StemCell Therapy

Introduction

Although novel drugs have successfully entered the clinical arena of heart failure with reduced ejection fraction (HFrEF), such as the PARADIGM-HF-derived angiotensin receptor neprilysin inhibitor (ARNI), disease-modifying therapies with a prognostic impact for patients affected by heart failure with preserved ejection fraction (HFpEF) are still lacking.15 HF is a complex and highly prevalent syndrome for which the heart undergoes a substantial structural remodeling in patients at risk for major cardiovascular diseases (CVDs) (Figure 1).16 Geneenvironment interactions can be mediated by specific patterns of epigenetic-sensitive changes (mainly DNA methylation and histone modifications) which may modulate the individual responsiveness to HF development.614 This complex molecular circuit seems to trigger early cardiomyocyte loss, cardiac-remodeling, and micro- and macrovascular damage contributing to the development of major CVDs which may lead to differential HF clinical phenotypes.614 Of note, the reversible nature of epigenetic-sensitive changes has been translated in the clinical management of specific hematological malignancies with the approval by the Food and Drug Administration (FDA) of some epidrugs, such as decitabine (Dacogen) and azacitidine (Vidaza), as DNA methylation inhibitors, as well as vorinostat (Zolinza), belinostat (Beleodaq), romidepsin (Istodax), and panobinostat (Farydak), as histone deacetylase inhibitors (HDACi).15 Epidrugs are now providing a novel vision for personalized therapy of HF and heart transplantation, opening up novel options for management of the affected patients.1518 At molecular level, we can classify the epidrugs in: direct epidrugs [eg, the bromodomain and extra-terminal (BET) protein inhibitor apabetalone]; and repurposed drugs with potential, indirect (non-classical) epigenetic-oriented interference by which they may exert cardioprotective functions [eg, hydralazine, metformin, statins, and sodium-glucose co-transporter-2 inhibitors (SGLT2i)] or nutraceutical compounds [eg, omega-3 polyunsaturated fatty acids (PUFAs)]. Encouraging results are coming from large randomized trials evaluating the putative beneficial effects of combining epidrugs with the conventional therapy in patients with HF.1422 Our goal is to update on the emerging epigenetic-based strategies which may be useful in the prevention and treatment of HFrEF and HFpEF (Figure 1).

Figure 1 The possible role of epitherapy in the current framework of HFrEF and HFpEF management. The unstable transition state from the ACC/AHA Stage A/B to Stage C/D-Acute/Hospitalized HF is the key point in the treatment of HFrEF and HFpEF. The epitherapy, mainly apabetalone, statins, metformin, SGLT2i, and PUFAs in addition to the standard of the care may improve personalized therapy of affected patients.

Abbreviations: HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; SGLT2i, sodium glucose co-transporter 2 inhibitors; PUFAs, polyunsaturated fatty acids.

The bromodomain and extra terminal domain (BET) proteins, including the ubiquitous BRD2, BRD3, BRD4, and the testis-restricted BRDT, are epigenetic readers (via bromodomains) existing in the form of nuclear multidomain docking platforms which control the cell-specific activation of gene expression profiles.23 Experimental data demonstrated that BETs regulate vascular cells, cardiac myocytes, and inflammatory cells,24 and their activity may be extended to the regulation of calcification, thrombosis, as well as lipid and lipoprotein metabolism, all of which participate in atherogenesis.2527 In particular, BRD4 facilitated the expression of multiple proinflammatory and proatherosclerotic targets involved in thrombosis, leukocyte adhesion, and endothelial barrier function, thus identifying BRD4 as a possible therapeutic target in CVD setting.24 The quinazolone (RVX-208), known as apabetalone, is a derivative of the plant polyphenol resveratrol. Apabetalone acts as a direct epidrug by selectively targeting the BET family member BRD4 to block its interaction with acetylated lysines located in histones.28 Apabetalone-BRD4 binding can impact cholesterol levels and inflammation; in fact, apabetalone stimulates ApoA-I gene expression and increases high-density lipoprotein (HDL).29,30 Besides, apabetalone may attenuate the development of cardiac hypertrophy31 and cardiac fibrosis,32 suggesting novel options for the management of HF.

Resverlogix developed apabetalone (RVX-208), a first-in-class, orally available, small molecule for the treatment of atherosclerosis and associated CVDs.20 BETonMACE (NCT02586155) is the first Phase 3 clinical trial evaluating the cardiovascular efficacy and safety of apabetalone.22 Recent results from the BETonMACE study have demonstrated that apabetalone is associated with a reduction in first HF hospitalization and cardiovascular death in patients with type 2 diabetes and recent acute coronary syndrome as compared to controls (placebo-treated patients).22 Additionally, a significant increase in HDL and a decrease in alkaline phosphatase levels have been observed following 24 weeks of apabetalone treatment as compared to the placebo group.22 However, investigators were unable to make a distinction between HF in the setting of preserved or reduced ejection fraction. Thus, further clinical trials should be designed to evaluate the putative beneficial effects of apabetalone in HFrEF and HFpEF, separately.

Preclinical studies demonstrated that pharmacological HDACi,3336 BET inhibitors,31,37 and DNA methylation inhibitors38 can attenuate cardiac remodeling (cardiomyocyte hypertrophy and fibrosis). Although not originally developed as epidrugs, hydralazine (anti-hypertensive drug), metformin, and SGLT2i (anti-diabetic drugs), statins (anti-dyslipidemic drugs), and PUFAs (nutraceuticals) might have downstream epigenetic-oriented effects in cardiac cells. Hydralazine, for example, lowers blood pressure by a direct relaxation of vascular smooth muscle; additionally, it may reduce DNA methylation and improve cardiac function through increasing sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) and modulating calcium homeostasis in cardiomyocytes.39 Statins are used as a first-line treatment to decrease serum cholesterol levels in dyslipidemic patients and as primary and secondary prophylaxis against atherosclerosis and associated CVDs.6 Many of their non-classical pleiotropic properties relevant for endothelial health are mediated by epigenetic mechanisms which improve blood flow, decrease LDL oxidation, enhance atherosclerotic plaque stability and decrease proliferation of vascular smooth muscle cells and platelet aggregation.6 Metformin is a first-line drug in the treatment of overweight and obese type 2 diabetic patients.10 Mechanistically, metformin may also have epigenetic-oriented effects through activating the AMP-activated protein kinase (AMPK) which, in turn, can phosphorylate and inhibit epigenetic enzymes such as histone acetyltransferases (HATs), class II HDAC, and DNA methyltransferases (DNMTs).40 Both metformin41,42 and statins43,44 may reduce cardiac fibrosis; however, whether their beneficial effects are mediated by epigenetic-oriented responses has yet to be demonstrated. Furthermore, SGLT2i are a new group of oral drugs used for treating type 2 diabetes and its cardiovascular/renal complications.45 Animal models have demonstrated that empagliflozin46,47 and dapagliflozin48 may improve hemodynamics in HF by increasing renal protection and cardiac fibrosis. Interestingly, inflammation and glucotoxicity (AGE/RAGE signaling) were epigenetically prevented by empagliflozin;49 this observation has provided insights about mechanisms by which SGLT2i can reduce cardiovascular mortality in man (EMPA-REG trial).50

An effective therapy for HFpEF has yet to be established. Hydralazine is frequently used in HFrEF, and represents a potential DNA methylation inhibitor.39 DNA methylation is the most studied direct epigenetic change with potential clinical implications in major CVDs and the development of HF.7,14 This epigenetic signature mainly involves methylation of CpG islands in the gene promoters leading to a specific long-term silencing of gene expression.7,14 A completed Phase 2 clinical trial (NCT01516346) evaluated the effect of prolonged therapy (24 weeks) with isosorbide dinitrate (ISDN) hydralazine on arterial wave reflections (primary endpoint) as well as left ventricular (LV) mass, fibrosis and diastolic function, and exercise capacity (6-minute walk test) in patients with HFpEF, New York Heart Association (NYHA) Class IIIV symptoms, and standard therapy as defined by ACEi, ARB, beta-blockers, or calcium channel blockers (CCBs).51 Results from this trial reported that ISDN, with or without hydralazine, had deleterious effects on reflection magnitude, LV remodeling, or submaximal exercise thus not supporting their routine use in patients with HFpEF.51

Metformin has been associated with a reduced mortality in patients with HFpEF, even if female gender was associated with worse outcomes.52 Recently, it has been observed that a long-term treatment with metformin can improve LV diastolic function and hypertrophy, decrease the incidence of new-onset HFpEF, and delay disease progression in patients with type 2 diabetes and hypertension.53 Besides, a prospective phase 2 clinical trial (NCT03629340) is testing the therapeutic efficacy of metformin in patients with pulmonary hypertension and HFpEF by evaluating exercise hemodynamics, functional capacity, skeletal muscle signaling, and insulin sensitivity. However, results have not been published. A recent study based on the JASPER registry, a multicenter, observational, prospective cohort of Japanese patients aged 20 years requiring hospitalization for acute HFpEF has reported that the use of statins could reduce mortality in affected patients without coronary heart disease.54 Furthermore, the use of statins was associated with improved clinical outcomes in patients with HFpEF but not in patients with HFrEF (or mid-range ejection fraction).55 A reduced rate of major adverse cardiac events, cardiovascular death and all-cause mortality was associated with SGLT2i treatment in both HFpEF and HFrEF patients as compared to placebo.56,57 However, the observed cardiovascular and renal benefits cannot be fully explained by improvement in risk factors (such as glycemia, blood pressure or dyslipidemias) suggesting that other molecular mechanisms may explain the cardiovascular benefits.56 Interestingly, the SGLT2i-related epigenetic interference may arise from their ability to increase the circulating and tissue levels of -hydroxybutyrate, a specific molecule able to generate a pattern of histone modifications (known as -hydroxybutyrylation) which are associated with the beneficial effects of fasting.58 Besides, the DELIVER (NCT03619213) multicenter, randomized, double-blind, placebo-controlled study of 6263 HFpEF patients will evaluate the effect of dapagliflozin 10 mg (1 per day) as compared to placebo in addition to the standard of care in order to reduce the composite of cardiovascular death or HF events. However, results have not yet been published.

The use of metformin has been generally considered a contraindication in HFrEF patients owing the potential risk of lactic acidosis; however, recent evidence has reported that metformin can provide beneficial effects in reducing the risk of incident HF and mortality in diabetic patients.5961 A completed, observational clinical trial (NCT03546062) has recently performed the evaluation of seriated cardiac biopsies from healthy implanted hearts in type 2 diabetes recipients during 12-month follow-up upon heart transplantation.21 Even if the intra-cardiomyocyte lipid accumulation in type 2 diabetes recipients may start in the early stages after heart transplantation, metformin therapy could reduce lipid accumulation independently of immunosuppressive therapy.21 The DANHEART trial (NCT03514108), a multicenter, randomized, double-blind, placebo-controlled study in 1500 patients with HFrEF will evaluate: 1) whether hydralazine-isosorbide dinitrate as compared to placebo may reduce the incidence of death and HF hospitalization, and 2) if metformin as compared to placebo may reduce the incidence of death, worsening of HF, acute myocardial infarction, and stroke in patients with diabetes or prediabetes. Two large randomized trials demonstrated that statins did not have beneficial effects in management of patients with HFrEF.62,63 Specifically, the CORONA phase 3 trial randomized more than 5000 patients with ischemic HFrEF to rosuvastatin as compared to placebo resulting in no benefits on the primary endpoints, as death from cardiovascular causes, nonfatal myocardial infarction, and nonfatal stroke.62 According to CORONA trial, the GISSI-HF study randomized almost 5000 patients with clinically apparent HF of any cause to rosuvastatin as compared to placebo and observed no benefits on the primary endpoints, as all-cause death or cardiovascular hospitalization.63 However, it is needed to highlight that both trials demonstrated that statins are safe in HF patients. In contrast with the previous evidence, the trial based on the Swedish Heart Failure Registry (21,864 patients with HFrEF, of whom 10,345 were treated with statins) reported an association between the use of statins and improved outcomes, as all-cause mortality, cardiovascular mortality, HF hospitalization, and combined all-cause mortality or cardiovascular hospitalization, especially in patients with ischemic HF.64 Thus, further randomized controlled trials focused on ischemic HF may be warranted. Omega-3 polyunsaturated fatty acids (PUFAs), mainly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are key players in modulating inflammatory process by limiting leucocyte chemotaxis, adhesion molecule expression, leucocyte-endothelium interaction as well as T cell reactivity.65 EPA and DHA are mainly gained from marine food consumption and large population-based studies have shown that Mediterranean diet with PUFA supplementation may aid to prevent CVDs owing to their ability in promoting the release of nitric oxide from endothelial cells and decreasing serum levels of triglycerides.66 Recent evidence has indicated that PUFAs can significantly affect the cellular epigenome mainly thought DNA methylation-sensitive mechanisms.67,68 The GISSI multicenter, double-blind trial enrolled 6975 HF patients (New York Heart Association class IIIV, irrespective of cause and LV ejection fraction) and randomized them to low dose (0.84 g per day) of PUFAs as compared to placebo. PUFAs supplementation reduced risk for total mortality and HF hospitalization when added to standard therapy.19 Furthermore, in the OMEGA-REMODEL trial, high-dose of PUFAs (3.4 g per day) for 6 months post-myocardial infarction reduced infarct size and non-infarct myocardial fibrosis as well as improved ventricular systolic function.69 Taken together, these results suggest that PUFAs may aid to prevent HFrEF. More recently, the MESA longitudinal trial including 6562 participants 45 to 84 years has demonstrated that higher plasma levels of EPA were significantly associated with reduced risk both in HFpEF and HFrEF.70

Although the possibility of improving the HF standard of care with epidrugs is still in its infancy, the BETonMACE study has provided promising results about the use of apabetalone in reducing hospitalization and cardiovascular death. Preclinical models of cardiac remodeling demonstrated that metformin, statins, SGLT2i, and PUFAs4148 can improve vascular health and cardiac fibrosis by modulating specific molecular pathways, and, in part, through downstream epigenetic interference, especially for hydralazine39 and empagliflozin (Figure 2).49 Of note, metformin and SGLT2i can impact on the epigenetic memory phenomenon. This latter suggests that an early glycemia normalization can arrest hyperglycemia-induced epigenetic processes associated with enhanced oxidative stress and glycation of cellular proteins and lipids.71,72 In parallel, an increasing number of clinical trials is evaluating the putative beneficial repurposing of metformin, statins, SGLT2i, and PUFAs in patients with HFpEF and/or HFrEF;19,6264,69,7375 however, despite experimental evidence, none of these trials evaluated their potential epigenetic effects involved in improving the cardiac function. This gap should be overcome to improve personalized therapy of patients with HF. Thus, further randomized trials are needed to clarify whether apabetalone, as well as non-canonical repurposed epidrugs, will really be able to save failing hearts in different HF clinical phenotypes or prevent irreversible damages in high-risk patients. In this context, Network Medicine approaches may help to evaluate a possible repurposing of epidrugs in patients with major CVDs.15,76,77

Figure 2 Direct and indirect epigenetic drugs in preclinical models of HF. Cardiac remodeling includes different pathological phenotypes and each type of drug can selectively improve inflammation, cardiac fibrosis and hypertrophy, calcium homeostasis, and lipid metabolism.

Abbreviations: HF, heart failure; SGLT2i, sodium glucose co-transporter 2 inhibitors.

This work was supported by PRIN2017F8ZB89 from Italian Ministry of University and Research (MIUR) (PI Prof Napoli) and Ricerca Corrente (RC) 2019 from Italian Ministry of Health (PI Prof. Napoli).

The authors report no conflicts of interest in this work.

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