Empagliflozin in Heart Failure With Predicted Preserved Versus Reduced Ejection Fraction: Data From the EMPA-REG OUTCOME Trial

BackgroundIn the EMPA-REG OUTCOME trial, ejection fraction (EF) data were not collected. In the subpopulation with heart failure (HF), we applied a new predictive model for EF to determine the effects of empagliflozin in HF with predicted reduced (HFrEF) vs preserved (HFpEF) EF vs no HF.Methods and ResultsWe applied a validated EF predictive model based on patient baseline characteristics and treatments to categorize patients with HF as being likely to have HF with mid-range EF (HFmrEF)/HFrEF (EF <50%) or HFpEF (EF ≥50%). Cox regression was used to assess the effect of empagliflozin vs placebo on cardiovascular death/HF hospitalization (HHF), cardiovascular and all-cause mortality, and HHF in patients with predicted HFpEF, HFmrEF/HFrEF and no HF. Of 7001 EMPA-REG OUTCOME patients with data available for this analysis, 6314 (90%) had no history of HF. Of the 687 with history of HF, 479 (69.7%) were predicted to have HFmrEF/HFrEF and 208 (30.3%) to have HFpEF. Empagliflozin's treatment effect was consistent in predicted HFpEF, HFmrEF/HFrEF and no-HF for each outcome (HR [95% CI] for the primary outcome 0.60 [0.31–1.17], 0.79 [0.51–1.23], and 0.63 [0.50–0.78], respectively; P interaction = 0.62).ConclusionsIn EMPA-REG OUTCOME, one-third of the patients with HF had predicted HFpEF. The benefits of empagliflozin on HF and mortality outcomes were consistent in nonHF, predicted HFpEF and HFmrEF/HFrEF.     

射血分数中间值的心力衰竭患者的临床特征及预后研究

背景射血分数中间值的心力衰竭(HFmrEF)作为心力衰竭新增分型,其病理生理机制、群体特征、合并症及临床特征与射血分数降低的心力衰竭(HFr EF)患者不尽相同。目的探讨HFmr EF患者的临床特征及预后,以期为HFmr EF患者的临床诊治提供一定参考。方法本研究为回顾性研究。选取2016年6月—2019年6月在石河子大学医学院第一附属医院血管内科住院治疗的心力衰竭患者654例作为研究对象,根据左心室射血分数(LVEF)分为HFr EF组(LVEF <40%,n=299)、HFmr EF组(40≤LVEF <50%,n=153)和射血分数保留的心力衰竭(HFp EF)组(LVEF≥50%,n=202)。收集三组患者基线资料、入院24 h内实验室检查指标及超声心动图检查指标。所有患者均随访1年,记录患者全因死亡情况和全因死亡时间、因心力衰竭再入院情况和因心力衰竭再入院时间。结果HFmr EF组与HFr EF组患者年龄小于HFp EF组,HFr EF组患者年龄小于HFmr EF组(P <0.05);HFr EF组患者女性占比低于HFmr EF组与HFp EF组(P <0.05);HFmr EF组与HFr EF组患者心率大于HFp EF组,纽约心脏病协会(NYHA)分级优于HFp EF组,有糖尿病病史、陈旧性心肌梗死病史者所占比例高于HFp EF组,有心房颤动病史、慢性阻塞性肺疾病(COPD)病史者所占比例低于HFp EF组(P <0.05)。HFmr EF组与HFr EF组患者血肌酐、血尿酸、空腹血糖、中性粒细胞与淋巴细胞比值(NLR)及氨基末端脑钠肽前体(NT-pro BNP)高于HFp EF组,高密度脂蛋白低于HFp EF组(P <0.05);HFr EF组患者血肌酐、血尿酸、空腹血糖、NLR及NT-pro BNP高于HFmr EF组,高密度脂蛋白低于HFmr EF组(P <0.05)。HFmr EF组和HFr EF组患者左心房内径和左心室舒张末期内径(LVEDD)大于HFp EF组,HFr EF组患者左心房内径和LVEDD大于HFmr EF组(P <0.05)。Spearman秩相关分析结果显示,心力衰竭分型与血肌酐(r=0.110)、血尿酸(r=0.264)、空腹血糖(r=0.139)、NLR(r=0.415)、NT-pro BNP(r=0.571)、左心房内径(r=0.246)及LVEDD(r=0.607)呈正相关,与高密度脂蛋白(r=-0.144)呈负相关(P <0.05)。本组患者随访过程中失访18例,失访率为2.7%,平均随访(12.0±1.6)个月。生存曲线分析结果显示,HFr EF组患者1年累积生存率和1年累积无心力衰竭再入院率低于HFp EF组和HFmr EF组,HFmr EF组患者1年累积无心力衰竭再入院率低于HFp EF组(P <0.05)。结论 HFmr EF患者的临床特征与HFr EF相似,其心力衰竭严重程度及左心室重构程度介于HFr EF与HFp EF之间,其1年累积生存率与HFp EF患者相似,均优于HFr EF患者,但其1年累积无心力衰竭再入院率低于HFpEF患者。     

Clinical Characteristics,Comorbidities and Prognosis in Patients With Heart Failure With Mid-Range Ejection Fraction

BackgroundPatients with left ventricular ejection fractions between 40% and 49% either discovered de novo, having declined from ≥50%, or improved from <40% have been described as heart failure (HF) with mid-range ejection fraction (HFmrEF). Though clinical signs and symptoms are similar to other phenotypes, possible prognostic differences and therapeutic responses reinforce the need for further understanding of patients’ characteristics especially in a rural community based population. The purpose of this study is to evaluate the clinical characteristics, comorbidities and prognosis of a rural patient population with HFmrEF.Materials and MethodsWe queried the electronic medical record from a community based university practice for all patients with a HF diagnosis. We included only those patients with >3 months follow-up and interpretable Doppler echocardiograms. We recorded demographic, Doppler-echo, and outcome variables (up to 2,083 days).ResultsThere were 633 HF patients: 42.4% with preserved ejection fraction (HFpEF, EF ≥50%), 36.4% with HFmrEF, and 21.0% with reduced ejection fraction (HFrEF, EF <40%). HFmrEF patients were older, had greater coronary disease prevalence, lower systolic blood pressure, elevated brain natriuretic peptide, lower hemoglobin, and higher creatinine than HFpEF. All-cause mortality was intermediate between HFrEF and HFpEF but was not significantly different. Landmark analysis revealed a trend toward greater second readmission in HFmrEF as compared to HFpEF (hazard ratio: 1.43 [0.96-2.14],P = 0.0767).ConclusionsRural patients with HFmrEF without an ambulatory HF clinic represent a higher percentage of HF patients than previously reported with greater coronary disease prevalence with comparable readmission rates and nonsignificantly different all-cause mortality.     

Effect of digoxin in patients with heart failure and mid‐range (borderline) left ventricular ejection fraction

Aims

To evaluate the effects of digoxin in patients with the newly described phenotype of heart failure (HF) and mid‐range ejection fraction (HFmrEF), attributed to mild left ventricular systolic dysfunction.

Methods and results

We carried out a retrospective analysis of the Digitalis Investigation Group (DIG) trial which had 7788 patients available for analysis with a left ventricular ejection fraction (LVEF) ranging between 3% and 85%. We compared the effect of digoxin to placebo in three mutually exclusive groups of patients defined by LVEF category: <40% (HF with reduced LVEF, HFrEF, n = 5874), 40–49% (HFmrEF, n = 1195) and ≥50% (HF with preserved LVEF, HFpEF, n = 719). The primary outcome was the composite of cardiovascular death or HF hospitalisation. Patients with HFmrEF resembled patients with HFrEF, more than those with HFpEF, with respect to age, sex and aetiology but were more like HFpEF patients with respect to blood pressure and the prevalence of hypertension. Event rates in patients with HFmrEF were similar to those in HFpEF and much lower than in HFrEF. Digoxin reduced the primary endpoint in patients with HFrEF, mainly due to reduced HF hospitalisation: the digoxin/placebo hazard ratio (HR) for HF hospitalisation was 0.71 [95% confidence interval (CI) 0.65–0.77]. The digoxin/placebo HR for HF hospitalisation in patients with HFmrEF was 0.80 (95% CI 0.63–1.03) and 0.85 (95% CI 0.62–1.17) in those with HFpEF. The digoxin/placebo HR for the composite of HF death or HF hospitalisation was 0.74 (95% CI 0.68–0.81) in HFrEF, 0.83 (95% CI 0.66–1.05) in HFmrEF and 0.88 (95% CI 0.65–1.19) in HFpEF.

Conclusions

In this study, event rates in patients with HFmrEF were closer to those in HFpEF than HFrEF. Digoxin had most effect on HF hospitalisation in patients with HFrEF, an intermediate effect in HFmrEF, and the smallest effect in HFpEF.

     

Remote patient management of heart failure across the ejection fraction spectrum: A pre-specified analysis of the TIM-HF2 trial

Aims

The benefit of non-invasive remote patient management (RPM) for patients with heart failure (HF) has been demonstrated. We evaluated the effect of left ventricular ejection fraction (LVEF) on treatment outcomes in the TIM-HF2 (Telemedical Interventional Management in Heart Failure II; NCT01878630) randomized trial.

Methods and results

TIM-HF2 was a prospective, randomized, multicentre trial investigating the effect of a structured RPM intervention versus usual care in patients who had been hospitalized for HF within 12 months before randomization. The primary endpoint was the percentage of days lost due to all-cause death or unplanned cardiovascular hospitalization. Key secondary endpoints were all-cause and cardiovascular mortality. Outcomes were assessed by LVEF in guideline-defined subgroups of ≤40% (HF with reduced EF [HFrEF]), 41–49% (HF with mildly reduced EF [HFmrEF]), and ≥50% (HF with preserved EF [HFpEF]). Out of 1538 participants, 818 (53%) had HFrEF, 224 (15%) had HFmrEF, and 496 (32%) had HFpEF. Within each LVEF subgroup, the primary endpoint was lower in the treatment group, i.e. the incidence rate ratio [IRR] remained below 1.0. Comparing intervention and control group, the percentage of days lost was 5.4% versus 7.6% for HFrEF (IRR 0.72, 95% confidence interval [CI] 0.54–0.97), 3.3% versus 5.9% for HFmrEF (IRR 0.85, 95% CI 0.48–1.50) and 4.7% versus 5.4% for HFpEF (IRR 0.93, 95% CI 0.64–1.36). No interaction between LVEF and the randomized group became apparent. All-cause and cardiovascular mortality were also reduced by RPM in each subgroup with hazard ratios <1.0 across the LVEF spectrum for both endpoints.

Conclusion

In the clinical set-up deployed in the TIM-HF2 trial, RPM appeared effective irrespective of the LVEF-based HF phenotype.     

Sympathetic activation and outcomes in chronic heart failure: Does the neurohormonal hypothesis apply to mid-range and preserved ejection fraction patients?

BackgroundSympathetic activity (SA) is increased in patients with heart failure and reduced ejection fraction (HFrEF) and is associated with poor outcomes. However, its clinical implications are less understood in HF with mid-range (HFmrEF) and preserved ejection fraction (HFpEF). We aimed to study SA across left ventricle ejection fraction (LVEF) groups and its association with clinical outcomes.Methods and ResultsSA estimated by norepinephrine (NE) levels was determined in 742 consecutive outpatients with chronic HF: 348 (47%) with HFrEF, 116 (16%) HFmrEF, and 278 (37%) HFpEF. After a mean follow-up of 15 months, 17% died. Adjusted analyses showed that patients with HFpEF and HFmrEF had lower estimated marginal means of NE levels compared to HFrEF (278 and 116 pg/mL, respectively, vs. 348 pg/mL; p-value=0.005). Adjusted Cox regression analyses showed that high norepinephrine levels independently predicted all-cause mortality (ACM) in all 3 groups. The strongest associations between high NE levels and cardiovascular mortality (CVM) were observed in HFmrEF (HR: 4.7 [1.33–16.68]), while the weakest association was in HFpEF (HR: 2.62 [1.08–6.35]).ConclusionsAdjusted analyses showed that HFpEF and HFmrEF were associated with lower SA compared to HFrEF. Nevertheless, increasing NE levels were independently associated with ACM and CVM in all three LVEF groups. The strongest association between high NE levels and CVM was present in HFmrEF patients, while the weakest was seen in HFpEF. These findings could explain why the response to neurohormonal therapies in patients with HFmrEF is similar to that of patients with HFrEF rather than with HFpEF.     

Serum uric acid and outcomes in patients with chronic heart failure through the whole spectrum of ejection fraction phenotypes: Analysis of the ESC-EORP Heart Failure Long-Term (HF LT) Registry

BackgroundRetrospective analyses of clinical trials indicate that elevated serum uric acid (sUA) predicts poor outcome in heart failure (HF). Uric acid can contribute to inflammation and microvascular dysfunction, which may differently affect different left ventricular ejection fraction (LVEF) phenotypes. However, role of sUA across LVEF phenotypes is unknown.ObjectivesWe investigated sUA association with outcome in a prospective cohort of HF patients stratified according to LVEF.MethodsThrough the Heart Failure Long-Term Registry of the European Society of Cardiology (ESC-EORP-HF-LT), 4,438 outpatients were identified and classified into: reduced (<40% HFrEF), mid-range (40–49% HFmrEF), and preserved (≥50% HFpEF) LVEF. Endpoints were the composite of cardiovascular death/HF hospitalization, and individual components.ResultsMedian sUA was 6.72 (IQ:5.48-8.20) mg/dl in HFrEF, 6.41 (5.02-7.77) in HFmrEF, and 6.30 (5.20-7.70) in HFpEF. At a median 372-day follow-up, the composite endpoint occurred in 648 (13.1%) patients, with 176 (3.6%) deaths and 538 (10.9%) HF hospitalizations. Compared with lowest sUA quartile (Q), Q-III and Q-IV were significantly associated with the composite endpoint (adjusted HR 1.68: 95% CI 1.11–2.54; 2.46: 95% CI 1.66–3.64, respectively). By univariable analyses, HFrEF and HFmrEF patients in Q-III and Q-IV, and HFpEF patients in Q-IV, showed increased risk for the composite endpoint (P<0.05 for all); after model-adjustment, significant association of sUA with outcome persisted among HFrEF in Q-IV, and HFpEF in Q-III-IV.ConclusionsIn a large, contemporary-treated cohort of HF outpatients, sUA is an independent prognosticator of adverse outcome, which can be appreciated in HErEF and HFpEF patients.     

Epidemiology and clinical characteristics of hospitalized elderly patients for heart failure with reduced,mid-range and preserved ejection fraction

Introduction: Elderly patients hospitalized with heart failure (HF) have high mortality rates and requires specific evidence based theraphy, however there are few studies which have focused on patients older than 80 years hospitalized with HF. The aim of the present study is to evaluate the overall clinical characteristics, management, and in-hospital outcomes of elderly patients hospitalized with HF.Methods: Journey-HF study was conducted in 37 different centers in Turkey and recruited 1606 patients who were hospitalized with HF between September 2015 and September 2016. In this study, clinical profile of patients ≥ 80 years old and 65-79 years old hospitalized with HF were described and compared based on EF-related classification: HFrEF (HF with reduced ejection fraction), HFmrEF (HF with mid-range ejection fraction) and HFpEF (HF with preserved ejection fraction).Results: A total of 1034 elder patients (71.6% 65–79 years old and 28.4% ≥80 years old) were recruited. Of the 65–79 years old patients 67.4% had HFrEF, 16.2% had HFmrEF and 16.3% had HFpEF. Among patients ≥80 years old 61.6% had HFrEF, 15.6% had HmrEF and 22.8% had HFpEF.When compared with patients with HFrEF and HFmrEF, patients ≥80 years old with HFpEF were more likely to be older, have atrial fibrilation (AF), and less likely to have diabetes mellitus (DM), coronary artery disease (CAD) or to be recieving an angiotensin-converting enzyme inhibitor (ACEi) or beta blocker theraphy. When compared to patients 65–79 years old with HFpEF, patients ≥80 years with HFpEF had a higher rate of AF and less likely DM. Acute coronary syndrome was the most common precipitant factor for hospitalization in both age groups with HFrEF group. Arrhythmia was a major precipitant factor for hospitalization of patients ≥80 years old with HFpEF. Non-compliance with theraphy was a major problem of patients ≥80 years old with HFrEF.Conclusion: Elderly patients with HFrEF, HFmrEF and HFpEF each had characterized unique patient profiles and the guideline recommended medications were less likely to be used in these patient populations. In hospital mortality rate is worrisome and reflects a need for more specific tretment strategy.     

Heart Failure With Midrange Ejection Fraction—What Is It,If Anything?

The patient cohort with left ventricular ejection fractions (LVEFs) of 41%-49%, which has been defined as heart failure with midrange ejection fraction (HFmrEF), represent a significant proportion of the heart failure (HF) population. Despite the clear cutoffs established by different society guidelines, confusion remains regarding the exact significance of midrange LVEF within the HF syndrome. Patients with LVEF 41%-49% represent a heterogeneous group of patients sharing pathophysiologic mechanisms, biomarker profiles, comorbidities, and clinical characteristics with patients with preserved and reduced LVEF. In this clinical review, we discuss the underlying pathophysiologic mechanisms that culminate in the clinical syndrome of HF and contribute to the disparities observed between HFpEF, HFrEF, and HFmrEF. We highlight differences and similarities in clinical characteristics and imaging features between HFpEF and HFrEF in an effort to disentangle the heterogeneous group of patients with midrange LVEF, but ultimately we conclude that LVEF should be seen as simply one important element of a continuum throughout the HF syndrome, and that although is useful, it is an oversimplification, because HF syndrome is more of a continuum. The underlying pathophysiology, etiology, and comorbidities of patients presenting with HF is becoming ever more important as the limitations of a classification solely based on LVEF are being better recognised, and as patient-specific personalisation of care is becoming ever more important.     

Tecido Adiposo Epicárdico nos Fenótipos de Insuficiência Cardíaca – Uma Metanálise

BackgroundEpicardial adipose tissue (EAT) is increased in comorbidities common in heart failure (HF). In this sense, EAT could potentially mediate effects that lead to an impaired cardiac function.ObjectivesThis meta-analysis aims to investigate if the amount of EAT in all-types of HF and each HF phenotype is significantly different from control patients.MethodsThis meta-analysis followed the Meta-analysis Of Observational Studies in Epidemiology guidelines. The search was performed in the MEDLINE, Embase, and Lilacs databases until November 2020. Two authors performed screening, data extraction, and quality assessment. A p-value <0.05 was defined as statistically significant.ResultsEight observational studies were included, comprehending 1,248 patients in total, from which 574 were controls, 415 had HF with reduced ejection fraction (HFrEF) and 259 had HF with mid-range or preserved ejection fraction (HFmrEF or HFpEF). The amount of EAT was not different between all types of HF and the control group (SMD = -0.66, 95% CI: -1.54 to 0.23, p =0.14). Analyzing each HF phenotype separately, patients with HFrEF had a reduced EAT when compared to the controls (SMD= -1.27, 95% CI: - 1.87 to -0.67, p <0.0001), while patients with HFmrEF or HFpEF showed an increased EAT when compared to controls (SMD= 1.24, 95% CI: 0.99 to 1.50, p <0.0001).ConclusionThe amount of EAT was not significantly different between all types of HF and the control group. In patients with HFrEF, the EAT volume was reduced, whereas in HFpEF and HFmrEF, the amount of EAT was significantly increased. PROSPERO registration number: CRD42019134441.     

Características e Tendências na Mortalidade em Diferentes Fenótipos de Insuficiência Cardíaca na Atenção Primária

Background:The classification of heart failure (HF) by phenotypes has a great relevance in clinical practice.Objective:The study aimed to analyze the prevalence, clinical characteristics, and outcomes between HF phenotypes in the primary care setting.Methods:This is an analysis of a cohort study including 560 individuals, aged ≥ 45 years, who were randomly selected in a primary care program. All participants underwent clinical evaluations, b-type natriuretic peptide (BNP) measurements, electrocardiogram, and echocardiography in a single day. HF with left ventricular ejection fraction (LVEF) < 40% was classified as HF with reduced ejection fraction (HFrEF), LVEF 40% to 49% as HF with mid-range ejection fraction (HFmrEF) and LVEF ≥ 50% as HF with preserved ejection fraction (HFpEF). After 5 years, the patients were reassessed as to the occurrence of the composite outcome of death from any cause or hospitalization for cardiovascular disease.Results:Of the 560 patients included, 51 patients had HF (9.1%), 11 of whom had HFrEF (21.6%), 10 had HFmrEF (19.6%) and 30 had HFpEF (58.8%). HFmrEF was similar to HFpEF in BNP levels (p < 0.001), left ventricular mass index (p = 0.037), and left atrial volume index (p < 0.001). The HFmrEF phenotype was similar to HFrEF regarding coronary artery disease (p = 0.009). After 5 years, patients with HFmrEF had a better prognosis when compared to patients with HFpEF and HFrEF (p < 0.001).Conclusion:The prevalence of ICFEI was similar to that observed in previous studies. ICFEI presented characteristics similar to ICFEP in this study. Our data show that ICFEi had a better prognosis compared to the other two phenotypes.     

射血分数中间范围心力衰竭预后的研究进展

射血分数中间范围心力衰竭(HFmrEF)作为一种特殊类型的心力衰竭表型,处于射血分数降低性心力衰竭(HFrEF)与射血分数保留性心力衰竭(HFpEF)之间的"灰色区域",目前研究对于HFmrEF是为一个独立的临床综合征还是介于HFrEF和HFpEF之间的"过渡阶段"存在一定争议.现对HFmrEF的流行病学、机制、治疗和...     

Right Ventricular Ejection Fraction and Beta-Blocker Effect in Heart Failure With Reduced Ejection Fraction

BackgroundA low right ventricular ejection fraction (RVEF) is a marker of poor outcomes in patients with heart failure with reduced ejection fraction (HFrEF). Beta-blockers improve outcomes in HFrEF, but whether this effect is modified by RVEF is unknown.Methods and ResultsOf the 2798 patients in Beta-Blocker Evaluation of Survival Trial (BEST), 2008 had data on baseline RVEF (mean 35%, median 34%). Patients were categorized into an RVEF of less than 35% (n = 1012) and an RVEF of 35% or greater (n = 996). We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) within each RVEF subgroup and formally tested for interactions between bucindolol and RVEF. The effect of bucindolol on all-cause mortality in 2008 patients with baseline RVEF (HR 0.88, 95% CI 0.75–1.02) is consistent with that in 2798 patients in the main trial (HR 0.90, 95% CI 0.78–1.02). Bucindolol use was associated with a lower risk of all-cause mortality in patients with an RVEF of 35% or greater (HR 0.70, 95% CI 0.55–0.89), but not in those with an RVEF of less than 35% (HR 1.02, 95% CI 0.83–1.24, P for interaction = .022). Similar variations were observed for cardiovascular mortality (P for interaction = .009) and sudden cardiac death (P for interaction = .018), but not for pump failure death (P for interaction = .371) or HF hospitalization (P for interaction = .251).ConclusionsThe effect of bucindolol on mortality in patients with HFrEF was modified by the baseline RVEF. If these hypothesis-generating findings can be replicated using approved beta-blockers in contemporary patients with HFrEF, then RVEF may help to risk stratify patients with HFrEF for optimization of beta-blocker therapy.     

Quantitative Metabolomics Reveals Heart Failure With Midrange Ejection Fraction as a Distinct Phenotype of Heart Failure

BackgroundHeart failure with midrange ejection fraction (HFmrEF) has been recently acknowledged as a separate phenotype, but metabolomics evaluation of this subtype remains largely unexamined.MethodsA quantitative metabolomics study on amino acids and acylcarnitines was performed to characterize different states of heart failure (HF) in 628 participants. Both multivariate orthogonal partial least squares- discriminant analysis and univariate Mann-Whitney U test were used to explore reliable metabolic profiles associated with different HF states. The resulting metabolites were further refined to obtain diagnostic metabolite scores (DMSs) with the use of ordinal logistic regression. Lasso-penalized regression was applied to produce a survival-associated prognostic metabolite score (PMS). The Cox proportional hazards model, Kaplan-Meier curves, and time-dependent receiver operating characteristics were used for a comprehensive assessment of prognostic value using PMS versus traditional clinical biomarkers.ResultsThe optimized models identified a panel of 15 differential metabolites that were shared across different HF states, whereas some metabolites were associated with a specific state. PMS consisting of 9 metabolites demonstrated an appreciably better prognostic value (hazard ratio [HR] 1.62, 95% confidence interval [CI] 1.25-2.1) vs the natural logarithm of N-terminal pro–B-type natriuretic peptide (Ln[NT-proBNP]; HR 1.23, 95% CI 0.94-1.61; P < 0.001). The overall area under the receiver operating characteristic curve value of PMS was superior to that of Ln(NT-proBNP) in risk prediction for patients with HFmrEF and HF with reduced ejection fraction (HFrEF) subtypes (P < 0.001).ConclusionsTargeted metabolomics has provided a novel understanding of the molecular mechanism underlying HF. Both DMS and PMS clearly demonstrated HFmrEF as a distinct phenotype between a mild HF with preserved ejection fraction state and a severe HFrEF state. PMS exhibited superior prognostic value than Ln(NT-proBNP). Further investigation is needed with independent large-scale validation.     

Sudden Cardiac Death in Heart Failure Patients With Preserved Ejection Fraction

BackgroundWhereas sudden cardiac death (SCD) risk has been recognized in heart failure (HF) patients with reduced ejection fraction (HFrEF), less is known about SCD risk in HF patients with preserved EF (HFpEF). We examined the incidence and predictors of SCD in HFpEF in a large population sample.Methods and ResultsMedical records of patients discharged with a primary diagnosis of HF from hospitals in Minneapolis–St Paul in 1995 and 2000 were abstracted. HFpEF was defined as EF ≥45%. SCD was defined as cardiac arrest or out-of-hospital death due to coronary heart disease (CHD) on death certificates. A total of 2,203 patients (age 70 ± 11 years, 53% male) were included. The 787 patients (36%) with HFpEF were older, more often female and more likely to have hypertension than the 1,416 (64%) with HFrEF. All-cause mortality (52% vs 58%; P = .01) and SCD (6% vs 14%; P < .0001) rates were lower in HFpEF than in HFrEF 5 years after hospital discharge. Age, sex, CHD, and length of index hospitalization were the only independent predictors of SCD in HFpEF.ConclusionsIncidence of SCD in HFpEF is lower than in HFrEF. Present markers of SCD in HFpEF are sparse and insufficient to identify the patient at risk.     

Meta-analysis of Exercise Training on Left Ventricular Ejection Fraction in Heart Failure with Reduced Ejection Fraction: A 10-year Update

BackgroundThe role of exercise training modality to attenuate left ventricular (LV) remodeling in heart failure patients with reduced ejection fraction (HFrEF) remains uncertain. The authors performed a systematic review and meta-analysis of published reports on exercise training (moderate-intensity continuous aerobic, high-intensity interval aerobic, and resistance exercise) and LV remodeling in clinically stable HFrEF patients.MethodsWe searched MEDLINE, Cochrane Central Registry of Controlled Trials, CINAHL, and PubMed (2007 to 2017) for randomized controlled trials of exercise training on resting LV ejection fraction (EF) and end-diastolic and end-systolic volumes in HFrEF patients.Results18 trials reported LV ejection fraction (LVEF) data, while 8 and 7 trials reported LV end-diastolic and LV end-systolic volumes, respectively. Overall, moderate-intensity continuous training (MICT) significantly increased LVEF (weighted mean difference, WMD = 3.79%; 95% confidence interval, CI, 2.08 to 5.50%) with no change in LV volumes versus control. In trials ≥6 months duration, MICT significantly improved LVEF (WMD = 6.26%; 95% CI 4.39 to 8.13%) while shorter duration (<6 months) trials modestly increased LVEF (WMD = 2.33%; 95% CI 0.84 to 3.82%). High-intensity interval training (HIIT) significantly increased LVEF compared to control (WMD = 3.70%; 95% CI 1.63 to 5.77%) but was not different than MICT (WMD = 3.17%; 95% CI −0.87 to 7.22%). Resistance training performed alone or combined with aerobic training (MICT or HIIT) did not significantly change LVEF.ConclusionsIn clinically stable HFrEF patients, MICT is an effective therapy to attenuate LV remodeling with the greatest benefits occurring with long-term (≥6 months) training. HIIT performed for 2 to 3 months is superior to control, but not MICT, for improvement of LVEF.     

Heart failure with mid‐range ejection fraction in CHARM: characteristics,outcomes and effect of candesartan across the entire ejection fraction spectrum

Aims

We tested the hypothesis that candesartan improves outcomes in heart failure (HF) with mid‐range ejection fraction [HFmrEF; ejection fraction (EF) 40–49%].

Methods and results

In 7598 patients enrolled in the CHARM Programme (HF across the spectrum of EF), we assessed characteristics, outcomes and treatment effect of candesartan according to EF. Patients with HFmrEF (n = 1322, 17%) were similar to those with HF with reduced EF (HFrEF; n = 4323, 57%) with respect to some characteristics, and intermediate between HFrEF and HF with preserved EF (HFpEF; n = 1953, 26%) with respect to others. Over a mean follow‐up of 2.9 years, the incidence rates for the primary outcome of cardiovascular death or HF hospitalization were 15.9, 8.5 and 8.9 per 100 patient‐years in HFrEF, HFmrEF and HFpEF. In adjusted analyses, the rates of the primary outcome declined with increasing EF up to 50%. For treatment effect, the incidence rates for the primary outcome for candesartan vs. placebo were 14.4 vs. 17.5 per 100 patient‐years in HFrEF [hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.75–0.91; P < 0.001], 7.4 vs. 9.7 per 100 patient‐years in HFmrEF (HR 0.76, 95% CI 0.61–0.96; P = 0.02), and 8.6 vs. 9.1 per 100 patient‐years in HFpEF (HR 0.95, 95% CI 0.79–1.14; P = 0.57). For recurrent HF hospitalization, the incidence rate ratios were 0.68 in HFrEF (95% CI 0.58–0.80; P < 0.001), 0.48 in HFmrEF (95% CI 0.33–0.70; P < 0.001), and 0.78 in HFpEF (95% CI 0.59–1.03; P = 0.08). With EF as a continuous spline variable, candesartan significantly reduced the primary outcome until EF well over 50% and recurrent HF hospitalizations until EF well over 60%.

Conclusion

Candesartan improved outcomes in HFmrEF to a similar degree as in HFrEF. ClinicalTrials.gov : CHARM Alternative NCT00634400, CHARM Added NCT00634309, CHARM Preserved NCT00634712     

Microalbuminúria e seu Significado Prognóstico em Pacientes com Insuficiência Cardíaca Aguda com Fração de Ejeção Preservada,Intermediária e Reduzida

BackgroundThe prevalence and significance of microalbuminuria have not been well studied in patients with different heart failure subtypes.ObjectiveThe prevalence and significance of microalbuminuria have not been well studied in patients with different heart failure subtypes. Therefore, we aimed to investigate the frequency and prognostic value of microalbuminuria in patients hospitalized for acute heart failure (AHF) with preserved ejection fraction (HFpEF), mid-range ejection fraction (HFmrEF), and reduced ejection fraction (HFrEF).MethodsAll consecutive adult patients referred to the hospital due to AHF between June 2016 and June 2019 were enrolled. Microalbuminuria is defined as urinary albumin to creatinine ratio (UACR) level in the range of 30–300 mg/g. Hospital mortality was the endpoint of this studyResultsOf the 426 AHF patients (mean age 70.64 ± 10.03 years, 53.3 % female), 50% had HFrEF, 38.3% had HFpEF, and 11.7% had HFmrEF at presentation.The prevalence of microalbuminuria was 35.2%, 28.8%, and 28.0% in HFrEF, HFpEF, and HFmrEF, respectively. A total of 19 (4.5%) patients died during the in-hospital course, and in-hospital mortality was higher in HFrEF patients (6.6%) compared to patients with HFpEF (2.5%) and HFmrEF (2.0%). Multivariate analysis showed that the presence of microalbuminuria predicted in-hospital mortality in patients with HFrEF and HFmrEF but not in HFpEF.ConclusionAlthough microalbuminuria was common in all subgroups of AHF patients, it has been found to predict prognosis only in patients with HFrEF and HFmrEF.     

Sedentary Time and Cumulative Risk of Preserved and Reduced Ejection Fraction Heart Failure: From the Multi-Ethnic Study of Atherosclerosis

BackgroundThis study examined the relationship between self-reported sedentary time (ST) and the cumulative risk of heart failure with preserved ejection fraction (HFpEF) and reduced ejection fraction (HFrEF) in a diverse cohort of U.S. adults 45–84 years of age.Methods and ResultsUsing data from the Multi-Ethnic Study of Atherosclerosis (MESA), we identified 6,814 subjects, all free of baseline cardiovascular disease. Cox regression was used to calculate the hazard ratios (HR) associated with risk of HFpEF and HFrEF. Weekly ST was dichotomized based on the 75th percentile (1890 min/wk). During ～11.2 years of follow-up there were 178 first incident HF diagnoses: 74 HFpEF and 69 HFrEF. Baseline ST >1890 min/wk was significantly associated with an increased risk of HFpEF (HR 1.87, 95% confidence interval [CI] 1.13–3.09, P = .01), but not of HFrEF. The relationship with HFpEF remained significant in fully adjusted models including physical activity and waist circumference (HR 2.16, 95% CI 1.23–3.78, P < .01). In addition, every 60-minute increase in weekly ST was associated with a 3% increased risk of HFpEF (HR 1.03, 95% CI 1.01–1.05, P < .01).ConclusionsSedentary time >1890 min/wk (～4.5 h/d) is a significant predictor of HFpEF, independently from physical activity and adiposity.