Cardiovascular Phenotype in HFpEF Patients With or Without Diabetes: A RELAX Trial Ancillary Study

Study Questions:

What are the clinical features, exercise capacity, and outcomes in patients with heart failure with preserved ejection fraction (HFpEF) with or without diabetes?


The RELAX (Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure with Preserved Ejection Fraction) study enrolled 216 stable outpatients with heart failure, an ejection fraction ≥50%, increased natriuretic peptide or intracardiac pressures, and reduced exercise capacity. Prospectively collected data included echocardiography, cardiac magnetic resonance, a comprehensive biomarker panel, exercise testing, and clinical events over 6 months. The association between diabetes and hospitalization for cardiovascular or renal causes during the 6-month study period was assessed by a chi-square test and a multivariable Cox proportional hazards model adjusted for known predictors (age, NYHA functional class, and glomerular filtration rate) of hospitalization in patients with heart failure.


Compared with nondiabetic patients (n = 123), diabetic HFpEF patients (n = 93) were younger, more obese, and more often male and had a higher prevalence of hypertension, renal dysfunction, pulmonary disease, and vascular disease (p < 0.05 for all). Uric acid, C-reactive protein, galectin-3, carboxy-terminal telopeptide of collagen type I, and endothelin-1 levels were higher in diabetic patients (p < 0.05 for all). Diabetic patients had more ventricular hypertrophy, but systolic and diastolic ventricular function parameters were similar in diabetic and nondiabetic patients except for a trend toward higher filling pressures (E/e′) in diabetic patients. Diabetic patients had worse maximal (peak oxygen uptake) and submaximal (6-minute walk distance) exercise capacity (p < 0.01 for both). Diabetic patients were more likely to have been hospitalized for heart failure in the year before study entry (47% vs. 28%, p = 0.004) and had a higher incidence of cardiac or renal hospitalization at 6 months after enrollment (23.7% vs. 4.9%, p < 0.001).


The authors concluded that HFpEF patients with diabetes are at increased risk of hospitalization and have reduced exercise capacity.


This study reports that in a cohort of patients with objective evidence of HFpEF and reduced exercise capacity, diabetic patients had a more severe disease phenotype characterized by more numerous comorbidities, increased left ventricular hypertrophy, and increased circulating markers of vasoconstriction, oxidative stress, inflammation, and fibrosis. The mechanisms of impaired exercise performance in diabetic patients are multifactorial, but appear to be largely due to peripheral factors. These findings support the need for therapeutic strategies targeting the distinctive pathophysiology of diabetes in HFpEF, and may have implications for the design of future clinical trials evaluating the HFpEF population. Given the high event rate among diabetic patients with HFpEF, it would appear that this cohort is worthy of targeted investigation.

Clinical Topics: Diabetes and Cardiometabolic Disease, Heart Failure and Cardiomyopathies, Noninvasive Imaging, Prevention, Acute Heart Failure, Heart Failure and Cardiac Biomarkers, Echocardiography/Ultrasound, Exercise, Hypertension, Stress

Keywords: Hypertrophy, Left Ventricular, Inflammation, Phosphodiesterase 5 Inhibitors, Exercise, Endothelin-1, Vascular Diseases, Oxidative Stress, Vasoconstriction, Galectin 3, Uric Acid, Natriuretic Peptides, C-Reactive Protein, Collagen Type I, Phenotype, Heart Failure, Ventricular Function, Glomerular Filtration Rate, Cyclic Nucleotide Phosphodiesterases, Type 5, Hospitalization, Magnetic Resonance Spectroscopy, Hypertension, Diabetes Mellitus, Lung Diseases, Echocardiography

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