Heart Failure with Preserved Ejection Fraction and 30-Day Readmission

Objective:Several studies identify heart failure (HF) as a potential risk for hospital readmission; however, studies on predictability of heart failure readmission is limited. The objective of this work was to investigate whether a specific type of heart failure (HFpEF or HFrEF) has a higher association to the rate of 30-day hospital readmission and compare their predictability with the two risk scores: HOSPITAL score and LACE index.Design:Retrospective study from single academic center.Methods:Sample size included adult patients from an academic hospital in a two-year period (2015 - 2017). Exclusion criteria included death, transfer to another hospital, and unadvised leave from hospital. Baseline characteristics, diagnosis-related group, and ICD diagnosis codes were obtained. Variables affecting HOSPITAL score and LACE index and types of heart failure present were also extracted. Qualitative variables were compared using Pearson chi² or Fisher’s exact test (reported as frequency) and quantitative variables using non-parametric Mann–Whitney U test (reported as mean ± standard deviation). Variables from univariate analysis with P values of 0.05 or less were further analyzed using multivariate logistic regression. Odds ratio was used to measure potential risk.Results:The sample size of adult patients in the study period was 1,916. All eligible cohort of patients who were readmitted were analyzed. Cumulative score indicators of HOSPITAL Score, LACE index (including the Charlson Comorbidity Index) predicted 30-day readmissions with P values of <0.001. The P value of HFpEF was found to be significant in the readmitted group (P < 0.001) compared to HFrEF (P = 0.141). Multivariate logistic regression further demonstrated the association of HFpEF with higher risk of readmission with odds ratio of 1.77 (95% CI: 1.25 – 2.50) and P value of 0.001.Conclusions:Our data from an academic tertiary care center supports HFpEF as an independent risk factor for readmission. Multidisciplinary management of HFpEF may be an important target for interventions to reduce hospital readmissions.     

Myocardial Strain for Identification of β-Blocker Responders in Heart Failure with Preserved Ejection Fraction

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Use of Nitrates and Risk of Cardiovascular Events in Patients With Heart Failure With Preserved Ejection Fraction

ObjectiveTo assess the association of nitrate use with cardiovascular events in patients with heart failure with preserved ejection fraction (HFpEF).Patients and MethodsPatient data were collected from the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist trial, which had been conducted at 233 sites in 6 countries from August 10, 2006, through January 31, 2012. The primary outcome was the occurrence of a major adverse cardiovascular event (cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke) or heart failure hospitalization. The association between nitrate use and cardiovascular risk was evaluated using Cox proportional hazards analysis. In addition, we verified the results using propensity score–matched patients.ResultsA total of 3417 patients with HFpEF were evaluated over a mean follow-up of 3.1 years, and 778 experienced a primary outcome event. The risk of primary outcome events was significantly higher in patients taking nitrates than in those not taking nitrates (hazard ratio [HR], 1.21; 95% CI, 1.01-1.46, P=.04). The risk of major adverse cardiovascular events was significantly higher in patients taking nitrates than in those not taking nitrates (HR, 1.32; 95% CI, 1.05-1.66, P=.01). Furthermore, the risk of hospitalization for heart failure was higher in patients taking nitrates (HR, 1.25; 95% CI, 0.99-1.60, P=.06), with propensity score–matched analyses revealing similar findings. In addition, a similar association was observed in various subgroups.ConclusionThis study reported that nitrate use in patients with HFpEF was associated with a significantly increased risk of cardiovascular events.     

Role of Cardiac Magnetic Resonance in Heart Failure with Preserved Ejection Fraction

Purpose of Review

Approximately half of the patients presenting with heart failure have preserved ejection fraction. These patients usually have a combination of underlying etiologies and may profit from individualized treatment. Failure of clinical trials without adequate understanding of the underlying problem highlights the need for an in-depth assessment of this complex clinical syndrome. This review seeks to discuss the role of cardiovascular magnetic resonance imaging (CMR) in improving diagnosis and targeted management of heart failure with preserved ejection fraction (HFpEF).

Recent Findings

Technical advances in tissue mapping techniques enable a virtual histopathological perspective to detect myocardial disease processes, such as inflammation, infiltration, and fibrosis. Myocardial perfusion imaging enables separation between regional ischemia due to epicardial coronary artery disease (CAD) and microvascular disease. Finally, computation of aortic pulse wave velocity (PWV) provides insight into the effects of the vascular stiffness on the efficiency of cardiac work.

Summary

A comprehensive CMR protocol enables identification of the underlying pathophysiology in patients with HFpEF, allows identification of important differential diagnoses in patients with specific diseases, and may lead to imaging-guided precision medicine in HFpEF.

     

Characterization of the Obese Phenotype of Heart Failure With Preserved Ejection Fraction: A RELAX Trial Ancillary Study

ObjectiveTo characterize the obese heart failure with preserved ejection fraction (HFpEF) phenotype in a multicenter cohort.Patients and MethodsThis was a secondary analysis of the randomized clinical trial RELAX (Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure with Preserved Ejection Fraction) performed between October 1, 2008, and February 1, 2012. Patients with HFpEF were classified by body mass index (BMI) as obese (BMI≥35 kg/m²) and nonobese (BMI<30 kg/m²) for comparison.ResultsObese patients with HFpEF (n=81) were younger (median age, 64 [interquartile range (IQR), 67-79] years vs 73 [IQR, 56-70] years; P<.001) but had greater peripheral edema (31% [25] vs 9% [6]; P<.001), more orthopnea (76% [56] vs 53% [35]; P=.005), worse New York Heart Association class (P=.006), and more impaired quality of life (P<.001) as compared with nonobese patients with HFpEF (n=70). Despite more severe signs and symptoms, obese patients with HFpEF had lower N-terminal pro B-type natriuretic peptide level (median, 481 [IQR, 176-1183] pg/mL vs 825 [IQR, 380-1679] pg/mL [to convert to pmol/L, multiply by 0.118]; P=.007) and lower left atrial volume index (median, 38 [IQR, 31-47] mL/m² vs 54 [IQR, 41-63] mL/m²; P<.001). Serum C-reactive protein (median, 5.0 [IQR, 2.4-9.9] mg/dL vs 2.7 [IQR, 1.6-5.4] mg/dL [to convert to mg/L, multiply by 10^?3]; P<.001) and uric acid (median, 7.8 [IQR, 6.1-8.7] mg/dL vs 6.8 [IQR, 5.5-8.3] mg/dL; P=.03) levels were higher in obese HFpEF, indicating greater systemic inflammation, than in nonobese HFpEF. Peak oxygen consumption was impaired in obese HFpEF (median, 11.1 [IQR, 9.6-14.4] mL/kg per minute vs 13.1 [IQR, 11.3-14.7] mL/kg per minute; P=.008), as was submaximal exercise capacity (6-minute walk distance, 272 [IQR, 200-332] m vs 355 [IQR, 290-415] m; P<.0001).ConclusionObese HFpEF is associated with decreased quality of life, worse symptoms of heart failure, greater systemic inflammation, worse exercise capacity, and higher metabolic cost of exertion as compared with nonobese HFpEF. Further study is required to understand the pathophysiology and potential distinct treatments for patients with the obese phenotype of HFpEF.Trial Registrationclinicaltrials.gov Identifier: NCT00763867     

Early Clinical Experience With AZD4831, A Novel Myeloperoxidase Inhibitor,Developed for Patients With Heart Failure With Preserved Ejection Fraction

We evaluated safety, tolerability, pharmacokinetics (PKs), and pharmacodynamics of AZD4831, a novel oral myeloperoxidase (MPO) inhibitor, in a randomized, single‐blind, placebo‐controlled study, following once‐daily multiple ascending dosing to steady‐state in healthy subjects. Target engagement was measured as specific MPO activity in plasma following ex vivo zymosan stimulation of whole blood. Except for generalized maculopapular rash in 4 of 13 subjects receiving the 2 highest doses, 15 and 45 mg AZD4831, no clinically relevant safety and tolerability findings were observed. AZD4831 was rapidly absorbed and plasma concentrations declined slowly with an elimination half‐life of ~ 60 hours. A dose/concentration‐effect relationship between MPO inhibition vs. AZD4831 exposure was established with > 50% MPO inhibition in plasma at concentrations in the low nanomolar range. Steady‐state levels were achieved within 10 days. Taken together, the PK profile, the sustained dose/concentration‐dependent MPO inhibition, and available clinical data support further clinical development of AZD4831 in patients with heart failure with preserved ejection fraction.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

☑ Myeloperoxidase (MPO) is reported to play a role in atherogenesis in humans and MPO plasma levels predict outcome of cardiovascular disease. In patients with chronic heart failure (HF), elevated plasma MPO levels are associated with more advanced HF. Additionally, elevated plasma MPO levels within an HF subject seem to be predictive of increased adverse clinical outcomes.

• WHAT QUESTION DID THIS STUDY ADDRESS?

☑ This was the first once‐daily multiple ascending dosing study of the MPO inhibitor AZD4831 in healthy subjects to explore safety, tolerability, pharmacokinetics, and pharmacodynamics at steady‐state conditions.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

☑ AZD4831 has a long half‐life consistent with once daily dosing. Except for incidence of generalized maculopapular rash at the highest doses, no clinically relevant safety and tolerability findings were observed

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

☑ Target engagement was established and a dose/concentration‐effect relationship between MPO inhibition vs. AZD4831 exposure was observed with half‐maximal inhibitory concentration values in the lower nanomolar range. The study showed that AZD4831 is a suitable drug candidate for further evaluation in patients with heart failure with preserved ejection fraction.

Cardiovascular disease (CVD) remains the major cause of death in the industrialized countries, despite significant advancement in clinical cardiology during the past 2 decades. Beyond optimal control of traditional risk factors, such as lipids, blood pressure, and glucose, targeting novel molecular pathways may further improve outcome in high‐risk patients with CVD by exerting direct beneficial effects on macrovascular and microvascular structure and function.Recently, the PROMIS study in heart failure with preserved ejection fraction (HFpEF) was reported and provided evidence that coronary microvascular dysfunction is highly prevalent in patients with HFpEF and that it correlates with several key features in this patient population, including disease severity, systemic endothelial dysfunction, as well as diastolic dysfunction. ¹ To date, no or limited pharmacological therapies are available for treatment of patients with HFpEF and a novel pharmacological intervention improving both macrovascular and microvascular status in these patients would be beneficial.Myeloperoxidase (MPO) is mainly present in granules of neutrophils, constituting 5% of the dry weight of the cells. In addition to neutrophils, there are also data suggesting the presence of MPO in monocytes and macrophages. MPO generates reactive chlorinating species, such as hypochlorous acid, the active component of bleach, which possesses potent bactericidal and viricidal activities and reacts with electron‐rich moieties of a large range of biomolecules. ² These actions mainly occur in the phagolysosome, but also in the extracellular compartment, as MPO can be released following neutrophil degranulation.Multiple lines of evidence suggest that MPO may play a role in atherogenesis in humans ² , ³ , ⁴ and MPO plasma levels predict outcome of CVD. ³ , ⁴ , ⁵ In chronic heart failure (HF), elevated plasma MPO levels are associated with more advanced disease. Additionally, elevated plasma MPO levels within an HF subject seem to be predictive of increased adverse clinical outcomes. ⁶ In addition, individuals with inherited low MPO activity are protected from leukocyte activation‐induced deterioration of vascular function. ⁷ Direct MPO administration in anaesthetized pigs increased the tone of conductance and resistance vessels and adversely affected myocardial blood flow, thereby strengthening the concept that MPO indeed acts as a modulator of vascular tone in vivo and identifying MPO as a systemic regulator of vasomotion in humans and thus a potential therapeutic target. Furthermore, the degree of MPO‐deficiency was correlated to improved vascular function, such that 50% difference in MPO activity was associated with a 5% absolute difference in flow mediated dilatation. ⁷ As published by Rudolph et al. in 2010, MPO is also involved in structural remodeling of the myocardium, leading to an increased vulnerability to atrial fibrillation. ⁸ Overall, recent evidence suggests that MPO may provide a mechanistic link among inflammation, oxidative stress, vascular dysfunction, and impaired cardiac remodeling. Thus, it is hypothesized that an MPO inhibitor (MPOi) will improve both macrovascular and microvascular status in patients with CVD.There is an offset between the MPOi concentration required to inhibit the MPO in the phagolysosome vs. that required to inhibit extracellular MPO activity. ⁹ From a biological perspective, we hypothesize that it is the extracellular MPO activity that causes the pathological microvascular dysfunction observed in CVD, whereas the intragranular MPO plays a physiological role in host defense.AZD4831 is a novel, potent, and selective MPOi with an in vitro half‐maximal inhibitory concentration of 0.7 nM for human MPO. The pharmacokinetics (PKs), safety, and tolerability, and the effect on uric acid, a down‐stream biomarker of MPO inhibition, following single ascending doses (SADs) in healthy volunteers has been reported. ¹⁰ The human plasma protein binding is 65%, and in vitro studies have indicated that CYP3A4/CYP3A5 is the predominant CYP isoform involved in the metabolism of AZD4831, although other elimination pathways are predicted to contribute to the overall elimination (i.e., non‐CYP450 mediated metabolism as well as renal clearance). ¹⁰ Here, we report the results from the first multiple ascending dose study with the objective to evaluate safety, tolerability, PKs, and pharmacodynamics of AZD4831 in healthy subjects. As an exploratory objective, plasma 4ß‐hydroxycholesterol levels were measured for assessment of potential CYP3A4/A5 induction.     

Cluster Scheme Approach to Foundational Heart Failure With Reduced Ejection Fraction Therapy

This review presents an evidence-based approach to heart failure with reduced ejection fraction (HFrEF), focusing on the foundational 4 drugs: renin-angiotensin-aldosterone system inhibitors/angiotensin receptor-neprilysin inhibitor, β-blockers, mineralocorticoid receptor antagonist, and sodium–glucose cotransporter-2 inhibitor. Given the benefits of the foundational 4 drugs, combined initiation of these therapies is preferable to the conventional paradigm of targeting maximally tolerated β-blockers and renin-angiotensin-aldosterone system inhibitors before adding other therapies. The conventional approach is linked to treatment gaps and delayed introduction of life-saving therapies in patients with HFrEF. The conventional approach was replaced with the cluster approach, based on large-scale randomized control trials. The cluster approach demonstrated a reduction in morbidity and mortality in patients with HFrEF.     

射血分数正常心力衰竭患者Fibrosis-4指数与右心室功能及预后的相关性研究

目的　探讨射血分数正常心力衰竭（heart failure with preserved ejection fraction,HFpEF）患者纤维化-4 指数（Fibrosis-4 index,F4I）与右心室功能及预后的相关性。方法　选取2017 年1 月~2018 年12 月辽阳市中心医院收治的116例HFpEF 患者为研究对象。采用全自动生化分析仪测定血清血肌酐（Serum creatinine,SCr）,总胆红素（total bilirubin,TBil）,血红蛋白（hemoglobin,Hb）,天冬氨酸氨基转移酶（aspartate aminotransferase,AST）和丙氨酸氨基转移酶（alanine aminotransferase,ALT）水平,采用全自动血液分析仪测定血小板计数（platelet count,PLT）,用酶联免疫吸附法测定血清N 末端脑利钠肽前体（N-terminal pro brain natriuretic peptide,NT-pro-BNP）水平。根据患者年龄,AST,ALT 和PLT计算F4I。行超声心动图检查,测定三尖瓣环状平面收缩期偏移（tricuspid annular plane systolic excursion,TAPSE）及三尖瓣环收缩期峰值速度（S’）。比较患者入院时及出院前血生化指标与心脏超声指标。采用Spearman 相关性分析出院前F4I 与TAPSE,S’ 的相关性,多元线性回归分析TAPSE,S’ 相关影响因素。对患者进行随访,统计主要不良心血管事件（major adverse cardiovascular events,MACE）发生情况,采用Cox 回归分析出院前F4I,NT-proBNP 与MACE 发生的关系,采用ROC 曲线分析出院前F4I 对HFpEF 患者MACE 发生的预测价值。结果　出院前TBil[0.61（0.40, 0.84）g/dl],AST[26.91（21.54, 35.26）IU/L],ALT[18.74（10.22, 28.54）IU/L],NT-proBNP[2 003.41（1 037.42, 2 820.43）pg/ml],F4I[2.89（2.07, 3.40）] 水平显著低于入院时[0.78（0.39,1.15）g/dl, 47.47（20.88, 67.83）IU/L, 36.98（19.75,61.78）IU/L,4 905.03（2 570.65, 7 644.43）pg/ml, 3.56（2.60, 4.54）],TAPSE[18.05（15.20,21.88）mm],S’（14.50±5.81cm /s）显著高于入院时[17.02（14.87,18.52）mm, 11.78±2.60cm/s],差异均有统计学意义（t/W= -2.238, -4.364, -4.735, -6.221, -4.178,-3.481, -4.694,均P ＜ 0.05）。相关性分析显示出院前F4I 与TAPSE,S’ 呈负相关（r=-0.825,-0.837,均P ＜ 0.05）。多元线性回归分析显示,F4I 可负向影响TAPSE,S’（β=-0.244,-0.266,均P ＜ 0.05）。经730 天随访,MACE 发生率为31.90%。多因素Cox 回归分析显示出院前F4I 是MACE 发生的独立风险因素（P=0.013）,随F4I 增高MACE 发生增高比为1.270（95%CI:1.052~1.532）。ROC 曲线分析显示,出院前F4I 预测HFpEF 患者发生MACE 的曲线下面积为0.740,敏感度和特异度分别为72.97%,79.75%。结论　F4I 水平与HFpEF 患者的右心室功能障碍呈负相关,高F4I 的HFpEF 患者MACE 发生风险较高,F4I 可作为HFpEF 患者右心室功能评估及预后评估的指标。     

Treatment of Heart Failure with Normal Left Ventricular Ejection Fraction

Underlying causes and precipitating causes of heart failure (HF) should be treated when possible. Persons with HF and normal left ventricular ejection fraction (LVEF) should have maintenance of sinus rhythm, treatment of hypertension, myocardial ischemia, dyslipidemia, and anemia, slowing of the ventricular rate below 90 bpm, and reduction of salt overload. First-line drug treatment in the management of these persons is the use of loop diuretics combined with beta blockers and angiotensin-converting enzyme (ACE) inhibitors. If persons are unable to tolerate ACE inhibitors because of cough, angioneurotic edema, rash, or altered taste sensation, angiotensin II type I receptor antagonists (ARBs) should be given. If HF persists despite diuretics, beta blockers, and ACE inhibitors or ARBs, isosorbide dinitrate plus hydralazine should be administered. Beta blockers, verapamil, diltiazem, and digoxin may be used to slow a rapid ventricular rate in persons with supraventricular tachyarrhythmias. Digoxin should not be used in persons with HF in sinus rhythm with normal LVEF. Exercise training should be encouraged in persons with mild to moderate HF to improve functional status and to decrease symptoms.