Cardiovascular Phenotype in HFpEF Patients With or Without Diabetes

Abstract

Background RELAX was a multicenter randomized trial of sildenafil versus placebo in heart failure and preserved ejection fraction (HFpEF) with rigorous entry criteria and extensive phenotypic characterization of participants. Objectives To characterize clinical features, exercise capacity, and outcomes in patients with HFpEF with or without diabetes and gain insight into contributing pathophysiologic mechanisms. Methods RELAX enrolled 216 stable outpatients with heart failure, EF ≥50%, elevated natriuretic peptide or intracardiac pressures, and reduced exercise capacity. Prospectively collected data included echocardiography, cardiac magnetic resonance imaging, a comprehensive biomarker panel, exercise testing, and clinical events over 6 months. Results Compared with non-diabetics (n=123), diabetic (n=93) HFpEF patients were younger, more obese, 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 diabetics (p<0.05 for all). Diabetic patients had more ventricular hypertrophy but systolic and diastolic ventricular function parameters were similar in diabetics and non-diabetics except for a trend toward higher filling pressures (E/e′) in diabetics. Diabetics 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 HF in the year prior to 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). Conclusions HFpEF patients with diabetes are at increased risk of hospitalization and have reduced exercise capacity. Multi-morbidity, impaired chronotropic reserve, left ventricular hypertrophy and activation of inflammatory, pro-oxidative, vasoconstrictor, and pro-fibrotic pathways may contribute to adverse outcomes in HFpEF patients with diabetes. (NCT00763867)

The Mitochondria in Diabetic Heart Failure: From Pathogenesis to Therapeutic Promise

“…As such, the intersection between diabetes and other cardiac stressors (ischemic, HTN, and renal disease) is perhaps a more tenable and relevant area for investigation. Along these lines, the influence of diabetes on HFpEF was recently reported in a subset of patients from the RELAX trial (61). In this analysis, diabetic patients had FIG.…”

Cardiac metabolism — A promising therapeutic target for heart failure

“…However, early stage HFpEF is instead considered a disorder of depleted cardiovascular reserve, with exercise testing required to confirm the diagnosis outside of acute decompensation (Borlaug, et al, 2010;Obokata, et al, 2016). Given the diversity of cardiovascular conditions associated with HFpEF and the identification of distinct phenotypes of the syndrome, it is generally accepted that HFpEF represents a range of diseases rather than a single distinct entity (Lindman, et al, 2014;Shah, et al, 2016), which further complicates the testing of new potential therapies. Indeed, it has recently been suggested that treatment of HFpEF should be targeted at components of the disease (e.g.…”

Clinical Phenotypes in Heart Failure With Preserved Ejection Fraction

“…As noted by others, a phenotype‐oriented approach to heart failure (HF) and, in particular, to HFpEF is needed 29, 30, 31. The diagnosis of HFpEF rests on the presence of signs and symptoms of HF and a normal left ventricular (LV) ejection fraction.…”