Myocardial Tissue Characterization in Heart Failure with Preserved Ejection Fraction: From Histopathology and Cardiac Magnetic Resonance Findings to Therapeutic Targets

Abstract

Heart failure with preserved ejection fraction (HFpEF) is a complex clinical syndrome responsible for high mortality and morbidity rates. It has an ever growing social and economic impact and a deeper knowledge of molecular and pathophysiological basis is essential for the ideal management of HFpEF patients. The association between HFpEF and traditional cardiovascular risk factors is known. However, myocardial alterations, as well as pathophysiological mechanisms involved are not completely defined. Under the definition of HFpEF there is a wide spectrum of different myocardial structural alterations. Myocardial hypertrophy and fibrosis, coronary microvascular dysfunction, oxidative stress and inflammation are only some of the main pathological detectable processes. Furthermore, there is a lack of effective pharmacological targets to improve HFpEF patients' outcomes and risk factors control is the primary and unique approach to treat those patients. Myocardial tissue characterization, through invasive and non-invasive techniques, such as endomyocardial biopsy and cardiac magnetic resonance respectively, may represent the starting point to understand the genetic, molecular and pathophysiological mechanisms underlying this complex syndrome. The correlation between histopathological findings and imaging aspects may be the future challenge for the earlier and large-scale HFpEF diagnosis, in order to plan a specific and effective treatment able to modify the disease's natural course.

Keywords: cardiac magnetic resonance; endomyocardial biopsy; heart failure; heart failure with preserved ejection fraction; myocardial tissue characterization; therapy.

Figure 1

Possible pathophysiological pathways and molecular mechanisms involved in heart failure with preserved ejection fraction (HFpEF). Depending on the prevalence of microvascular dysfunction or excessive and abnormal collagen deposition, two main different pathophysiological HFpEF patterns could be outlined: (1) an HFpEF pattern with impaired passive phase of diastolic function, caused by altered quantity and quality of interstitial collagen, but with normal microcirculation (expressed by the blue arrow) and (2) an HFpEF pattern with impaired active phase of diastolic function, induced by structural and functional microvascular alteration, with secondary interstitium involvement (expressed by the orange arrow). In the lower part of the figure, the main molecular mechanisms observed in HFpEF have been illustrated.

Figure 2

Schematic representation of the main myocardial and coronary histopathological and pathophysiological alterations observed in heart failure with preserved ejection fraction (HFpEF). Cellular and interstitial involvement, coronary microvascular dysfunction, genetic and epigenetic imbalance and the inflammation-metabolic pathway are the main substrates leading to HFpEF. Each of the listed mechanism implies many molecular and ultrastructural alterations. RAAS: renin angiotensin aldosterone system; TGF-β: transforming growth factor beta; IgG1: immunoglobulin G1; IgG3: immunoglobulin G3; PDH: pyruvate dehydrogenase; ALT: alanine aminotransferase; SIRT3: sirtuin-3; NO: nitric oxide.