Molecular Underpinnings of Left Ventricular Diastolic Impairment

Abstract

Heart failure with preserved ejection fraction (HFpEF) poses a substantial challenge in contemporary cardiovascular medicine, representing a complex clinical syndrome characterised by impaired cardiac function despite a preserved left ventricular ejection fraction (LVEF). Unlike its counterpart, heart failure with reduced ejection fraction (HFrEF), HFpEF poses unique diagnostic and therapeutic challenges fuelling the need for a deeper understanding of its underlying pathophysiology.

The clinical landscape of HFpEF is marked by its rising prevalence, accounting for the majority of all heart failure cases worldwide, particularly among the elderly and those with comorbidities such as hypertension, diabetes and obesity. Distinguishing HFpEF from other cardiovascular conditions and refining diagnostic criteria remain formidable tasks, necessitating ongoing research into more precise diagnostic tools and criteria.

Beyond clinical observations, HFpEF reveals its complex nature at the molecular and cellular levels. Vascular dysfunction, myocardial fibrosis, inflammation and impaired diastolic relaxation emerge as pivotal contributors to HFpEF’s development and progression. To unravel the intricacies of this syndrome, researchers turn to preclinical animal models, among which the ‘two-hit’ model proposed by Joseph Hill’s group holds significance. These models provide a unique opportunity to simulate and study the multifaceted aspects of HFpEF, aiding in the translation of experimental findings to clinical insights.

Cardiomyocyte hypertrophy, extracellular matrix remodelling, and the intricate interplay of inflammatory mediators contribute to the diastolic dysfunction characteristic of HFpEF. Utilising preclinical models, researchers gain insights into these mechanisms, laying the groundwork for the development of novel pharmacological agents and therapeutic strategies tailored to address the specific pathophysiological distinctions of HFpEF.