Epigenetic Therapies for Heart Failure: Current Insights and Future Potential

Abstract

Despite the current reductionist approach providing an optimal indication for diagnosis and treatment of patients with heart failure with reduced ejection fraction (HFrEF), there are no standard pharmacological therapies for heart failure with preserved ejection fraction (HFpEF). Although in its infancy in cardiovascular diseases, the epigenetic-based therapy ("epidrugs") is capturing the interest of physician community. In fact, an increasing number of controlled clinical trials is evaluating the putative beneficial effects of: 1) direct epigenetic-oriented drugs, eg, apabetalone, and 2) repurposed drugs with a possible indirect epigenetic interference, eg, metformin, statins, sodium glucose transporter inhibitors 2 (SGLT2i), and omega 3 polyunsaturated fatty acids (PUFAs) in both HFrEF and HFpEF, separately. Apabetalone is the first and unique direct epidrug tested in cardiovascular patients to date, and the BETonMACE trial has reported a reduction in first HF hospitalization (any EF value) and cardiovascular death in patients with type 2 diabetes and recent acute coronary syndrome, suggesting a possible role in secondary prevention. Patients with HFpEF seem to benefit from supplementation to the standard therapy with statins, metformin, and SGLT2i owing to their ability in reducing mortality. In contrast, the vasodilator hydralazine, with or without isosorbide dinitrate, did not provide beneficial effects. In HFrEF, metformin and SGLT2i could reduce the risk of incident HF and mortality in affected patients whereas clinical trials based on statins provided mixed results. Furthermore, PUFAs diet supplementation was significantly associated with reduced cardiovascular risk in both HFpEF and HFrEF. Future large trials will reveal whether direct and indirect epitherapy will remain a work in progress or become a useful way to customize the therapy in the real-world management of HFpEF and HFrEF. Our goal is to discuss the recent advancement in the epitherapy as a possible way to improve personalized therapy of HF.

Machine Learning and Bioinformatics Framework Integration to Potential Familial DCM-Related Markers Discovery

“…In conclusion, including an original ML method in a classic RNA-seq bioinformatic analysis, we showed that some additional features could emerge, and it is possible to draw out a more complete biological picture of the pathophysiology of HF [ 29 ]. Although a limitation of the study may be the low sample size due to the type of biospecimen, as these samples are rare, the study represents a significant contribution in the research area investigated.…”

Epigenetic remodeling in heart failure with preserved ejection fraction

“…Over the last decade, a growing number of epigenetic compounds were unveiled and tested for the treatment of a wide spectrum of human diseases [43]. Of note, several of these drugs have already been approved by the Food and Drugs Administration (FDA) (Table 1) [44][45][46][47][48][49][50][51]. Inhibitors of histone deacetylases (HDAC) -such as sodium butyratehave shown to blunt myocardial inflammation (i.e.…”

The roles and mechanisms of epigenetic regulation in pathological myocardial remodeling

“…The repurposed drugs with a possible indirect epigenetic interference, including metformin, statins, sodium glucose transporter inhibitors 2 (SGLT2i), and omega 3 polyunsaturated fatty acids (PUFAs), have been identified by a number of preclinical and clinical experiments as having the cardioprotective effects in cardiac cells (163,192). Specifically, it was reported that metformin could ameliorate cardiac fibrosis (193).…”

“…Statins may also participate in the prevention and treatment of CVDs through histone modifications (195). There are still few randomized trials have been carried out to evaluate whether the potential epigenetic-oriented effects of these non-canonical repurposed drugs, which were not originally developed as epidrugs, were involved in their cardioprotective effects against different clinical phenotypes of heart failure (163).…”