Zooming in on the Microvasculature in Heart Failure With Preserved Ejection Fraction

Abstract

Heart failure (HF) with preserved ejection fraction (HFpEF) has traditionally been viewed as a form of hypertensive heart disease with increased left ventricular (LV) afterload ultimately leading to HFpEF. However, HFpEF patients typically have numerous other comorbidities.1 Although the severity of LV remodeling and ventricular vascular dysfunction2 and the rate of adverse outcomes3 are greater in patients with HFpEF than in patients with comorbidities alone, some argue that HFpEF is not a distinct syndrome but rather a collection of comorbidities masquerading as HF. See Article by Srivaratharajah et al More recently, based on integrative physiological studies in human HFpEF, the biology of nitric oxide–cyclic guanosine monophosphate–protein kinase G signaling, and elegant studies of human HFpEF myocardium, Paulus and Tschope synthesized an alternate HFpEF pathophysiologic paradigm.1 This paradigm postulates that multimorbidity creates a systemic proinflammatory milieu, coronary microvascular endothelial inflammation, and migration of inflammatory cells to the myocardium with production of proinflammatory cytokines, myocardial inflammation, and subsequent fibrosis. Further, they propose that microvascular endothelial inflammation promotes oxidative stress with generation of oxidative/nitrosative species, which limits myocardial nitric oxide–cyclic guanosine monophosphate–protein kinase G signaling by diminishing nitric oxide bioavailability and oxidizing downstream nitric oxide targets, thus promoting cardiomyocyte hypertrophy. Impaired protein kinase G activity and peroxynitrite-stimulated phosphatases are proposed to alter the phosphorylation status of proteins that influence myofiber relaxation and stiffness and, thus, further impair LV diastolic function. This paradigm has sparked great interest in therapies that target impaired myocardial cyclic guanosine monophosphate–protein kinase G signaling in HFpEF. However, the Paulus paradigm has an important correlate in that an established consequence of coronary microvascular endothelial inflammation is impaired coronary microvascular endothelial function and ultimately coronary microvascular remodeling and rarefaction with decreased microvascular density (MVD).4 The potential impact of diffuse microvascular endothelial inflammation on the functional and …