In 2003, an Australian woman was convicted by a jury of smothering and killing her four children over a 10-year period. Each child died suddenly and unexpectedly during a sleep period, at ages ranging from 19 days to 18 months. In 2019 we were asked to investigate if a genetic cause could explain the children's deaths as part of an inquiry into the mother's convictions.

The coronavirus disease 2019 (COVID-19) is associated with cardiovascular clinical manifestations, including cardiac arrhythmias.

Use of the 12-lead electrocardiogram (ECG) is fundamental for the assessment of heart disease, including arrhythmias, but cannot always reveal the underlying mechanism or the location of the arrhythmia origin. Electrocardiographic imaging (ECGi) is a non-invasive multi-lead ECG-type imaging tool that enhances conventional 12-lead ECG. Although it is an established technology, its continuous development has been shown to assist in arrhythmic activation mapping and provide insights into the mechanism of cardiac resynchronization therapy (CRT). This review addresses the validity, reliability, and overall feasibility of ECGi for use in a diverse range of arrhythmias. A systematic search limited to full-text human studies published in peer-reviewed journals was performed through Medline via PubMed, using various combinations of three key concepts: ECGi, arrhythmia, and CRT. A total of 456 studies were screened through titles and abstracts. Ultimately, 42 studies were included for literature review. Evidence to date suggests that ECGi can be used to provide diagnostic insights regarding the mechanistic basis of arrhythmias and the location of arrhythmia origin. Furthermore, ECGi can yield valuable information to guide therapeutic decision-making, including during CRT. Several studies have used ECGi as a diagnostic tool for atrial and ventricular arrhythmias. More recently, studies have tested the value of this technique in predicting outcomes of CRT. As a non-invasive method for assessing cardiovascular disease, particularly arrhythmias, ECGi represents a significant advancement over standard procedures in contemporary cardiology. Its full potential has yet to be fully explored.

Myotonic dystrophy is an autosomal dominant genetic disease of nucleotide expansion resulting in neuromuscular disease with two distinct subtypes. There are significant systemic manifestations of this condition including progressive muscular decline, neurologic abnormalities, and cardiac disease. Given the higher prevalence of cardiac dysfunction compared to the general population, there is significant interest in early diagnosis and prevention of cardiac morbidity and mortality. Cardiac dysfunction has an origin in abnormal and unstable nucleotide repeats in the DMPK and CNBP genes which have downstream effects leading to an increased propensity for arrhythmias and left ventricular systolic dysfunction. Current screening paradigms involve the use of routine screening electrocardiograms, ambulatory electrocardiographic monitors, and cardiac imaging to stratify risk and suggest further invasive evaluation. The most common cardiac abnormality is atrial arrhythmia, however there is significant mortality in this population from high-degree atrioventricular block and ventricular arrhythmia. In this review, we describe the cardiac manifestations of myotonic dystrophy with an emphasis on arrhythmia which is the second most common cause of death in this population after respiratory failure.

No abstract available

The renin-angiotensin-aldosterone system (RAAS) plays a major role in cardiovascular health and disease. Short-term RAAS activation controls water and salt retention and causes vasoconstriction, which are beneficial for maintaining cardiac output in low blood pressure and early stage heart failure. However, prolonged RAAS activation is detrimental, leading to structural remodeling and cardiac dysfunction. Natriuretic peptides (NPs) are activated to counterbalance the effect of RAAS and sympathetic nervous system by facilitating water and salt excretion and causing vasodilation. Neprilysin is a major NP-degrading enzyme that degrades multiple vaso-modulatory substances. Although the inhibition of neprilysin alone is not sufficient to counterbalance RAAS activation in cardiovascular diseases (e.g., hypertension and heart failure), a combination of angiotensin receptor blocker and neprilysin inhibitor (ARNI) was highly effective in several clinical trials and may modulate the risk of atrial and ventricular arrhythmias. This review summarizes the possible link between ARNI and cardiac arrhythmias and discusses potential underlying mechanisms, providing novel insights about the therapeutic role and safety profile of ARNI in the cardiovascular system.

SCN5A encodes alpha subunit of the major sodium channel (Nav1.5) in human cardiac tissue. Malfunction of this cardiac sodium channel is associated with a variety of cardiac arrhythmias and myocardial inherited diseases.

Because of demographic aging, the prevalence of arterial hypertension (HTN) and cardiac arrhythmias, namely atrial fibrillation (AF), is progressively increasing. Not only are these clinical entities strongly connected, but, acting with a synergistic effect, their association may cause a worse clinical outcome in patients already at risk of ischemic and/or haemorrhagic stroke and, consequently, disability and death. Despite the well-known association between HTN and AF, several pathogenetic mechanisms underlying the higher risk of AF in hypertensive patients are still incompletely known. Although several trials reported the overall clinical benefit of renin-angiotensin-aldosterone inhibitors in reducing incident AF in HTN, the role of this class of drugs is greatly reduced when AF diagnosis is already established, thus hinting at the urgent need for primary prevention measures to reduce AF occurrence in these patients. Through a thorough review of the available literature in the field, we investigated the basic mechanisms through which HTN is believed to promote AF, summarising the evidence supporting a pathophysiology-driven approach to prevent this arrhythmia in hypertensive patients, including those suffering from primary aldosteronism, a non-negligible and under-recognised cause of secondary HTN. Finally, in the hazy scenario of AF screening in hypertensive patients, we reviewed which patients should be screened, by which modality, and who should be offered oral anticoagulation for stroke prevention.

We ascertained the prevalence of ictal arrhythmias to explain the high rate of sudden unexpected death in epilepsy (SUDEP) in Dravet syndrome (DS).

Metabolic and bariatric surgery (MBS) has been shown to improve medical problems; however, there are known arrhythmias that can occur after MBS (i.e., sick sinus syndrome [SSS] and sinus bradyarrhythmias). While the literature in this area contains case reports, there is a lack of published data on a state or national level. We used a large state administrative database to evaluate the occurrence of cardiac arrhythmias after MBS.

The parasympathetic nervous system plays an important role in the pathophysiology of atrial fibrillation. Catheter ablation, a minimally invasive procedure deactivating abnormal firing cardiac tissue, is increasingly becoming the therapy of choice for atrial fibrillation. This is inevitably associated with the obliteration of cardiac cholinergic neurons. However, the impact on ventricular electrophysiology is unclear. Here we show that cardiac cholinergic neurons modulate ventricular electrophysiology. Mechanical disruption or pharmacological blockade of parasympathetic innervation shortens ventricular refractory periods, increases the incidence of ventricular arrhythmia and decreases ventricular cAMP levels in murine hearts. Immunohistochemistry confirmed ventricular cholinergic innervation, revealing parasympathetic fibres running from the atria to the ventricles parallel to sympathetic fibres. In humans, catheter ablation of atrial fibrillation, which is accompanied by accidental parasympathetic and concomitant sympathetic denervation, raises the burden of premature ventricular complexes. In summary, our results demonstrate an influence of cardiac cholinergic neurons on the regulation of ventricular function and arrhythmogenesis.

Cardiac arrhythmias are one of the most important remote complications after kidney injury. Renal ischemia reperfusion (I/R) is a major cause of acute renal injury predisposing to several remote dysfunctions, including cardiac electrical disturbance. Since IL-1β production dependent on NLRP3 represents a link between tissue malfunctioning and cardiac arrhythmias, here we tested the hypothesis that longer ventricular repolarization and arrhythmias after renal I/R depend on this innate immunity sensor.

No abstract available

Connexin-43 (Cx43) is the most abundant protein forming gap junction channels (GJCs) in cardiac ventricles. In multiple cardiac pathologies, including hypertrophy and heart failure, Cx43 is found remodeled at the lateral side of the intercalated discs of ventricular cardiomyocytes. Remodeling of Cx43 has been long linked to spontaneous ventricular arrhythmia, yet the mechanisms by which arrhythmias develop are still debated. Using a model of dystrophic cardiomyopathy, we previously showed that remodeled Cx43 function as aberrant hemichannels (non-forming GJCs) that alter cardiomyocyte excitability and, consequently, promote arrhythmias. Here, we aim to evaluate if opening of remodeled Cx43 can serve as a general mechanism to alter cardiac excitability independent of cellular dysfunction associated with a particular cardiomyopathy. To address this issue, we used a genetically modified Cx43 knock-in mouse (S3A) that promotes cardiac remodeling of Cx43 protein without apparent cardiac dysfunction. Importantly, when S3A mice were subjected to cardiac stress using the β-adrenergic agonist isoproterenol (Iso), they displayed acute and severe arrhythmias, which were not observed in WT mice. Pretreatment of S3A mice with the Cx43 hemichannel blocker, Gap19, prevented Iso-induced abnormal electrocardiographic behavior. At the cellular level, when compared with WT, Iso-treated S3A cardiomyocytes showed increased membrane permeability, greater plasma membrane depolarization, and Ca2+ overload, which likely caused prolonged action potentials, delayed after depolarizations, and triggered activity. All these cellular dysfunctions were also prevented by Cx43 hemichannel blockers. Our results support the notion that opening of remodeled Cx43 hemichannels, regardless of the type of cardiomyopathy, is sufficient to mediate cardiac-stress-induced arrhythmogenicity.

Ischaemic cardiac arrhythmias cause a large proportion of sudden cardiac deaths worldwide. The ischaemic arrhythmogenesis is primarily because of the dysfunction and adverse remodelling of sarcolemma ion channels. However, the potential regulators of sarcolemma ion channel turnover and function in ischaemic cardiac arrhythmias remains unknown. Our previous studies indicate that dynamin-2 (DNM2), a cardiac membrane-remodelling GTPase, modulates ion channels membrane trafficking in the cardiomyocytes. Here, we have found that DNM2 plays an important role in acute ischaemic arrhythmias. In rat ventricular tissues and primary cardiomyocytes subjected to acute ischaemic stress, the DNM2 protein and transcription levels were markedly down-regulated. This DNM2 reduction was coupled with severe ventricular arrhythmias. Moreover, we identified that the down-regulation of DNM2 within cardiomyocytes increases the action potential amplitude and prolongs the re-polarization duration by depressing the retrograde trafficking of Nav1.5 and Kir2.1 channels. These effects are likely to account for the DNM2 defect-induced arrhythmogenic potentials. These results suggest that DNM2, with its multi-ion channel targeting properties, could be a promising target for novel antiarrhythmic therapies.

Action potentials generated in the sinoatrial node (SAN) dominate the rhythm and rate of a healthy human heart. Subsequently, these action potentials propagate to the whole heart via its conduction system. Abnormalities of impulse generation and/or propagation in a heart can cause arrhythmias. For example, SAN dysfunction or conduction block of the atrioventricular node can lead to serious bradycardia which is currently treated with an implanted electronic pacemaker. On the other hand, conduction damage may cause reentrant tachyarrhythmias which are primarily treated pharmacologically or by medical device-based therapies, including defibrillation and tissue ablation. However, drug therapies sometimes may not be effective or are associated with serious side effects. Device-based therapies for cardiac arrhythmias, even with well developed technology, still face inadequacies, limitations, hardware complications, and other challenges. Therefore, scientists are actively seeking other alternatives for antiarrhythmic therapy. In particular, cells and genes used for repairing cardiac conduction damage/defect have been investigated in various studies both in vitro and in vivo. Despite the complexities of the excitation and conduction systems of the heart, cell and gene-based strategies provide novel alternatives for treatment or cure of cardiac arrhythmias. This review summarizes some highlights of recent research progress in this field.

Background The extent of cardiac dysfunction post-COVID-19 varies, and there is a lack of data on arrhythmic burden. Methods and Results This was a combined multicenter prospective cohort study and cross-sectional case-control study. Cardiac function assessed by echocardiography in patients with COVID-19 3 to 4 months after hospital discharge was compared with matched controls. The 24-hour ECGs were recorded in patients with COVID-19. A total of 204 patients with COVID-19 consented to participate (mean age, 58.5 years; 44% women), and 204 controls were included (mean age, 58.4 years; 44% women). Patients with COVID-19 had worse right ventricle free wall longitudinal strain (adjusted estimated mean difference, 1.5 percentage points; 95% CI, -2.6 to -0.5; P=0.005) and lower tricuspid annular plane systolic excursion (-0.10 cm; 95% CI, -0.14 to -0.05; P<0.001) and cardiac index (-0.26 L/min per m2; 95% CI, -0.40 to -0.12; P<0.001), but slightly better left ventricle global strain (-0.8 percentage points; 95% CI, 0.2-1.3; P=0.008) compared with controls. Reduced diastolic function was twice as common compared with controls (60 [30%] versus 29 [15%], respectively; odds ratio, 2.4; P=0.001). Having dyspnea or fatigue were not associated with cardiac function. Right ventricle free wall longitudinal strain was worse after intensive care treatment. Arrhythmias were found in 27% of the patients, mainly premature ventricular contractions and nonsustained ventricular tachycardia (18% and 5%, respectively). Conclusions At 3 months after hospital discharge with COVID-19, right ventricular function was mildly impaired, and diastolic dysfunction was twice as common compared with controls. There was little evidence for an association between cardiac function and intensive care treatment, dyspnea, or fatigue. Ventricular arrhythmias were common, but the clinical importance is unknown. Registration URL: http://clinicaltrials.gov. Unique Identifier: NCT04535154.

Cerebral ischemia/reperfusion (I/R) could increase the reactive oxidative stress in the cardiomyocytes. Also, some studies report cardiac arrhythmias following oxidative stressor such as I/R. Hence, this study was aimed to investigate the effects of ellagic acid (EA) against arrhythmias in a cerebral I/R model.

Cardiac functionality is dependent on a balanced protein turnover. Accordingly, regulated protein decay is critical to maintain cardiac function. Here we demonstrate that deficiency of SPRED2, an intracellular repressor of ERK-MAPK signaling markedly expressed in human heart, resulted in impaired autophagy, heart failure, and shortened lifespan. SPRED2-/- mice showed cardiomyocyte hypertrophy, cardiac fibrosis, impaired electrical excitability, and severe arrhythmias. Mechanistically, cardiomyocyte dysfunction resulted from ERK hyperactivation and dysregulated autophagy, observed as accumulation of vesicles, vacuolar structures, and degenerated mitochondria. The diminished autophagic flux in SPRED2-/- hearts was reflected by a reduced LC3-II/LC3-I ratio and by decreased Atg7, Atg4B and Atg16L expression. Furthermore, the autophagosomal adaptors p62/SQSTM1 and NBR1 and lysosomal Cathepsin D accumulated in SPRED2-/- hearts. In wild-type hearts, SPRED2 interacted physically with p62/SQSTM1, NBR1, and Cathepsin D, indicating that SPRED2 is required for autophagolysosome formation in regular autophagy. Restored inhibition of MAPK signaling by selumetinib led to an increase in autophagic flux in vivo. Therefore, our study identifies SPRED2 as a novel, indispensable regulator of cardiac autophagy. Vice versa, SPRED2 deficiency impairs autophagy, leading to cardiac dysfunction and life-threatening arrhythmias.

In the wake of the controversy surrounding the SYMPLICITY HTN-3 trial and data from subsequent trials, this review aims to perform an updated and more comprehensive review of the impact of renal sympathetic denervation on cardiac arrhythmias.