The role of titin and extracellular matrix remodelling in heart failure with preserved ejection fraction.

C. Franssen,A. González Miqueo

doi:10.1007/s12471-016-0812-z

Abstract

Heart failure with preserved ejection fraction (HFpEF) is characterised by a high incidence of metabolic comorbidities that share the potential to induce both systemic and coronary microvascular inflammation and oxidative stress. These pathophysiological alterations contribute to increased passive stiffness of the myocardium and to diastolic dysfunction, both hallmarks of HFpEF. Passive myocardial stiffness depends mainly on two components: the extracellular matrix (ECM) and the cardiomyocytes. Quantitative and qualitative changes in collagen metabolism leading to myocardial fibrosis determine the ECM-based stiffness of the myocardium. Different noninvasive diagnostic tools to assess myocardial fibrosis are being developed, some of which have demonstrated to correlate with clinical status and prognosis. Cardiomyocytes mainly alter the passive stiffness through alterations in the giant myofilament titin, which serves as a spring. By modifying its phosphorylation state or by direct oxidative effects, titin determines cardiomyocyte-based passive stiffness. Probably the relative importance of cardiomyocyte-based changes is more important in the beginning of the disease, whereas ECM-based changes become more prominent in the more advanced stages. The present review focuses on these changes in ECM and cardiomyocytes in HFpEF and their potential prognostic and therapeutic implications.

Highlights

In contrast to heart failure with a reduced ejection fraction (HFrEF), patients with heart failure with a preserved ejection fraction (HFpEF) still do not benefit from evidence-based treatment options in the absence of a profound knowledge about its pathophysiology
The signs and symptoms of HFpEF are based on increased myocardial stiffness, leading to diastolic left ventricular (LV) dysfunction, which is defined as the inability of the heart to fill to an adequate end-diastolic volume at acceptably low pressures in the absence of endocardial or pericardial disease [8]
The first indications about HFpEF pathophysiology were based on human myocardial biopsy samples, which showed myocardial fibrosis with an increased collagen volume fraction (CVF) in HFpEF patients compared with controls [12]

Summary

Introduction

In contrast to heart failure with a reduced ejection fraction (HFrEF), patients with heart failure with a preserved ejection fraction (HFpEF) still do not benefit from evidence-based treatment options in the absence of a profound knowledge about its pathophysiology. In the following years many studies addressed epidemiological, clinical and fundamental aspects in HFpEF This eventually led to a novel paradigm in HFpEF pathophysiology with a central role for metabolic comorbidities on top with downstream effects such as inflammation and oxidative stress, eventually interfering with normal myocardial function [3]. Non-cardiac comorbidities such as obesity, arterial hypertension and diabetes mellitus are highly prevalent in HFpEF [4] These comorbidities generate a chronic, systemic inflammatory state and diverse markers of inflammation have been found to be associated with the diagnosis and prognosis of HFpEF [5, 6].

The extracellular matrix in HFpEF

Prognostic relevance of myocardial fibrosis

Functional relevance of myocardial fibrosis in diastolic dysfunction

Cardiomyocytes in HFpEF

Conclusions