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Key Points The myocardium adapts to continued stress—either physiological or pathological—by modulating gene expression in its constituent cells Methylation of cytosine and post-translational chemical alteration of histones—known as epigenetic modification—render regulatory elements of genes more or less permissive to interaction with the transcriptional machinery These alterations create an epigenetic landscape, or 'epigenome', that is probably specific to a particular physiological or pathological state A plethora of noncoding RNAs, such as microRNAs and long noncoding RNAs, is centrally involved in the regulation of probably all biological processes, including gene expression Epigenetic modifications and noncoding RNAs form an integrated and highly complex regulatory network to control gene expression; heart failure is associated with disruption of this network The reversibility of epigenetic modifications and the relative ease with which noncoding RNAs can be manipulated augur well for the development of much-needed novel pharmaceuticals for treatment of heart failure Cardiomyocyte function is regulated by epigenetic modifications (to cytosine residues on DNA, and post-translational acetylation or methylation of histones), as well as by noncoding RNAs (such as microRNAs and long noncoding RNAs). In this Review, Greco and Condorelli describe the complex roles of these two layers of gene-expression regulation in the pathogenesis of cardiac hypertrophy and failure. The regulatory networks governing gene expression in cardiomyocytes are under intense investigation, not least because dysregulation of the gene programme has a fundamental role in the development of a failing myocardium. Epigenetic modifications and functional non-protein-coding RNAs (ncRNAs) are important contributors to this process. The epigenetic modifications that regulate transcription comprise post-translational changes to histones—the proteins around which DNA is wound—as well as modifications to cytosine residues on DNA. The most studied of the histone changes are acetylation and methylation. Histone acetylation is known to be important in cardiac physiology and pathophysiology, but the roles of other histone modifications and of cytosine methylation are only starting to be investigated. Understanding of the role of microRNAs has also seen major advancements, but the function of long ncRNAs is less well defined. Moreover, the connection between ncRNAs and epigenetic modifications is poorly understood in the heart. In this Review, we summarize new insights into how these two layers of gene-expression regulation might be involved in the pathogenesis of cardiac hypertrophy and failure, and how we are only beginning to appreciate the complexity of the interactive network of which they are part.

Mutations in LMNA , which encodes the nuclear proteins Lamin A/C, can cause cardiomyopathy and conduction disorders. Here, we employ induced pluripotent stem cells (iPSCs) generated from human cells carrying heterozygous K219T mutation on LMNA to develop a disease model. Cardiomyocytes differentiated from these iPSCs, and which thus carry K219T- LMNA , have altered action potential, reduced peak sodium current and diminished conduction velocity. Moreover, they have significantly downregulated Na v 1.5 channel expression and increased binding of Lamin A/C to the promoter of SCN5A , the channel’s gene. Coherently, binding of the Polycomb Repressive Complex 2 (PRC2) protein SUZ12 and deposition of the repressive histone mark H3K27me3 are increased at SCN5A . CRISPR/Cas9-mediated correction of the mutation re-establishes sodium current density and SCN5A expression. Thus, K219T- LMNA cooperates with PRC2 in downregulating SCN5A , leading to decreased sodium current density and slower conduction velocity. This mechanism may underlie the conduction abnormalities associated with LMNA-cardiomyopathy. Mutation of LMNA , encoding Lamin A/C nuclear proteins, cause dilated cardiomyopathy and conduction disorders. Here, the authors show that patient-specific iPSC-derived CMs carrying the K219T LMNA mutation have downregulated Na v 1.5 channels due to dynamic cooperation of Lamin A/C and Polycomb repressor complex 2 at the SCN5A promoter.

Novel coronavirus disease 2019 (COVID-19) is associated with a hypercoagulable state, characterized by abnormal coagulation parameters and by increased incidence of cardiovascular complications. With this study, we aimed to investigate the activation state and the expression of transmembrane proteins in platelets of hospitalized COVID-19 patients. We investigated transmembrane proteins expression with a customized mass cytometry panel of 21 antibodies. Platelets of 8 hospitalized COVID-19 patients not requiring intensive care support and without pre-existing conditions were compared to platelets of healthy controls (11 donors) with and without in vitro stimulation with thrombin receptor-activating peptide (TRAP). Mass cytometry of non-stimulated platelets detected an increased surface expression of activation markers P-Selectin (0.67 vs. 1.87 median signal intensity for controls vs. patients, p  = 0.0015) and LAMP-3 (CD63, 0.37 vs. 0.81, p  = 0.0004), the GPIIb/IIIa complex (4.58 vs. 5.03, p  < 0.0001) and other adhesion molecules involved in platelet activation and platelet–leukocyte interactions. Upon TRAP stimulation, mass cytometry detected a higher expression of P-selectin in COVID-19 samples compared to controls ( p  < 0.0001). However, we observed a significantly reduced capacity of COVID-19 platelets to increase the expression of activation markers LAMP-3 and P-Selectin upon stimulation with TRAP. We detected a hyperactivated phenotype in platelets during SARS-CoV-2 infection, consisting of highly expressed platelet activation markers, which might contribute to the hypercoagulopathy observed in COVID-19. In addition, several transmembrane proteins were more highly expressed compared to healthy controls. These findings support research projects investigating antithrombotic and antiplatelet treatment regimes in COVID-19 patients, and provide new insights on the phenotypical platelet expression during SARS-CoV-2 infection.

The bidirectional link between heart and brain has intrigued scientists for ages, but little is known on the underlying mechanism. In their recent study, Fischer and colleagues (Islam et al , 2021) propose a mechanism by which heart failure‐induced cognitive decline is linked to epigenetic changes that affect gene expression in neurons of hippocampus. Graphical Abstract The bidirectional link between heart and brain has intrigued scientists for ages, but little is known on the underlying mechanism. G. Condorelli and M. Matteoli highlight an epigenetic mechanism that may explain the heart‐failure induced cognitive decline (Islam et al , this issue of EMBO Mol Med ).

Adult vascular smooth muscle cells (VSMCs) dedifferentiate in response to extracellular cues such as vascular damage and inflammation. Dedifferentiated VSMCs are proliferative, migratory, less contractile, and can contribute to vascular repair as well as to cardiovascular pathologies such as intimal hyperplasia/restenosis in coronary artery and arterial aneurysm. We here demonstrate the role of ubiquitin-like containing PHD and RING finger domains 1 (UHRF1) as an epigenetic master regulator of VSMC plasticity. UHRF1 expression correlated with the development of vascular pathologies associated with modulation of noncoding RNAs, such as microRNAs. miR-145 - pivotal in regulating VSMC plasticity, which is reduced in vascular diseases - was found to control Uhrf1 mRNA translation. In turn, UHRF1 triggered VSMC proliferation, directly repressing promoters of cell-cycle inhibitor genes (including p21 and p27) and key prodifferentiation genes via the methylation of DNA and histones. Local vascular viral delivery of Uhrf1 shRNAs or Uhrf1 VSMC-specific deletion prevented intimal hyperplasia in mouse carotid artery and decreased vessel damage in a mouse model of aortic aneurysm. Our study demonstrates the fundamental role of Uhrf1 in regulating VSMC phenotype by promoting proliferation and dedifferentiation. UHRF1 targeting may hold therapeutic potential in vascular pathologies.

Methylation at 5-cytosine (5-mC) is a fundamental epigenetic DNA modification associated recently with cardiac disease. In contrast, the role of 5-hydroxymethylcytosine (5-hmC)—5-mC’s oxidation product—in cardiac biology and disease is unknown. Here we assess the hydroxymethylome in embryonic, neonatal, adult and hypertrophic mouse cardiomyocytes, showing that dynamic modulation of hydroxymethylated DNA is associated with specific transcriptional networks during heart development and failure. DNA hydroxymethylation marks the body of highly expressed genes as well as distal regulatory regions with enhanced activity. Moreover, pathological hypertrophy is characterized by a shift towards a neonatal 5-hmC distribution pattern. We also show that the ten-eleven translocation 2 (TET2) enzyme regulates the expression of key cardiac genes, such as Myh7 , through 5-hmC deposition on the gene body and at enhancers. Thus, we provide a genome-wide analysis of 5-hmC in the cardiomyocyte and suggest a role for this epigenetic modification in heart development and disease. 5-hydroxymethylation of cysteine (5-hmC) plays a role in epigenetic regulation. Here the authors analyse the hydroxymethylome in embryonic, neonatal, adult and hypertrophic mouse cardiomyocytes and show that the dynamic modulation of hydroxymethylated DNA is important for cardiomyocyte gene expression programming in heart development and failure.

Heart failure (HF) is a leading cause of mortality. Inflammation is implicated in HF, yet clinical trials targeting pro-inflammatory cytokines in HF were unsuccessful, possibly due to redundant functions of individual cytokines. Searching for better cardiac inflammation targets, here we link T cells with HF development in a mouse model of pathological cardiac hypertrophy and in human HF patients. T cell costimulation blockade, through FDA-approved rheumatoid arthritis drug abatacept, leads to highly significant delay in progression and decreased severity of cardiac dysfunction in the mouse HF model. The therapeutic effect occurs via inhibition of activation and cardiac infiltration of T cells and macrophages, leading to reduced cardiomyocyte death. Abatacept treatment also induces production of anti-inflammatory cytokine interleukin-10 (IL-10). IL-10-deficient mice are refractive to treatment, while protection could be rescued by transfer of IL-10-sufficient B cells. These results suggest that T cell costimulation blockade might be therapeutically exploited to treat HF. Abatacept is an FDA-approved drug used for treatment of rheumatoid arthritis. Here the authors show that abatacept reduces cardiomyocyte death in a mouse model of heart failure by inhibiting activation and heart infiltration of T cells and macrophages, an effect mediated by IL-10, suggesting a potential therapy for heart failure.

Hutchinson–Gilford progeria syndrome (HGPS) is a rare pathology caused by a specific mutation ( c .1824C>T; p .G608G) in the LMNA gene (Eriksson et al , 2003 ). In healthy conditions, LMNA encodes lamins A and C, two major structural nuclear proteins. The mutation creates a splice site in exon 11, resulting in ubiquitous expression of progerin, an aberrant lamin A precursor. Mutations of LMNA can cause laminopathies, a group of diseases with a wide spectrum of, often overlapping, tissue‐specific phenotypes. HGPS is probably one of the most devastating forms of laminopathy. Affected patients display signs of accelerated aging, such as lack of subcutaneous fat, hair loss, joint contractures, and skin thinning, and usually die prematurely from cardiovascular complications. Atherosclerosis is one of the most severe and clinically relevant features of HGPS, manifesting in the absence of classical risk factors, such as increased low‐density lipoprotein and C‐reactive protein (Gordon et al , 2005 ). In this issue, Hamczyk et al ( 2019 ) describe a mechanism for HGPS‐related atherosclerosis. Graphical Abstract G. Condorelli and E. Di Pasquale highlight the work of Hamczyk et al (in this issue of EMBO Molecular Medicine ) describing a mechanism for Hutchinson Gilford Progeria Syndrome (HGPS)‐related atherosclerosis, one of the most severe and clinically relevant features of HGPS.

Myocardial infarction causes 7.3 million deaths worldwide, mostly for fibrillation that electrically originates from the damaged areas of the left ventricle. Conventional cardiac bypass graft and percutaneous coronary interventions allow reperfusion of the downstream tissue but do not counteract the bioelectrical alteration originated from the infarct area. Genetic, cellular, and tissue engineering therapies are promising avenues but require days/months for permitting proper functional tissue regeneration. Here we engineered biocompatible silicon carbide semiconductive nanowires that synthetically couple, via membrane nanobridge formations, isolated beating cardiomyocytes over distance, restoring physiological cell-cell conductance, thereby permitting the synchronization of bioelectrical activity in otherwise uncoupled cells. Local in-situ multiple injections of nanowires in the left ventricular infarcted regions allow rapid reinstatement of impulse propagation across damaged areas and recover electrogram parameters and conduction velocity. Here we propose this nanomedical intervention as a strategy for reducing ventricular arrhythmia after acute myocardial infarction. Silicon-based materials have the ability to support bioelectrical activity. Here the authors show how injectable silicon carbide nanowires reduce arrhythmias and rapidly restore conduction in a myocardial infarction model.

Aerobic fitness, measured as maximal oxygen uptake (VO2max), is a good indicator of cardiovascular health, and a strong predictor of cardiovascular mortality. Biomarkers associated with low VO2max may therefore represent potential early markers of future cardiovascular disease (CVD). The aim of this study was to assess whether circulating microRNAs (miRs) are associated with VO2max-level in healthy individuals. In a screening study, 720 miRs were measured in serum samples from healthy individuals (40-45 yrs) with high (n = 12) or low (n = 12) VO2max matched for gender, age and physical activity. Candiate miRs were validated in a second cohort of subjects with high (n = 38) or low (n = 38) VO2max. miR-210 and miR-222 were found to be higher in the low VO2max-group (p<0.05). In addition, miR-21 was increased in male participants with low VO2max (p<0.05). There were no correlations between traditional risk factors for CVD (blood pressure, cholesterol, smoking habit, or obesity) and miR-21, miR-210 and miR-222. DIANA-mirPath identified 611 potential gene-targets of miR-21, miR-210 and miR-222, and pathway analysis indicated alterations in several important signaling systems in subjects with low VO2max. Potential bias involve that blood was collected from non-fasting individuals, and that 8 performed exercise within 24 h before sampling. In conclusion, we found that miR-210, miR-21, and miR-222 were increased in healthy subjects with low VO2max. The lack of association between these three miRs, and other fitness related variables as well as traditional CVD risk factors, suggests that these miRs may have a potential as new independent biomarkers of fitness level and future CVD.