By Van Selby, MD

Assistant Professor of Medicine, University of California, San Francisco, Cardiology Division, Advanced Heart Failure Section

Dr. Selby reports no financial relationships relevant to this field of study.

SYNOPSIS: In a retrospective cohort of patients presenting with heart failure with preserved ejection fraction, functional impairment was primarily driven by body mass index, diastolic dysfunction, and pulmonary vascular disease. New York Heart Association functional class, right ventricular dysfunction, and natriuretic peptide levels were the strongest predictors of death or heart failure hospitalization.

SOURCES: Dalos D, Mascherbauer J, Zotter-Tufaro C, et al. Functional status, pulmonary artery pressure, and clinical outcomes in heart failure with preserved ejection fraction. J Am Coll Cardiol 2016;68:189-199.

Kitzman DW, Shah SJ. The HFpEF obesity phenotype: The elephant in the room. J Am Coll Cardiol 2016;68:200-203.

Heart failure with preserved ejection fraction (HFpEF) is associated with significant morbidity and mortality. The primary symptom of HFpEF, breathlessness (often assessed using the New York Heart Association [NYHA] Functional Classification), is the major contributor to reduced quality of life. However, the specific parameters that predict functional impairment, and their relationship to clinical outcomes, is not well defined in the HFpEF population.

To identify the specific mechanisms underlying symptoms and adverse outcomes, Dalos et al retrospectively reviewed 193 patients presenting with HFpEF treated at a single institution between 2011 and 2015. HFpEF was defined according to current guideline recommendations: signs or symptoms of heart failure (HF), left ventricular ejection fraction (LVEF) > 50%, N-terminal pro B-type natriuretic peptide (NT-proBNP) > 220 pg/mL, and echocardiographic evidence of left ventricular (LV) diastolic dysfunction. Right heart catheterization, with a pulmonary artery wedge pressure > 12 mmHg, confirmed the diagnosis. Patients with diagnoses such as cardiac amyloid, hypertrophic cardiomyopathy, and significant coronary artery disease were excluded. The authors first examined predictors of advanced NYHA functional class, and in a separate analysis examined NYHA class as a predictor of adverse outcomes (cardiac death and/or HF hospitalization).

In multivariate logistic regression models, the strongest independent predictors of increased NYHA functional class were advanced age (P = 0.007), higher body mass index (BMI; P = 0.002), previous HF hospitalization (P = 0.005), higher NT-proBNP levels (P < 0.001), diastolic function by echocardiography (P = 0.031), and higher diastolic pulmonary arterial pressure (P < 0.001).

During 22 months of follow-up, 64 patients reached the combined endpoint of cardiac death and/or HF hospitalization. Independent predictors of the combined endpoint were NYHA class III or IV (hazard ratio [HR], 2.1; P = 0.04), higher NT-proBNP level (HR = 1.7 per quartile; P < 0.001), and impaired right ventricular function by visual assessment (HR, 2.4; P = 0.001). The authors concluded that symptoms of breathlessness in HFpEF are multifactorial and largely related to increased BMI, LV diastolic dysfunction, and the pulmonary vasculature, and these should be targets of future therapeutic interventions.

COMMENTARY

Exercise intolerance is a primary symptom in patients suffering from HF and a major contributor to reduced quality of life in this population. Because HFpEF frequently is associated with comorbidities such as pulmonary disease, atrial fibrillation, and chronic kidney disease, it can be difficult to identify the primary causes of dyspnea and adverse outcomes in this population.

The authors characterized their HFpEF cohort well, using clinical, echocardiographic, and invasive hemodynamic parameters. Using the NYHA functional classification, they found left and right ventricular function, as well as the pulmonary vasculature, determine exercise intolerance. As the authors argued, these should be considered potential targets for future HFpEF therapies. Small studies of vasodilator therapy for HFpEF have produced promising results. However, these findings have not been replicated in large, multicenter trials.

The strong association identified in this study between increased BMI and symptomatology (as assessed by NYHA class) is particularly intriguing and potentially useful in the management of HFpEF. Obesity is common in the HFpEF population, and the link between obesity and development of HFpEF is well established. There are several potential explanations for this relationship, including inflammation, hypertension, and insulin resistance. Adiposity also promotes systolic, diastolic, arterial, and skeletal muscle dysfunction. The authors built on these epidemiological and pathophysiologic associations and rightly argue that adiposity, along with the hemodynamic abnormalities, should be considered a potential therapeutic target in HFpEF.

In an accompanying editorial, Kitzman and Shah wrote that surprisingly little attention has been given to the role of increased adiposity in HFpEF and its potential as a therapeutic target. In fact, many of the pivotal clinical trials of HFpEF have specifically excluded patients with high BMI. They cited several recent studies showing the benefits of weight loss, whether through bariatric surgery or calorie restriction, in reducing the incidence of HF and improving symptoms in HFpEF patients. The Dalos et al study further strengthens the argument for obesity as a therapeutic target in HFpEF by establishing the link between BMI and symptoms.

This study clarifies the contributors to both exercise intolerance and adverse outcomes in HFpEF, emphasizing the pathophysiologic importance of obesity, diastolic dysfunction, and pulmonary vascular disease. Hopefully these findings will guide future research into therapies for this condition. For now, more aggressive management of obesity is a relatively low-risk intervention that may benefit patients with HFpEF and persistent symptoms despite appropriate therapy.