https://orcid.org/0000-0002-7552-3522
‘Heart failure with preserved ejection fraction (HFpEF) affects more women than men, suggesting sex to play a key role in disease evolution’: this is an already established evidence in cardiovascular clinical practice.1But, predicting changes in left ventricle ejection fraction (LVEF) towards values <50% that occur over time in HFpEF patients in both women and men remains one of the major unsolved clinical issues. But the million dollar question is: How it would be possible?
A recent study by Cao et colleagues2 has provided an elegant mechanistic explanation supporting the hypothesis that the ‘secret’ of sex bias in HFpEF might be locked, at least in part, in heart mitochondrial function (Figure 1). The study has described a new experimental approach that integrates genetics and big data (RNA sequencing) technologies in both animal models and HF patients. The core hypothesis that mitochondria drive the sex bias in HFpEF-related diastolic dysfunction was investigated by using RNA-sequencing data of left ventricles from a previous study of isoprotenerol-induced cardiomyopathy in a panel of genetically different inbred strains of female mice, known as Hybrid Mouse Diversity Panel (ISO-HMDP). Briefly, across the HMDP cohort the left ventricles of female mice showed lower levels of mtDNA content as well as lower levels of mitochondrial gene expression, as compared with male mice. An aspect of particular interest in this study was the validation of data from cardiomyocytes of mouse HMDP cohort in a previously published database of HF patients,3 even if irrespective from LVEF. From a clinical perspective, the most promising result arises from the acyl-CoA synthetase long chain family member 6 (Acsl6) gene encoding a mitochondrial protein involved in lipid metabolism. Data showed that Acsl6 expression levels were significantly lower in hearts of female than male mice. Besides, adenoviral-mediated administration of Acsl6 gene in the hearts of C57BL/6 J mice was sufficient to decrease heart weight, E/e’ ratio, and left ventricle mass supporting that Acsl6 overexpression may attenuate diastolic dysfunction in HFpEF.
Unsolved clinical challenges in HFpEF. In the upper panel, we show the possible key role of mitochondrial dysfunction underlying diastolic dysfunction in women mediated by the Acls6 gene (Cao et al., Nat Comm, 2021). In the bottom panel, we propose a longitudinal research approach based on liquid biopsy, omics, and network-oriented bioinformatics to identify key drivers of LVEF decline. This strategy would be useful to identify HFpEF patients who are more prone to LVEF decline over time.
However, the route from bench to bedside is long and full of pitfalls. The urgent need of HFpEF cardiac biospecimens is the ‘Achilles Heel’ for advancing our knowledge about disease pathophysiology, and certainly less the lack of high-fidelity animal models.4 Unfortunately, HFpEF patients rarely undergo heart transplantation than HF with reduced EF (HFrEF), and in situ cardiac biopsies are performed by only a handful of centres worldwide. Thus, molecular characterization, in particular of living myocytes, is extremely limited. Recently, the first transcriptome5 and metabolome6 profiles in myocardium from prospectively identified HFpEF patients were generated showing that it would be possible to identify differential HFpEF clinical phenotypes by the omics biomarkers. Beyond this exciting perspective, this dataset is a highly precious source to validate preclinical findings by Cao et al.2 Another group performed plasma metabolomic profiling to identify novel circulating biomarkers of mitochondrial dysfunction in HFpEF vs. HFrEF.7 In this era of Network Medicine, the most ambitious goal would be to combine multi-omics molecular profiles (also at single-cell level), clinical data, and imaging features to identify the HFpEF-specific interactome at single-patient level.8–12 One of the most addressed network-oriented strategies is the repurposing of drugs in cardiovascular field.8–12 Drug repurposing implies the use of approved drugs and compounds to new indications, and it is a cost-effective and time-unconsuming way for developing new drugs since they have already been proven safe in humans. For example, the recent EMPEROR-Preserved13 (NCT03057951) and DELIVER14 (NCT03619213) clinical trials showed that the inhibitors of the sodium-glucose transporter 2 (SGLT2i), which were initially developed for diabetes, were also effective in reducing cardiovascular death and hospitalizations in HFpEF patients. To establish the implications of Cao et al.,2 investigators should consider ‘repurposed drugs’, such as the SGLT2i, that may modulate Acsl6 gene expression and, possibly, improve diastolic function in a sex-specific manner.
Although a deeper molecular knowledge on sex bias may help to customize treatments in HFpEF patients, the magnifying glass should be placed on another open debate. A substantial number of patients with HFpEF show a decline to LVEF <50%. Is HFpEF an early manifestation of HFrEF? Which and when HFpEF patients are more prone to a decline in LVEF less than 50%? To answer these hard questions, there is needed a change of course in designing research strategies. Evaluating longitudinal changes of LVEF in HFpEF patients with the support of liquid-based assays (mainly peripheral blood), omics biomarkers, and bioinformatics may be useful to reveal key time-specific molecular drivers of progression from HFpEF to HF with mildly reduced EF (HFmrEF) and HFrEF (Figure 1, bottom panel). Then, validating results from circulating cells in cardiac (mainly) and non-cardiac tissues may help to identify biomarkers and drug targets useful to arrest or at least retard disease progression. As compared to other omics, epigenomics (mainly DNA methylation) captures the complex interplay between genetics and environment, thus this layer of biological information is particularly suitable to measure molecular changes longitudinally,11 possibly influenced by sex. In our experience, DNA methylome profiling of circulating CD4+ T lymphocytes revealed locus-specific associations with hemodynamics in patients with pulmonary arterial hypertension,15 a highly frequent comorbidity of HFpEF.
Our key message is that it is no longer time for animal models in HFpEF but research must start from the patients. Certainly, the road ahead is long, but novel horizons are being to be traced.
Conflict of interest: None declared.
Data availability statement
The data underlying this article are available in the article and in its online supplementary material.
