Heart failure with preserved ejection fraction (HFpEF) in type 2 diabetes mellitus: from pathophysiology to therapeutics

Abstract

Type 2 diabetes mellitus (T2DM or T2D) is a devastating metabolic abnormality featured by insulin resistance, hyperglycemia, and hyperlipidemia. T2D provokes unique metabolic changes and compromises cardiovascular geometry and function. Meanwhile, T2D increases the overall risk for heart failure (HF) and acts independent of classical risk factors including coronary artery disease, hypertension, and valvular heart diseases. The incidence of HF is extremely high in patients with T2D and is manifested as HF with preserved, reduced, and midrange ejection fraction (HFpEF, HFrEF, and HFmrEF, respectively), all of which significantly worsen the prognosis for T2D. HFpEF is seen in approximately half of the HF cases and is defined as a heterogenous syndrome with discrete phenotypes, particularly in close association with metabolic syndrome. Nonetheless, management of HFpEF in T2D remains unclear, largely due to the poorly defined pathophysiology behind HFpEF. Here, in this review, we will summarize findings from multiple preclinical and clinical studies as well as recent clinical trials, mainly focusing on the pathophysiology, potential mechanisms, and therapies of HFpEF in T2D.

Keywords: heart failure with preserved ejection fraction; pathophysiology; therapies; type 2 diabetes mellitus.

Figure 1

Pathology of HFpEF with T2D. Metabolic disturbances such as hyperglycemia, hypertension, hyperinsulinemia, obesity, and renal disease prompt the development of HFpEF in T2D. T2D patients with HFpEF often exhibit LVDD and small LV cavities with elevated LV filling pressures, as well as vascular damage, including endothelial and coronary microvascular dysfunction. T2D and obesity are intertwined and are accompanied by EAT buildup, deteriorating myocardial inflammation, and fibrosis. EAT leads to mechanical stress as a pericardial restraint for LV function. Abnormal hemodynamics between myocardium and pericardium increase pericardial pressure and LVEDP and reduce LV transmural pressure, resulting in higher pulmonary capillary pressure. LA, left atrium; PCWP, pulmonary capillary wedge pressure.

Figure 2

Molecular mechanisms behind HFpEF with T2D. Various metabolic abnormalities in T2D play an essential role in conjunction with the buildup of proinflammatory cytokines and ROS. Other confounding factors, including hyperglycemia, lipotoxicity, and increased levels of FFA, insulin, and AGEs, also contribute to HFpEF. Compromised NO bioavailability and sensitivity, oxidative stress and inflammation, and impaired angiogenesis are involved. Crucial molecular contributors to pathological hypertrophy include G protein-coupled receptors, stress hormone ligands, and signaling kinases in T2D with HFpEF. Relaxation period includes active and passive phases. Downregulated insulin signaling is a hallmark of T2D along with changes in other signaling cascades, including downregulated AMPK signaling and hyperactivated PKC and MAPK. IL6, interleukin 6; IL13, interleukin 13; OXPHOS, oxidative phosphorylation; TCA, tricarboxylic acid cycle; TNFα, tumor necrosis factor-α.