical circulatory support (MCS) in patients with acute myocardial infarction (AMI) complicated with cardiogenic shock (CS) remains unknown. Therefore, in this study we aimed to analyze which MCS (intra-aortic balloon pumping (IABP) or IMPELLA) is associated with better outcomes in patients with AMI-related CS.</p><p><b><i>Methods and Results:</i></b> This systematic review and meta-analysis used a random-effects model to account for potential heterogeneity. Risk ratios (RRs) and 95% confidence intervals (CIs) were used for the dichotomous outcomes. The PubMed, Web of Science, and CENTRAL databases were searched up to April 30, 2023. The risk of bias was evaluated using the Revised Cochrane risk-of-bias tool for randomized trials (RoB2) tool, and the certainty of evidence was evaluated according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) tool. Two randomized controlled trials were included in the meta-analysis. For the primary outcome of 30-day survival, IMPELLA probably improves the outcome by a small amount compared with IABP (RR0.94 [95% CI 0.5–1.53], 29 fewer per 1,000 [95% CI from 204 fewer to 258 more], low certainty of evidence).</p><p><b><i>Conclusions:</i></b> We could not show a survival benefit of IMPELLA compared with IABP in patients with AMI complicated by CS. Further investigation is required to resolve this issue.</p>

DOI： 10.1253/circrep.cr-25-0161

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Language：English   Publisher：The Japanese Circulation Society  

<p><b><i>Background:</i></b> Inotropes play a significant role in the treatment of cardiogenic shock (CS). Phosphodiesterase 3 inhibitors (PDE3i) are being used with increasing frequency, despite limited supporting evidence.</p><p><b><i>Methods and Results:</i></b> We performed a systematic review to assess the clinical importance of PDE3i in CS. The search included studies that compared the effect of ‘PDE3i with or without inotropes’ with ‘No PDE3i with or without inotropes’ in patients with cardiogenic shock. Early death, cardiac arrest, and initiation of renal replacement therapy were assessed as outcomes. We identified 2 randomized controlled trials (RCT) with a total of 224 patients who met the eligibility requirements from the PubMed, Web of Science, and CENTRAL databases, up until October 31, 2024. One RCT compared milrinone with dobutamine (DOB), and another compared enoximone with levosimendan. Meta-analysis revealed that PDE3i were neither superior nor inferior for the outcomes in the total cohort (odds ratio [OR] 1.47, 95% confidence interval [CI] 0.35–6.26 for early deaths; OR 1.14, 95% CI 0.42–3.14 for cardiac arrest; OR 1.53, 95% CI 0.80–2.92 for the initiation of renal replacement therapy).</p><p><b><i>Conclusions:</i></b> The present systematic review revealed no difference in outcomes, early deaths, cardiac arrest and initiation of renal replacement therapy when using PDE3i in patients with CS treated with or without other inotropes.</p>

DOI： 10.1253/circrep.cr-25-0152

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Authorship：Lead author   Language：English   Publisher：Jacc Heart Failure  

DOI： 10.1016/j.jchf.2025.102648

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Language：English   Publisher：The Japanese Circulation Society  

<p><b><i>Background:</i></b> Cardiogenic shock, a life-threatening condition frequently encountered in emergency departments, requires rapid diagnosis and management. Point-of-care ultrasound (POCUS) is widely used as a bedside tool; however, its impact on prognosis in patients with suspected cardiogenic shock remains unclear. This systematic review aimed to evaluate whether POCUS improves the clinical outcomes in these patients.</p><p><b><i>Methods and Results:</i></b> We searched PubMed, Web of Science, and Cochrane Library up to December 31, 2023, for studies evaluating the prognostic impact of POCUS in adults with undifferentiated shock, including cardiogenic shock. From 3,759 identified records, 2 studies (1 randomized controlled trial [RCT] and 1 observational study) involving 5,711 patients with shock were included. The RCT showed no significant differences in in-hospital mortality between the POCUS and non-POCUS groups (relative risk [RR] 0.99 [95% confidence interval (CI) 0.64–1.51]). The observational study reported higher mortality in patients receiving POCUS before intervention (RR 1.25 [95% CI 1.12–1.39]). Overall, POCUS did not significantly reduce mortality in patients with suspected cardiogenic shock. Given the limited number and quality of available studies, the certainty of evidence was low (RCT) and very low (observational study).</p><p><b><i>Conclusions:</i></b> Although POCUS plays an essential role in diagnosis and clinical decision-making, our review suggests that it may not significantly improve prognosis in patients with suspected cardiogenic shock. Further studies are required to determine its prognostic value.</p>

DOI： 10.1253/circrep.CR-25-0108

Open Access

PubMed

CiNii Research

Language：English   Publisher：The Japanese Circulation Society  

<p><b><i>Background:</i></b> Cardiogenic shock, cardiac tamponade, and pulmonary embolism are critical conditions in cardiovascular emergencies, characterized by high mortality rates. Early diagnosis and treatment are essential to improve outcomes. Point-of-care ultrasound (POCUS) has emerged as a noninvasive tool for evaluating shock. However, further assessment through the latest meta-analyses is necessary to comprehensively evaluate its diagnostic accuracy in cardiogenic emergencies. Therefore, in this study, we conducted a systematic review and meta-analysis to evaluate the diagnostic accuracy of POCUS in patients with cardiogenic and obstructive shock.</p><p><b><i>Methods and Results:</i></b> Up to December 31, 2023, we systematically reviewed 9 studies reporting all 4 values (true positive, false positive, false negative, and true negative) published in the PubMed, Web of Science, and CENTRAL databases: 8 studies assessed cardiac shock, and 8 assessed obstructive shock separately. For cardiac shock, the pooled sensitivity was 86.1% (95% confidence interval [CI]: 71.5–93.9%), and specificity was 95.8% (95% CI: 94.0–97.2%). For obstructive shock, the pooled sensitivity was 77.5% (95% CI: 62.5–87.6%) and specificity was 97.6% (95% CI: 93.9–99.1%). The area under the curve was 0.96 (95% CI: 0.95–0.98) for cardiogenic shock and 0.94 (95% CI: 0.88–0.98) for obstructive shock.</p><p><b><i>Conclusions:</i></b> This meta-analysis suggested that POCUS has reasonable diagnostic accuracy for cardiogenic and obstructive shock, particularly with high pooled specificity.</p>

DOI： 10.1253/circrep.CR-25-0105

Open Access

PubMed

CiNii Research

Language：English   Publisher：The Japanese Circulation Society  

<p><b><i>Background:</i></b> Congestive heart failure (CHF) is associated with worse clinical outcomes in patients with non-ST-elevation acute coronary syndrome (NSTE-ACS); however, the optimal timing of invasive intervention in NSTE-ACS with CHF remains unclear. In this study, we assessed the impact of early vs. delayed invasive strategies on mortality and cardiac events by synthesizing a systematic review of randomized controlled trials of patients with NSTE-ACS.</p><p><b><i>Methods and Results:</i></b> We searched MEDLINE, CENTRAL, and the Web of Science for randomized controlled trials comparing early and delayed invasive strategies in patients with NSTE-ACS and CHF, published before February 2023. Observational studies were excluded. The primary endpoint was a composite of all-cause mortality and myocardial infarction at 2 years. Two eligible studies, including 310 participants, were identified. The primary endpoint occurred in 40 (24.5%) of 163 patients in the early invasive strategy group, compared with 39 (26.5%) of 147 patients in the delayed invasive strategy group, and the effect of an early invasive strategy on the primary outcome was uncertain (risk ratio 0.95 [95% confidence interval 0.66–1.37]). The certainty of the evidence was rated very low.</p><p><b><i>Conclusions:</i></b> The effects of an early invasive strategy in patients with NSTE-ACS and CHF remains uncertain, with no clear reduction in composite outcome of mortality and myocardial infarction at 2 years compared with delayed intervention.</p>

DOI： 10.1253/circrep.CR-25-0104

Open Access

PubMed

CiNii Research

Language：English   Publisher：The Japanese Circulation Society  

<p><b><i>Background:</i></b> The optimal timing for mechanical circulatory support (MCS) initiation in patients with acute myocardial infarction complicated by cardiogenic shock (CS) is unknown, so in this study we analyzed whether MCS implementation before percutaneous coronary intervention (PCI) is associated with better outcomes compared to after PCI.</p><p><b><i>Methods and Results:</i></b> We conducted a systematic review and meta-analysis using a random-effects model to account for potential heterogeneity. Risk ratios and 95% confidence intervals were used for dichotomous outcomes. PubMed, Web of Science, and CENTRAL were searched up to April 30, 2023. Certainty of evidence was evaluated according to the Risk of Bias in Non-Randomized Studies of Interventions-I tool. A total of 14 observational studies met the inclusion criteria. We found that venoarterial-extracorporeal membrane oxygenation (VA-ECMO) may have little to no positive effect on short-term survival, but the evidence was very uncertain. Impella use probably increases short-term survival (moderate certainty of evidence), whereas the timing of intra-aortic balloon pump (IABP) insertion improves outcomes (very low certainty of evidence). Pre- and post-PCI MCS implementation may result in little to no difference in bleeding complications or stroke incidence across all device types (low to very low certainty of evidence).</p><p><b><i>Conclusions:</i></b> Early Impella implementation before PCI may increase short-term survival, whereas the timing of ECMO or IABP implementation may have little to no effect on outcomes; however, the evidence is very uncertain.</p>

DOI： 10.1253/circrep.CR-25-0098

Open Access

PubMed

CiNii Research

Language：English   Publisher：The Japanese Circulation Society  

<p><b><i>Background:</i></b> The utility of coronary computed tomography angiography (CCTA) in patients with non-ST-elevation acute coronary syndrome (NSTE-ACS), particularly among low-risk individuals presenting to the emergency department (ED), remains unclear. We conducted a systematic review to assess the clinical benefits of CCTA in low-risk patients presenting to the ED with chest pain.</p><p><b><i>Methods and Results:</i></b> A systematic search of MEDLINE, CENTRAL, and Web of Science was performed for randomized controlled trials (RCTs) published up to March 23, 2023, comparing CCTA performed in the ED with standard care in low-risk patients with NSTE-ACS. Low-risk status was defined as resolved symptoms at ED presentation and no troponin elevation or ischemic ECG changes. Seven RCTs were extracted from the databases. No significant differences were observed between the CCTA and standard care groups in all-cause mortality, non-fatal myocardial infarction, ED revisits, or radiation exposure. However, hospital length of stay was significantly shorter and healthcare costs were slightly lower in the CCTA group. Conversely, revascularization and invasive coronary angiography were significantly more frequent in this group.</p><p><b><i>Conclusions:</i></b> In low-risk patients with NSTE-ACS, CCTA performed in the ED did not reduce adverse clinical events but was associated with shorter hospital stays and marginally reduced healthcare costs. These findings suggest that CCTA may be a useful tool that supports the safe and early discharge of selected patients.</p>

DOI： 10.1253/circrep.CR-25-0114

Open Access

PubMed

CiNii Research

Language：English   Publisher：ASAIO Journal  

We describe a modified Park’s stitch technique incorporating systematic free margin alignment to achieve complete elimination of aortic regurgitation in patients with a left ventricular assist device. The technique involves a two-step approach: first, free margin alignment of all three cusps using single interrupted 6-0 polypropylene sutures placed at the nodules of Arantius to achieve precise coaptation, followed by conventional Park’s stitch using mattress sutures with autologous pericardial pledgets for central closure. The alignment sutures remain in place to provide reinforcement. This modification addresses the central redundancy created by prolapsing or elongated cusps while maintaining the theoretical advantages of Park’s stitch. In six consecutive patients (mean age, 56.5 years; 66.7% destination therapy), complete elimination of aortic insufficiency was immediately achieved with a median cross-clamp time of 30.5 min (interquartile range, 26.8–41.3 min). At follow-up (median, 8 months), five of the six patients had maintained zero regurgitation, while the remaining patient had developed only trivial regurgitation. This systematic approach to free margin alignment before Park’s stitch may offer improved durability compared with conventional techniques, particularly for destination therapy patients requiring extended support. ASAIO Journal 2025; XX:XX–XX

DOI： 10.1097/MAT.0000000000002545

Open Access

Scopus

PubMed

Authorship：Lead author,　Last author,　Corresponding author   Language：English   Publisher：Jacc Heart Failure  

DOI： 10.1016/j.jchf.2025.102576

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Scopus

PubMed

Language：English   Publisher：The Japanese Circulation Society  

<p><b><i>Background:</i></b> Breast cancer is the most common cancer in women. Although anti-human epidermal growth factor receptor 2 (HER2) therapy is effective in patients with HER2-positive breast cancer, it occasionally induces cancer therapy-related cardiac dysfunction (CTRCD). This study aimed to determine the factors associated with CTRCD in patients with HER2-positive breast cancer treated with trastuzumab.</p><p><b><i>Methods and Results:</i></b> We retrospectively analyzed the data of 286 patients with breast cancer who received trastuzumab. Accordingly, patients were categorized into CTRCD (+) and CTRCD (−) groups to elucidate the factors associated with cardiotoxicity. The median age of patients was 54 years. CTRCD was observed in 13 (4.5%) patients, and 2 (0.7%) patients had severe symptomatic heart failure, with a New York Heart Association class ≥III. All patients with CTRCD had a history of epirubicin use, and patients receiving both trastuzumab and pertuzumab had significantly higher rates of CTRCD (P=0.003); the history of pertuzumab administration was an independent predictor of CTRCD development. The median duration from trastuzumab initiation to CTRCD onset and from CTRCD onset to recovery was 244 (interquartile range [IQR] 164–333) and 122 ([IQR] 38–186) days, respectively.</p><p><b><i>Conclusions:</i></b> In HER2-positive breast cancer, CTRCD occurred more frequently in patients using anthracycline followed by trastuzumab and pertuzumab simultaneously. Systolic dysfunction was reversible in all patients, and normalization of cardiac function took approximately 4 months from CTRCD onset.</p>

DOI： 10.1253/circrep.CR-25-0036

Open Access

Web of Science

PubMed

CiNii Research

Language：English   Publisher：Journal of Cardiology  

Background: Chronic kidney disease (CKD) strongly affects prognosis in patients with heart failure (HF). However, the difference in the implementation of guideline-directed medical therapy (GDMT) during HF-related hospitalization between patients with and without CKD and its association with worsening heart failure (WHF) events remain unclear. Methods: A post-hoc analysis was conducted using data from a retrospective, multicenter, observational registry of patients hospitalized for HF with a left ventricular ejection fraction (LVEF) of <50 %. The primary endpoint was a composite of outpatient WHF, HF-related hospitalization, and all-cause mortality. Results: Of the 442 patients, 246 had CKD (56 %). These patients were older and had a higher prevalence of HF. At admission, the GDMT score was higher in patients with CKD than in those without CKD [3 (interquartile range, 1–5) vs. 1 (0–4)]; at discharge, the GDMT score was lower in patients with CKD [5 (3–7) vs. 6 (4.5–8)]. Optimized GDMT implementation at discharge, defined as a GDMT score of ≥6, was independently associated with improved prognosis in both groups. Conclusions: In-hospital GDMT implementation was less optimized in patients with CKD compared with those without. Nevertheless, optimized GDMT implementation at discharge was associated with a lower incidence of adverse events, regardless of CKD status, among patients hospitalized with HF.

DOI： 10.1016/j.jjcc.2025.08.007

Scopus

PubMed

Language：English   Publisher：Journal of Cardiac Failure  

Background: Acute heart failure (AHF) is associated with high mortality rates, and contemporary medical treatments provide limited benefits in survival. Emerging evidence suggests that exogenous ketone bodies may have beneficial cardiovascular effects in patients with heart failure. The KETO-AHF (KETOne Supplements in Patients Hospitalized for Acute Heart Failure) trial is designed to assess the clinical benefits of initiating ketone supplementation with 1,3-butanediol compared with placebo in patients hospitalized for AHF with reduced ejection fraction. Methods: KETO-AHF is a multicenter, randomized, double-blind, placebo-controlled trial investigating the effects of 1,3-butanediol (33 g 3 times daily) in patients hospitalized for AHF. Patients with symptoms and signs of AHF requiring intravenous loop diuretics and/or vasoactive treatment, elevated natriuretic peptides, and a left ventricular ejection fraction ≤ 35%, whether de novo or known heart failure, will be enrolled within 5 days of hospital admission. Participants will be randomized 1:1 to receive either 1,3-butanediol or placebo for a 30-day treatment period. The study aims to enroll 125 patients in each group. The primary endpoint is a hierarchical composite of all-cause mortality, heart failure rehospitalization, 6-minute walk test improvement, and reduction in NT-proBNP levels at 30 days. Conclusion: The KETO-AHF trial will provide insights into the effects of supplementation with the ketone body 1,3-butanediol in patients hospitalized for AHF.

DOI： 10.1016/j.cardfail.2025.07.013

Open Access

Scopus

PubMed

Language：English   Publisher：Journal of Cardiology  

Background: Right ventricular dysfunction (RVD) and right ventricular (RV) afterload are recognized prognostic factors in patients with heart failure with reduced ejection fraction (HFrEF). Hemodynamic phenotyping based on RVD and RV afterload may help identify clinically meaningful subgroups within the HFrEF population. This study aimed to investigate the prognostic associations of pulmonary artery pulsatility index (PAPi) and pulmonary arterial capacitance (PAC) in patients with HFrEF. Methods and results: We retrospectively analyzed a cohort of 156 patients with HFrEF who underwent right heart catheterization. Patients were categorized into four groups based on median PAPi and PAC values. The primary endpoint was a composite of cardiovascular death or heart failure-related hospitalization over a median follow-up of 2.9 years. Kaplan–Meier analysis demonstrated a significant difference in event-free survival across the groups. In multivariate Cox proportional analysis, patients with low PAPi and PAC had significantly worse outcomes than those with high values. Incorporating PAPi and PAC values into the Meta-analysis Global Group in Chronic Heart Failure risk score enhanced the prognostic value of the C-index from 0.658 to 0.703, with a ΔC-index of 0.045. Conclusion: Combining PAPi and PAC provides additional prognostic value in patients with HFrEF. Incorporating these parameters into clinical assessment may enhance risk stratification and guide future phenotype-specific therapeutic strategies.

DOI： 10.1016/j.jjcc.2025.07.012

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PubMed

Authorship：Lead author   Language：English   Publisher：The Japanese Circulation Society  

<p><b><i>Background:</i></b> A pulmonary artery catheter (PAC) provides detailed hemodynamic data, and managing a patient with cardiogenic shock (CS) using a PAC potentially improves patient outcomes. Therefore, in this systematic review and meta-analysis we aimed to evaluate whether a PAC is associated with better outcomes in patients with CS.</p><p><b><i>Methods and Results:</i></b> Studies comparing PAC and non-PAC management in patients with CS were identified from the PubMed, Web of Science, and CENTRAL databases. There were no randomized controlled trials (RCTs). Of the 19 studies that met the inclusion criteria, 12 without a critical risk of bias were analyzed. PAC use was associated with lower in-hospital mortality when evaluated as a dichotomous outcome. Similar trends were observed in the time-to-event analyses. Substantial heterogeneity was observed across the studies. Subgroup analysis revealed better outcomes with PAC in patients with CS related to heart failure, but not in those with acute coronary syndrome. Sensitivity analyses, which included studies with a critical risk of bias, showed consistent trends favoring PAC use for crude in-hospital mortality. The overall certainty of the evidence was very low because of inconsistencies and biases.</p><p><b><i>Conclusions:</i></b> The PAC-guided CS management was associated with better in-hospital mortality, particularly in patients with heart failure-related CS. However, RCTs that evaluated the efficacy of PAC use as a primary purpose were not included, necessitating further RCTs to confirm these findings.</p>

DOI： 10.1253/circrep.CR-25-0088

Open Access

Web of Science

PubMed

CiNii Research

Authorship：Corresponding author   Language：English   Publisher：Journal of Cardiology  

Background: Trace elements, including zinc, copper, and selenium may influence heart failure prognosis due to their roles in mitochondrial function. Previous studies have reported associations between individual trace element abnormalities—such as low serum zinc, high serum copper, and low selenium levels—and adverse clinical outcomes, including reduced exercise capacity in patients with heart failure. However, the impact of multiple trace element abnormalities remains poorly understood. This study aimed to explore the prevalence of these abnormalities, both individually and in combination, and evaluate the association between multiple abnormalities and outcomes in patients with acute heart failure. Methods: We analyzed patients with acute heart failure admitted to the Nagoya University Hospital between January 2012 and May 2024. Zinc, copper, and selenium levels were measured upon admission. Results: Among the 147 patients, 39 % had zinc deficiency, 52 % had copper excess, and 61 % had selenium deficiency. At least one trace element abnormality was observed in 84 % of patients, and two or three abnormalities were observed in 51 % of patients. Patients with multiple abnormalities had lower albumin levels, higher C-reactive protein levels, and lower hemoglobin levels than those without multiple abnormalities. Over a median follow-up of 196 days, all-cause death was more frequently observed in patients with two or three abnormalities than those with zero or one abnormality (adjusted hazard ratio, 3.78, 95 % confidence interval, 1.23–11.6). Conclusions: Multiple trace element abnormalities are common in patients with acute heart failure and are associated with poor clinical outcomes. These findings suggest correcting trace element abnormalities may be a potential target in heart failure management.

DOI： 10.1016/j.jjcc.2025.07.009

Scopus

PubMed

Language：English   Publisher：ASAIO Journal  

External outflow graft obstruction (EOGO) is a known complication in left ventricular assist devices (LVADs), particularly around limited spaces such as the bend relief in HeartMate pumps. While EOGO in HeartMate 3 commonly occurs due to accumulation of biodebris between the bend relief and outflow graft, the incidence of EOGO in the HeartWare Ventricular Assist Device (HVAD) is much lower (0.006 events per patient-year) than that in HeartMate 3 because of the unique grid-like strain relief structure. We report an atypical case of EOGO in a 59 year old man with previous coronary artery bypass grafting who developed progressive dyspnea and decreased pump flow 4 years after HVAD implantation. Surgical exploration revealed aggressive ingrowth of dense fibrinous tissue into the strain relief, causing outflow graft compression. Pump flow improved dramatically after debridement. This case demonstrates that EOGO can occur in any LVAD when the outflow graft passes through a confined space, such as with dense adhesions due to prior surgery. This case report implies that strategies to prevent EOGO in LVADs may require not only bend relief fenestration to avoid biodebris accumulation but also improvement of confined spaces around the outflow graft such as adhesions after surgery.

DOI： 10.1097/MAT.0000000000002513

Scopus

PubMed

Language：English   Publisher：Acta Cardiologica  

Background: Both atrial fibrillation (AF) and right ventricular dysfunction (RVD) are prognostic factors in patients with heart failure (HF). However, the association between AF and RVD in patients with HF is not fully understood. The pulmonary artery pulsatility index (PAPi), obtained via right heart catheterisation, is a hemodynamic index of the right ventricular function. We investigated the clinical impact of PAPi in patients with HF and concomitant AF. Methods: This was a single-center, retrospective cohort study involving consecutive patients who underwent right heart catheterisation for HF between January 2016 and December 2018. Patients with acute decompensated phase of HF were excluded. The primary endpoint was a composite of all-cause death or hospitalisation due to HF. Results: A total of 347 patients with compensated HF were enrolled. The median follow-up duration was 3.2 years. Patients with AF had lower PAPi levels compared to those without AF. Multiple regression analysis revealed that AF was independently associated with reduced PAPi levels (partial regression coefficient −0.116, 95% confidence intervals [CIs] − 0.174 to −0.058; p < 0.001). Multivariate Cox regression analysis further revealed that low PAPi was an independent predictor of the incidence of the primary endpoint in patients with HF and AF (HR 1.861, 95% CIs 1.076–3.219, p = 0.026). Conclusion: AF was associated with reduced PAPi levels in patients with HF. Low PAPi independently predicted the prognosis of patients with AF and HF. Measuring PAPi provides useful information for the management of patients with HF and concomitant AF.

DOI： 10.1080/00015385.2025.2510705

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PubMed

Language：English   Publisher：Scientific Reports  

This study was performed to investigate the prognostic value of assessing symptom burden using the Edmonton Symptom Assessment System (ESAS) in older patients with Heart Failure (HF). This prospective cohort study was performed in consecutive patients ≥ 60 years old hospitalized with HF at a university hospital between September 2020 and June 2023. ESAS was used to assess nine common symptoms at hospital discharge (total score: 0–90) with higher scores indicating greater severity. The primary outcome was the combined event of HF readmission and all-cause mortality within 6 months. The median ESAS sum score in the study population consisting of 306 patients (median age, 79 years; 54.9% male) was 13 points. The commonly reported moderate-to-severe symptoms were impaired well-being (34.9%), anxiety (27.5%), drowsiness (25.8%), tiredness (24.9%), and depression (22.2%). In multivariate analyses, ESAS sum score was significantly associated with the combined event (adjusted hazard ratio for each 5-point increase, 1.10 (95% confidence interval: 1.04–1.17; p < 0.001). Inclusion of ESAS sum score in the risk model significantly increased both continuous net reclassification improvement (p = 0.028) and integrated discrimination improvement (p = 0.002) for the primary outcome. Comprehensive assessment of symptom burden with ESAS provided additional prognostic information to conventional risk factors in older patients with HF.

DOI： 10.1038/s41598-025-06615-4

Open Access

Web of Science

Scopus

PubMed

Language：English   Publisher：The Japanese Circulation Society  

<p><b><i>Background:</i></b> Right ventricular dysfunction (RVD), driven by right ventricular (RV) afterload, is prognostic in patients with heart failure with preserved ejection fraction (HFpEF). Hemodynamic phenotyping based on RVD and RV afterload may provide useful information for the management of HFpEF. This study investigated the prognostic impacts of the pulmonary artery pulsatility index (PAPi) and pulmonary arterial capacitance (PAC) in patients with HFpEF.</p><p><b><i>Methods and Results:</i></b> A retrospective cohort of 246 HFpEF patients who underwent right heart catheterization was analyzed. Patients were divided into 4 groups according to the median PAPi and PAC values. The primary endpoint was a composite of all-cause death or heart failure-related hospitalization over a median follow-up of 4.1 years. Kaplan-Meier analysis showed significant stratification of event-free survival among the groups (log-rank P=0.003). Multivariate Cox proportional analysis revealed that patients with low PAPi and PAC exhibited worse outcomes than those with the high PAPi and PAC (hazard ratio 3.205; 95% confidence interval [CI] 1.401–7.330; P=0.006). Incorporating PAPi and PAC values into the MAGGIC risk score improved the C-index from 0.671 to 0.720 (∆C-index 0.050; 95% CI 0.004–0.095; P=0.032).</p><p><b><i>Conclusions:</i></b> A combination of PAPi and PAC improved prognostic ability in patients with HFpEF. Future investigations into treatments for these new hemodynamic phenotypes may improve clinical outcomes of patients with HFpEF.</p>

DOI： 10.1253/circj.CJ-25-0092

Open Access

Web of Science

Scopus

PubMed

CiNii Research

Language：English   Publisher：The Japanese Circulation Society  

<p><b><i>Background:</i></b> Adherence to contemporary guideline-directed medical therapy (GDMT) and its association with incident outpatient worsening heart failure (WHF) events after discharge in hospitalized patients with heart failure (HF) remain unclear.</p><p><b><i>Methods and Results:</i></b> The PRE-UPFRONT-HF study was a retrospective multicenter observational registry of patients hospitalized for HF between June 2022 and March 2023 with a left ventricular ejection fraction <50%. Data on medications at admission, discharge, and 6 months after admission were collected. Outpatient WHF was defined as intravenous diuretic therapy and/or intensification of oral diuretics in outpatient settings (e.g., without hospitalization). Less than half the 442 patients registered were on all 4 GDMT medications (β-blockers, renin-angiotensin-aldosterone system inhibitors, mineralocorticoid receptor antagonists, and sodium-glucose cotransporter 2 inhibitors) at discharge and 6 months after admission. Better GDMT implementation, defined by a simple GDMT score above the median, was significantly associated with a lower incidence of composite outcomes of death, HF hospitalization, and WHF (P<0.001), as well as outpatient WHF events alone (P=0.035), which remained significant even after adjusting for covariates. In addition, outpatient WHF was associated with subsequent worse prognoses, including mortality (hazard ratio 6.52; P<0.001).</p><p><b><i>Conclusions:</i></b> GDMT implementation during hospitalization for HF is suboptimal, even in the contemporary era. Patients with better GDMT implementation at discharge had a lower incidence of outpatient WHF, which was associated with subsequent mortality.</p>

DOI： 10.1253/circj.CJ-24-1020

Open Access

Web of Science

Scopus

PubMed

CiNii Research

Language：English   Publisher：The Japanese Circulation Society  

DOI： 10.1253/circj.CJ-25-0192

Open Access

Web of Science

PubMed

CiNii Research

Language：English   Publisher：Journal of the American Heart Association  

BACKGROUND: The collection of race and ethnicity data in clinical trials using standardized categories is recommended by the US Food and Drug Administration, although this is primarily for domestic reasons. The applicability and understanding of the categories in multinational trials are uncertain. METHODS: We analyzed patient-level data from 13 major heart failure trials, examining race and ethnicity data recorded by country, as recommended by the Food and Drug Administration: “American Indian or Alaska Native,” “Asian,” “Black or African American,” “Native Hawaiian or Other Pacific Islander,” and “White” for race and “Hispanic or Latino” as a minimum for ethnicity (with an expanded list of ethnicities available). RESULTS: Of the 54 087 patients studied, approximately 32.3% were women. In the United States, 77% of patients were reported to be of White race and 19% of Black race with very few assigned to another race category (1% Asian, 0.7% Native American, 0.2% Native Hawaiian or other Pacific islander, and 1.4% “other”). In Europe, race was almost uniformly reported as White, and a similar racial homogeneity was reported in Asia (Asian race). Conversely, in Latin America, 8.9% of patients were described as “American Indian or Alaska Native,” with a very high proportion in specific countries (eg, 36% in Guatemala and 21% in Mexico). In the United States, 6.2% of participants were reported to have Hispanic/Latino ethnicity but most patients in Latin America were reported to have this ethnicity; conversely, few patients had this ethnicity reported outside the Americas, including in Spain and Portugal. Among patients designated as Asian race, specific ethnicities (eg, Indian, Japanese etc) almost completely overlapped with the country of origin. CONCLUSIONS: This study highlights the challenges of applying standardized race and, particularly, ethnicity categories in global clinical trials. A multistakeholder approach is needed to improve the collection of race and ethnicity data in clinical trials.

DOI： 10.1161/JAHA.124.037810

Open Access

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PubMed

Language：English   Publisher：Journal of the American College of Cardiology  

DOI： 10.1016/j.jacc.2025.04.011

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PubMed

Language：English   Publisher：Clinical and Experimental Nephrology  

Background: Protein-energy wasting (PEW), a unique weight loss linked to nutritional and metabolic abnormalities, is common in patients undergoing hemodialysis (HD) and associated with adverse outcomes. This study investigated whether extended-hours HD combined with a liberalized diet could overcome PEW and improve survival. Methods: The body mass index (BMI) and survival outcomes in patients undergoing extended-hours HD were evaluated for up to 8 years using data from the LIBeralized diet Extended-houRs hemodialysis Therapy (LIBERTY) cohort. Extended-hours HD was defined as weekly dialysis length ≥ 18 h. Results: The LIBERTY cohort included 402 patients who initiated extended-hours HD. An increase in the length and frequency of HD sessions was observed over time, with approximately 70% and 20% of patients undergoing extended-hours HD for > 21 h/week and > 3 sessions/week at 5 years, respectively. The BMI and percentage creatinine generation rate were maintained over time, with no substantial increase in the phosphorus and potassium levels. The estimated BMI initially increased, and thereafter plateaued over time in patients with a baseline BMI < 25 kg/m², whereas it decreased gradually in patients with a baseline BMI ≥ 25 kg/m² after several years from baseline. Ninety-one patients died, and 108 discontinued extended-hours HD during the median follow-up period of 6.2 years (interquartile range, 3.5–8.0), yielding a 5-year survival rate of 85%. Conclusions: Extended-hours HD with a liberalized diet may help achieve favorable survival outcomes and maintain nutritional status. Thus, it is a promising treatment option for managing PEW in patients undergoing HD.

DOI： 10.1007/s10157-024-02602-7

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researchmap

Language：English   Publisher：BMC Cardiovascular Disorders  

Background: Dynamic chest radiography (DCR) can estimate haemodynamic parameters in patients with heart failure (HF). Atrial fibrillation (AF) often coexists with HF; however, owing to its sometimes paroxysmal nature and minimal or absent symptoms, many patients with AF remain undiagnosed. Additional tools for AF diagnosis may be beneficial; therefore, we evaluated the ability of DCR to distinguish patients with HF in sinus rhythm (SR) from those with AF. Methods: In this small-sample pilot study, 20 patients with HF (median age, 67 years; males, 85%) underwent 12-lead electrocardiography and DCR on the same day. Aortic arch (Ao), right atrial (RA), right and left pulmonary artery (PA), and left ventricular (LV) apex pixel values (PVs) were measured. Seventeen patients were in SR and three demonstrated AF on 12-lead electrocardiography before DCR. Results: The PV and PV change rate waveforms of the Ao, RA, PAs, and LV apex were regular in SR and irregular with AF. The difference between patients in SR and those with AF was particularly clear in the LV apex PV change rate waveforms. In addition, the heart rates (HRs) of patients in SR and with AF could be calculated from the PV change rate waveforms and were similar to those calculated by 12-lead electrocardiography. Conclusions: DCR can detect AF in patients with HF and may be able to infer HR.

DOI： 10.1186/s12872-025-04820-7

Open Access

Web of Science

Scopus

PubMed

Language：English   Publisher：Scientific Reports  

Despite the efficacy of many therapies for heart failure, it remains a leading cause of morbidity and mortality worldwide, with many patients progressing to advanced stages of the condition. Since the standard treatment for heart failure includes small-molecule drugs targeting G protein-coupled receptors (GPCRs), GPCRs are still considered novel targets for the diagnosis and treatment of cardiovascular diseases. Corticotropin-releasing hormone receptor 2, a highly expressed GPCR in cardiomyocytes, and its ligand, urocortin2 (UCN2), have been reportedly associated with cardiovascular diseases; however, their clinical significance remains unclear. In this study, a UCN2 measurement assay was developed to measure blood UCN2 levels in patients with heart failure. The assay showed that blood UCN2 values indicated a negative relationship with cardiac ejection fraction in 52 patients with heart failure. Blood UCN2 levels were not correlated with brain natriuretic peptide, a standard marker of heart failure, and were higher in patients with cardiomyopathy than in those with heart failure, suggesting that measuring blood UCN2 levels may be a novel test for assessing the pathophysiology of heart failure.

DOI： 10.1038/s41598-025-99509-4

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Authorship：Corresponding author   Language：English   Publisher：ASAIO Journal  

External outflow graft obstruction (OGO) in durable left ventricular assist devices (LVADs) is a rare but critical complication. Detecting external OGO can be challenging because of its nonspecific symptoms and a wide variety of differential diagnoses. We report the case of a 45 year old man with LVAD admitted with complaints of recurrent syncope and frequent low-flow alarms. Laboratory tests and chest radiography revealed no specific findings. Transthoracic echocardiography via the left subcostal approach revealed an outflow graft compressed by a low-echo area within a bend relief. This finding led to a diagnosis of external OGO, which was consistent with what was observed on contrast-enhanced computed tomography. The patient underwent surgery and the gelatinous substance compressing the outflow graft was successfully removed. This case highlights the utility of transthoracic echocardiography as a noninvasive and effective method for detecting external OGOs, emphasizing its role as a valuable tool for the initial screening of patients with suspected OGO.

DOI： 10.1097/MAT.0000000000002406

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Language：English   Publisher：Journal of Artificial Organs  

Percutaneous mechanical circulatory support utilizing micro-axial flow pumps, such as the Impella group of devices, has become a life-saving technique in the treatment of refractory cardiogenic shock, with ever-increasing success rates. A 30-year-old man presented with acute decompensated heart failure and a severely reduced left ventricular ejection fraction (17%). Despite initial treatment with inotropic drugs and intra-aortic balloon pump support, his hemodynamic status remained unstable. Transition to Impella CP mechanical circulatory support was made on day 6 owing to persistently low systolic blood pressure. A significant decline in platelet count prompted suspicion of heparin-induced thrombocytopenia (HIT), later confirmed by positive platelet-activated anti-platelet factor 4/heparin antibody and a 4Ts score of 6 points. Argatroban was initially used as the purge solution, but owing to complications, a switch to Impella 5.0 and a bicarbonate-based purge solution (BBPS) was performed. Despite additional veno-arterial extracorporeal membrane oxygenation support on day 24, the patient, aiming for ventricular assist device treatment and heart transplantation, died from infection and multiple organ failure. Remarkably, the Impella CP continued functioning normally until the patient’s demise, indicating stable Impella pump performance using BBPS. This case highlights the usefulness of BBPS as an alternative to conventional Impella heparin purge solution when HIT occurs.

DOI： 10.1007/s10047-024-01452-0

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Language：English   Publisher：International Journal of Cardiovascular Imaging  

Dynamic chest radiography (DCR) can estimate haemodynamic parameters in heart failure (HF). However, no studies have evaluated its ability to determine cardiac systolic function in HF. This experimental study investigates the correlation between left ventricular (LV) ejection fraction (LVEF) and DCR image parameters in HF. Ninety-one patients with acute HF (median age, 58 years; males, 75%) (cardiologist diagnosis using the Framingham criteria) underwent DCR and transthoracic echocardiography after treatment for the uncompensated phase of HF. The LV apex pixel value (PV) change was measured by DCR. Correlations between the PV change and LVEF, as well as sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) of DCR, were evaluated. LVEF and LV apex PV change were correlated in all patients (R = 0.428, P < 0.001) and in patients with LVEF < 50% (n = 38; R = 0.355, P = 0.029), < 40% (n = 31; R = 0.343, P = 0.059), and < 30% (n = 23; R = 0.321, P = 0.135). There was no significant correlation for patients with LVEF ≥ 50% (n = 53; R = − 0.004, P = 0.980). The LV apex PV change rate cutoff values for identifying LVEF < 50%, < 40%, and < 30% were 9.3% (AUC: 0.761, sensitivity: 0.698, specificity: 0.789, P < 0.001), 5.5% (AUC: 0.765, sensitivity: 0.883, specificity: 0.645, P < 0.001), and 5.5% (AUC: 0.767, sensitivity: 0.838, specificity: 0.696, P < 0.001), respectively. DCR may be useful to identify LV systolic dysfunction based on LVEF in acute HF.

DOI： 10.1007/s10554-025-03332-x

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Language：English   Publisher：Circulation Heart Failure  

BACKGROUND: How different combinations of comorbidities influence risk at the patient level and population level in patients with heart failure with mildly reduced ejection fraction/heart failure with preserved ejection fraction is unknown. We aimed to investigate the prevalence of different combinations of cardiovascular and noncardiovascular comorbidities (ie, multimorbidity) and associated risk of death at the patient level and population level. METHODS: Using patient-level data from the TOPCAT trial (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) and PARAGON-HF trial (Prospective Comparison of ARNI With ARB Global Outcomes in HF With Preserved Ejection Fraction), we investigated the 5 most common cardiovascular and noncardiovascular comorbidities and the resultant 45 comorbidity pairs. Cox proportional hazard models were used to calculate the population-attributable fractions for all-cause mortality and the relative excess risk due to interaction for each comorbidity pair. RESULTS: Among 6504 participants, 95.2% had at least 2 of the 10 most prevalent comorbidities. The comorbidity pair with the greatest patient-level risk was stroke and peripheral artery disease (adjusted hazard ratio, 1.88 [95% CI, 1.27-2.79]), followed by peripheral artery disease and chronic obstructive pulmonary disease (1.81 [95% CI, 1.31-2.51]), and coronary artery disease and stroke (1.67 [95% CI, 1.33-2.11]). The pair with the highest population-level risk was hypertension and chronic kidney disease (CKD; adjusted population-attributable fraction, 14.8% [95% CI, 9.2%-19.9%]), followed by diabetes and CKD (13.3% [95% CI, 10.6%-16.0%]), and hypertension and diabetes (11.9% [95% CI, 7.1%-16.5%). A synergistic interaction (more than additive risk) was found for the comorbidity pairs of stroke and coronary artery disease (relative excess risk due to interaction, 0.61 [95% CI, 0.13-1.09]), diabetes and CKD (relative excess risk due to interaction, 0.46 [95% CI, -0.15 to 0.77]), and obesity and CKD (relative excess risk due to interaction, 0.24 [95% CI, 0.01-0.46]). CONCLUSIONS: The risk associated with comorbidity pairs differs at the patient and population levels in heart failure with mildly reduced ejection fraction/heart failure with preserved ejection fraction. At the population level, hypertension, CKD, and diabetes account for the greatest risk, whereas at the patient level, polyvascular disease and chronic obstructive pulmonary disease are the most important.

DOI： 10.1161/CIRCHEARTFAILURE.124.011598

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Language：English   Publisher：Quantitative Imaging in Medicine and Surgery  

DOI： 10.21037/qims-24-1679

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Language：English   Publisher：Journal of the American College of Cardiology  

Background: Hypertension is common in patients with heart failure with mildly reduced or preserved ejection fraction (HFmrEF/HFpEF), and current guidelines recommend treating systolic blood pressure (SBP) to a target <130 mm Hg. However, data supporting treatment to this target are limited. Additionally, pulse pressure (PP), a marker of aortic stiffness, has been associated with increased risk of cardiovascular events, but its prognostic impact in HFpEF has not been extensively studied. Objectives: This study aimed to explore the impact of baseline SBP and PP on cardiovascular outcomes in patients with HFmrEF or HFpEF. Methods: The I-PRESERVE (Irbesartan in Heart Failure With Preserved Ejection Fraction), TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist)–Americas, PARAGON-HF (Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor With Angiotensin-Receptor Blocker Global Outcomes in HF With Preserved Ejection Fraction), and DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure) trials were global, randomized clinical trials testing irbesartan, spironolactone, sacubitril/valsartan, and dapagliflozin, respectively, against either a placebo or an active comparator (valsartan, in PARAGON-HF), in patients with heart failure and a left ventricular ejection fraction ≥40% (in DELIVER) or ≥45% (in the other trials). The relationship between continuous baseline SBP and PP, and the primary endpoint (first heart failure hospitalization or cardiovascular death) was analyzed with restricted cubic splines. We further evaluated the prognostic impact of SBP categories (<120, 120-129, 130-139, and ≥140 mm Hg) and PP quartiles on the primary endpoint. Results: A total of 16,950 patients (mean age 71 ± 9 years; 49% male; mean SBP 131 ± 15 mm Hg; mean PP 55 ± 14 mm Hg) were included. The relationship between SBP and the primary endpoint was J-shaped, with the lowest risk at 120 to 130 mm Hg. A similar pattern was found for PP, with the lowest risk at 50 to 60 mm Hg. The highest SBP category (reference: 120-129 mm Hg) and PP quartile (reference: 46-54 mm Hg) were associated with a higher risk of the primary outcome (HR: 1.22; 95% CI: 1.10-1.34 and HR: 1.22; 95% CI: 1.11-1.34, respectively). Higher PP was associated with greater cardiovascular risk, regardless of SBP. Conclusions: Our analysis of a large pooled dataset from 4 clinical trials, including >16,900 patients with HFmrEF/HFpEF, indicates a J-shaped relationship between both SBP and PP and cardiovascular risk. The lowest risk was observed at SBP levels between 120 and 130 mm Hg and PP values between 50 and 60 mm Hg (I-PRESERVE [Irbesartan in Heart Failure With Preserved Systolic Function], NCT00095238; TOPCAT [Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist], NCT00094302; PARAGON-HF [Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction], NCT01920711; DELIVER [Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure], NCT03619213)

DOI： 10.1016/j.jacc.2024.11.007

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Language：English   Publisher：Jacc Heart Failure  

Background: The value of generic quality of life (QoL) instruments in heart failure (HF) is uncertain. Objectives: In this study, the authors sought to quantify individual dimension scores and the EuroQol 5-Dimension questionnaire (EQ-5D) Level Sum Score (LSS) in patients with HF with reduced, mildly reduced, or preserved ejection fraction, the association between those scores and outcomes, and the impact of treatment with dapagliflozin on the scores. Methods: Analyses were conducted using patient-level data from DAPA-HF and DELIVER trials. Cox proportional hazards regression models were used to assess the association between EQ-5D scores (each dimension and LSS) and clinical outcomes. Sankey diagrams were used to illustrate changes in individual patient EQ-5D dimensions from baseline to 8 months’ follow-up. Results: Of the 11,007 patients randomized in DAPA-HF and DELIVER, 10,135 (92.1%) completed the instrument at baseline. Scores varied markedly by question with 37%, 30%, and 33% of patients reporting no, slight, or moderate or greater problem, respectively for mobility; 67%, 20%, and 13% for self-care; 40%, 33%, and 27% for usual activities; 45%, 32%, and 23% for pain/discomfort; and 57%, 27%, and 16% for anxiety/depression. Patients with higher (worse) EQ-5D-LSS were more frequently female, had more comorbidities, and had worse HF status. Compared with patients free from any problem across all dimensions (ie, an EQ-5D-LSS of 5), the HRs for the composite outcome of time to first cardiovascular death or worsening HF were 1.27 (95% CI: 1.10-1.47), 1.70 (95% CI: 1.46-1.98), and 2.31 (95% CI: 1.88-2.85) in patients with EQ-5D-LSS of 6-10, 11-15, and 16-25 points, respectively. Dapagliflozin led to greater improvement and less worsening in mobility (OR: 1.13 [95% CI: 1.04-1.23]; P = 0.004), self-care (OR: 1.13 [95% CI: 1.02-1.24]; P = 0.016), usual activities (OR: 1.11 [95% CI: 1.02-1.21]; P = 0.015), and anxiety/depression (OR: 1.10 [95% CI: 1.01-1.21]; P = 0.034) after 8 months. The number needed to treat for 1 patient to report improvement in EQ-5D-LSS was 31 (95% CI: 20-72). Conclusions: The EQ-5D revealed problems not often associated (eg, pain) with HF or commonly quantified in HF (eg, anxiety/depression). Dapagliflozin improved multiple QoL dimensions, and possibly anxiety/depression. (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure [DAPA-HF]; NCT03036124; Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure [DELIVER]; NCT03619213)

DOI： 10.1016/j.jchf.2024.10.020

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Language：English   Publisher：Journal of the American Heart Association  

BACKGROUND: The importance of nutritional status is underappreciated in patients with heart failure (HF). This study aimed to describe the range of the prognostic nutrition index (PNI), and the clinical characteristics and outcomes according to PNI, in patients with HF with preserved ejection fraction (HFpEF) and reduced ejection fraction (HFrEF). The primary outcome was the composite of HF hospitalization or cardiovascular death. METHODS AND RESULTS: Individual patient data from the PARAGON-HF (Prospective Comparison of ARNI [Angiotensin Receptor– Neprilysin Inhibitor] with ARB [Angiotensin Receptor Blocker] Global Outcomes in HFpEF) and PARADIGM-HF (Prospective Comparison of ARNI With ACEI [Angiotensin-Converting Enzyme Inhibitor] to Determine Impact on Global Mortality and Morbidity in HF) trials were used to examine patient characteristics and outcomes according to quartiles of PNI. Cox regression was used to analyze clinical outcomes, and multivariable fractional polynomial interaction analysis to examine the effects of sacubitril-valsartan, according to PNI. Patients with lower PNI (poorer nutrition) were older, frailer, and had more comorbidities and worse HF status, with greater congestion. Patients with lower PNI had biomarker abnormalities indicating inflammation, bone marrow suppression, and increased collagen turnover, among other physiologic perturbations. Lower PNI was associated with worse outcomes; that is, the rate of the primary end point among patients in the first quartile was 11.31 (10.20–12.54) compared with 7.09 (6.17–8.14) per 100 personyears in the fourth quartile. These associations persisted after adjustment for other prognostic variables. PNI did not modify the effects of sacubitril-valsartan in HFrEF although sacubitril/valsartan seemed to have a greater benefit in patients with HFpEF with a higher PNI. CONCLUSIONS: Nutritional status, assessed using PNI, is an independent predictor of poor outcomes in HF. Evaluation of nutritional status in clinical practice, the causes of undernutrition, and whether undernutrition should be a therapeutic target, are all worthy of further investigation in HF.

DOI： 10.1161/JAHA.124.037782

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Language：English   Publisher：European Journal of Heart Failure  

Aims: In the absence of randomized trial evidence, we performed a large observational analysis of the association between beta-blocker (BB) use and clinical outcomes in patients with heart failure (HF) and mildly reduced (HFmrEF) and preserved ejection fraction (HFpEF). Methods and results: We pooled individual patient data from four large HFmrEF/HFpEF trials (I-Preserve, TOPCAT, PARAGON-HF, and DELIVER). The primary outcome was the composite of cardiovascular death or HF hospitalization. Among the 16 951 patients included, the mean left ventricular ejection fraction (LVEF) was 56.8%, and 13 400 (79.1%) had HFpEF (LVEF ≥50%). Overall, 12 812 patients (75.6%) received a BB. The median bisoprolol-equivalent dose of BB was 5.0 (Q1–Q3: 2.5–5.0) mg with BB continuation rates of 93.1% at 2 years (in survivors). The unadjusted hazard ratio (HR) for the primary outcome did not differ between BB users and non-users (HR 0.98, 95% confidence interval [CI] 0.91–1.05), but the adjusted HR was lower in BB users than non-users (0.81, 95% CI 0.74–0.88), and this association was maintained across LVEF (pinteraction = 0.88). In subgroup analyses, the adjusted risk of the primary outcome was similar in BB users and non-users with or without a history of myocardial infarction, hypertension, or a baseline heart rate <70 bpm. By contrast, a better outcome with BB use was seen in patients with atrial fibrillation compared to those without atrial fibrillation (pintreraction = 0.02). Conclusions: In this observational analysis of non-randomized BB treatment, there was no suggestion that BB use was associated with worse HF outcomes in HFmrEF/HFpEF, even after extensive adjustment for other prognostic variables.

DOI： 10.1002/ejhf.3383

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Language：English   Publisher：The Japanese Circulation Society  

<p><b><i>Background:</i></b> The number of older people in Japan is increasing more quickly than in other countries; with this aging of society, the number of elderly patients hospitalized for acute heart failure (HF) is also increasing. The treatment and prognosis of acute HF may be changing, but there are insufficient recent data, especially for octogenarian and older patients.</p><p><b><i>Methods and Results:</i></b> This study investigated the characteristics and treatment of acute HF patients in Japan. From 2018 to 2020, 1,146 patients from 7 Tokai area hospitals were followed for at least 1 year. The mean age was 78 years. Compared with patients aged <80 years, those aged ≥80 years were more likely to be female (57.4% vs. 34.2%), have a lower body mass index (22.2 vs. 24.9 kg/m²), and have HF with preserved ejection fraction (43.1% vs. 21.4%), and less likely to have HF with reduced ejection fraction (38.9% vs. 61.7%). During hospitalization, 6.5% died. After discharge, patients faced high risks of rehospitalization for HF and death (27.6 and 14.2 per 100 patient-years, respectively). Notably, prescription rates of HF medications have declined over time for all patients, but especially for those aged ≥80 years.</p><p><b><i>Conclusions:</i></b> Guideline-directed medical therapy should be provided based on a thorough understanding of an individual’s background rather than withheld simply because of clinical inertia due to a patient’s advanced age.</p>

DOI： 10.1253/circj.CJ-24-0299

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Authorship：Lead author   Language：English   Publisher：European Journal of Heart Failure  

Aims: The primary aim was to evaluate the effect of dapagliflozin according to QRS duration across the spectrum of left ventricular ejection fraction (LVEF), given that prolongation of QRS duration is associated with less favourable ventricular remodelling with pharmacological therapy and worse outcomes. Methods and results: A pooled analysis of the DAPA-HF and DELIVER trials, excluding patients with a paced rhythm and cardiac resynchronization therapy. Overall, 4008 patients had heart failure (HF) with reduced ejection fraction (HFrEF), and 5816 had HF with mildly reduced/preserved ejection fraction (HFmrEF/HFpEF). QRS duration was <120 ms in 7039 patients (71.7%), 120–149 ms in 1725 (17.6%), and ≥150 ms in 1060 patients (10.8%). The median follow-up time was 23 months. The rate of the primary composite outcome of cardiovascular death or worsening HF was 9.2 (95% confidence interval [CI] 8.7–9.7), 14.3 (13.0–15.7), and 15.9 (14.1–17.9) per 100 patient-years in the <120, 120–149, and ≥150 ms groups, respectively. This gradient in event rates was observed both in HFrEF and HFmrEF/HFpEF. Dapagliflozin, compared with placebo, reduced the risk of the primary outcome consistently across the QRS duration subgroups (hazard ratio [95% CI] 0.75 [0.67–0.85], 0.79 [0.65–0.96], and 0.89 [0.70–1.13] in the <120, 120–149, and ≥150 ms groups, respectively; p for interaction = 0.28). The effect of dapagliflozin on the primary outcome was consistent across the QRS duration regardless of HF phenotype that is, HFrEF or HFmrEF/HFpEF. Conclusions: Prolongation of QRS duration is associated with worse outcomes irrespective of HF phenotype. Dapagliflozin reduced the risk of the primary outcome, regardless of QRS duration, in DAPA-HF and DELIVER.

DOI： 10.1002/ejhf.3350

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DOI： 10.1016/j.jjcc.2024.04.006

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Language：English   Publisher：European Journal of Heart Failure  

Aims: Although the prevalence of heart failure (HF) increases markedly with advancing age, surprisingly little is known about HF in the very elderly. The aim of this study was to describe the clinical characteristics and outcomes of octogenarians with HF. Methods and results: Individual participant meta-analysis of patients with HF and reduced, mildly reduced, and preserved ejection fraction (HFrEF, HFmrEF, and HFpEF, respectively) enrolled in eight large randomized trials. Overall, the proportion of octogenarians was 1518 of 20 168 patients (7.5%) with HFrEF, 610 of 4609 (13.2%) with HFmrEF, and 3130 of 15 354 (20.4%) with HFpEF. Regardless of HF phenotype, octogenarian patients were more often female and had more comorbidities, more symptoms and signs of congestion, and worse health status (but not quality of life), in comparison to patients aged <80 years. The incidence (per 100 person-years) of the composite of cardiovascular death or HF hospitalization was 13.3 (95% confidence interval [CI] 12.7–14.0) in octogenarians versus 9.5 (95% CI 9.3–9.7) in non-octogenarians (adjusted hazard ratio [aHR] 1.40, 95% CI 1.32–1.48). Each component of the composite was more frequent in octogenarians with rates of cardiovascular mortality of 7.0 (95% CI 6.5–7.4) per 100 person-years versus 4.9 (95% CI 4.8–5.1) in non-octogenarians (aHR 1.60, 95% CI 1.48–1.72, p < 0.001). Octogenarians received less evidence-based therapy, especially mineralocorticoid receptor antagonists, than younger patients. Conclusion: Despite worse health status and higher hospitalization and mortality rates, octogenarians were undertreated compared to younger patients.

DOI： 10.1002/ejhf.3417

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Authorship：Lead author   Language：English   Publisher：JACC: Heart Failure  

Background: Although some patients with heart failure (HF) with mildly reduced/preserved ejection fraction have low natriuretic peptide levels, there are no large-scale systematic studies of how common these individuals are or what happens to them. Objectives: The purpose of this study was to examine the proportion of patients in the I-PRESERVE (Irbesartan in Heart Failure with Preserved Ejection Fraction) trial with an N-terminal pro–B-type natriuretic peptide (NT-proBNP) level <125 pg/mL, their clinical characteristics, and outcomes. Methods: I- PRESERVE enrolled patients with symptomatic HF and a LVEF ≥45% but who did not have NT-proBNP or body mass index inclusion/exclusion criteria. Baseline NT-proBNP was measured after enrollment but not reported to investigators. The primary outcome in this analysis was the composite of cardiovascular death or HF hospitalization. Results: Overall, 808 of 3,480 patients (23.2%) had NT-proBNP <125 pg/mL. Patients with a low NT-proBNP were younger (68.6 years vs 72.6 years; P < 0.001), were less often men (36.1% vs 40.9%; P = 0.015), and had a higher body mass index (48.4% vs 38.7% obese; P < 0.001) than those with a higher NT-proBNP level. Patients with a low NT-proBNP had less atrial fibrillation (8.5% vs 35.1%; P < 0.001), myocardial infarction, diabetes, chronic obstructive pulmonary disease, and anemia but better kidney function. Patients with a lower NT-proBNP level had less marked echocardiographic abnormalities and were less likely to experience cardiovascular death or HF hospitalization; adjusted HR: 0.35 (95% CI: 0.27-0.46; P < 0.001). However, health status was similarly impaired in patients with lower and higher NT-proBNP levels (median Minnesota Living with Heart Failure Questionnaire 43 vs 43; P = 0.95). Conclusions: Almost one-quarter of patients with HF with mildly reduced/preserved ejection fraction had a low NT-proBNP level. Although these patients have a favorable prognosis, compared to those with a high NT-proBNP level, they have similarly impaired health status which should be a target for treatment. (Irbesartan in Heart Failure With Preserved Systolic Function [I- PRESERVE]; NCT00095238)

DOI： 10.1016/j.jchf.2024.04.027

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Language：English   Publisher：European Journal of Heart Failure  

Aims: Compared to heart failure (HF) with reduced ejection fraction, HF with preserved ejection fraction (HFpEF), and HF with mildly reduced ejection fraction (HFmrEF) are increasing in prevalence, yet little is known about the geographic variation in patient characteristics, treatments and outcomes among these two HF phenotypes. The aim of this study was to investigate geographic differences in HFpEF and HFmrEF. Methods and results: We conducted an individual patient analysis of five clinical trials enrolling patients with HFpEF or HFmrEF from North America (NA), Latin America (LA), Western Europe (WE), Central/Eastern Europe and Russia (CEER), and Asia-Pacific (AP). We compared regions using descriptive statistics and multivariable regression models. Among the 19 959 patients included, 4066 (23.1%) had HFmrEF and 15 353 (76.9%) HFpEF. Regardless of HF phenotype, patients from WE were oldest, and those in CEER youngest. LA had the largest portion of females and NA most black patients. Obesity and diabetes were most prevalent in NA and hypertension and coronary heart disease most common in CEER. Self-reported health status varied strikingly and was the worst in NA and best in AP. Among patients with HFmrEF, rates of the primary composite endpoint (cardiovascular death or HF hospitalization) were: NA 12.56 per 100 patient-years (/100py), AP 11.67/100py, CEER 10.12/100py, LA 8.90/100py, and WE 8.43/100py, driven by differences in the rate of HF hospitalization. The corresponding values in HFpEF were 11.47/100py, 7.80/100py, 5.47/100py, 5.92/100py, and 7.80/100py, respectively. Conclusions: There is substantial geographic variation in patient characteristics, treatment and outcomes among patients with HFpEF and HFmrEF. These findings have implications for interpretation and generalizability of trial results, design and conduct of future trials, and optimization of care for these patients.

DOI： 10.1002/ejhf.3352

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Authorship：Last author,　Corresponding author   Language：Japanese   Publisher：診断と治療社  

DOI： 10.34433/dt.0000000864

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Language：English   Publisher：European Journal of Heart Failure  

Aims: Although much is known about the usefulness of heart failure (HF)-specific instruments for assessing patient well-being, less is known about the value of generic instruments for the measurement of health-related quality of life (HRQL) in HF. The aim of this study was to assess the relationship between the EuroQol 5-dimension 5-level (EQ-5D-5L) visual analogue scale (VAS) and index scores, clinical characteristics, and outcomes in patients with HF and the effect of dapagliflozin on these scores. Methods and results: We performed a patient-level pooled analysis of the DAPA-HF and DELIVER trials, which investigated the effectiveness and safety of dapagliflozin in patients with HF and reduced ejection fraction (HFrEF) and mildly reduced/preserved ejection fraction (HFmrEF/HFpEF), respectively. Patients reporting higher (better) EQ-5D-5L VAS and index scores had a lower prevalence of comorbidities, including atrial fibrillation and hypertension, than patients with a worse score. They were also more likely to have better investigator-reported (New York Heart Association class) and patient-self-reported (Kansas City Cardiomyopathy Questionnaire) health status and lower median N-terminal pro-B-type natriuretic peptide levels. Compared to patients with the lowest scores (Q1), those with higher EQ-5D-5L VAS scores had better outcomes: the hazard ratio for the composite of cardiovascular death or worsening HF was 0.81 (95% confidence interval 0.72–0.91) in Q2, 0.74 (0.65–0.84) in Q3, and 0.62 (0.54–0.72) in Q4. The risk of each component of the composite outcome, and all-cause death, was also lower in patients with better scores. Similar findings were observed for the index score. Treatment with dapagliflozin improved both EQ-5D-5L VAS and index scores across the range of ejection fraction. Conclusions: Both higher (better) EQ-5D-5L VAS and index scores were associated with better outcomes. Dapagliflozin treatment improved EQ-5D-5L VAS and index scores, irrespective of ejection fraction.

DOI： 10.1002/ejhf.3263

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Language：English   Publisher：International Journal of Cardiology  

Background: The natural history of aortic stenosis (AS) progression, especially before severe AS development, is not well documented. We aimed to investigate the time course of peak aortic jet velocity (Vmax) and AS progression risk according to baseline Vmax, particularly whether there is a Vmax threshold. Methods: In a retrospective multicenter cohort study of patients on hemodialysis with aortic valve calcification, we investigated the time series of Vmax and the relationship between the baseline Vmax and progression to severe AS by analyzing longitudinal echocardiographic data. Results: Among 758 included patients (mean age, 71 years; 65% male), patients with Vmax <1.5, 1.5–1.9, 2.0–2.4, 2.5–2.9, and 3.0–3.9 m/s were 395 (52%), 216 (29%), 85 (11%), 39 (5.1%), and 23 (3.0%), respectively. The Vmax slope was gradual (mean 0.05–0.07 m/s/year) at Vmax <2 m/s, but steeper (mean 0.13–0.21 m/s/year) at Vmax ≥2 m/s. During a median 3.2-year follow-up, 52 (6.9%) patients developed severe AS. While patients with Vmax <2 m/s rarely developed severe AS, the risk of those with Vmax ≥2 m/s increased remarkably with an increasing baseline Vmax; the adjusted incidence rates in patients with Vmax <1.5, 1.5–1.9, 2.0–2.4, 2.5–2.9, and 3.0–3.9 m/s were 0.59, 0.57, 4.25, 13.8, and 56.1 per 100 person-years, respectively; the adjusted hazard ratio per 0.2 m/s increase in the baseline Vmax was 1.49 (95% confidence interval: 1.32–1.68) when Vmax ≥2 m/s. Conclusions: The risk of progression to severe AS increased with the baseline Vmax primarily at ≥2 m/s; a Vmax threshold of 2 m/s was observed.

DOI： 10.1016/j.ijcard.2024.131822

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Language：English   Publisher：JAMA Cardiology  

Importance: Accurate risk prediction of morbidity and mortality in patients with heart failure with preserved ejection fraction (HFpEF) may help clinicians risk stratify and inform care decisions. Objective: To develop and validate a novel prediction model for clinical outcomes in patients with HFpEF using routinely collected variables and to compare it with a biomarker-driven approach. Design, Setting, and Participants: Data were used from the Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure (DELIVER) trial to derive the prediction model, and data from the Angiotensin Receptor Neprilysin Inhibition in Heart Failure With Preserved Ejection Fraction (PARAGON-HF) and the Irbesartan in Heart Failure With Preserved Ejection Fraction Study (I-PRESERVE) trials were used to validate it. The outcomes were the composite of HF hospitalization (HFH) or cardiovascular death, cardiovascular death, and all-cause death. A total of 30 baseline candidate variables were selected in a stepwise fashion using multivariable analyses to create the models. Data were analyzed from January 2023 to June 2023. Exposures: Models to estimate the 1-year and 2-year risk of cardiovascular death or hospitalization for heart failure, cardiovascular death, and all-cause death. Results: Data from 6263 individuals in the DELIVER trial were used to derive the prediction model and data from 4796 individuals in the PARAGON-HF trial and 4128 individuals in the I-PRESERVE trial were used to validate it. The final prediction model for the composite outcome included 11 variables: N-terminal pro-brain natriuretic peptide (NT-proBNP) level, HFH within the past 6 months, creatinine level, diabetes, geographic region, HF duration, treatment with a sodium-glucose cotransporter 2 inhibitor, chronic obstructive pulmonary disease, transient ischemic attack/stroke, any previous HFH, and heart rate. This model showed good discrimination (C statistic at 1 year, 0.73; 95% CI, 0.71-0.75) in both validation cohorts (C statistic at 1 year, 0.71; 95% CI, 0.69-0.74 in PARAGON-HF and 0.75; 95% CI, 0.73-0.78 in I-PRESERVE) and calibration. The model showed similar discrimination to a biomarker-driven model including high-sensitivity cardiac troponin T and significantly better discrimination than the Meta-Analysis Global Group in Chronic (MAGGIC) risk score (C statistic at 1 year, 0.60; 95% CI, 0.58-0.63; delta C statistic, 0.13; 95% CI, 0.10-0.15; P <.001) and NT-proBNP level alone (C statistic at 1 year, 0.66; 95% CI, 0.64-0.68; delta C statistic, 0.07; 95% CI, 0.05-0.08; P <.001). Models derived for the prediction of all-cause and cardiovascular death also performed well. An online calculator was created to allow calculation of an individual's risk. Conclusions and Relevance: In this prognostic study, a robust prediction model for clinical outcomes in HFpEF was developed and validated using routinely collected variables. The model performed better than NT-proBNP level alone. The model may help clinicians to identify high-risk patients and guide treatment decisions in HFpEF.

DOI： 10.1001/jamacardio.2024.0284

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Language：English   Publisher：Journal of Cardiac Failure  

Background: Patients with heart failure with reduced ejection fraction (HFrEF) and sinus rhythm have a heightened risk of stroke. Whether anticoagulation benefits these patients is uncertain. In this post hoc analysis of the A Study to Assess the Effectiveness and Safety of Rivaroxaban in Reducing the Risk of Death, Myocardial Infarction, or Stroke in Participants with Heart Failure and Coronary Artery Disease Following an Episode of Decompensated Heart Failure (COMMANDER-HF) trial we evaluated how a previously validated risk model consisting of 3 variables (history of prior stroke, insulin-treated diabetes, and N-terminal pro-B-type natriuretic peptide level) would perform, compared with plasma D-dimer, for stroke prediction and estimation of the benefit of low-dose rivaroxaban. Methods and Results: Stroke risk and treatment effect were computed across risk score and plasma D-dimer tertiles. Risk score was available in 58% of the COMMANDER-HF population (n = 2928). Over a median follow-up of 512 days (range 342–747 days), 60 patients experienced a stroke (14.6 per 1000 patient-years). The risk model did not identify patients at higher risk of stroke and showed a low overall prognostic performance (C-index = 0.53). The effect of rivaroxaban on stroke was homogeneous across risk score tertiles (P-interaction = .67). Among patients in whom the risk score was estimated, D-dimer was available in 2343 (80%). D-dimer had an acceptable discrimination performance for stroke prediction (C-index = 0.66) and higher plasma D-dimer concentrations were associated with higher rates of stroke (ie, tertile 3 vs tertile 1, hazard ratio 3.65, 95% confidence interval 1.59–8.39, P = .002). Treatment with low-dose rivaroxaban reduced the incidence of stroke in patients at highest risk by D-dimer levels (ie, >515 ng/mL, hazard ratio 0.42, 95% confidence interval 0.18–0.95, P-interaction = .074), without any safety concerns. Conclusions: In our analysis, plasma D-dimer concentrations performed better than a previously described 3-variable risk score for stroke prediction in patients with heart failure with reduced ejection fraction, a recent clinical worsening and sinus rhythm as enrolled in the COMMANDER-HF trial. In these patients, a raised plasma D-dimer concentration identified patients who might benefit most from rivaroxaban.

DOI： 10.1016/j.cardfail.2023.11.020

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Authorship：Corresponding author   Language：English   Publisher：International Heart Journal Association  

<p>Troponin (Tn) is a biomarker related to myocardial necrosis and is elevated in patients with myocarditis. This study aimed to investigate the association between cardiac Tn levels and the course of cardiac function, and prognosis in patients with fulminant myocarditis (FM) receiving percutaneous mechanical circulatory support (MCS).</p><p>We used data from a multicenter retrospective registry, CHANGE PUMP 2, which included 216 patients with FM who required MCS. Among them, 141 patients whose Tn levels were available were analyzed. The patients were divided into low and high Tn groups according to the median values of TnT and TnI.</p><p>The median age was 54 years, and 59.6% were male. The TnT and TnI on day 1 (at MCS initiation) were 3.8 (1.4-10.0) and 21.4 (8.4-68.8) ng/mL. While the left ventricular ejection fraction (LVEF) was similar on day 1 (25.0% versus 24.5%), the low Tn group showed better LVEF improvement on day 7 than the high Tn group (45.0% versus 25.3%, P < 0.001). LVEF at 1 year after admission was higher in the low Tn group (65.0% versus 59.7%, P = 0.039). The low Tn group had a better 90-day composite endpoint in death, durable left ventricular assist device implantation, and heart transplantation compared to the high Tn group (hazard ratio 0.47, 95% CI 0.23-0.95).</p><p>Tn levels were associated with short- and long-term cardiac recovery and adverse outcomes in patients with FM receiving MCS due to cardiogenic shock.</p>

DOI： 10.1536/ihj.23-589

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Language：English   Publisher：JACC: Heart Failure  

Heart failure (HF) is a complex syndrome traditionally classified by left ventricular ejection fraction (LVEF) cutpoints. Although LVEF is prognostic for risk of events and predictive of response to some HF therapies, LVEF is a continuous variable and cutpoints are arbitrary, often based on historical clinical trial enrichment decisions rather than physiology. Holistic evaluation of the treatment effects for therapies throughout the LVEF range suggests the standard categorization paradigm for HF merits modification. The multidisciplinary Heart Failure Collaboratory reviewed data from large-scale HF clinical trials and found that many HF therapies have demonstrated therapeutic benefit across a large range of LVEF, but specific treatment effects vary across that range. Therefore, HF should practically be classified by association with an LVEF that is reduced or not reduced, while acknowledging uncertainty around the precise LVEF cutpoint, and future research should evaluate new therapies across the continuum of LVEF.

DOI： 10.1016/j.jchf.2023.11.005

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DOI： doi: 10.1002/ehf2.14558

DOI： doi: 10.1002/ehf2.14558

Language：English   Publisher：European Journal of Heart Failure  

Aim: Blood urea nitrogen (BUN) to creatinine ratio is associated with worse outcomes in acute heart failure (HF) but little is known about its importance in chronic HF. Methods and results: We combined individual patient data from clinical trials (HF with reduced ejection fraction [HFrEF]: PARADIGM-HF, ATMOSPHERE and DAPA-HF, and HF with preserved ejection fraction [HFpEF]: PARAGON-HF and I-PRESERVE). The primary outcome examined was a composite time to first HF hospitalization or cardiovascular death; its components and all-cause death were also examined. Each HF phenotype was categorized according to median BUN/creatinine ratio, generating four groups that is, HFpEF ≤ and >median BUN/creatinine ratio and HFrEF ≤ and >median BUN/creatinine ratio. The association between BUN/creatinine ratio and outcomes was evaluated using the Kaplan–Meier estimator and Cox proportional hazard models. Overall, 28 820 patients were analysed. The median (IQR) BUN/creatinine ratio was 20.1 (Q1–Q3 16.7–24.7) in HFpEF and 18.7 (15.2–22.8) in HFrEF. In both HFpEF and HFrEF, higher BUN/creatinine ratio was associated with older age, female sex, and diabetes, but similar estimated glomerular filtration rate (eGFR). The risk of each outcome examined was significantly higher in patients with BUN/creatinine ratio ≥median, compared to <median, even after adjustment for other prognostic variables, including N-terminal pro-B-type natriuretic peptide (NT-proBNP) and eGFR. Conclusion: Higher BUN/creatinine ratio was associated with worse outcomes in patients with chronic HF across the spectrum of left ventricular ejection fraction, independently of eGFR and NT-proBNP. BUN/creatinine ratio may reflect neurohumoral activation (especially increased arginine vasopressin), altered renal blood flow or other pathophysiologic mechanisms not incorporated in conventional prognostic variables.

DOI： 10.1002/ejhf.3114

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Language：English   Publisher：JACC: Asia  

Background: Patients with heart failure (HF) with mildly reduced or preserved ejection fraction in Asia may have different clinical characteristics and outcomes compared with patients from other parts of the world. Objectives: The purpose of this study was to investigate the clinical characteristics, safety, and efficacy of dapagliflozin in patients in Asia vs outside Asia in the DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure) trial. Methods: In the DELIVER trial, patients with HF and left ventricular ejection fraction >40% were enrolled across 353 sites in 20 countries. The effects of dapagliflozin vs placebo on primary (composite of worsening HF or cardiovascular death) and secondary outcomes were compared in patients from Asia vs outside Asia. Results: Among 6,263 participants, 1,226 (19.6%) were enrolled in Asia. Participants from Asia were less likely to have diabetes, hypertension, history of myocardial infarction, or obesity. After adjusting for clinically relevant characteristics, those in Asia had similar risks of primary composite outcome compared with those from outside Asia (HR: 0.97; 95% CI: 0.82-1.15). Those in Asia had a lower risk of all-cause mortality compared with those enrolled outside Asia (HR: 0.54; 95% CI: 0.44-0.66). Enrollment from Asia did not modify the effect of dapagliflozin on the primary outcome (Pinteraction = 0.54). Serious adverse events and rates of drug discontinuation were also balanced in both treatment arms, irrespective of enrollment in Asia vs outside Asia. Conclusions: In the global DELIVER trial, dapagliflozin reduced the risk of CV death or worsening HF events and was well tolerated among participants enrolled in both Asia and other geographic regions.

DOI： 10.1016/j.jacasi.2023.10.005

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Authorship：Lead author   Language：English   Publisher：European Heart Journal - Cardiovascular Pharmacotherapy  

Background Randomized controlled trials (RCTs) have assessed the effects of renin–angiotensin system (RAS) blockers in adults with and aims coronavirus disease 2019 (COVID-19). This meta-analysis provides estimates of the safety and efficacy of treatment with (vs. without) RAS blockers from these trials. Methods PubMed, Web of Science, and ClinicalTrials.gov were searched (1 March–12 April 2023). Event/patient numbers were extracted, comparing angiotensin-converting enzyme (ACE) inhibitor/angiotensin-receptor blocker (ARB) treatment with no treatment, for the outcomes: intensive care unit (ICU) admission, mechanical ventilation, vasopressor use, acute kidney injury (AKI), renal replacement therapy (RRT), acute myocardial infarction, stroke/transient ischaemic attack, heart failure, thromboembolic events, and all-cause death. Fixed-effects meta-analysis estimates were pooled. Results Sixteen RCTs including 3492 patients were analysed. Compared with discontinuation of RAS blockers, continuation was not associated with increased risk of ICU [risk ratio (RR) 0.96, 0.66–1.41], ventilation (RR 0.77, 0.55–1.09), vasopressors (RR 0.92, 0.58–1.44), AKI (RR 1.01, 0.40–2.56), RRT (RR 1.01, 0.46–2.21), or thromboembolic events (RR 1.07, 0.36–3.19). RAS blocker initiation was not associated with increased risk of ICU (RR 0.71, 0.47–1.08), ventilation (RR 1.12, 0.91–1.38), AKI (RR 1.28, 0.89–1.86), RRT (RR 1.66, 0.89–3.12), or thromboembolic events (RR 1.20, 0.06–23.70), although vasopressor use increased (RR 1.27, 1.02–1.57). The RR for all-cause death in the continuation/discontinuation trials was 1.24 (0.80–1.92), and 1.22 (0.96–1.55) in the initiation trials. In patients with severe/critical COVID-19, RAS blocker initiation increased the risk of all-cause death (RR 1.31, 1.01–1.72). Conclusion ACE inhibitors and ARBs may be continued in non-severe COVID-19 infection, where indicated. Conversely, initiation of RAS blockers may be harmful in critically ill patients. PROSPERO registration number: CRD42023408926.

DOI： 10.1093/ehjcvp/pvad067

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Language：English   Publisher：JACC: Cardiovascular Imaging  

Background: Fluorodeoxyglucose positron emission tomography (18F-FDG-PET) can noninvasively assess active inflammatory myocardium in patients with cardiac sarcoidosis (CS). Prednisolone (PSL) is the initial drug of choice for active CS; however, its efficacy has not been prospectively evaluated. Moreover, there are no alternative systematic treatment strategies. Objectives: The goal of this study was to evaluate the efficacy of methotrexate (MTX) in patients refractory to PSL assessed by using cardiac metabolic activity (CMA) in 18F-FDG-PET. Methods: A total of 59 patients with active CS were prospectively enrolled. CMA (standardized uptake value × accumulation area) was used as an indicator of active inflammation, and a 6-month regimen of PSL therapy was introduced, followed by a second FDG scan. Poor responders to PSL therapy (CMA reduction rate <70%) and patients with recurrent CS (CMA reduction rate ≥70% after initial PSL therapy but CMA recurred after an additional 6 months of therapy) were randomly assigned to the MTX or repeat PSL (re-PSL) therapy groups for another 6 months. Results: Fifty-six patients completed the initial 6-month PSL therapy regimen. Median CMA reduced from 203.3 to 1.0 (P < 0.001), and 47 patients were allocated to the response group, 9 to the poor response group, and 2 to the recurrent group. Accordingly, 11 patients were randomly assigned to the MTX (n = 5) or re-PSL (n = 6) groups. After 6 months, neither group showed a significant reduction in CMA values. MTX was comparable to re-PSL in reducing CMA. Conclusions: The 6-month regimen of PSL was a potent therapeutic tool for active CS. When MTX was added to low-dose PSL in patients refractory to the initial PSL therapy, there was no significant difference compared with re-PSL. Further studies are needed to evaluate the therapeutic potential of MTX for active CS, including how MTX works when it is administered in higher doses or for longer periods.

DOI： 10.1016/j.jcmg.2023.05.017

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DOI： doi: 10.1159/000534518

DOI： doi: 10.1159/000534518

Authorship：Lead author   Language：English   Publisher：Circulation: Heart Failure  

BACKGROUND: Although elevated resting heart rate (HR) is associated with a higher risk of cardiovascular events in patients with heart failure with reduced ejection fraction in sinus rhythm (SR), the relationship between HR and outcomes among patients with heart failure with mildly reduced ejection fraction/heart failure with preserved ejection fraction and in those with atrial fibrillation (AF) is uncertain. The aims of this study were to examine the association between baseline HR and outcomes across the range of left ventricular ejection fraction, in patients with and without AF, and evaluate the effect of dapagliflozin according to HR. METHODS: A patient-level pooled analysis of the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure; heart failure with reduced ejection fraction) and DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure trial; heart failure with mildly reduced ejection fraction/heart failure with preserved ejection fraction) trials. The primary outcome of each was the composite of worsening heart failure or cardiovascular death. RESULTS: Among patients with SR (n=6401, 64%), the rate of the primary outcome was higher in those with higher HR: 16.8 versus 7.7 per 100 person-years for ≥80 bpm versus <60 bpm. The relationship between HR and risk was steeper in heart failure with reduced ejection fraction versus heart failure with mildly reduced ejection fraction/heart failure with preserved ejection fraction. HR was not associated with outcomes in patients in AF for either heart failure phenotype. The benefit of dapagliflozin on the primary outcome was consistent across the HR range in both SR (Pinteraction=0.28) and AF (Pinteraction=0.56), for example, for SR <60 bpm, hazard ratio for dapagliflozin versus placebo 0.72 (95% CI, 0.55-0.95); 60 to 69 bpm, 0.78 (0.63-0.97); 70 to 79 bpm, 0.73 (0.59-0.91); ≥80 bpm, 0.77 (0.61-0.97). The benefit was consistent across HR range in both heart failure with reduced ejection fraction and heart failure with mildly reduced ejection fraction/heart failure with preserved ejection fraction. CONCLUSIONS: The risk of worsening heart failure or cardiovascular death increased with increasing baseline HR among patients in SR, but this association was not seen among patients in AF, irrespective of left ventricular ejection fraction. The benefit of dapagliflozin was consistent across HR range, irrespective of left ventricular ejection fraction or rhythm. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT03036124 and NCT03619213.

DOI： 10.1161/CIRCHEARTFAILURE.123.010898

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Language：English   Publisher：European Journal of Heart Failure  

Aims: Patients with heart failure (HF) and mildly reduced ejection fraction (HFmrEF) and preserved ejection fraction (HFpEF) are often treated with calcium channel blockers (CCBs), although the safety of CCBs in these patients is uncertain. We aimed to investigate the association between CCB use and clinical outcomes in patients with HFmrEF/HFpEF; CCBs were examined overall, as well as by subtype (dihydropyridine and non-dihydropyridine). Methods and results: We pooled individual patient data from four large HFpEF/HFmrEF trials. The association between CCB use and outcomes was assessed. Among the 16 954 patients included, the mean left ventricular ejection fraction (LVEF) was 56.8%, and 13 402 (79.0%) had HFpEF (LVEF ≥50%). Altogether, 5874 patients (34.6%) received a CCB (87.6% dihydropyridines). Overall, the risks of death and HF hospitalization were not higher in patients treated with a CCB, particularly dihydropyridines. The risk of pump failure death was significantly lower (hazard ratio [HR] 0.76, 95% confidence interval [CI] 0.60–0.96), while the risk of stroke was higher (HR 1.26, 95% CI 1.06–1.50) in patients treated with a CCB compared to those not. These risks remained different in patients treated and not treated with a CCB after adjustment for other prognostic variables. Although the majority of patients were treated with dihydropyridine CCBs, the pattern of outcomes was broadly similar for both dihydropyridine and non-dihydropyridine CCBs. Conclusion: Although this is an observational analysis of non-randomized treatment, there was no suggestion that CCBs were associated with worse HF outcomes. Indeed, CCB use was associated with a lower incidence of pump failure death.

DOI： 10.1002/ejhf.3044

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Language：English   Publisher：European Journal of Heart Failure  

Aim: Although education in self-management is thought to be an important aspect of the care of patients with heart failure, little is known about whether self-rated knowledge of self-management is associated with outcomes. The aim of this study was to assess the relationship between patient-reported knowledge of self-management and clinical outcomes in patients with heart failure and reduced ejection fraction (HFrEF). Methods and results: Using individual patient data from three recent clinical trials enrolling participants with HFrEF, we examined patient characteristics and clinical outcomes according to responses to the ‘self-efficacy’ questions of the Kansas City Cardiomyopathy Questionnaire. One question quantifies patients' understanding of how to prevent heart failure exacerbations (‘prevention’ question) and the other how to manage complications when they arise (‘response’ question). Self-reported answers from patients were pragmatically divided into: poor (do not understand at all, do not understand very well, somewhat understand), fair (mostly understand), and good (completely understand). Cox-proportional hazard models were used to evaluate time-to-first occurrence of each endpoint, and negative binomial regression analysis was performed to compare the composite of total (first and repeat) heart failure hospitalizations and cardiovascular death across the above-defined groups. Of patients (n = 17 629) completing the ‘prevention’ question, 4197 (23.8%), 6897 (39.1%), and 6535 (37.1%) patients had poor, fair, and good self-rated knowledge, respectively. Of those completing the ‘response’ question (n = 17 637), 4033 (22.9%), 5463 (31.0%), and 8141 (46.2%) patients had poor, fair, and good self-rated knowledge, respectively. For both questions, patients with ‘poor’ knowledge were older, more often female, and had a worse heart failure profile but similar treatment. The rates (95% confidence interval) per 100 person-years for the primary composite outcome for ‘poor’, ‘moderate’ and ‘good’ self-rated knowledge in answer to the ‘prevention’ question were 12.83 (12.11–13.60), 12.08 (11.53–12.65) and 11.55 (11.00–12.12), respectively, and for the ‘response’ question were 12.88 (12.13–13.67), 12.22 (11.60–12.86) and 11.56 (11.07–12.07), respectively. The lower event rates in patients with ‘good’ self-rate knowledge were accounted for by lower rates of cardiovascular (and all-cause) death and not hospitalization for worsening heart failure. Conclusions: Poor patient-reported ‘self-efficacy’ may be associated with higher rates of mortality. Evaluation of knowledge of ‘self-efficacy’ may provide prognostic information and a guide to which patients may benefit from further education about self-management.

DOI： 10.1002/ejhf.2944

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DOI： 10.1016/j.jacc.2023.06.021

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Language：English   Publisher：Journal of the American College of Cardiology  

Background: Because clinical characteristics and prognosis vary by geographic region in patients with heart failure (HF), the response to treatment may also vary. A previous report suggested that the efficacy of sodium-glucose cotransporter-2 inhibitor efficacy in heart failure with reduced ejection fraction (HFrEF) may be modified by region. Objectives: The goal of this study was to examine the efficacy and safety of dapagliflozin in patients with HF according to geographic region. Methods: We conducted a patient-level pooled analysis of the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) and DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure) trials, which evaluated the effects of dapagliflozin in HFrEF and heart failure with mildly reduced ejection fraction (HFmrEF)/heart failure with preserved ejection fraction (HFpEF), respectively. The primary outcome was the composite of worsening HF or cardiovascular death. Results: Among 11,007 patients, 5,159 (46.9%) were enrolled in Europe, 1,528 (13.9%) in North America, 1,998 (18.2%) in South America, and 2,322 (21.1%) in Asia. The rate of the primary outcome (per 100 person-years) was higher in North America (13.9 [95% CI: 12.5-15.4]) than in other regions: Europe 10.8 (95% CI: 10.1-11.5), South America 10.0 (95% CI: 9.0-11.1), and Asia 10.5 (95% CI: 9.5-11.5). The benefit of dapagliflozin on the primary outcome was not modified by region: dapagliflozin vs placebo HR: Europe, 0.85 (95% CI: 0.75-0.96); North America, 0.75 (95% CI: 0.61-0.93); South America, 0.72 (95% CI: 0.58-0.89); and Asia, 0.74 (95% CI: 0.61-0.91) (P interaction = 0.40). This was the same when evaluated separately for HFrEF (P interaction = 0.39) and HFmrEF/HFpEF (P interaction = 0.84). Patients in North America discontinued randomized treatment more frequently than did those elsewhere (placebo discontinuation: 21.8% in North America vs 6.4% in South America), but discontinuation rates did not differ between placebo and dapagliflozin by region. Conclusions: The efficacy and safety of dapagliflozin were consistent across global regions despite geographic differences in patient characteristics, background treatment, and event rates.

DOI： 10.1016/j.jacc.2023.05.056

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Language：English   Publisher：European Journal of Heart Failure  

Aim: Chronic obstructive pulmonary disease (COPD) is common in heart failure with a mildly reduced or preserved ejection fraction (HFmrEF/HFpEF) and is associated with worse outcomes. In a pre-specified analysis of DELIVER, we investigated the relationship between COPD status and outcomes, and the efficacy and safety of dapagliflozin, compared with placebo, according to COPD status. Methods and results: Patients with severe pulmonary disease (including COPD) were excluded from the trial. The primary outcome was a composite of cardiovascular death or worsening heart failure. Of the 6261 patients with data on baseline COPD status, 694 (11.1%) had a known history of this condition. The risk of the primary endpoint was higher in patients with mild-to-moderate COPD compared with those without COPD (adjusted hazard ratio [HR] 1.28, 95% confidence interval [CI] 1.08–1.51). The benefit of dapagliflozin on the primary outcome was consistent irrespective of COPD status (no COPD: HR 0.82 [95% CI 0.72–0.93]; COPD: HR 0.82 [95% CI 0.62–1.10]; pinteraction = 0.98). Consistent effects were observed for heart failure, cardiovascular, and all-cause hospitalization, and deaths, and composites of these. Dapagliflozin, as compared with placebo, improved the Kansas City Cardiomyopathy Questionnaire scores from baseline to 8 months to a similar extent in patients with and without mild-to-moderate COPD (pinteraction ≥ 0.63). Adverse events and treatment discontinuation were not more frequent with dapagliflozin than with placebo irrespective of COPD status. Conclusions: Mild-to-moderate COPD is common in patients with HFmrEF/HFpEF and is associated with worse outcomes. The beneficial effects of dapagliflozin compared with placebo on clinical events and symptoms were consistent, regardless of COPD status. Clinical Trial Registration: ClinicalTrials.gov NCT03619213.

DOI： 10.1002/ejhf.3000

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Language：English   Publisher：European Journal of Heart Failure  

Aim: Patients with heart failure (HF) often suffer from a range of comorbidities, which may affect their health status. The aim of this study was to assess the impact of different comorbidities on health status in patients with HF and reduced (HFrEF) and preserved ejection fraction (HFpEF). Methods and results: Using individual patient data from HFrEF (ATMOSPHERE, PARADIGM-HF, DAPA-HF) and HFpEF (TOPCAT, PARAGON-HF) trials, we examined the Kansas City Cardiomyopathy Questionnaire (KCCQ) domain scores and overall summary score (KCCQ-OSS) across a range of cardiorespiratory (angina, atrial fibrillation [AF], stroke, chronic obstructive pulmonary disease [COPD]) and other comorbidities (obesity, diabetes, chronic kidney disease [CKD], anaemia). Of patients with HFrEF (n = 20 159), 36.2% had AF, 33.9% CKD, 33.9% diabetes, 31.4% obesity, 25.5% angina, 12.2% COPD, 8.4% stroke, and 4.4% anaemia; the corresponding proportions in HFpEF (n = 6563) were: 54.0% AF, 48.7% CKD, 43.4% diabetes, 53.3% obesity, 28.6% angina, 14.7% COPD, 10.2% stroke, and 6.5% anaemia. HFpEF patients had lower KCCQ domain scores and KCCQ-OSS (67.8 vs. 71.3) than HFrEF patients. Physical limitations, social limitations and quality of life domains were reduced more than symptom frequency and symptom burden domains. In both HFrEF and HFpEF, COPD, angina, anaemia, and obesity were associated with the lowest scores. An increasing number of comorbidities was associated with decreasing scores (e.g. KCCQ-OSS 0 vs. ≥4 comorbidities: HFrEF 76.8 vs. 66.4; HFpEF 73.7 vs. 65.2). Conclusions: Cardiac and non-cardiac comorbidities are common in both HFrEF and HFpEF patients and most are associated with reductions in health status although the impact varied among comorbidities, by the number of comorbidities, and by HF phenotype. Treating/correcting comorbidity is a therapeutic approach that may improve the health status of patients with HF.

DOI： 10.1002/ejhf.2962

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Language：English   Publisher：European Heart Journal  

Aims Stroke is an important problem in patients with heart failure (HF), but the intersection between the two conditions is poorly studied across the range of ejection fraction. The prevalence of history of stroke and related outcomes were investigated in patients with HF. Methods and results Individual patient meta-analysis of seven clinical trials enrolling patients with HF with reduced (HFrEF) and preserved ejection fraction (HFpEF). Of the 20 159 patients with HFrEF, 1683 (8.3%) had a history of stroke, and of the 13 252 patients with HFpEF, 1287 (9.7%) had a history of stroke. Regardless of ejection fraction, patients with a history of stroke had more vascular comorbidity and worse HF. Among those with HFrEF, the incidence of the composite of cardiovascular death, HF hospitalization, stroke, or myocardial infarction was 18.23 (16.81–19.77) per 100 person-years in those with prior stroke vs. 13.12 (12.77–13.48) in those without [hazard ratio 1.37 (1.26–1.49), P < 0.001]. The corresponding rates in patients with HFpEF were 14.16 (12.96–15.48) and 9.37 (9.06–9.70) [hazard ratio 1.49 (1.36–1.64), P < 0.001]. Each component of the composite was more frequent in patients with stroke history, and the risk of future stroke was doubled in patients with prior stroke. Among patients with prior stroke, 30% with concomitant atrial fibrillation were not anticoagulated, and 29% with arterial disease were not taking statins; 17% with HFrEF and 38% with HFpEF had uncontrolled systolic blood pressure (≥140 mmHg). Conclusion Heart failure patients with a history of stroke are at high risk of subsequent cardiovascular events, and targeting underutilization of guideline-recommended treatments might be a way to improve outcomes in this high-risk population.

DOI： 10.1093/eurheartj/ehad338

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Language：English   Publisher：Annals of Nuclear Medicine  

Background: Delayed heart-to-mediastinum ratio (HMR) has been associated with catecholamine levels and contractile reserve in dilated cardiomyopathy (DCM); however, there is scant evidence regarding the association between cardiac sympathetic activity and left ventricular reverse remodeling (LV-RR). We calculated the 123I-metaiodobenzylguanidine (123I-mIBG) HMR and washout rate (WR) in patients with DCM and investigated their associations with LV-RR. Methods: From April 2003 to January 2020, in 120 patients with DCM who underwent 123I-mIBG scintigraphy. 66 patients undergoing follow-up echo and taking a beta-blocker from baseline were examined the relationship between 123I-mIBG and LV-RR. After that, this prognostic value for composite cardiac events was evaluated in the entire 120 patients. Results: In LV-RR analysis, patients were 50.4 ± 12.2 years, with a mean left ventricular ejection fraction of 28.6%. Of 66 patients, 28 (42.4%) achieved LV-RR. Multiple logistic regression analysis of LV-RR revealed that not delayed HMR but the WR (cutoff value: 13.5%) was an independent predictor of LV-RR (odds ratio 6.514, p = 0.002). In the analysis for composite cardiac events, even though WR itself does not have the prognostic capacity, Kaplan–Meier survival curves divided by the cutoff value (delayed HMR = 2.0, WR = 13.5) showed that delayed HMR and WR values enabled the stratification of high-risk patients (log-rank p < 0.001). Conclusions: The 123I-mIBG WR was associated with the prevalence of LV-RR in patients taking 100% of beta-blockers and 98.5% of renin-angiotensin system inhibitors. Reflecting the contractile reserve, the combined assessment of the delayed HMR and WR could be used to further precisely stratify the patients with DCM.

DOI： 10.1007/s12149-023-01838-9

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Authorship：Lead author   Language：English   Publisher：Circulation: Heart Failure  

BACKGROUND: The rate of stroke in patients with heart failure (HF) and preserved ejection fraction but without atrial fibrillation (AF), is uncertain as is whether it is possible to reliably predict the risk of stroke in these patients. METHODS: We validated a previously developed simple risk model for stroke among patients enrolled in the I-Preserve trial (Irbesartan in Heart Failure With Preserved Systolic Function) and PARAGON-HF trial (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction). The risk model consisted of 3 variables: history of previous stroke, insulin-treated diabetes, and plasma N-terminal pro-B-type natriuretic peptide level. RESULTS: Of the 8924 patients included in the pooled trial dataset, 5126 patients did not have AF at baseline. Among patients without AF, 190 (3.7%) experienced a stroke over a median follow-up of 3.6 years (rate 10.5 per 1000 patient-years). The risk for stroke increased with increasing risk score: second tertile hazard ratio, 1.78 (95% CI, 1.17-2.71); third tertile hazard ratio, 3.03 (95% CI, 2.06-4.47), with the first tertile as reference. For patients in the third tertile, the occurrence rate of stroke was 17.7 per 1000 patient-years, similar to that in patients with AF not receiving anticoagulation (20.7 per 1000 patient-years), and those with AF who were receiving anticoagulation (14.5 per 1000 patient-years). Model discrimination was good with a C index of 0.81 (0.68-0.91) and a simple score could be created from the model. CONCLUSIONS: A simple risk model can detect a subset of HF and preserved ejection fraction patients without AF who have a higher risk for stroke. The balance of risk-to-benefit in these individuals may justify the use of prophylactic anticoagulation, but this hypothesis needs to be prospectively evaluated. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT00095238 and NCT01920711.

DOI： 10.1161/CIRCHEARTFAILURE.122.010377

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DOI： 10.1016/j.jccase.2023.02.021

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Language：English   Publisher：European Heart Journal  

Aims: The 2021 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation combining creatinine and cystatin C provides a better estimation of glomerular filtration rate (GFR) compared to the creatinine-only equation. Methods and results: CKD-EPI creatinine-cystatin C equation (creatinine-cystatin) was compared to creatinine-only (creatinine) equation in a subpopulation of Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure (PARADIGM-HF). Patients were categorized according to difference in eGFR using the two equations: Group 1 (<-10 mL/min/1.73 m2, i.e. creatinine-cystatin more than 10 mL/min lower than creatinine), Group 2 (>-10 and <10 mL/min/1.73 m2), and Group 3 (>10 mL/min/1.73 m2, i.e. creatinine-cystatin more than 10 mL/min higher than creatinine). Cystatin C and creatinine were available in 1966 patients at randomization. Median (interquartile range) eGFR difference was -0.7 (-6.4-4.8) mL/min/1.73 m2. Compared to creatinine, creatinine-cystatin led to a substantial reclassification of chronic kidney disease stages. Overall, 212 (11%) and 355 (18%) patients were reallocated to a better and worse eGFR category, respectively. Compared to patients in Group 2, those in Group 1 (lower eGFR with creatinine-cystatin) had higher mortality and those in Group 3 (higher eGFR with creatinine-cystatin) had lower mortality. Increasing difference in eGFR (due to lower eGFR with creatinine-cystatin compared to creatinine) was associated with increasing elevation of biomarkers (including N-terminal pro-B-type natriuretic peptide and troponin) and worsening Kansas City Cardiomyopathy Questionnaire clinical summary score. The reason why the equations diverged with increasing severity of heart failure was that creatinine did not rise as steeply as cystatin C. Conclusion: The CKD-EPI creatinine-only equation may overestimate GFR in sicker patients. Clinical Trial Registration: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT01035255.

DOI： 10.1093/eurheartj/ehad210

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Language：English   Publisher：European Heart Journal Cardiovascular Imaging  

Aims: Aortic valve calcification in aortic sclerosis, a precursor of aortic stenosis (AS), is not always present in all three leaflets; how calcification develops in each leaflet is unknown. We aimed to investigate the natural history of calcification development in each aortic valve leaflet and the prognostic value of the number of calcified leaflets. Methods and results: In a retrospective multicentre cohort study of patients undergoing haemodialysis without AS, we observed calcification development in each aortic valve leaflet using echocardiography. We investigated the association between the number of calcified leaflets and AS development and mortality using time-to-event analysis. Among the 1507 patients (mean age, 66 years; 66% male) included in the longitudinal echocardiography analysis, 709 (47%) had aortic sclerosis at baseline: one-leaflet calcified, 370 (52%); two-leaflet calcified, 215 (30%); and three-leaflet calcified, 124 (17%). The median time for one calcified leaflet increase was 3-4 years, and 251 (17%) patients developed AS during a median 3.2-year follow-up. The increased number of calcified aortic valve leaflets was associated with developing AS; compared with that of one-leaflet calcified, the adjusted hazard ratios (aHRs) [95% confidence intervals (CIs)] of two- and three-leaflet calcified were 2.12 (1.49-3.00) and 4.43 (3.01-6.52), respectively; the aHR (95% CI) per one calcified leaflet increase was 2.24 (1.96-2.55). It was also associated with all-cause mortality; the aHR (95% CI) per one calcified leaflet increase was 1.18 (1.08-1.27). Conclusion: The number of calcified aortic valve leaflets strongly predicted AS development and even mortality in patients undergoing haemodialysis, suggesting the usefulness of assessing calcification for each valve leaflet separately using echocardiography.

DOI： 10.1093/ehjci/jead020

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Aims: Dapagliflozin resulted in significant and sustained reductions in first and recurrent heart failure (HF) hospitalizations among patients with HF across the spectrum of ejection fraction. How treatment with dapagliflozin differentially impacts hospitalization for HF of varying complexity is not well studied. Methods and results: In the DELIVER and DAPA-HF trials, we examined the effects of dapagliflozin on adjudicated HF hospitalizations of varying complexity and hospital length of stay (LOS). HF hospitalizations requiring intensive care unit stay, intravenous vasoactive therapies, invasive/non-invasive ventilation, mechanical fluid removal or mechanical circulatory support were categorized as complicated. The balance was classified as uncomplicated. Of the total 1209 HF hospitalizations reported in DELIVER, 854 (71%) were uncomplicated and 355 (29%) were complicated. Of the total 799 HF hospitalizations reported in DAPA-HF, 453 (57%) were uncomplicated and 346 (43%) were complicated. Relative to patients experiencing a first uncomplicated HF hospitalization, those with complicated HF hospitalizations had a significantly higher in-hospital mortality both in DELIVER (16.7% vs. 2.3%, p < 0.001) and DAPA-HF (15.1% vs. 3.8%, p < 0.001). Dapagliflozin similarly reduced total ‘uncomplicated’ (DELIVER: rate ratio [RR] 0.67, 95% confidence interval [CI] 0.55–0.82 and DAPA-HF: RR 0.69, 95% CI 0.54–0.87) and ‘complicated’ HF hospitalizations (DELIVER: RR 0.82, 95% CI 0.63–1.06 and DAPA-HF: RR 0.75, 95% CI 0.58–0.97). Dapagliflozin consistently reduced hospitalizations irrespective of their LOS: <5 days (DELIVER: RR 0.76, 95% CI 0.58–0.99 and DAPA-HF: RR 0.58, 95% CI 0.42–0.80) or ≥5 days (DELIVER: RR 0.71, 95% CI 0.58–0.86 and DAPA-HF: RR 0.77, 95% CI 0.62–0.94). Conclusion: A substantial proportion of hospitalizations (∼30–40%) among patients with HF irrespective of ejection fraction required intensification of treatment beyond standard intravenous diuretics. Such patients experienced significantly higher in-hospital mortality. Treatment with dapagliflozin consistently reduced HF hospitalizations regardless of severity of inpatient course or LOS. Clinical Trial Registration: ClinicalTrials.gov, DELIVER (NCT03619213) and DAPA-HF (NCT03036124).

DOI： 10.1002/ejhf.2912

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DOI： 10.1016/j.jccase.2023.01.005

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Language：English   Publisher：European Journal of Radiology  

Purpose: Dynamic chest radiography allows for non-invasive cardiopulmonary blood flow assessment. However, data on its use for heart failure hemodynamic assessment are scarce. We utilized dynamic chest radiography to estimate heart failure hemodynamics. Method: Twenty heart failure patients (median age, 67 years; 17 men) underwent dynamic chest radiography and right heart catheterization. The analyzed images were 16-bit images (grayscale range: 0–65,535). Right atrial, right pulmonary artery, and left ventricular apex pixel values (average of the grayscale values of all pixels within a region of interest) were measured. The correlations of the minimum, maximum, mean, amount of change, and rate of change in pixel values with right atrial pressure, pulmonary artery pressure, pulmonary artery wedge pressure, and cardiac index were analyzed. Results: The mean right atrial pixel value and mean right atrial pressure (R = −0.576, P = 0.008), mean right pulmonary artery pixel value and mean pulmonary artery pressure (R = −0.546, P = 0.013), and left ventricular apex pixel value change rate and mean pulmonary artery wedge pressure (R = −0.664, P = 0.001) or cardiac index (R = 0.606, P = 0.005) were correlated. The left ventricular apex pixel value change rate identified low cardiac index (area under the curve, 0.792; 95% confidence interval, 0.590–0.993; P = 0.031) and low cardiac index with high pulmonary artery wedge pressure (area under the curve, 0.902; 95% confidence interval, 0.000–1.000; P = 0.030). Conclusions: Dynamic chest radiography is a minimally invasive tool for heart failure hemodynamic assessment.

DOI： 10.1016/j.ejrad.2023.110729

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DOI： 10.3390/jpm13040630

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Language：English   Publisher：Journal of Artificial Organs  

The Impella 5.0 is an axial-flow percutaneous ventricular assist device used in patients with cardiogenic shock. Although the recommended period of use is 10 days or less, weaning can be delayed because of ongoing hemodynamic instability. In clinical practice, this device sometimes malfunctions during long-term management with heparin and must be replaced; however, the relationship between the duration of support with the initial and replacement Impella 5.0 and the changes in value of the purge system has not been fully elucidated. From July 2018 to May 2021, Impella 5.0 was implanted and used for more than 10 days in 11 patients at our institution. Four patients required Impella replacement because of device malfunction and the second Impella had purge system malfunction in all cases. The second Impella was used for a significantly shorter time than the first Impella (p = 0016). We calculated the ratio of purge pressure to purge flow rate and found that the ratio exceeded 50 mm Hg/mL/h in all cases with purge system malfunction. In conclusion, it is important to construct a treatment strategy considering the duration of use, because the risk of purge system malfunction is high after replaced Impella 5.0.

DOI： 10.1007/s10047-022-01337-0

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DOI： 10.1093/eurheartj/ehac801

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Background: We evaluated the impact of a standardized driveline care strategy, including a subfascial-tunneling method and dressing protocol, on the incidence of driveline infection (DLI). Methods: DLI data from all HeartMate II (HMII) and HeartMate 3 (HM3) patients (including exchange devices) were retrospectively collected between 2013 and 2021. The driveline subfascial-tunneling method was altered in three steps (A: right direct; B: left triple, C: right triple), and the shower protocol was changed in two steps (A: with/without cover, B: with cover). Disinfection was individually tailored after changing the shower protocol. Complications associated with morbidity and mortality were evaluated for each modification. Results: During the study period, 80 devices were implanted (HMII, n = 54; HM3, n = 26). The 8-year incidence of DLI was 15% (n = 8) in HMII patients and 0% in HM3 patients (p = 0.039). DLI was not associated with hospital mortality. The modified dressing protocol and tunneling method was associated with a significantly better DLI incidence rate in comparison to the previous one: Protocol-A (n = 17), Protocol-B (n = 63), 35% vs 3% (p = 0.0009), Method-A (n = 13), Method-B (n = 42), Method-C (n = 25), 46% vs 5% vs 0% (p = 0.0001). The rete of freedom form DLI at 1, 2, and 3 years had also significant difference between groups: Protocol-A and Protocol-B, 80%, 54%, 54% vs 96%, 96%, 96%, respectively (p < 0.0001), Method-A, Method-B and Method-C, 76%, 44%, 44%, vs 94%, 94%, 94% vs 100%, 100%, respectively (p < 0.0001). Conclusions: A standardized triple driveline tunneling strategy and waterproof dressing protocol reduced driveline infection in HM3 patients to 0%.

DOI： 10.1111/aor.14426

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Heart failure (HF) is a systemic inflammatory disease that causes hypotrophy and skeletal muscle loss. The Global Leadership Initiative on Malnutrition (GLIM) criteria have been developed as a novel evaluation index for malnutrition, with reported usefulness in HF caused by ischemic heart disease. However, reports on the usefulness of malnutrition evaluated by the GLIM criteria in non-ischemic dilated cardiomyopathy (NIDCM) and its relationship with psoas muscle volume are lacking. We investigated the prognostic value of malnutrition evaluated using the GLIM criteria and its association with psoas muscle volume in patients with NIDCM. We enrolled 139 consecutive patients with NIDCM between December 2000 and June 2020. Malnutrition was evaluated using the GLIM criteria on admission. The median follow-up period was 4.7 years. Cardiac events were defined as a composite of cardiac death, hospitalization for worsening HF, and lethal arrhythmia. Furthermore, we measured the psoas muscle volume using computed tomography volumetry in 48 patients. At baseline, the median age was 50 years, and 132 patients (95.0%) had New York Heart Association functional class I or II HF. The median psoas muscle volume was 460.8 cm3. A total of 26 patients (18.7%) were malnourished according to the GLIM criteria. The Kaplan–Meier survival analysis showed that malnourished patients had more cardiac events than non-malnourished patients (log-rank, P < 0.001). The multivariate Cox proportional hazards regression analysis revealed that GLIM criteria-based malnutrition was an independent determinant of cardiac events (hazard ratio, 2.065; 95% confidence interval, 1.166–3.656; P = 0.014). Psoas muscle volume, which was assessed in a total of 48 patients, was lower in malnourished than in non-malnourished patients (median, 369.0 vs. 502.3 cm3; P = 0.035) and correlated with body mass index (r = 0.441; P = 0.002). Nutritional screening using the GLIM criteria may be useful in predicting future cardiac events in patients with NIDCM, reflecting a potential relationship between malnutrition and a low psoas muscle volume.

DOI： 10.1007/s00380-022-02113-z

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Language：English   Publisher：European Journal of Heart Failure  

Aims: The effects of adding a sodium–glucose cotransporter 2 (SGLT2) inhibitor to a mineralocorticoid receptor antagonist (MRA) or an angiotensin receptor–neprilysin inhibitor (ARNI) in patients with heart failure (HF) and mildly reduced ejection fraction (HFmrEF) and preserved ejection fraction (HFpEF) are uncertain, even though the use of all three drugs is recommended in recent guidelines. Methods and results: The efficacy and safety of dapagliflozin added to background MRA or ARNI therapy was examined in patients with HFmrEF/HFpEF enrolled in the DELIVER trial. The primary outcome was the composite of worsening HF or cardiovascular death. Of 6263 patients, 2667 (42.6%) were treated with an MRA and 301 (4.8%) with an ARNI at baseline. Patients taking either were younger, more often men and had lower systolic blood pressure and ejection fraction; they were also more likely to have prior HF hospitalization. The benefit of dapagliflozin was similar whether patients were receiving these therapies. The hazard ratio for the effect of dapagliflozin compared to placebo on the primary outcome was 0.86 (95% confidence interval [CI] 0.74–1.01) for MRA non-users versus 0.76 (95% CI 0.64–0.91) for MRA users (pinteraction = 0.30). The corresponding values for ARNI non-users and users were 0.82 (95% CI 0.73–0.92) and 0.74 (95% CI 0.45–1.22), respectively (pinteraction = 0.75). None of the adverse events examined was more common with dapagliflozin compared to placebo overall or in the MRA and ARNI subgroups. Conclusions: The efficacy and safety of dapagliflozin were similar, regardless of background treatment with an MRA or ARNI. SGLT2 inhibitors may be added to other treatments recommended in recent guidelines for HFmrEF/HFpEF.

DOI： 10.1002/ejhf.2722

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DOI： 10.1016/j.jccase.2022.09.002

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DOI： 10.1001/jamacardio.2022.3736

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In the original publication of the article, the values of “Phenotypic criteria” were aligned incorrectly in Table 1. The correct Table 1 is provided below.

DOI： 10.1007/s00380-022-02139-3

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Aims: Biomarker-driven prognostic models incorporating N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hs-cTnT) in heart failure (HF) with preserved ejection fraction (HFpEF) are lacking. We aimed to generate a biomarker-driven prognostic tool for patients with chronic HFpEF enrolled in EMPEROR-Preserved. Methods and results: Multivariable Cox regression models were created for (i) the primary composite outcome of HF hospitalization or cardiovascular death, (ii) all-cause death, (iii) cardiovascular death, and (iv) HF hospitalization. PARAGON-HF was used as a validation cohort. NT-proBNP and hs-cTnT were the dominant predictors of the primary outcome, and in addition, a shorter time since last hospitalization, New York Heart Association (NYHA) class III or IV, history of chronic obstructive pulmonary disease (COPD), insulin-treated diabetes, low haemoglobin, and a longer time since HF diagnosis were key predictors (eight variables, all p < 0.001). The consequent primary outcome risk score discriminated well (c-statistic = 0.75) with patients in the top 10th of risk having an event rate >22× higher than those in the bottom 10th. A model for HF hospitalization alone had even better discrimination (c = 0.79). Empagliflozin reduced the risk of cardiovascular death or hospitalization for HF in patients across all risk levels. NT-proBNP and hs-cTnT were also the dominant predictors of all-cause and cardiovascular mortality followed by history of COPD, low albumin, older age, left ventricular ejection fraction ≥50%, NYHA class III or IV and insulin-treated diabetes (eight variables, all p < 0.001). The mortality risk model had similar discrimination for all-cause and cardiovascular mortality (c-statistic = 0.72 for both). External validation provided c-statistics of 0.71, 0.71, 0.72, and 0.72 for the primary outcome, HF hospitalization alone, all-cause death, and cardiovascular death, respectively. Conclusions: The combination of NT-proBNP and hs-cTnT along with a few readily available clinical variables provides effective risk discrimination both for morbidity and mortality in patients with HFpEF. A predictive tool-kit facilitates the ready implementation of these risk models in routine clinical practice.

DOI： 10.1002/ejhf.2607

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Authorship：Corresponding author   Language：English   Publisher：Journal of Artificial Organs  

A left ventricular assist device (LVAD) is a treatment option for patients with end-stage heart failure; however, a certain number of patients on durable LVADs are diagnosed with malignancy. Radiation therapy (RT) for patients with durable LVADs has safety concerns, because RT may interfere with the device. Herein, we report a case of RT during durable LVAD management. A 48-year-old man with a durable LVAD was diagnosed with sinusitis. As his symptoms were resistant to drug therapy, endoscopic sinus surgery was performed, and extranodal NK/T-cell lymphoma, nasal type (ENKL) was pathologically detected. Since RT was the first-line treatment for ENKL, we conducted two types of irradiation experiments to determine whether RT can be safely performed in patients with durable LVADs as follows: (1) assessing the extent of the radiation levels at each site and evaluating device malfunction by irradiating the lesion sites in the patient model with the same protocol as planned, and (2) evaluating device malfunction by directly irradiating the durable LVAD equipment once at the scheduled total dose. The radiation doses at the pump, driveline, system controller, power cable, and power module of the durable LVAD reached 7.86 cGy, 6.34 cGy, 0.66 cGy, 0.38 cGy, and 0.14 cGy, respectively. In both experiments, durable LVAD malfunction or any type of alarm was not observed. We concluded that RT could be safely performed with chemotherapy in this patient and our irradiation experiments can be applied to RT for other malignancies.

DOI： 10.1007/s10047-022-01312-9

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The spleen is an important immune organ that releases erythrocytes and monocytes and destroys aged platelets. It also reserves 20–30% of the total blood volume, and its size decreases in hypovolemic shock. However, the clinical significance of splenic size in patients with heart failure (HF) remains unclear. We retrospectively analyzed the data of 206 patients with clinically stable HF gathered between January 2001 and August 2020 and recorded in a single-center registry. All patients underwent right heart catheterization and computed tomography (CT). Splenic size was measured using CT volumetry. The primary outcomes were composite cardiac events occurring for the first time during follow-up, namely, cardiac death and hospitalization for worsening HF. The median splenic volume and splenic volume index (SVI) were 118.0 mL and 68.9 mL/m2, respectively. SVI was positively correlated with cardiac output (r = 0.269, P < 0.001) and stroke volume (r = 0.228, P = 0.002), and negatively correlated with systemic vascular resistance (r = − 0.302, P < 0.001). Seventy cardiac events occurred, and the optimal receiver operating characteristic curve SVI cutoff value for predicting cardiac events was 68.9 mL/m2. The median blood adrenaline concentration was higher in the low-SVI group than the high-SVI group (0.039 ng/mL vs. 0.026 ng/mL, respectively; P = 0.004), and the low-SVI group experienced more cardiac events (log-rank test, P < 0.001). Multivariate Cox proportional hazards regression revealed that a low SVI was an independent predictor of cardiac events, even when adjusted for the validated HF risk score, blood–brain natriuretic peptide concentration, blood catecholamine concentrations, and hemodynamic parameters. Splenic size reflects hemodynamics, including systemic circulating blood volume status and sympathetic nerve activity, and is associated with HF prognosis.

DOI： 10.1007/s00380-022-02030-1

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The HATCH score is employed as a risk assessment tool for atrial fibrillation (AF) development. However, the impact of the HATCH score on the long-term adverse outcomes in patients with acute heart failure (AHF) remains unknown. We investigated the clinical value of the HATCH score in patients with AHF. From a multicenter AHF registry, we retrospectively evaluated 1543 consecutive patients who required hospitalization owing to AHF (median age, 78 [69–85] years; 42.3% women) from January 2012 to December 2019. These patients were divided into five risk groups based on their HATCH score at admission (scores 0, 1, 2, 3, and 4–7). The correlation between the HATCH score and the composite outcome, including all-cause mortality and re-hospitalization due to HF, was analyzed using Kaplan–Meier and Cox proportional-hazard analyses. The median HATCH score was 2 [1–3], and the median age was 78 years (69–85 years). During the follow-up period (median, 16.8 months), the composite endpoint occurred in 691 patients (44.8%), including 416 (27%) patients who died (with 65 [4.2%] in-hospitalization deaths) and 455 (29.5%) patients requiring re-hospitalizations due to HF. The Kaplan–Meier analysis showed a significant increase in the composite endpoint with an increasing HATCH score (log-rank, p < 0.001). The multivariate Cox regression model revealed that the HATCH score was an independent predictor of the composite endpoint (hazard ratio [HR] 1.181; 95% confidence interval [CI]: 1.111–1.255; p < 0.001) with all-cause mortality (HR 1.153, 95% CI 1.065–1.249; p < 0.001) and re-hospitalizations due to HF (HR 1.21; 95% CI 1.124–1.303; p < 0.001) in patients with AHF, regardless of the presence or absence of AF, ejection fraction, and etiology. The HATCH score is an independent predictor of adverse outcomes in patients with AHF.

DOI： 10.1007/s00380-022-02035-w

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DOI： doi: 10.1016/j.cjco.2022.03.008.

DOI： doi: 10.1016/j.cjco.2022.03.008.

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DOI： 10.1016/j.jccase.2022.02.004

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A 53-year-old woman with no significant medical history developed cardiogenic shock 4 days after receiving the second dose of the COVID-19 mRNA vaccine (BNT162b2, Pfizer/BioNtech). The patient required extracorporeal membrane oxygenation and an Impella device. Based on significant hemoconcentration, decreased plasma protein levels, and pathologic findings in myocardial specimens, the patient was diagnosed with vaccination-induced fulminant systemic capillary leak syndrome (SCLS) with severe cardiac dysfunction. This case highlights that SCLS can occur after COVID-19 mRNA vaccination and may be associated with cardiac dysfunction. In patients with cardiogenic shock, hemoconcentration, and hypoalbuminemia after vaccination, SCLS should be considered.

DOI： 10.1016/j.cjco.2022.03.008

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DOI： 10.1007/s10047-022-01311-w

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Language：English   Publisher：The Japanese Circulation Society  

<p><b><i>Background:</i></b> Many patients with dilated cardiomyopathy (DCM) progress to heart failure (HF), although some demonstrate left ventricular (LV) reverse remodeling (LVRR), which is associated with better outcomes. The pulmonary artery diameter (PAD) to ascending aortic diameter (AoD) ratio has been used as a prognostic predictor in patients with HF, although this tool’s usefulness in predicting LVRR remains unknown.</p><p><b><i>Methods and Results:</i></b> Data from a prospective observational study of 211 patients diagnosed in 2000–2020 with DCM were retrospectively analyzed. Sixty-nine patients with New York Heart Association class I or II HF were included. LVRR was observed in 23 patients (33.3%). The mean LV ejection fraction (29%) and LV end-diastolic dimension (64.5 mm) were similar in patients with and without LVRR. The PAD/AoD ratio was significantly lower in patients with LVRR than those without (81.4% vs. 92.4%, respectively; P=0.003). The optimal PAD/AoD cut-off value for detecting LVRR was 0.9 according to the receiver operating characteristic curve analysis. Multivariate analysis identified a PAD/AoD ratio ≥0.9 as an independent predictor of presence/absence of LVRR. Cardiac events were significantly more common in patients with a PAD/AoD ratio ≥0.9 than those with a ratio <0.9, after a median follow up of 2.5 years (log-rank, P=0.007).</p><p><b><i>Conclusions:</i></b> The PAD/AoD ratio can predict LVRR in patients with DCM.</p>

DOI： 10.1253/circj.CJ-21-0786

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DOI： doi: 10.1016/j.cjco.2022.02.004

DOI： doi: 10.1016/j.cjco.2022.02.004

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Cardiogenic shock with fulminant myocarditis is a life-threatening diagnosis. Extracorporeal membrane oxygenation (ECMO) with an Impella for left ventricle unloading is often required to maintain the haemodynamics. However, the small peripheral vascularity in small-bodied patients interrupts the upgrade from ECMO to Impella5.0, which usually requires grafting to a femoral artery or subclavian artery of at least 7 mm in size. This report outlines the external iliac artery approach, named the “ILIPELLA” technique, which uses a reconstructed external iliac artery to introduce Impella5.0 in patients with small peripheral vascularity.

DOI： 10.1016/j.hlc.2021.12.007

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DOI： 10.1016/j.cjco.2022.02.004

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Aims: Autotaxin (ATX) promotes myocardial inflammation, fibrosis, and the subsequent cardiac remodelling through lysophosphatidic acid production. However, the prognostic impact of serum ATX in non-ischaemic dilated cardiomyopathy (NIDCM) has not been clarified. We investigated the prognostic impact of serum ATX in patients with NIDCM. Methods and results: We enrolled 104 patients with NIDCM (49.8 ± 13.4 years, 76 men). We divided the patients into two groups using different cutoffs of median serum ATX levels for men and women: high-ATX group and low-ATX group. Cardiac events were defined as a composite of cardiac death and heart failure resulting in hospitalization. Median ATX level was 203.5 ng/mL for men and 257.0 ng/mL for women. Brain natriuretic peptide levels [224.0 (59.6–689.5) pg/mL vs. 96.5 (40.8–191.5) pg/mL, P = 0.010] were higher in the high-ATX group than low-ATX group, whereas high-sensitivity C-reactive protein and collagen volume fraction levels in endomyocardial biopsy samples were not significantly different between the two groups. Kaplan–Meier survival analysis revealed that the event-free survival rate was significantly lower in the high-ATX group than low-ATX group (log-rank; P = 0.007). Cox proportional hazard analysis revealed that high-ATX was an independent determinant of composite cardiac events. In both sexes, serum ATX levels did not correlate with high-sensitivity C-reactive protein levels and collagen volume fraction but had a weak correlation with brain natriuretic peptide levels (men; spearman's rank: 0.274, P = 0.017, women; spearman's rank: 0.378, P = 0.048). Conclusion: High serum ATX levels can be associated with increasing adverse clinical outcomes in patients with NIDCM. These results indicate serum ATX may be a novel biomarker or therapeutic target in NIDCM.

DOI： 10.1002/ehf2.13817

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DOI： doi: 10.1016/j.jccase.2022.02.004

DOI： doi: 10.1016/j.jccase.2022.02.004

Authorship：Lead author,　Corresponding author   Language：English  

DOI： 10.1016/j.jccase.2021.09.008

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Language：English   Publisher：BMC Research Notes  

Objective: Spleen volume increases in patients with advanced heart failure (HF) after left ventricular assist device (LVAD) implantation. However, the relationship between spleen volume and exercise tolerance (peak oxygen consumption [VO2]) in these patients remains unknown. In this exploratory study, we enrolled 27 patients with HF using a LVAD (median age: 46 years). Patients underwent blood testing, echocardiography, right heart catheterization, computed tomography (CT), and cardiopulmonary exercise testing. Spleen size was measured using CT volumetry, and the correlations/causal relationships of factors affecting peak VO2 were identified using structural equation modeling. Results: The median spleen volume was 190.0 mL, and peak VO2 was 13.2 mL/kg/min. The factors affecting peak VO2 were peak heart rate (HR; β = 0.402, P =.015), pulmonary capillary wedge pressure (PCWP; β = − 0.698, P =.014), right ventricular stroke work index (β = 0.533, P =.001), blood hemoglobin concentration (β = 0.359, P =.007), and spleen volume (β = 0.215, P =.041). Spleen volume correlated with peak HR, PCWP, and hemoglobin concentration, reflecting sympathetic activity, cardiac preload, and oxygen-carrying capacity, respectively, and was thus related to peak VO2. These results suggest an association between spleen volume and exercise tolerance in advanced HF.

DOI： 10.1186/s13104-022-05939-y

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Background: Follistatin-like 1 (FSTL1) is a myocyte-secreted glycoprotein that could play a role in myocardial maintenance in response to harmful stimuli. We investigated the association between serum FSTL1 levels, especially focused on transcardiac gradient and the hemodynamics, to explore the prognostic impact of FSTL1 levels in patients with dilated cardiomyopathy (DCM). Methods: Thirty-two ambulatory patients with DCM (23 men; mean age 59 years) were prospectively enrolled. Blood samples were simultaneously collected from the aortic root (Ao), coronary sinus (CS), as well as from the peripheral vein during cardiac catheterization in stable conditions. The transcardiac gradient of FSTL1 was calculated by the difference between serum FSTL1 levels of CS and Ao (FSTL1CS-Ao). Patients were divided into two groups based on the median of FSTL1CS-Ao: Low FSTL1CS-Ao group, <0 ng/mL; High FSTL1CS-Ao group, ≥0 ng/mL. Cardiac events were defined as a composite of cardiac deaths and hospitalizations for worsening heart failure. Results: Mean left ventricular ejection fraction and median plasma B-type natriuretic peptide levels were 30.9% and 92.3 pg/mL, respectively. FSTL1CS-Ao was negatively correlated with pulmonary capillary wedge pressure (r = -0.400, p = 0.023). Kaplan-Meier survival analysis showed that event-free survival rate was significantly lower in the Low FSTL1CS-Ao group than in the High FSTL1CS-Ao group (p = 0.013). Cox regression analyses revealed that the transcardiac gradient of FSTL1 was an independent predictor for cardiac events. Receiver operating characteristic curve analysis showed that the cut-off value of FSTL1CS-Ao for the prediction of cardiac events was -4.09 ng/mL with sensitivity of 82% and specificity of 86% (area under the curve, 0.87). Conclusions: Fifty percent of patients had negative transcardiac gradient of FSTL1. Reduced transcardiac gradient of FSTL1 might be a novel prognostic predictor in DCM patients with impaired hemodynamics.

DOI： 10.1016/j.jjcc.2021.07.005

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Authorship：Lead author,　Corresponding author   Language：English   Publisher：International Journal of Artificial Organs  

Introduction: Choice of mechanical circulatory support to stabilize hemodynamics until cardiac recovery or next treatment is a strategic cornerstone for improving outcomes in patients with severe cardiogenic shock. We aimed to clarify the difference in treatment course and outcomes with the use of Impella 5.0 and an extracorporeal left ventricular assist device (eLVAD) in patients with cardiogenic shock refractory to medical therapy or other mechanical circulatory support. Methods: We performed a retrospective medical record review of consecutive patients who were implanted with Impella 5.0 or eLVAD as a bridge to decision at our medical center. Results: A total of 26 patients (median age 40 years, 16 males) were analyzed. Of seven patients managed with Impella 5.0, the Impella 5.0 was removed successfully in two patients and five patients underwent surgery for durable LVAD implantation. Of 19 patients managed with eLVAD, the eLVAD was successfully removed in 3 patients, 9 patients required durable LVAD, and 7 patients died during eLVAD management. The period between Impella 5.0 or eLVAD implantation to durable LVAD surgery was significantly shorter with Impella 5.0 (58 vs 235 days, p = 0.001). Cardiopulmonary bypass time was significantly shorter and a significantly smaller amount of red blood cell transfusion was required with Impella 5.0 (149 vs 192 min, p = 0.042; 7.0 vs 15.0 units, p = 0.019). There were four massive stroke events with eLVAD, but no massive stroke event with Impella 5.0. Conclusion: Impella 5.0 facilitates smoother management as a bridge to decision and reduces surgical invasiveness during durable LVAD implantation.

DOI： 10.1177/03913988211040530

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We retrospectively analyzed data from the Medical Information Mart for Intensive Care-III critical care database to determine whether visually-assessed right ventricular (RV) dysfunction was associated with clinical outcomes in septic shock patients. Associations between visually-assessed RV dysfunction by echocardiography and in-hospital mortality, lethal arrhythmia, and hemodynamic indicators to determine the prognostic value of RV dysfunction in patients with septic shock were analyzed. Propensity score analysis showed RV dysfunction was associated with increased risk of in-hospital death in patients with septic shock (adjusted odds ratio [OR] 2.15; 95% confidence interval [CI] 1.99–2.32; P < 0.001). In multivariate logistic regression analysis, RV dysfunction was associated with in-hospital death (OR 2.19; 95% CI 1.91–2.53; P < 0.001), lethal arrhythmia (OR 2.19; 95% CI 1.34–3.57; P < 0.001), and tendency for increased blood lactate levels (OR 1.31; 95% CI 1.14–1.50; P < 0.001) independent of left ventricular (LV) dysfunction. RV dysfunction was associated with lower cardiac output, pulmonary artery pressure index, and RV stroke work index. In patients with septic shock, visually-assessed RV dysfunction was associated with in-hospital mortality, lethal arrhythmia, and circulatory insufficiency independent of LV dysfunction. Visual assessment of RV dysfunction using echocardiography might help to identify the short-term prognosis of patients with septic shock by reflecting hemodynamic status.

DOI： 10.1038/s41598-021-98397-8

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Background and aims: Mild-to-moderate aortic stenosis (AS) and aortic sclerosis, a precursor of AS, are associated with mortality in the general population; however, their association in patients undergoing hemodialysis with higher morbidity of AS is unknown. Thus, we investigated the mortality of aortic sclerosis and mild-to-moderate AS in patients undergoing hemodialysis. Methods: This was a retrospective multicenter cohort study of consecutive patients undergoing hemodialysis at nine dialysis facilities who underwent screening echocardiography between January 2008 and December 2019. We investigated the mortality of patients with aortic sclerosis or mild-to-moderate AS using multivariable Cox proportional hazards regression. Results: Among 1,878 patients undergoing hemodialysis, those with normal aortic valves, aortic sclerosis, mild AS, moderate AS, severe AS, and prosthetic aortic valves were 844 (45%), 793 (42%), 161 (8.6%), 38 (2.0%), 11 (0.6%), and 31 (1.7%), respectively. After excluding patients with severe AS and prosthetic aortic valves, we performed comparative analysis on 1,836 patients (mean age, 67 years; 66% male). In a median follow-up of 3.6 years, crude death rates (per 100 person-years) were 5.2, 10.6, and 13.0 in patients with normal aortic valves, aortic sclerosis, and mild-to-moderate AS, respectively. Compared with normal aortic valves, both aortic sclerosis and mild-to-moderate AS were associated with all-cause and cardiovascular death: adjusted hazard ratios (95% confidence intervals) were 1.36 (1.13–1.65) and 1.36 (1.02–1.80) for all-cause death; and 1.52 (1.06–2.17) and 1.74 (1.04–2.92) for cardiovascular death, respectively. Conclusions: Aortic sclerosis and mild-to-moderate AS were independent risk factors for all-cause and cardiovascular death in patients undergoing hemodialysis.

DOI： 10.1016/j.atherosclerosis.2021.06.910

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Aims: In recent decades, haemodynamic parameters have been estimated for risk stratification and determining treatment strategies for patients with non-ischaemic dilated cardiomyopathy (DCM). In various invasive procedures, the cardiac pumping capability is defined as cardiac power output (CPO), which is calculated by multiplying cardiac output by the mean arterial pressure. Lower CPO values in advanced heart failure predict adverse outcomes. However, few studies discuss the prognostic value of CPO in mild-to-moderate phase patients. This study aimed to determine the value of the cardiac power index (CPI) obtained from the resting CPO for predicting the prognosis of patients with New York Heart Association Functional Class II or III DCM. Methods and results: From March 2000 to January 2020, a total of 623 cardiomyopathy patients were evaluated for haemodynamic parameters. Patients with secondary cardiomyopathy, ischaemic cardiomyopathy, valvular heart disease, and Class IV cardiomyopathy were excluded. A total of 176 DCM patients fulfilled the criteria for inclusion. Patients were 51.7 ± 12.5 years old (mean ± standard deviation) with a mean left ventricular ejection fraction of 32.1 ± 9.2%. The patients were divided into two groups by their median CPI (CPI < 0.52, low-CPI; CPI ≥ 0.52, high-CPI). No significant differences were found in the left ventricular end-diastolic diameter, left ventricular ejection fraction, or pulmonary arterial wedge pressure between the groups. The probability of cardiac event-free survival was significantly lower for low-CPI than for high-CPI groups by Kaplan–Meier analysis (P = 0.012), even with no significant difference between the high and low cardiac index groups (P = 0.069). Furthermore, Cox proportional hazards regression analysis revealed that, in addition to the CPI, the systolic and mean arterial pressure involved in CPI calculation were independent predictors of cardiac events. Indeed, among these factors, mean arterial pressure had the strongest prognostic ability. Conclusions: Although CPI is effective for stratifying DCM and predicting cardiac events in patients with Class II/III DCM, this prognostic value depends on mean arterial pressure.

DOI： 10.1002/ehf2.13446

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Authorship：Corresponding author   Language：English   Publisher：ESC Heart Failure  

Aims: Patients with acute heart failure (AHF) often present with an increased heart rate (HR), and the HR changes dramatically after initial treatment for AHF. However, the HR change after admission and the relationship between HR change in the early phase and prognosis have not been fully elucidated. Methods and results: From a multicentre AHF registry, we retrospectively evaluated 1527 consecutive patients admitted with AHF. HR change (%) was calculated by [HR (at admission) − HR (24 h after admission)] × 100∕HR (at admission). The median HR change was 15.1% (range, 2.0–28.4%). The HR decreased most in the first 24 h and then gradually thereafter [admission: 98 (81–117) b.p.m., 24 h: 80 (70–92) b.p.m., 48 h: 78 (68–90) b.p.m., and 72 h: 77 (67–88) b.p.m.]. In Kaplan–Meier analysis, the cumulative event-free rates in the composite endpoint of death and rehospitalization due to AHF showed better according to larger HR change (P = 0.012, log rank). Cox proportional hazards analysis showed that HR change was a prognostic factor for composite endpoint adjusted by age and sex [hazard ratio, 0.995; 95% confidence interval (CI), 0.991–0.998; P = 0.006]. HR change was associated with outcome adjusted by age and sex in patients with sinus rhythm (hazard ratio, 0.993; 95% CI, 0.988–0.999; P = 0.015), but not in patients with atrial fibrillation (hazard ratio, 0.996; 95% CI, 0.990–1.002; P = 0.15). Conclusions: A decrease in HR in the first 24 h after admission indicates better prognosis in patients with AHF, although the prognostic influence may differ between patients with sinus rhythm and those with atrial fibrillation.

DOI： 10.1002/ehf2.13388

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DOI： doi: 10.1016/j.ekir.2021.07.013

DOI： doi: 10.1016/j.ekir.2021.07.013

Language：English   Publisher：Cardio-Oncology  

Background: The emergence of immune checkpoint inhibitors (ICIs) has brought about a paradigm shift in cancer treatment as the use of these drugs has become more frequent and for a longer duration. As a result of T-cell-mediated inflammation at the programmed cell death-1, programmed death-ligand-1, and cytotoxic T-lymphocyte antigen-4 pathways, immune-related adverse events (irAEs) occur in various organs and can cause a rare but potentially induced cardiotoxicity. Although irAEs are associated with the efficacy of ICI therapy and better prognosis, there is limited information about the correlation between irAEs and cardiotoxicity and whether the benefits of irAEs apply to patients with underlying cardiovascular disease. This study aimed to investigate the association of irAEs and treatment efficacy in patients undergoing ICI therapy with and without a cardiovascular history. Methods: We performed a retrospective review of the medical records of 409 consecutive patients who received ICI therapy from September 2014 to October 2019. Results: Median patient age was 69 years (29.6% were female). The median follow-up period was 278 days. In total, 69 (16.9%) patients had a history of any cardiovascular disease and 14 (3.4%) patients experienced cardiovascular irAEs after ICI administration. The rate of cardiovascular irAEs was higher in patients with prior non-cardiovascular irAEs than without. The prognosis of patients with irAEs (+) was significantly better than that of the patients without irAEs (P < 0.001); additionally, this tendency did not depend on the presence or absence of a cardiovascular history. Furthermore, the Cox proportional hazards analysis revealed that irAEs were an independent predictor of mortality. Conclusions: Although cardiovascular irAEs may be related to prior non-cardiovascular irAEs under ICI therapy, the occurrence of irAEs had a better prognostic impact and this tendency was not affected by cardiovascular history.

DOI： 10.1186/s40959-021-00112-z

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DOI： 10.1007/s00380-020-01765-z

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Other Link： https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=iroffice_5964&SrcAuth=WosAPI&KeyUT=WOS:000609999900002&DestLinkType=FullRecord&DestApp=WOS_CPL

Language：English   Publisher：International Journal of Artificial Organs  

The spleen serves as a blood volume reservoir for systemic volume regulation in heart failure (HF) patients. Changes are seen in spleen size in advanced HF patients after left ventricular assist device (LVAD) implantation. The pulsatility index (PI) is an indicator of native heart contractility with hemodynamic changes in patients using LVAD. We hypothesized that the splenic volume was associated with the PI, reflecting the hemodynamics in advanced HF patients with LVADs. Herein, we investigated the relationship between splenic volume and PI in these patients. Forty-four patients with advanced HF underwent implantation of HeartMate II® (Abbott, Chicago, IL, USA) as a bridge to heart transplantation at the Nagoya University Hospital between October 2013 and June 2019. The data of 27 patients (21 men, median age 46 years) were analyzed retrospectively. All patients underwent blood tests, echocardiography, right heart catheterization, and computed tomography (CT). Spleen size was measured via CT volumetry; the splenic volume (median: 190 mL) correlated with right arterial pressure (r = 0.431, p = 0.025) and pulmonary capillary wedge pressure (r = 0.384, p = 0.048). On multivariate linear regression analysis, the heart rate (β = −0.452, p = 0.003), pump power (β = −0.325, p = 0.023), and splenic volume (β = 0.299, p = 0.038) were independent determinants of PI. The splenic volume was associated with PI, reflecting the cardiac preload in advanced HF patients with LVADs. Thus, spleen measurement using CT may help estimate the systemic volume status and understand the hemodynamic conditions in LVAD patients.

DOI： 10.1177/0391398820957019

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Aims: Left ventricular reverse remodelling (LVRR) is a well-established predictor of a good prognosis in patients with dilated cardiomyopathy (DCM). The prediction of LVRR is important when developing a long-term treatment strategy. This study aimed to assess the clinical predictors of LVRR and establish a scoring system for predicting LVRR in patients with DCM that can be used at any institution. Methods and results: We consecutively enrolled 131 patients with DCM and assessed the clinical predictors of LVRR. LVRR was defined as an absolute increase in left ventricular ejection fraction (LVEF) from ≥10% to a final value of >35%, accompanied by a decrease in left ventricular end-diastolic dimension (LVEDD) ≥ 10% on echocardiography at 1 ± 0.5 years after a diagnosis of DCM. The mean patient age was 50.1 ± 11.9 years. The mean LVEF was 32.2 ± 9.5%, and the mean LVEDD was 64.1 ± 12.5 mm at diagnosis. LVRR was observed in 45 patients (34%) at 1 ± 0.5 years. In a multivariate analysis, hypertension [odds ratio (OR): 6.86; P = 0.002], no family history of DCM (OR: 10.45; P = 0.037), symptom duration <90 days (OR: 6.72; P < 0.001), LVEF <35% (OR: 13.66; P < 0.0001), and QRS duration <116 ms (OR: 5.94; P = 0.005) were found to be independent predictors of LVRR. We scored the five independent predictors according to the ORs (1 point, 2 points, 1 point, 2 points, and 1 point, respectively), and the total LVRR predicting score was calculated by adding these scores. The LVRR rate was stratified by the LVRR predicting score (0–2 points: 0%; 3 points: 6.7%; 4 points: 17.4%; 5 points: 48.2%; 6 points: 79.2%; and 7 points: 100%). The cut-off value of the LVRR predicting score was >5 in receiver-operating characteristic curve analysis (area under the curve: 0.89; P < 0.0001; sensitivity: 87%; specificity: 78%). An LVRR predicting score of >5 was an independent predictor compared with the presence of late gadolinium enhancement on cardiovascular magnetic resonance or the severity of fibrosis on endomyocardial biopsy (OR: 11.79; 95% confidence interval: 2.40–58.00; P = 0.002). Conclusions: The LVRR predicting score using five predictors including hypertension, no family history of DCM, symptom duration <90 days, LVEF <35%, and QRS duration <116 ms can stratify the LVRR rate in patients with DCM. The LVRR predicting score may be a useful clinical tool that can be used easily at any institution.

DOI： 10.1002/ehf2.13216

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DOI： 10.1016/j.jccase.2020.11.007

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Authorship：Corresponding author   Language：English   Publisher：HeartRhythm Case Reports  

DOI： 10.1016/j.hrcr.2020.12.004

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Authorship：Lead author   Language：English   Publisher：International Journal of Artificial Organs  

Background: Hemodynamic parameters at rest are known to correlate poorly with peak oxygen uptake (VO2) in heart failure. However, we hypothesized that hemodynamic parameters at rest could predict exercise capacity in patients with left ventricular assist device (LVAD), because LVAD pump rotational speed does not respond during exercise. Therefore, we investigated the relationships between hemodynamic parameters at rest (measured with right heart catheterization) and exercise capacity (measured with cardiopulmonary exercise testing) in patients with implantable LVAD. Methods: We performed a retrospective medical record review of patients who received implantable LVAD at our institution from November 2013 to December 2017. Results: A total of 20 patients were enrolled in this study (15 males; mean age, 45.8 years; median duration of LVAD support, 356 days). The mean peak VO2 and cardiac index (CI) were 13.5 mL/kg/min and 2.6 L/min/m2, respectively. CI and hemoglobin level were significantly associated with peak VO2 (CI: r = 0.632, p = 0.003; hemoglobin: r = 0.520, p = 0.019). In addition, pulmonary capillary wedge pressure, right atrial pressure, and right ventricular stroke work index were also significantly associated with peak VO2. In multiple linear regression analysis, CI and hemoglobin level remained independent predictors of peak VO2 (CI: β = 0.559, p = 0.006; hemoglobin: β = 0.414, p = 0.049). Conclusions: CI at rest and hemoglobin level are associated with poor exercise capacity in patients with LVAD.

DOI： 10.1177/0391398820949888

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DOI： 10.1016/j.ijcard.2020.09.056

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DOI： 10.1177/0391398820942526

DOI： 10.1177/0391398820942526

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Language：English   Publisher：Journal of Cardiology Cases  

A 37-year-old man diagnosed with diffuse large B-cell lymphoma two weeks previously, visited our emergency department with sudden dyspnea. He had a severe respiratory failure with saturated percutaneous oxygen at 80% (room air). Chest radiography showed a large amount of left pleural effusion. After 1000 mL of the effusion was urgently drained, reexpansion pulmonary edema (RPE) occurred. Despite ventilator management, oxygenation did not improve and venovenous extracorporeal membrane oxygenation (VV-ECMO) was initiated in the intensive care unit. The next day, contrast-enhanced computed tomography showed a massive thrombus in the right pulmonary artery, at this point the presence of pulmonary thromboembolism (PTE) was revealed. Fortunately, the patient's condition gradually improved with anticoagulant therapy and VV-ECMO support. VV-ECMO was successfully discontinued on day 4, and chemotherapy was initiated on day 8. We speculated the following mechanism in this case: blood flow to the right lung significantly reduced due to acute massive PTE, and blood flow to the left lung correspondingly increased, which could have caused RPE in the left lung. Therefore, our observations suggest that drainage of pleural effusion when contralateral blood flow is impaired due to acute PTE may increase the risk of RPE. <Learning objective: This is a case of reexpansion pulmonary edema (RPE) in the left lung following acute pulmonary thromboembolism (PTE) in the right lung associated with malignant lymphoma, managed by venovenous extracorporeal membrane oxygenation. Contralateral pleural drainage could increase the risk of RPE because contralateral pulmonary blood flow is assumed to increase when PTE obstructs blood flow. Pleural drainage should be performed carefully in patients with malignant tumors because PTE may be hidden.>

DOI： 10.1016/j.jccase.2020.08.013

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Language：English   Publisher：一般社団法人 日本移植学会  

<p>44歳女性、Duchenne型筋ジストロフィーの保因者。頻回の入退院を繰り返し、NYHA III～IV度で推移した。最高酸素摂取量は7.7mL/min/kgまで低下し、10回の心不全増悪による入院に至った。左室駆出率は14%、左室拡張末期径は84mmであった。心臓移植適応検討に向けた精査にて、甲状腺右葉に結節影を認めた。甲状腺乳頭癌と診断され、心臓移植の適応外と判断された。年齢およびT3N1aM0からStage 1と診断され、甲状腺全摘出術および気管周囲リンパ節郭清が行われた。当時はDestination Therapy/Bridge to Decision目的の植込型補助人工心臓は装着できず、カテコラミン持続投与あるいは体外式補助人工心臓装着下に、心臓移植適応となる寛解治癒後5年を待つ方針も検討されたが、長期にわたる入院下での移植待機生活には耐えられない旨の申し出があり、その後4回の心不全増悪入院を繰り返し、翌年永眠された。現行の適応基準では、悪性腫瘍は絶対的除外条件のひとつであるが、本症例の適応外要因となった甲状腺乳頭癌Stage 1の5年生存率は99%以上であり、5年の再発・死亡回避率も90％程度に至る。実際、2016年のISHLTのlisting criteriaにおいても、癌のタイプ、治療への反応性、転移などにより、再発リスクが低い場合には心臓移植も考慮されるべきと記されている。再発リスクが低く生命予後が担保されうる悪性腫瘍合併例では、心臓移植適応に再考の余地があるのではないかと考える。</p>

DOI： 10.11386/jst.56.supplement_s504

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Language：English   Publisher：The Japanese Society of Internal Medicine  

<p>High-output heart failure caused by a tumor-related arteriovenous fistula in adults is a rare clinical condition. We herein report a case of high-output heart failure caused by an arteriovenous fistula associated with renal cell carcinoma and a literature review of 29 published cases to date. Renal cell carcinoma seems to be the most common underlying tumor. For the diagnosis, right heart catheterization and enhanced computed tomography (CT) are considered useful. The removal of the underlying tumor and arteriovenous fistula is the best treatment for heart failure. </p>

DOI： 10.2169/internalmedicine.6962-20

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Authorship：Corresponding author   Language：English   Publisher：Journal of Artificial Organs  

The Impella is an axial-flow percutaneous ventricular assist device for cardiogenic shock. In this report, we describe two patients who developed aortic insufficiency (AI) associated with Impella and required surgical intervention upon implantation of the durable left ventricular assist device (LVAD). Both patients presented with cardiogenic shock and underwent insertion of Impella 5.0 as a bridge to decision. The cardiac function in these patients did not improve and obtaining approval for heart transplantation required time. They were managed with Impella for 91 and 98 days, respectively. In both cases, moderate AI that was not present before Impella insertion was observed when the Impella was removed. Therefore, we performed aortic valve closure to control the AI during durable LVAD implantation. In patients with durable LVAD implantation, AI may occur and progress after the operation in several cases. Aortic valve surgery is often performed to prevent deterioration of AI, especially in patients with AI before the surgery. Hence, AI is an important complication following Impella device implantation as a bridge to decision. Careful observation of AI is essential when the Impella is removed as the evaluation of AI by echocardiogram during Impella management is cumbersome because of device-generated artifacts.

DOI： 10.1007/s10047-020-01184-x

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Language：English   Publisher：Journal of Cardiology Cases  

We treated two patients with COVID-19 pneumonia requiring mechanical ventilation. Case 1 was a 73-year-old Japanese man. Computed tomography (CT) revealed ground-glass opacities in both lungs. He had severe respiratory failure with a partial pressure of oxygen in arterial blood/fraction of inspiratory oxygen ratio (P/F ratio) of 203. Electrocardiogram showed a heart rate (HR) of 56 beats/min, slight ST depression in leads II, III, and aVF, and mild saddle-back type ST elevation in leads V1 and V2. High-sensitivity cardiac troponin T (cTnT) level was slightly elevated. Despite a high fever and hypoxemia, his HR remained within 50–70 beats/min. Case 2 was a 52-year-old Japanese woman. CT revealed ground-glass opacities in the lower left lung. Electrocardiogram showed a HR of only 81 beats/min, despite a body temperature of 39.2 °C, slight ST depression in leads V4, V5, V6, and a prominent U wave in multiple leads. She had an elevated cTnT and a P/F ratio of 165. Despite a high fever and hypoxemia, her HR remained within 50–70 beats/min. Both patients had a poor compensatory increase in their HR, despite their critical status. Relative bradycardia could be a cardiovascular complication and is an important clinical finding in patients with COVID-19. <Learning objective: We report two Japanese cases of COVID-19 pneumonia with relative bradycardia as a condition and no significant compensatory increase in heart rate despite high fever and severe hypoxemia. Relative bradycardia in COVID-19 might be associated with myocardial injury due to not only direct viral involvement but also systemic inflammation. We should carefully observe the occurrence of relative bradycardia because it could potentially be a clinical sign of COVID-19.>

DOI： 10.1016/j.jccase.2020.07.015

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DOI： doi: 10.1016/j.jccase.2020.11.007

DOI： doi: 10.1016/j.jccase.2020.11.007

Language：English   Publisher：European Heart Journal - Case Reports  

Background Kawasaki disease (KD) is a self-limiting form of systemic vasculitis. KD usually occurs in infants and young children and is rarely seen in adolescents. On rare occasions, KD is accompanied with reduced organ perfusion due to systolic hypotension, a condition known as Kawasaki disease shock syndrome (KDSS). The multifactorial causes of KDSS may include intensive vasculitis with capillary leak, myocardial dysfunction, and release of proinflammatory cytokines. However, the mechanisms underlying the pathophysiology of KDSS have not been fully elucidated. Case summary A febrile 17-year-old male with cervical lymphadenopathy developed extreme shock with rapid cardiac dysfunction and reduced organ perfusion. Electrocardiogram revealed ST elevation in the precordial leads and increased serum levels of cardiac enzyme levels. Endomyocardial biopsy at the acute phase revealed CD3 , CD4 or CD8 , and CD20- lymphocytes and CD68 macrophages within infiltrates in the myocardium with mild interstitial fibrosis. He was treated with intravenous immunoglobulin (IVIG) and followed by glucocorticoids with mechanical circulatory support. His cardiac function recovered rapidly with no apparent adverse effects. Discussion Our results suggest that KDSS may be a form of myocarditis, a condition in which inflammatory cells infiltrate the myocardium. Early immunosuppressive therapy, including IVIG and glucocorticoid therapy, may limit the severity of disease and improve the prognosis. As shown by this case, an accurate diagnosis of KD and KDSS will lead to early intervention and improved prognosis even among those in an older cohort.

DOI： 10.1093/ehjcr/ytaa304

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Authorship：Corresponding author   Language：English   Publisher：Canadian Journal of Cardiology  

Background: Delirium is a common adverse event observed in patients admitted to the intensive care unit (ICU). However, the prognostic value of delirium and its determinants have not been thoroughly investigated in patients with acute heart failure (AHF). Methods: We investigated 408 consecutive patients with AHF admitted to the ICU. Delirium was diagnosed by means of the Confusion Assessment Method for ICU tool and evaluated every 8 hours during the patients’ ICU stays. Results: Delirium occurred in 109 patients (26.7%), and the in-hospital mortality rate was significantly higher in patients with delirium (13.8% vs 2.3%; P < 0.001). Multivariate logistic regression analysis showed that delirium independently predicted in-hospital mortality (odds ratio [OR] 4.33, confidence interval [CI] 1.62-11.52; P = 0.003). Kaplan-Meier analysis showed that the 12-month mortality rate was significantly higher in patients with delirium compared with those without (log-rank test: P < 0.001), and Cox proportional hazards analysis showed that delirium remained an independent predictor of 12-month mortality (hazard ratio 2.19, 95% CI 1.49-3.25; P < 0.001). The incidence of delirium correlated with severity of heart failure as assessed by means of the Get With The Guidelines–Heart Failure risk score (chi-square test: P = 0.003). Age (OR 1.05, 95% CI 1.02-1.09; P = 0.003), nursing home residential status (OR 3.32, 95% CI 1.59-6.94; P = 0.001), and dementia (OR 5.32, 95% CI 2.83-10.00; P < 0.001) were independently associated with the development of delirium. Conclusions: Development of delirium during ICU stay is associated with short- and long-term mortality and is predicted by the severity of heart failure, nursing home residential, and dementia status.

DOI： 10.1016/j.cjca.2020.01.006

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Language：English   Publisher：JACC: Case Reports  

Recent developments in immune checkpoint inhibitors (ICIs) have provided new treatment strategies for advanced cancer. However, ICIs lead to an imbalance between T cell–mediated inflammatory responses and immune tolerance in the myocardium. Here we report the first case that implicates the contribution of ICI-induced vasculitis to myocardial injury. (Level of Difficulty: Intermediate.)

DOI： 10.1016/j.jaccas.2020.07.028

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Authorship：Corresponding author   Language：English   Publisher：Canadian Journal of Cardiology  

A 43-year-old man was admitted to a referring hospital for cardiogenic shock caused by dilated cardiomyopathy. Intra-aortic balloon pump and percutaneous venoarterial extracorporeal membrane oxygenation (VA-ECMO) were started initially; however, a thrombus was detected in the left ventricle. After transfer to our institution, we performed thrombectomy through minithoracotomy. Subsequently, an Impella 5.0 device was inserted via the left subclavian artery. His cardiac function gradually improved, and both VA-ECMO and the Impella 5.0 could be weaned off. He was discharged without any thromboembolic event. Impella insertion with thrombectomy was possible, minimally invasive, and effective for a patient with intraventricular thrombosis associated with VA-ECMO.

DOI： 10.1016/j.cjca.2020.04.005

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Language：English   Publisher：Circulation Heart Failure  

DOI： 10.1161/CIRCHEARTFAILURE.120.007164

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Language：English   Publisher：The Japanese Circulation Society  

<p><b><i>Background:</i></b>Right ventricular dysfunction (RVD) in the setting of left ventricular (LV) myocardial damage is a major cause of morbidity and mortality, and the pulmonary artery pulsatility index (PAPi) is a novel hemodynamic index shown to predict RVD in advanced heart failure. However, it is unknown whether PAPi can predict the long-term prognosis of dilated cardiomyopathy (DCM) even in the mild to moderate phase. This study aimed to assess the ability of PAPi to stratify DCM patients without severe symptoms.</p><p><b><i>Methods and Results:</i></b>Between April 2000 and March 2018, a total of 162 DCM patients with stable symptoms were evaluated, including PAPi, and followed up for a median of 4.91 years. The mean age was 50.9±12.6 years and the mean LV ejection fraction (EF) was 30.5±8.3%. When divided into 2 groups based on median value of PAPi (low, L-PAPi [<3.06] and high, H-PAPi [≥3.06]), even though there were no differences in B-type natriuretic peptide or pulmonary vascular resistance, the probability of cardiac event survival was significantly higher in the L-PAP than in the H-PAP group by Kaplan-Meier analysis (P=0.018). Furthermore, Cox’s proportional hazard regression analysis revealed that PAPi was an independent predictor of cardiac events (hazard ratio: 0.782, P=0.010).</p><p><b><i>Conclusions:</i></b>Even in patients identified with DCM in the mild to moderate phase, PAPi may help stratify DCM and predict cardiac events.</p>

DOI： 10.1253/circj.CJ-20-0279

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Language：English   Publisher：International Journal of Artificial Organs  

In the management of venoarterial extracorporeal membrane oxygenation, some patients present persistently closed aortic valve. However, little is known about the variables that contribute to persistently closed aortic valve. We investigated the factors that could predict persistently closed aortic valve at the time of venoarterial extracorporeal membrane oxygenation initiation. We investigated 17 patients who presented closed aortic valve immediately after the introduction of venoarterial extracorporeal membrane oxygenation. Patients who presented closed aortic valve 24 h after introduction of venoarterial extracorporeal membrane oxygenation were defined as the Closed-AV group (n = 8), while those whose aortic valve remained opened after 24 h were defined as the Open-AV group (n = 9). All patients were managed by concomitant use of intra-aortic balloon pumping. At baseline, there were no significant differences between mean arterial blood pressure, central venous pressure, and left ventricular ejection fraction. However, Closed-AV group had significantly lower mean pulmonary artery pressure and pulmonary artery pulse pressure compared to those of Open-AV group (mean pulmonary artery pressure: 15 ± 6 mmHg vs 25 ± 8 mmHg, p = 0.01; pulmonary artery pulse pressure: 3 ± 2 mmHg vs 8 ± 3 mmHg, p < 0.01). Logistic regression analyses revealed that the lower mean pulmonary artery pressure and pulmonary artery pulse pressure had the predictive value of closed aortic valve within 24 h after venoarterial extracorporeal membrane oxygenation initiation (mean pulmonary artery pressure: odds ratio = 0.78, 95% confidence interval = 0.58–0.95, p < 0.01; pulmonary artery pulse pressure: odds ratio = 0.18, 95% confidence interval = 0.01–0.61, p < 0.01). Lower mean pulmonary artery pressure and pulmonary artery pulse pressure values could predict persistent closed aortic valve 24 h after venoarterial extracorporeal membrane oxygenation initiation. Left ventricular preload derived from right heart function may have a major impact on aortic valve status.

DOI： 10.1177/0391398820901841

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Language：English   Publisher：Nagoya Journal of Medical Science  

A 46-year-old Japanese woman visited a nearby hospital because of diplopia after flu-like symptoms. One month later, she presented with blepharoptosis and external ophthalmoplegia. Laboratory tests showed a high creatine kinase concentration (3146 U/L). She underwent intravenous immunoglobulin therapy; however, her symptoms did not improve, prompting transfer to our institute. On admission, transthoracic echocardiography revealed 30% of left ventricular ejection fraction and edema of the left ventricular wall. Coronary angiography showed no significant coronary stenosis. An endomyocardial biopsy resulted in a diagnosis of acute myocarditis. On the following day, she needed a temporary pacemaker because she had complete atrioventricular block and intra-aortic balloon pump because of cardiogenic shock. Intravenous immunoglobulin therapy was again administered and her cardiac function gradually recovered. She was successfully weaned off her temporary pacemaker and intra-aortic balloon pump on Day 5 after improvement in her complete atrioventricular block. Steroid therapy administered from Day 9 was effective in reducing her creatine kinase concentrations. However, contrast-enhanced magnetic resonance imaging revealed inflammation of the scalene, semispinalis cervicis, sternocleidomastoid, and intercostal muscles. On Day 25, her cardiac function had recovered to a left ventricular ejection fraction of 59%. Finally, she was successfully discharged on Day 45 after undergoing rehabilitation.

DOI： 10.18999/nagjms.82.3.585

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Language：English   Publisher：International Heart Journal Association  

<p>The metabolism of branched-chain amino acids (BCAAs) is reported to change in heart failure (HF) and correlate with cardiac function. However, the effect of BCAAs on HF remains controversial. We investigate the prognostic value of the plasma BCAA level in nonischemic dilated cardiomyopathy (NIDCM).</p><p>This study enrolled 39 NIDCM patients, who underwent plasma amino acid (AA) analysis. The ratio of BCAAs to total AAs was calculated. All patients were divided into two groups at the median of BCAA/total AA ratio; high BCAA/total AA group (≥ 0.15, <i>n</i> = 20) and low BCAA/total AA group (< 0.15, <i>n</i> = 19). A cardiac event was defined as a composite of cardiac death, hospitalization for worsening HF, and lethal arrhythmia.</p><p>The mean age was 51.1 ± 12.3 years and left ventricular ejection fraction (LVEF) was 32.7 ± 10.1%. In the low BCAA/total AA group, the body mass index and the total cholesterol level were lower than in the high BCAA/total AA group. The BCAA/total AA ratio was positively correlated with LVEF (<i>r</i> = 0.35, <i>P</i> = 0.031) and negatively correlated with brain natriuretic peptide (<i>r</i> = −0.37, <i>P</i> = 0.020). The low BCAA/total AA group had a lower cardiac event-free rate (5-year: 100% versus 73%; <i>P</i> = 0.019). In univariate analysis, angiotensin converting enzyme inhibitor or angiotensin II receptor blocker (hazard ratio: 0.045, <i>P</i> = 0.0014), hemoglobin (hazard ratio: 0.49 per 1 g/dL, <i>P</i> = 0.0022), and BCAA/total AA ratio < 0.15 (hazard ratio: not available, <i>P</i> = 0.0066) were major predictors for cardiac events.</p><p>The BCAA/total AA ratio might be a useful predictor for future cardiac events in patients with NIDCM.</p>

DOI： 10.1536/ihj.20-010

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The spleen has been recognized as an important organ that holds a reserve of 20% to 30% of the total blood volume. Spleen contraction and splenic volume reduction occur in patients with hypovolemic shock. However, the change in the spleen volume and the association between spleen size and hemodynamic parameters remain unclear in patients with advanced heart failure (HF) who need left ventricular assist device (LVAD) support. This study was performed to investigate the change in spleen size and the relationship between spleen size and hemodynamic parameters before and after LVAD implantation in patients with advanced HF. We enrolled 20 patients with advanced HF on LVAD support. All patients underwent right heart catheterization and computed tomography before and after LVAD implantation. The spleen size was measured by computed tomography volumetry. We excluded patients with a mean right atrial pressure (RAP) of <5 mm Hg because of the possibility of hypovolemia and those with a cardiac index of >2.2 L/min/m2 before LVAD implantation. The splenic volume significantly increased from 160.6 ± 46.9 mL before LVAD implantation to 224.6 ± 73.5 mL after LVAD implantation (P <.001). Before LVAD implantation, there was a significant negative correlation between spleen volume and systemic vascular resistance (SVR). After LVAD implantation, however, there were significant correlations between spleen volume and the cardiac index, RAP, and pulmonary capillary wedge pressure despite the absence of a significant correlation between spleen volume and SVR. Furthermore, one patient developed reworsening HF because of LVAD failure due to pump thrombosis. In this case, the splenic volume was 212 mL before LVAD implantation and increased to 418 mL after LVAD implantation, although it decreased to 227 mL after LVAD failure. The spleen size may change depending on hemodynamics in patients with advanced HF with LVAD support, reflecting sympathetic nerve activity and the systemic volume status.

DOI： 10.1111/aor.13658

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Language：English   Publisher：Journal of Cardiology  

Background: Heart failure (HF) is a hypercatabolic state that promotes branched-chain amino acid (BCAA) catabolic activity in the heart and skeletal muscle and reduces protein synthesis in the liver. Consequently, plasma free aromatic amino acids (AAAs) are increased. We investigated the prognostic value of the BCAA/AAA ratio (Fischer's ratio, FR) in patients with HF. Methods: We enrolled 157 consecutive patients hospitalized for worsening HF (81 men, 76 women; mean ± SD age 75 ± 14 years). Plasma BCAA levels (i.e. total leucine, isoleucine, valine) and AAA levels (i.e. total tyrosine, phenylalanine) were measured at a time when the patients were stabilized (at discharge). FR was calculated as the combined plasma BCAA levels divided by the AAA level. Cardiac events were defined as a composite of cardiac death and hospitalization for worsening HF. Results: The patients were divided into two groups based on the median FR (high-FR group: FR ≥ 3.1, n = 78; low-FR group: FR < 3.1, n = 79). Compared with the high-FR group, low-FR patients were older, had more prior hospitalizations for HF, lower albumin and cholinesterase levels, and lower geriatric nutritional risk index (GNRI). Altogether, 46 cardiac events occurred during the follow-up period (221 ± 135 days), including 14 cardiac deaths and 32 hospitalizations for worsening HF. In a Kaplan–Meier survival analysis, the low-FR group had more cardiac events than the high-FR group (log-rank, p < 0.001). The best cut-off value of FR was determined as 2.9 in the receiver operating characteristic curve for cardiac events. A multivariate Cox proportional hazards regression analysis showed that being in the low-FR group was an independent determinant of cardiac events from parameters of liver function tests and GNRI. Conclusions: FR might be useful for predicting future cardiac events in patients with HF, reflecting nutritional status which cannot be assessed by liver function tests and GNRI.

DOI： 10.1016/j.jjcc.2019.12.016

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DOI： 10.18999/nagjms.82.1.129

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Language：English   Publisher：Journal of Cardiology Cases  

A 51-year-old male, previously diagnosed with central diabetes insipidus due to lymphocytic hypophysitis, presented with fever and dyspnea for 1 week. On arrival, he exhibited hypotension (85/60 mmHg) and sinus tachycardia (110 bpm). His electrocardiogram revealed mild ST elevation on V2–V4. Echocardiography indicated a near-normal (50%) left ventricular ejection fraction (LVEF), although the inferior wall of the left ventricle exhibited severe hypokinesis. Fulminant myocarditis and circulatory insufficiency were suspected, and treatment with dobutamine, 3 μg/kg/min, was started. His LVEF gradually decreased to 20%. On day 17, he developed cardiogenic shock due to ventricular tachycardia and underwent peripheral venous–arterial extracorporeal membrane oxygenation and intra-aortic balloon pumping. Although he did not exhibit polyuria, intravenous vasopressin infusion (0.5 U/h) was performed to maintain normonatremia. Endomyocardial biopsy results revealed the infiltration of scattered giant cells (GCs) and extensive lymphocytes. Despite immunosuppressive therapy (methylprednisolone and cyclosporine), his cardiac function did not recover. On day 36, he received a biventricular assist device; however, he died on day 47 due to the progression of sepsis and multiple organ failure. We speculate that a deficient expression of programmed cell death protein-1 was the cause of both GC myocarditis and lymphocytic hypophysitis. <Learning objective: We describe a fatal case of fulminant giant cell myocarditis complicated by central diabetes insipidus due to lymphocytic hypophysitis. Normonatremia was maintained with intravenous vasopressin 0.5 U/h, and circulatory status was maintained with mechanical circulatory support. We speculate that T-cell programmed cell death protein 1 dysregulation was the common cause of the two disorders.>

DOI： 10.1016/j.jccase.2019.08.011

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Language：English   Publisher：Annals of Nuclear Medicine  

Objectives: Information on the relationship between myocardial damage assessed by myocardial scintigraphy and prognosis in patients with Anderson–Fabry disease (AFD) is lacking. We therefore aimed to investigate the prognostic impacts of myocardial thallium-201 (201Tl) and iodine-123 beta-methyl 15-para-iodophenyl 3(R, S)-methylpentadecanoic acid (123I-BMIPP) dual scintigraphy in patients with AFD. Methods: Eighteen consecutive patients with AFD underwent resting myocardial 201Tl/123I-BMIPP dual scintigraphy. Total defect scores (TDS) on both images were calculated visually according to the 17-segment model using a 5-point scoring system. The mismatch score (MS) was calculated as ‘TDS on 123I-BMIPP—TDS on 201Tl’. Results: Six major adverse cardiac events (MACEs) were recorded during a mean follow-up of 6.7 ± 4.2 years (three heart failure requiring hospitalization and three cardiac deaths). Left ventricular mass index, left atrial diameter, brain natriuretic peptide, TDS on 123I-BMIPP, and MS were all significantly greater in patients with MACEs compared with those without. Kaplan–Meier analysis indicated that high TDS on 123I-BMIPP and high MS were associated with poor event-free survival. Conclusion: TDS on 123I-BMIPP was a better prognostic determinant in patients with AFD than TDS on 201Tl. Myocardial 201Tl/123I-BMIPP dual scintigraphy may thus be a useful noninvasive modality for evaluating prognosis in patients with AFD.

DOI： 10.1007/s12149-019-01406-0

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Language：English   Publisher：Heart and Vessels  

Hypertrophic cardiomyopathy (HCM) with severe diastolic dysfunction is a major cause of heart failure and sudden cardiac death (SCD) associated with lethal arrhythmia. Although various risk factors for cardiac events have been reported in HCM patients, previous studies have reported that some HCM patients exhibit either no risk or a low risk of SCD experienced cardiac events. The mid-diastolic transmitral flow velocity curve (mitral L-wave) is an echocardiographic index of left ventricular compliance, and it has been reported as one of the parameters of advanced diastolic dysfunction assessed noninvasively. However, little is known about the association between the mitral L-wave and long-term clinical outcomes in HCM patients without SCD risk factors. Between July 2005 and February 2016, 112 patients were diagnosed with HCM and 96 patients without risk factors were enrolled. After excluding 3 patients whom we could not detect L-wave more than once, 93 patients (mean age 57.7 ± 13.1 years, 33 females) were divided into the following two groups, according to the presence or absence of the mitral L-wave: Group L (+) (with the mitral L-wave) and Group L (−) (without the mitral L-wave). The correlations between the mitral L-wave and rates of cardiac events were investigated. The mitral L-wave was present in 14 (15.1%) patients [Group L]. During the follow-up period [4.7 (2.9–7.5) years], patients experienced 7 cardiac events. Kaplan–Meier survival analysis showed that the event-free rate was significantly lower in Group L (+) than in Group L (−) (log-rank P = 0.002). Additionally, in multivariate analysis, L-wave positivity was identified as independent predictors of cardiac events. Existence of the mitral L-wave can predict cardiac events, even in HCM patients without SCD risk factors.

DOI： 10.1007/s00380-019-01440-y

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Authorship：Lead author   Language：English   Publisher：ESC Heart Failure  

Aims: In acute heart failure (AHF), immobilization is caused because of unstable haemodynamics and dyspnoea, leading to protein wasting. Neuromuscular electrical stimulation (NMES) has been reported to preserve muscle mass and improve functional outcomes in chronic disease. NMES may be effective against protein wasting frequently manifested in patients with AHF; however, whether NMES can be implemented safely without any adverse effect on haemodynamics has remained unknown. This study aimed to examine the feasibility of NMES in patients with AHF. Methods and results: Patients with AHF were randomly assigned to the NMES or control group. The intensity of the NMES group was set at 10–20% maximal voluntary contraction level, whereas the control group was limited at a visible or palpable level of muscle contraction. The sessions were performed 5 days per week since the day after admission. Before the study implementation, we set the feasibility criteria with following items: (i) change in systolic blood pressure (BP) > ±20 mmHg during the first session; (ii) increase in heart rate (HR) > +20 b.p.m. during the first session; (iii) development of sustained ventricular arrhythmia, atrial fibrillation (AF), and paroxysmal supraventricular tachycardia during all sessions; (iv) incidence of new-onset AF during the hospitalization period < 40%; and (v) completion of the planned sessions by >70% of patients. The criteria of feasibility were set as follows; the percentage to fill one of (i)–(iii) was <20% of the total subjects, and both (iv) and (v) were satisfied. A total of 73 patients (median age 72 years, 51 men) who completed the first session were analysed (NMES group, n = 34; control group, n = 39). Systolic BP and HR variations were not significantly different between two groups (systolic BP, P = 0.958; HR, P = 0.665). Changes in BP > ±20 mmHg or HR > +20 b.p.m. were observed in three cases in the NMES group (8.8%) and five in the control group (12.8%). New-onset arrhythmia was not observed during all sessions in both groups. During hospitalization, one patient newly developed AF in the NMES group (2.9%), and one developed AF (2.6%) and two lethal ventricular arrhythmia in the control group. Thirty-one patients in the NMES group (91%) and 33 patients in the control group (84%) completed the planned sessions during hospitalization. This study fulfilled the preset feasibility criteria. Conclusions: NMES is feasible in patients with AHF from immediately after admission.

DOI： 10.1002/ehf2.12504

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<p><b><i>Background:</i></b>Intravenous vasodilators are commonly used in patients with hypertensive acute decompensated heart failure (ADHF), but little is known about their optimal use in blood pressure (BP) management to avoid acute kidney injury (AKI). The purpose of this study was to investigate the association between systolic BP (SBP) changes and the incidence of AKI in patients with hypertensive ADHF.</p><p><b><i>Methods and Results:</i></b>Post-hoc analysis was performed on a prospectively enrolled cohort. We investigated 245 patients with ADHF and SBP >140 mmHg on arrival (mean age, 76 years; 40% female). We defined “SBP-fall” as the maximum percent reduction in SBP 6 h after intravenous treatment. AKI was defined as serum creatinine (SCr) ≥0.3 mg/dL, or urine output <0.5 mL/kg/h (n=66) at 48 h. Mean SBP and SCr levels on arrival were 180 mmHg and 1.21 mg/dL, respectively. Patients with AKI had significantly larger SBP-fall than the others (36.7±15.3% vs. 27.2±15.3%, P<0.0001). Logistic regression analysis showed an odds ratio per 10% SBP-fall for AKI of 1.49 (95% confidence interval 1.29–1.90, P=0.001). SBP-fall was significantly associated with the number of concomitant used intravenous vasodilators (P=0.001). The administration of carperitide was also independently associated with increased incidence of AKI.</p><p><b><i>Conclusions:</i></b>Larger SBP-fall from excessive vasodilator use is associated with increased incidence of AKI in patients with hypertensive ADHF.</p>

DOI： 10.1253/circj.CJ-19-0333

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Language：English   Publisher：American Journal of Cardiology  

Purpose: Diastolic dysfunction preceding systolic dysfunction is considered an important interaction in cardiomyopathy with poor prognosis. The aim of this study was to compare left ventricular (LV) isovolumic relaxation with the other parameters as a potential prognostic marker for patients with idiopathic dilated cardiomyopathy (IDC) and hypertrophic cardiomyopathy (HC). Methods: A total of 145 patients with IDC and 116 with HC were evaluated for hemodynamic parameters; LV pressure was directly measured by a micromanometer catheter, and relaxation half-time (T1/2) was used to determine LV isovolumic relaxation. The median follow-up period was 4.7 years. Results: The mean ages of the patients with IDC and HC were 52.0 ± 12.0 and 57.1 ± 12.4 years, respectively. Each patient group was further divided into 2 groups based on the median value of T1/2: (1) <41.0 ms (D-L group) and ≥41.0 ms (D-H group) (2) <38.5 ms (H-L group) and ≥38.5 ms (H-H group). Kaplan-Meier analysis showed a significantly higher probability of cardiac events in the D-H group than in the D-L group (p = 0.001) and in the H-H group than in the H-L group (p = 0.028). Further, Cox proportional hazard regression analysis revealed that T1/2 was an independent predictor of cardiac events for patients with IDC (hazard ratio 1.109; p = 0.007) and HC (hazard ratio 1.062; p = 0.041). In conclusion, regardless of the type of cardiomyopathy, T1/2 as a measure of LV isovolumic relaxation function was found to be associated with the occurrence of cardiac events.

DOI： 10.1016/j.amjcard.2019.05.005

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DOI： 10.1016/j.jccase.2019.02.004

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Authorship：Lead author   Language：English   Publishing type：Doctoral thesis   Publisher：The Japanese Circulation Society  

<p><b><i>Background: </i></b>The aim of this study was to assess specialty-related differences in the treatment for patients with acute heart failure (AHF) in the acute phase and subsequent prognostic differences. </p><p><b><i>Methods and Results: </i></b>We analyzed hospitalizations for AHF in REALITY-AHF, a multicenter prospective registry focused on very early presentation and treatment in patients with AHF. All patients were classified according to the medical specialty of the physicians responsible for contributed most to decisions regarding the initial diagnosis and treatment after the emergency department (ED) arrival. Patients initially managed by emergency physicians (n=614) or cardiologists (n=911) were analyzed. After propensity-score matching, vasodilators were used less often by emergency physicians than by cardiologists at 90 min after ED arrival (29.8% vs. 46.1%, P<0.001); this difference was also observed at 6, 24, and 48 h. Cardiologists administered furosemide earlier than emergency physicians (67 vs. 102 min, P<0.001). However, the use of inotropes, noninvasive ventilation, and endotracheal intubation were similar between groups. In-hospital mortality did not differ between patients managed by emergency physicians and those managed by cardiologists (4.1% vs. 3.8%, odds ratio 1.12; 95% confidence interval 0.58–2.14). </p><p><b><i>Conclusions: </i></b>Despite differences in initial management, no prognostic difference was observed between emergency physicians and cardiologists who performed the initial management of patients with AHF. </p>

DOI： 10.1253/circj.CJ-18-0724

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Authorship：Lead author   Language：English   Publisher：Journal of Cardiology Cases  

We report the case of a 58-year-old man with dilated cardiomyopathy who was hospitalized because of worsening heart failure. As his symptoms were refractory even with the administration of inotropes, he was given peripheral venoarterial extracorporeal membrane oxygenation (VA-ECMO) upon transfer to our hospital. On admission, serum creatinine was 2.62 mg/dL and total bilirubin 10.8 mg/dL. The cannulas inserted were 16-Fr for infusion and 21-Fr for drainage. When the blood flow was increased to 2.14 L/min/m² to improve organ dysfunction, the aortic valve became continuously close with the mean arterial pressure of 85 mmHg. Therefore, we administrated vasodilators to decrease mean arterial pressure, or left ventricular afterload, which achieved opening aortic valve continuously. After the cannula sizes were scaled up to 18Fr for infusion and 24Fr for drainage to gain further blood flow, the aortic valve opened continuously and mean pulmonary pressure decreased. Our strategy to maintain adequate flow rate of VA-ECMO using vasodilator, “high-flow/vasodilation method” achieved hemodynamic stability. Additionally, the concentration of serum creatinine and total bilirubin gradually decreased to within the normal range, although the patient succumbed 58 days after transfer to our hospital. <Learning objective: Venoarterial extracorporeal membrane oxygenation (VA-ECMO) is often used as a first-line mechanical circulatory support in patients with severe heart failure. However, its management is difficult and not established. We discuss the efficacy and potency of our “high-flow/vasodilation method” in the management of VA-ECMO.>

DOI： 10.1016/j.jccase.2018.05.002

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publisher：Canadian Journal of Cardiology  

A 60-year-old man was diagnosed with melanoma. After receiving 13 infusions of nivolumab, he had fulminant myocarditis. The myocardial biopsy specimen revealed extensive lymphocytic infiltration, interstitial edema, and myocardial necrosis, with predominant CD4+, CD8+, CD20− and programmed death-1− markers. Programmed death-1 ligand 1 (PD-L1) was predominantly expressed on the surface of the damaged myocardium. Although it is reported that myocarditis induced by the human anti-programmed death-1 inhibitor nivolumab therapy rarely occurred at > 2 months use in clinical trials, this case showed that even if at a late phase, long-term use of immune checkpoint inhibitors might to lead immune-related adverse events including myocarditis.

DOI： 10.1016/j.cjca.2018.03.007

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：The Japanese Circulation Society  

<p><b><i>Background:</i></b>Skeletal muscle pump function may play a key role in maintaining cardiac output (CO), because of the lack of cardiac contractility reserve during incremental exercise in heart failure (HF) patients. We aimed to investigate the relationship between lower leg pump function and surrogate measures of CO during cardiopulmonary exercise testing (CPX) in HF patients.</p><p><b><i>Methods and Results:</i></b>Consecutive cardiac patients referred for CPX had their lower leg ejection fraction (LgEF) measured using strain gauge plethysmography as a marker of skeletal muscle pump function. We analyzed 88 patients, including 65 HF patients and 23 control subjects. Unlike the control subjects, LgEF correlated with peak oxygen consumption (V̇O₂) and peak oxygen (O₂) pulse (peak V̇O₂: r=0.280, P=0.024; peak O₂ pulse: r=0.540, P<0.001) in HF patients. Significant relationships among LgEF, peak V̇O₂, and peak O₂ pulse were observed in HF patients with reduced EF (peak V̇O₂: r=0.367, P=0.026; peak O₂ pulse: r=0.658, P<0.001), whereas LgEF in HF patients with preserved EF showed a weak correlation only with peak O₂ pulse (r=0.407, P=0.032). LgEF was selected as an independent determinant of peak V̇O₂ (β=0.187, P=0.036) and peak O₂ pulse (β=0.520, P<0.001) in HF patients.</p><p><b><i>Conclusions:</i></b>Lower leg skeletal muscle function may contribute to exercise capacity through an indirect mechanism on cardiac function in HF.</p>

DOI： 10.1253/circj.CJ-17-0927

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publisher：Journal of Cardiology  

Background: Myocardial fibrosis is associated with poor prognosis in nonischemic dilated cardiomyopathy (NIDCM) patients. The Selvester QRS score on 12-lead electrocardiogram is associated with both the amount of myocardial scar and poor prognosis in myocardial infarction patients. However, its use in NIDCM patients is limited. We investigated the prognostic value of the QRS score and its association with collagen volume fraction (CVF) in NIDCM patients. Methods: We enrolled 91 consecutive NIDCM patients (66 men, 53 ± 13 years) without permanent pacemakers or cardiac resynchronization therapy devices. The Selvester QRS score was calculated by two expert cardiologists at NIDCM diagnosis. All patients were followed up over 4.5 ± 3.2 years. Cardiac events were defined as a composite of cardiac death, hospitalization for worsening heart failure, and lethal arrhythmia. We also evaluated CVF using endomyocardial biopsy samples. Results: At baseline, the left ventricular ejection fraction was 32 ± 9%, plasma brain natriuretic peptide level was 80 [43–237] pg/mL, and mean Selvester QRS score was 4.1 points. Twenty cardiac events were observed (cardiac death, n = 1; hospitalization for worsening heart failure, n = 16; lethal arrhythmia, n = 3). Cox proportional hazard regression analysis revealed that the Selvester QRS score was an independent determinant of cardiac events (hazard ratio, 1.32; 95% confidence interval, 1.05–1.67; p = 0.02). The best cut-off value was determined as 3 points, with 85% sensitivity and 47% specificity (area under the curve, 0.688, p = 0.011). In Kaplan–Meier survival analysis, the QRS score ≥3 group had more cardiac events than the QRS score <3 group (log-rank, p = 0.007). Further, there was a significant positive correlation of Selvester QRS score with CVF (r = 0.46, p < 0.001). Conclusions: The Selvester QRS score can predict future cardiac events in NIDCM, reflecting myocardial fibrosis assessed by CVF.

DOI： 10.1016/j.jjcc.2017.09.002

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Language：English   Publisher：Journal of Cardiology  

Background Catecholamine sensitivity estimated using a dobutamine stress test (DST) is recognized as a measure of the beta-adrenergic myocardial contractile reserve, which is involved with left ventricular reverse remodeling (LV-RR). We investigated whether the prognostic ability of the DST for LV-RR could predict cardiac events. Methods There was a total of 192 enrolled patients with dilated cardiomyopathy (DCM). DCM was defined as a LV ejection fraction (LV-EF) ≤45% and LV end-diastolic dimension (LVDd) ≥55 mm. One hundred patients were subjected to micromanometer-based measurement of the maximal first derivative of LV pressure (LVdP/dtmax), an index of LV contractility, at baseline and following the infusion of dobutamine (10 μg/kg/min) via a pigtail catheter. Percentage changes in LVdP/dtmax from the baseline to peak values under dobutamine stress (ΔLVdP/dtmax) were also calculated. After excluding 17 patients who received cardiac resynchronization therapy within 3 months of undergoing DST (n = 15) and who did not receive follow-up echocardiography (n = 2), 83 patients were enrolled (52.5 ± 12.3 years). Results During the follow-up period (4.7 ± 2.6 years), LV-RR was recognized in 49 of 83 patients (59.0%). A multivariate logistic regression analysis revealed that ΔLVdP/dtmax (hazard ratio: 1.024, p = 0.007) and the symptom duration (hazard ratio: 0.977, p = 0.003) were independent predictors of LV-RR. A receiver operating characteristic curve analysis revealed a ΔLVdP/dtmax cut-off value of 75.1% for LV-RR and a significantly lower cardiac event rate in the ΔLVdP/dtmax ≥ 75.1% group (p = 0.045). Conclusions ΔLVdP/dtmax estimated using DST was a useful predictor of LV-RR and cardiac events in patients with DCM.

DOI： 10.1016/j.jjcc.2017.02.005

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Language：English   Publisher：Annals of Noninvasive Electrocardiology  

Background: The clinical significance of electrocardiogram in the assessment of patients with idiopathic dilated cardiomyopathy (IDCM) is currently unknown. The aim of this study was to determine the feasibility of recording serial changes in Sokolow–Lyon voltage (∆%QRS-voltage) in one year to estimate left ventricular reverse remodeling (LVRR) and predict a prognosis of IDCM patients under tailored medical therapy. Methods: Sixty-eight consecutive patients with mild symptoms (52.1 ± 13 years old; 69% men; NYHA I/II/III/IV; 33/29/6/0) underwent electrocardiography and echocardiography at baseline and 12 month follow-up (follow-up period: 3.9 years). Results: LVRR was observed in 30 patients (44.1%). The ∆%QRS-voltage was significantly lower in the LVRR group (LVRR; −26.9%, non-LVRR: −9.2%, p <.001). Univariate analysis showed that ∆%QRS-voltage correlated with ∆%LV end-diastolic diameter (r =.634, p <.001), and with ∆%LV ejection fraction and ∆%LV mass index (r = −.412, p <.001; r =.429, p <.001 respectively). Using receiver operating characteristic curve analysis for the estimation of LVRR, ∆%QRS of −14.7% showed optimal sensitivity (63.2%) and specificity (83.3%) (AUC = 0.775, p <.001). The composite endpoints of cardiac death (n = 0), hospitalization for advanced heart failure (n = 11) and fatal arrhythmia (n = 2) were observed in 13 patients during the follow-up period. Kaplan–Meier analysis showed significantly higher event-free rate in patients of the low ∆%QRS-voltage group (<−14.7%) (83%) than those of the high group (66%, p =.022). Conclusions: The present study showed that decrease in Sokolow–Lyon voltage is associated with improvement in cardiac function and favorable prognosis in IDCM patients on medical therapy, suggesting that this index is a feasible marker for response to treatment of IDCM.

DOI： 10.1111/anec.12431

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Publisher：Clinical and Experimental Nephrology  

Background: Blood pressure is influenced by hereditary factors and dietary habits. The objective of this study was to examine the effect of dietary salt consumption and single-nucleotide polymorphisms (SNPs) on blood pressure (BP). Methods: This was a cross-sectional analysis of 2728 male participants who participated in a health examination in 2009. Average dietary salt consumption was estimated using electronically collected meal purchase data from cafeteria. A multivariate analysis, adjusting for clinically relevant factors, was conducted to examine whether the effect on BP of salt consumption, SNPs, and interaction between salt consumption and each SNP. This study examined the SNPs AGT rs699 (Met235Thr), ADD1 rs4961 (Gly460Trp), NPPA rs5063 (Val32Met), GPX1 rs1050450 (Pro198Leu), and AGTR1 rs5186 (A1166C) in relation to hypertension and salt sensitivity. Results: BP was not significantly associated with SNPs or salt consumption. The interaction between salt consumption and SNPs with systolic BP showed a significant association in NPPA rs5063 (Val32Met) (P = 0.023) and a marginal trend toward significance in rs4961 and rs1050450 (P = 0.060 and 0.067, respectively). Conclusion: The effect of salt consumption on BP differed by genotype. Dietary salt consumption and genetic variation can predict a high risk of hypertension.

DOI： 10.1007/s10157-016-1315-3

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Language：English   Publisher：Journal of Cardiology  

Background Little is known about whether the alteration of cholesterol metabolism reflects abdominal organ impairments due to heart failure. Therefore, we investigated the prognostic value of cholesterol metabolism by evaluating serum campesterol and lathosterol levels in patients with early-stage nonischemic dilated cardiomyopathy (NIDCM). Methods We enrolled 64 patients with NIDCM (median age 57.5 years, 31% female) with New York Heart Association functional class I/II. Serum campesterol and lathosterol levels were measured in all patients. The patients were then divided into four subsets based on the median non-cholesterol sterol levels (campesterol 3.6 μg/mL, lathosterol 1.4 μg/mL): reference (R-subset), high-campesterol/high-lathosterol; absorption-reduced (A-subset), low-campesterol/high-lathosterol; synthesis-reduced (S-subset), high-campesterol/low-lathosterol; double-reduced (D-subset), low-campesterol/low-lathosterol. Endpoint was a composite of cardiac events, including cardiac-related death, hospitalization for worsening heart failure, and lethal arrhythmia. Results Median brain natriuretic peptide (BNP) level was 114 pg/mL. Mean left ventricular ejection fraction was 31.4%. D-subset had the lowest total cholesterol level and cardiac index and the highest BNP level and pulmonary capillary wedge pressure. D-subset also had the highest cardiac event rate during the mean 3.8 years of follow-up (log-rank p = 0.001). Multivariate regression analysis showed that D-subset was an independent determinant of cardiac events. The receiver operating characteristic curve analysis revealed that total cholesterol <153 mg/dL was a best cut-off value for discrimination of the D-subset. Conclusions The combined reduction of campesterol and lathosterol that indicated intestinal cholesterol absorption and liver synthesis predicts future cardiac events in patients with mildly symptomatic NIDCM.

DOI： 10.1016/j.jjcc.2016.08.012

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Authorship：Lead author   Language：English   Publisher：Circulation: Heart Failure  

DOI： 10.1161/CIRCHEARTFAILURE.117.003826

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Language：English   Publisher：Japan Atherosclerosis Society  

<p><i><b>Aim</b></i>: Fast-progressing vascular calcification (VC) is accompanied by renal atrophy and functional deterioration along with atherosclerosis in patients with chronic kidney disease (CKD). However, the relationship between VC progression and renal functional and/or morphological changes remains unclear.</p><p><i><b>Methods</b></i>: We included 70 asymptomatic patients with CKD without hemodialysis in our study. To identify temporal variations, the coronary artery calcification score (CACS), abdominal aortic calcification index (ACI), and renal parenchymal volume index (RPVI) were determined via spiral computed tomography scans taken during the study. We investigated significant factors related to annualized variations of CACS (<i>Δ</i>CACS/y) and ACI (<i>Δ</i>ACI/y).</p><p><i><b>Results</b></i>: During the follow-up period (4.6 years), median values of CACS [in Agatston units (AU)] and ACI increased from 40.2 to 113.3 AU (<i>p</i>=0.053) and from 13.2 to 21.7% (<i>p</i>=0.036), respectively. Multivariate analysis revealed that CACS at baseline (<i>p</i>＜0.001) and diabetes mellitus (DM) status (<i>p</i>=0.037) for <i>Δ</i>CACS/y and ACI at baseline (<i>p</i>=0.017) and hypertension (HT) status (<i>p</i>= 0.046) for <i>Δ</i>ACI/y were significant independent predictors. Furthermore, annualized RPVI variation was significantly related to both <i>Δ</i>CACS/y and <i>Δ</i>ACI/y (R=−0.565, <i>p</i>＜0.001, and R=−0.289, <i>p</i>=0.015, respectively). On the other hand, independent contributions of the estimated glomerular filtration rate (eGFR) and annualized eGFR variation to VC progression were not confirmed.</p><p><i><b>Conclusion</b></i>: The degree of VC at baseline, DM, HT, and changes in renal volume, but not eGFR, had a strong impact on VC progression in patients with CKD.</p>

DOI： 10.5551/jat.39271

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