Genetics and Epigenetics of Arrhythmia and Heart Failure

Heart failure (HF) is the end stage of several pathological cardiac conditions including myocardial infarction, cardiac hypertrophy and hypertension. Various molecular and cellular mechanisms are involved in the development of HF. At the molecular level, the onset of HF is associated with reprogramming of gene expression, including downregulation of the alpha-myosin heavy chain (α-MHC) gene and sarcoplasmic reticulum Ca2+ ATPase genes and reactivation of specific fetal cardiac genes such as atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP). These deviations in gene expression result in structural and electrophysiological changes, which eventually progress to HF. Cardiac arrhythmia is caused by altered conduction properties of the heart, which may arise in response to ischemia, inflammation, fibrosis, aging or from genetic factors. Because changes in the gene transcription program may have crucial consequences as deteriorated cardiac function, understanding the molecular mechanisms involved in the process has become a priority in the field. In this context, various studies besides having identified different DNA methylation patterns in HF patients, have also focused on specific disease processes and their underlying mechanisms, also introducing new concepts such as epigenomics. This review highlights specific genetic mutations associated to the onset and progression of HF, also providing an introduction to epigenetic mechanisms such as histone modifications, DNA methylation and RNA-based modification, and highlights the relation between epigenetics, arrhythmogenesis and HF

Adaptive capacity of the right ventricle: why does it fail?

Only in recent years has the right ventricle (RV) function become appreciated to be equally important to the left ventricle (LV) function to maintain cardiac output. Right ventricular failure is, irrespectively of the etiology, associated with impaired exercise tolerance and poor survival. Since the anatomy and physiology of the RV is distinctly different than that of the LV, its adaptive mechanisms and the pathways involved are different as well. RV hypertrophy is an important mechanism of the RV to preserve cardiac output. This review summarizes the current knowledge on the right ventricle and its response to pathologic situations. We will focus on the adaptive capacity of the right ventricle and the molecular pathways involved, and we will discuss potential therapeutic interventions

miR-199b-5p is a regulator of left ventricular remodeling following myocardial infarction

Myocardial infarction (MI), the globally leading cause of heart failure, morbidity and mortality, involves post-MI ventricular remodeling, a complex process including acute injury healing, scar formation and global changes in the surviving myocardium. The molecular mechanisms involved in adverse post-infarct left ventricular remodeling still remain poorly defined. Recently, microRNAs have been implicated in the development and progression of various cardiac diseases as crucial regulators of gene expression. We previously demonstrated that in a murine model of pressure overload, a model of heart failure secondary to aortic stenosis or chronic high blood pressure, elevated myocardial expression of miR-199b-5p is sufficient to activate calcineurin/NFAT signaling, leading to exaggerated cardiac pathological remodeling and dysfunction. Given the differences in left ventricular remodeling secondary to post-infarct healing and pressure overload, we evaluated miR-199b function in post-MI remodeling. We confirmed that the expression of miR-199b is elevated in the post-infarcted heart. Transgenic animals with cardiomyocyte-restricted overexpression of miR-199b-5p displayed exaggerated pathological remodeling after MI, reflected by severe systolic and diastolic dysfunction and fibrosis deposition. Conversely, therapeutic silencing of miR-199b-5p in MI-induced cardiac remodeling by using an antagomir to specifically inhibit endogenous miR-199b-5p in vivo, resulted in efficient suppression of cardiac miR-199b-5p expression and attenuated cardiac dysfunction and dilation following MI. Mechanistically, miR-199b-5p influenced the expression of three predicted target genes in post-infarcted hearts, dual specificity tyrosine-phosphorylation-regulated kinase 1A (Dyrk1a), the notch1 receptor and its ligand jagged1. In conclusion, here we provide evidence supporting that stress-induced miR-199b-5p participates in post-infarct remodeling by simultaneous regulation of distinct target genes

miR-199b-5p is a regulator of left ventricular remodeling following myocardial infarction

Myocardial infarction (MI), the globally leading cause of heart failure, morbidity and mortality, involves post-MI ventricular remodeling, a complex process including acute injury healing, scar formation and global changes in the surviving myocardium. The molecular mechanisms involved in adverse post-infarct left ventricular remodeling still remain poorly defined. Recently, microRNAs have been implicated in the development and progression of various cardiac diseases as crucial regulators of gene expression. We previously demonstrated that in a murine model of pressure overload, a model of heart failure secondary to aortic stenosis or chronic high blood pressure, elevated myocardial expression of miR-199b-5p is sufficient to activate calcineurin/NFAT signaling, leading to exaggerated cardiac pathological remodeling and dysfunction. Given the differences in left ventricular remodeling secondary to post-infarct healing and pressure overload, we evaluated miR-199b function in post-MI remodeling. We confirmed that the expression of miR-199b is elevated in the post-infarcted heart. Transgenic animals with cardiomyocyte-restricted overexpression of miR-199b-5p displayed exaggerated pathological remodeling after MI, reflected by severe systolic and diastolic dysfunction and fibrosis deposition. Conversely, therapeutic silencing of miR-199b-5p in MI-induced cardiac remodeling by using an antagomir to specifically inhibit endogenous miR-199b-5p in vivo, resulted in efficient suppression of cardiac miR-199b-5p expression and attenuated cardiac dysfunction and dilation following MI. Mechanistically, miR-199b-5p influenced the expression of three predicted target genes in post-infarcted hearts, dual specificity tyrosine-phosphorylation-regulated kinase 1A (Dyrk1a), the notch1 receptor and its ligand jagged1. In conclusion, here we provide evidence supporting that stress-induced miR-199b-5p participates in post-infarct remodeling by simultaneous regulation of distinct target genes

Chronic hypoxia leads to an increase in Fulton index.

<p>(a) Experimental groups. (b) Study design. (c) Representative images of whole hearts (upper panels), haematoxylin & eosin (H&E) stained 4-chamber paraffin sections (second panels), high magnification H&E stained free right ventricular wall histological sections (third panels), high magnification sirius red stained free right ventricular wall sections (lower panels. The following groups are compared: normoxia on normal chow diet (N/Cu+), normoxia on copper depleted diet (N/Cu-), hypoxia on normal chow diet (H/Cu+) and hypoxia on copper depleted diet (H/Cu-). (d) Heartweight corrected for bodyweight in grams per gram. (n = 9) *P<0.05. (e) Fulton index calculated as ratio of RV free wall weight over septum plus LV free wall weight. (f) Liverweight in grams. (g) Lungweight in grams. (h) Bodyweight in grams. (i) Representative images of wheat germ agglutinin (WGA) stained sections. (j) Quantification of average cell surface area using WGA stained sections. (n≥610) *P<0.05 (mean ± s.e.m.).</p

Chronic hypoxia induces a decrease in right ventricular ejection fraction.

<p>Right ventricular ejection fraction (EF) measured by MRI at 4 and 8 weeks. The following groups are compared: normoxia on normal chow diet (N/Cu+), normoxia on copper depleted diet (N/Cu), hypoxia on normal chow diet (H/Cu+) and hypoxia on copper depleted diet (H/Cu-). (b) Right ventricular end systolic volumes in cm³ and (c) right ventricular end diastolic volumes in cm³. (n = 6) (d) Griffonia simplicifolia 1 (GS-1)-stain on representative right ventricular free wall paraffin sections. (e) Quantification of GS-1 stain, expressed as relative vessel number. (f) Real-time PCR analysis of transcript abundance for cardiac stress marker genes in right ventricles at 8 weeks. (n = 3) *P<0.05 (mean ± s.e.m.).</p

MicroRNA-216a is essential for cardiac angiogenesis

While it is experimentally supported that impaired myocardial vascularization contributes to a mismatch between myocardial oxygen demand and supply, a mechanistic basis for disruption of coordinated tissue growth and angiogenesis in heart failure remains poorly understood. Silencing strategies that impair microRNA biogenesis have firmly implicated microRNAs in the regulation of angiogenesis, and individual microRNAs prove to be crucial in developmental or tumor angiogenesis. A high-throughput functional screening for the analysis of a whole-genome microRNA silencing library with regard to their phenotypic effect on endothelial cell proliferation as a key parameter, revealed several anti- and pro-proliferative microRNAs. Among those was miR-216a, a pro-angiogenic microRNA which is enriched in cardiac microvascular endothelial cells and reduced in expression under cardiac stress conditions. miR-216a null mice display dramatic cardiac phenotypes related to impaired myocardial vascularization and unbalanced autophagy and inflammation, supporting a model where microRNA regulation of microvascularization impacts the cardiac response to stress