Cardiac Repolarization in Health and Disease.

Abnormal cardiac repolarization is at the basis of life-threatening arrhythmias in various congenital and acquired cardiac diseases. Dysfunction of ion channels involved in repolarization at the cellular level are often the underlying cause of the repolarization abnormality. The expression pattern of the gene encoding the affected ion channel dictates its impact on the shape of the T-wave and duration of the QT interval, thereby setting the stage for both the occurrence of the trigger and the substrate for maintenance of the arrhythmia. Here we discuss how research into the genetic and electrophysiological basis of repolarization has provided us with insights into cardiac repolarization in health and disease and how this in turn may provide the basis for future improved patient-specific management.

Genome-wide association analyses identify new Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility.

Brugada syndrome (BrS) is a cardiac arrhythmia disorder associated with sudden death in young adults. With the exception of SCN5A, encoding the cardiac sodium channel NaV1.5, susceptibility genes remain largely unknown. Here we performed a genome-wide association meta-analysis comprising 2,820 unrelated cases with BrS and 10,001 controls, and identified 21 association signals at 12 loci (10 new). Single nucleotide polymorphism (SNP)-heritability estimates indicate a strong polygenic influence. Polygenic risk score analyses based on the 21 susceptibility variants demonstrate varying cumulative contribution of common risk alleles among different patient subgroups, as well as genetic associations with cardiac electrical traits and disorders in the general population. The predominance of cardiac transcription factor loci indicates that transcriptional regulation is a key feature of BrS pathogenesis. Furthermore, functional studies conducted on MAPRE2, encoding the microtubule plus-end binding protein EB2, point to microtubule-related trafficking effects on NaV1.5 expression as a new underlying molecular mechanism. Taken together, these findings broaden our understanding of the genetic architecture of BrS and provide new insights into its molecular underpinnings.

Sex- and age specific association of new-onset atrial fibrillation with in-hospital mortality in hospitalised COVID-19 patients.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a systemic disease with cardiovascular involvement, including cardiac arrhythmias. Notably, new-onset atrial fibrillation (AF) and atrial flutter (AFL) during hospitalisation in COVID-19 patients has been associated with increased mortality. However, how this risk is impacted by age and sex is still poorly understood. METHODS: For this multicentre cohort study, we extracted demographics, medical history, occurrence of electrical disorders and in-hospital mortality from the large international patient registry CAPACITY-COVID. For each electrical disorder, prevalence during hospitalisation was calculated. Subsequently, we analysed the incremental prognostic effect of developing AF/AFL on in-hospital mortality, using multivariable logistic regression analyses, stratified for sex and age. RESULTS: In total, 5782 patients (64% male; median age 67) were included. Of all patients 11.0% (95% CI 10.2-11.8) experienced AF and 1.6% (95% CI 1.3-1.9) experienced AFL during hospitalisation. Ventricular arrhythmias were rare (<0.8% (95% CI 0.6-1.0)) and a conduction disorder was observed in 6.3% (95% CI 5.7-7.0). An event of AF/AFL appeared to occur more often in patients with pre-existing heart failure. After multivariable adjustment for age and sex, new-onset AF/AFL was significantly associated with a poorer prognosis, exemplified by a two- to three-fold increased risk of in-hospital mortality in males aged 60-72 years, whereas this effect was largely attenuated in older male patients and not observed in female patients. CONCLUSION: In this large COVID-19 cohort, new-onset AF/AFL was associated with increased in-hospital mortality, yet this increased risk was restricted to males aged 60-72 years.

Minor hypertrophic cardiomyopathy genes, major insights into the genetics of cardiomyopathies.

Hypertrophic cardiomyopathy (HCM) was traditionally described as an autosomal dominant Mendelian disease but is now increasingly recognized as having a complex genetic aetiology. Although eight core genes encoding sarcomeric proteins account for >90% of the pathogenic variants in patients with HCM, variants in several additional genes (ACTN2, ALPK3, CSRP3, FHOD3, FLNC, JPH2, KLHL24, PLN and TRIM63), encoding non-sarcomeric proteins with diverse functions, have been shown to be disease-causing in a small number of patients. Genome-wide association studies (GWAS) have identified numerous loci in cardiomyopathy case-control studies and biobank investigations of left ventricular functional traits. Genes associated with Mendelian cardiomyopathy are enriched in the putative causal gene lists at these loci. Intriguingly, many loci are associated with both HCM and dilated cardiomyopathy but with opposite directions of effect on left ventricular traits, highlighting a genetic basis underlying the contrasting pathophysiological effects observed in each condition. This overlap extends to rare Mendelian variants with distinct variant classes in several genes associated with HCM and dilated cardiomyopathy. In this Review, we appraise the complex contribution of the non-sarcomeric, HCM-associated genes to cardiomyopathies across a range of variant classes (from common non-coding variants of individually low effect size to complete gene knockouts), which provides insights into the genetic basis of cardiomyopathies, causal genes at GWAS loci and the application of clinical genetic testing.

Variant Intronic Enhancer Controls SCN10A-short Expression and Heart Conduction.

BACKGROUND: Genetic variants in SCN10A, encoding the neuronal voltage-gated sodium channel NaV1.8, are strongly associated with atrial fibrillation, Brugada syndrome, cardiac conduction velocities, and heart rate. The cardiac function of SCN10A has not been resolved, however, and diverging mechanisms have been proposed. Here, we investigated the cardiac expression of SCN10A and the function of a variant-sensitive intronic enhancer previously linked to the regulation of SCN5A, encoding the major essential cardiac sodium channel NaV1.5. METHODS: The expression of SCN10A was investigated in mouse and human hearts. With the use of CRISPR/Cas9 genome editing, the mouse intronic enhancer was disrupted, and mutant mice were characterized by transcriptomic and electrophysiological analyses. The association of genetic variants at SCN5A-SCN10A enhancer regions and gene expression were evaluated by genome-wide association studies single-nucleotide polymorphism mapping and expression quantitative trait loci analysis. RESULTS: We found that cardiomyocytes of the atria, sinoatrial node, and ventricular conduction system express a short transcript comprising the last 7 exons of the gene (Scn10a-short). Transcription occurs from an intronic enhancer-promoter complex, whereas full-length Scn10a transcript was undetectable in the human and mouse heart. Expression quantitative trait loci analysis revealed that the genetic variants in linkage disequilibrium with genetic variant rs6801957 in the intronic enhancer associate with SCN10A transcript levels in the heart. Genetic modification of the enhancer in the mouse genome led to reduced cardiac Scn10a-short expression in atria and ventricles, reduced cardiac sodium current in atrial cardiomyocytes, atrial conduction slowing and arrhythmia, whereas the expression of Scn5a, the presumed enhancer target gene, remained unaffected. In patch-clamp transfection experiments, expression of Scn10a-short-encoded NaV1.8-short increased NaV1.5-mediated sodium current. We propose that noncoding genetic variation modulates transcriptional regulation of Scn10a-short in cardiomyocytes that impacts NaV1.5-mediated sodium current and heart rhythm. CONCLUSIONS: Genetic variants in and around SCN10A modulate enhancer function and expression of a cardiac-specific SCN10A-short transcript. We propose that noncoding genetic variation modulates transcriptional regulation of a functional C-terminal portion of NaV1.8 in cardiomyocytes that impacts on NaV1.5 function, cardiac conduction velocities, and arrhythmia susceptibility.

High heart rate associated early repolarization causes J-waves in both zebra finch and mouse.

High heart rates are a feature of small endothermic-or warm-blooded-mammals and birds. In small mammals, the QT interval is short, and local ventricular recordings reveal early repolarization that coincides with the J-wave on the ECG, a positive deflection following the QRS complex. Early repolarization contributes to short QT-intervals thereby enabling brief cardiac cycles and high heart rates. We therefore hypothesized high hearts rates associate with early repolarization and J-waves on the ECG of endothermic birds. We tested this hypothesis by comparing isolated hearts of zebra finches and mice and recorded pseudo-ECGs and optical action potentials (zebra finch, n = 8; mouse, n = 8). In both species, heart rate exceeded 300 beats per min, and total ventricular activation was fast (QRS < 10 ms). Ventricular activation progressed from the left to the right ventricle in zebra finch, whereas it progressed from apex-to-base in mouse. In both species, the early repolarization front followed the activation front, causing a positive J-wave in the pseudo-ECG. Inhibition of early repolarization by 4-aminopyridine reduced J-wave amplitude in both species. Action potential duration was similar between ventricles in zebra finch, whereas in mouse the left ventricular action potential was longer. Accordingly, late repolarization had opposite directions in zebra finch (left-right) and mouse (right-left). This caused a similar direction for the zebra finch J-wave and T-wave, whereas in the mouse they were discordant. Our findings demonstrate that early repolarization and the associated J-wave may have evolved by convergence in association with high heart rates.

Prophylactic (hydroxy)chloroquine in COVID-19: Potential relevance for cardiac arrhythmia risk.

(Hydroxy)chloroquine ((H)CQ) is being investigated as a treatment for COVID-19, but studies have so far demonstrated either no or a small benefit. However, these studies have been mostly performed in patients admitted to the hospital and hence likely already (severely) affected. Another suggested approach uses prophylactic (H)CQ treatment aimed at preventing either severe acute respiratory syndrome coronavirus 2 infection or the development of disease. A substantial number of clinical trials are planned or underway aimed at assessing the prophylactic benefit of (H)CQ. However, (H)CQ may lead to QT prolongation and potentially induce life-threatening arrhythmias. This may be of particular relevance to patients with preexisting cardiovascular disease and those taking other QT-prolonging drugs. In addition, it is known that a certain percentage of the population carries genetic variant(s) that reduces their repolarization reserve, predisposing them to (H)CQ-induced QT prolongation, and this may be more relevant to female patients who already have a longer QT interval to start with. This review provides an overview of the current evidence on (H)CQ therapy in patients with COVID-19 and discusses different strategies for prophylactic (H)CQ therapy (ie, preinfection, postexposure, and postinfection). In particular, the potential cardiac effects, including QT prolongation and arrhythmias, will be addressed. Based on these insights, recommendations will be presented as to which preventive measures should be taken when giving (H)CQ prophylactically, including electrocardiographic monitoring.

Epidemiology of inherited arrhythmias.

The primary electrical disorders are a group of inherited cardiac ventricular arrhythmias that are a major cause of sudden cardiac death in young individuals. Inherited ventricular arrhythmias result from mutations in genes encoding cardiac ion channels or their modulatory subunits. Advances in genetic screening in the past three decades have led to the assembly of large patient cohorts with these disorders. Studies in these patients, as well as in the general population, have striven to define the prevalence of these inherited arrhythmias and the characteristics of patients with different genetic subtypes of the disease. In this Review, we provide a comprehensive update on the epidemiology of inherited ventricular arrhythmias, focusing on natural history, prevalence and patient demographics. In addition, we summarize the various founder populations (groups of individuals with a disease that is caused by a genetic defect inherited from a common ancestor) that have been identified for some of these disorders and which lead to increased prevalence in some geographical regions. To date, although numerous studies have markedly increased our understanding of the epidemiology of these disorders, demographic data, especially from non-Western countries, remain scarce. Furthermore, defining the true prevalence of these disorders remains challenging. International collaboration will undoubtedly accelerate the collection of demographic information and improve the accuracy of prevalence data.