Is HFpEF Caused by Coronary Microvascular Disease?

Abstract

Heart failure is responsible for one of eight deaths in the United States. Despite advances in the treatment of heart failure, e.g., beta1‐adrenergic antagonists, angiotensin converting enzyme inhibitors, these therapies are successful only in one type of HF—heart failure with reduced ejection fraction (HFrEF). Another type of heart failure termed HFpEF (heart failure with preserved ejection fraction) presents a far more difficult condition, because there have been no successful clinical trials demonstrating an effective therapy. Moreover, epidemiological data show the prevalence of HFpEF is increasing while that of HFrEF is decreasing. In some studies of patients with non‐obstructive coronary disease, categorized by poor coronary reserve without obstructive coronary artery lesions, HFpEF is observed. Because such patients have coronary microvascular disease, we proposed that a murine model of coronary microvascular disease may also present with HFpEF. In mice null for Kv1.5 channels (KO), a model of inadequate coronary metabolic dilation, we have observed poor exercise tolerance, shortened lifespan, and ventricular fibrosis. We hypothesized that inadequate metabolic dilation in the KO mice leads to chronic coronary insufficiency, i.e., inadequate myocardial blood flow, which would lead to cardiac apoptosis resulting in diffuse fibrosis, stiffening, and culminating in HFpEF. Although many laboratories use standard echocardiographic measurements of diastolic function as verification of HFpEF, such measurements may be spurious in small animals, such as mice, because several indices of diastolic function are heart rate dependent. To overcome this hindrance, we directly evaluated left ventricular diastolic stiffness by measuring LV pressure‐volume (PV) loops, using the slope of the end‐diastolic pressure and volume points (in anesthetized mice using a PV solid‐state transducer). LV PV loops were measured in anesthetized, wild‐type control (WT) and the KO mice during changes in preload induced by slow volume infusion. The series of PV loops were superimposed, and a computer best fit the diastolic PV points to a line, where the slope of the PV line reflects LV diastolic elastance (stiffness). The average slope of the LV end‐diastolic PV lines were roughly doubled in the KO vs WT (P<0.05), indicating increased stiffness. Moreover, LV end‐diastolic pressures were nearly tripled in the KO vs WT, 7.3±1.6 vs 2.8±1.7 mmHg, respectively. (P<0.05). In conclusion, a model of inadequate coronary dilation in mice, which we believe parallels patients with coronary microvascular disease, leads to increased stiffening of the left ventricle and HFpEF.