Leveraging clinical epigenetics in heart failure with preserved ejection fraction: a call for individualized therapies

Abstract

Described as the 'single largest unmet need in cardiovascular medicine', heart failure with preserved ejection fraction (HFpEF) remains an untreatable disease currently representing 65% of new heart failure diagnoses. HFpEF is more frequent among women and associates with a poor prognosis and unsustainable healthcare costs. Moreover, the variability in HFpEF phenotypes amplifies complexity and difficulties in the approach. In this perspective, unveiling novel molecular targets is imperative. Epigenetic modifications-defined as changes of DNA, histones, and non-coding RNAs (ncRNAs)-represent a molecular framework through which the environment modulates gene expression. Epigenetic signals acquired over the lifetime lead to chromatin remodelling and affect transcriptional programmes underlying oxidative stress, inflammation, dysmetabolism, and maladaptive left ventricular remodelling, all conditions predisposing to HFpEF. The strong involvement of epigenetic signalling in this setting makes the epigenetic information relevant for diagnostic and therapeutic purposes in patients with HFpEF. The recent advances in high-throughput sequencing, computational epigenetics, and machine learning have enabled the identification of reliable epigenetic biomarkers in cardiovascular patients. Contrary to genetic tools, epigenetic biomarkers mirror the contribution of environmental cues and lifestyle changes and their reversible nature offers a promising opportunity to monitor disease states. The growing understanding of chromatin and ncRNAs biology has led to the development of several Food and Drug Administration approved 'epidrugs' (chromatin modifiers, mimics, anti-miRs) able to prevent transcriptional alterations underpinning left ventricular remodelling and HFpEF. In the present review, we discuss the importance of clinical epigenetics as a new tool to be employed for a personalized management of HFpEF.

Keywords: Epigenetics • Heart failure • Chromatin changes • Non-coding RNAs • Precision medicine.

Role of environmental factors and epigenetic processing in the pathogenesis of HFpEF.

Figure 1

Main risk factors and molecular alterations underlying HFpEF. The clustering of risk factors precipitates metabolic abnormalities, inflammation, and oxidative stress leading to structural and functional alterations underlying HFpEF. Accumulation of free radicals and inflammatory molecules in different cardiac cells affect cardiac remodelling and function at several levels, including microvascular function, cardiomyocyte stiffness, and fibrosis. eNOS, endothelial nitric oxide synthase; ICAM-1, intercellular adhesion molecule 1; NO, nitric oxide; ROS, reactive oxygen species; TNFα, tumour necrosis factor alpha; VCAM-1, vascular cell adhesion molecule 1.

Figure 2

Environmental factors and epigenetic processing in HFpEF. Over the course of life, several factors (environmental, foetal, placental maternal) induce epigenetic signals (DNA methylation, histone modifications, non-coding RNAs), which alter chromatin accessibility and transcription of genes implicated in left ventricular hypertrophy, fibrosis, inflammation, endothelial dysfunction, and metabolic dysfunction. These modifications may significantly contribute to the development of comorbidities (obesity, insulin resistance) and HFpEF. HFpEF, heart failure with preserved ejection fraction.

Figure 3

Main epigenetic alterations potentially involved in HFpEF. Alterations of DNA methylation, histone modifications, and non-coding RNA landscape promote transcriptional changes leading to key HFpEF features namely cardiac fibrosis, hypertrophy, and microvascular dysfunction. The main epigenetic signals implicated in this progression are shown.