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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 Na V 1.5, 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 Na V 1.5 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. Genome-wide association analyses identify new susceptibility loci for Brugada syndrome. Functional studies implicate microtubule-related trafficking effects on sodium channel expression as an underlying molecular mechanism.

Patients with short QT syndrome (SQTS) may present with syncope, ventricular fibrillation or sudden cardiac death. Six SQTS susceptibility genes, encoding cation channels, explain <25% of SQTS cases. Here we identify a missense mutation in the anion exchanger (AE3)-encoding SLC4A3 gene in two unrelated families with SQTS. The mutation causes reduced surface expression of AE3 and reduced membrane bicarbonate transport. Slc4a3 knockdown in zebrafish causes increased cardiac pH i , short QTc, and reduced systolic duration, which is rescued by wildtype but not mutated SLC4A3 . Mechanistic analyses suggest that an increase in pH i and decrease in [Cl − ] i shortened the action potential duration. However, other mechanisms may also play a role. Altered anion transport represents a mechanism for development of arrhythmia and may provide new therapeutic possibilities. Mutations in potassium and calcium channel genes have been associated with cardiac arrhythmias. Here, Jensen et al. show that an anion transporter chloride-bicarbonate exchanger AE3 is also responsible for the genetically-induced mechanism of cardiac arrhythmia, suggesting new therapeutic targets for this disease

We investigated the effects of intermittent hypoxia (IH), such as that encountered in severe obstructive sleep apnea (OSA) patients, on the development and severity of myocardial ischemia-related ventricular arrhythmias. Rats were exposed to 14 days of IH (30 s at 5%O 2 and 30 s at 21%O 2 , 8 h·day −1 ) or normoxia (N, similar air-air cycles) and submitted to a 30-min coronary ligature. Arterial blood pressure (BP) and ECG were recorded for power spectral analysis, ECG interval measurement and arrhythmia quantification. Left ventricular monophasic action potential duration (APD) and expression of L-type calcium (LTCC) and transient receptor potential (TRPC) channels were assessed in adjacent epicardial and endocardial sites. Chronic IH enhanced the incidence of ischemic arrhythmias, in particular ventricular fibrillation (66.7% vs. 33.3% in N rats, p < 0.05). IH also increased BP and plasma norepinephine levels along with increased low-frequency (LF), decreased high-frequency (HF) and increased LF/HF ratio of heart rate and BP variability. IH prolonged QTc and Tpeak-to-Tend intervals, increased the ventricular APD gradient and upregulated endocardial but not epicardial LTCC, TRPC1 and TRPC6 (p < 0.05). Chronic IH, is a major risk factor for sudden cardiac death upon myocardial ischemia through sympathoactivation and alterations in ventricular repolarization, transmural APD gradient and endocardial calcium channel expression.

Ryanodine Receptors (RyRs) are massive channels that release Ca 2+ from the endoplasmic and sarcoplasmic reticulum. Hundreds of mutations are linked to malignant hyperthermia (MH), myopathies, and arrhythmias. Here, we explore the first MH mutation identified in humans by providing cryo-EM snapshots of the pig homolog, R615C, showing that it affects an interface between three solenoid regions. We also show the impact of apo-calmodulin (apoCaM) and how it can induce opening by bending of the bridging solenoid, mediated by its N-terminal lobe. For R615C RyR1, apoCaM binding abolishes a pathological ‘intermediate’ conformation, distributing the population to a mixture of open and closed channels, both different from the structure without apoCaM. Comparisons show that the mutation primarily affects the closed state, inducing partial movements linked to channel activation. This shows that disease mutations can cause distinct pathological conformations of the RyR and facilitate channel opening by disrupting interactions between different solenoid regions. Ryanodine Receptors (RyRs) release Ca2+ from the endoplasmic and sarcoplasmic reticulum. Mutations in RyR are linked to malignant hyperthermia (MH), myopathies, and arrhythmias. Here, a collection of cryoEM structures provides insights into the molecular consequences of MHrelated RyR mutation R615C, and how apoCaM opens RyR1.

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. Catheter ablation is a common therapy for atrial fibrillation but disrupts cardiac cholinergic neurons. Here the authors report that cholinergic neurons innervate heart ventricles and show that their ablation leads to increased susceptibility to ventricular arrhythmias in mouse models and in patients.

Key Points After initial reports of the successful treatment of patients with angina, left cardiac sympathetic denervation (LCSD) entered clinical practice in the 1970s for patients with long QT syndrome (LQTS) LCSD prevents arrhythmias of ischaemic origin, raises the threshold for ventricular fibrillation (VF), does not induce postdenervation supersensitivity, improves the capacity of coronary arteries to dilate, and preserves cardiac contractility The different effects of LCSD versus right cardiac sympathetic denervation are explained by the fact that the left-sided cardiac sympathetic nerves are quantitatively dominant at the ventricular level LCSD has proved to be highly effective in preventing life-threatening cardiac arrhythmias in patients with LQTS, catecholaminergic polymorphic ventricular tachycardia, or those at high cardiovascular risk after myocardial infarction Preliminary data, and important effects on VF threshold, suggest that LCSD might be useful in many conditions characterized by high risk of life-threatening arrhythmias, including ischaemic, dilated, and hypertrophic cardiomyopathy Cardiologists should discuss the advantages and disadvantages of LCSD compared with those of an implantable cardioverter–defibrillator with all patients, particularly children, who are at risk of arrhythmic sudden death Left cardiac sympathetic denervation (LCSD) has antiarrhythmic and antifibrillatory effects that are beneficial for patients with channelopathies, such as long QT syndrome or catecholaminergic polymorphic ventricular tachycardia. In this Review, Peter Schwartz expertly summarizes the development and current indications for LCSD, including emerging evidence for a potential beneficial effect in patients with ischaemic cardiomyopathy or heart failure. Experimental and clinical evidence indicating an antiarrhythmic effect of cardiac sympathetic denervation has been available for 100 years. Experimental data show that left cardiac sympathetic denervation (LCSD), in particular, is not only antiarrhythmic, but also antifibrillatory—an effect exquisitely important for any clinical condition associated with a high risk of ventricular fibrillation and sudden cardiac death. LCSD has additional effects on both the coronary circulation and the mechanical performance of the left ventricle, with important implications for patients with ischaemic cardiomyopathy. Evidence also shows that LCSD increases the vagal activity directed to the heart, which has potential implications for the management of heart failure. In this Review, the current and novel clinical indications for LCSD are discussed, particularly in the context of results obtained in patients with channelopathies, such as long QT syndrome and catecholaminergic polymorphic ventricular tachycardia.

Synaptosomal-associated protein 25 kDa (SNAP25) is essential for vesicular trafficking and protein docking at presynaptic membranes in the nervous system, yet its role in the heart remains poorly understood. Here, we show an unrecognized function of SNAP25, which is selectively expressed in the atria, in regulating atrial electrical remodeling and the onset of atrial fibrillation (AF). SNAP25 protein is downregulated in the atria of AF patients. Cardiomyocyte-specific knockout of SNAP25 in male mice significantly shortens the atrial effective refractory period and action potential duration (APD), increasing susceptibility to AF, which is attributed to elevated Kv1.5 current and membrane expression. Blocking Kv1.5 channels effectively restores atrial APD and reduces AF incidence. Mechanistically, SNAP25 deficiency reduces the internalization of Kv1.5 from the cell surface membrane to early endosomes. In human iPSC-derived atrial cardiomyocytes, SNAP25 deficiency similarly elevates arrhythmic activity and accelerates repolarization. In conclusion, this study reveals that SNAP25 regulates AF susceptibility by controlling the trafficking of the atrial-specific Kv1.5 channel, highlighting SNAP25 as a promising therapeutic target for atrial arrhythmias. While SNAP25 is critical for neural electrical communication, its cardiac role is unknown. Here the authors show that it governs atrial electrical stability by directing Kv1.5 channel trafficking, with therapeutic implications for atrial fibrillation.

Between 1/15,000–1/50,000 passengers suffer in-flight medical emergencies (IFME) with cardiac arrest accounting for 0.3 %. Confined space can have a negative impact on quality of chest compressions during cardiopulmonary resuscitation (CPR), thus we have conducted a randomized controlled study to find the most effective approach of performing CPR in a one – vs. two-rescuer method in a simulated airliner cabin. We randomized 20 healthcare professionals to perform a set of 10 min Basic Life Support (BLS, chest compressions and bag-mask-ventilation) in a one- vs. two-rescuer scenario and in confined space vs. open space in a randomized order using a full-body manikin. The primary outcome was compression depth as sensitive marker for differences in CPR-quality. The study was registered on clinicaltrials.gov (NCT02002481). Mixed ANOVAs with post-hoc false-discovery-rate adjusted pairwise comparisons indicated that one- vs. two-rescuer method showed differences in no-flow-time (confined: 8.05 ± 0.17 vs. 24.25 ± 1.05 s/2min and open space: 7.51 ± 0.02 vs. 21.31 ± 0.43 s/2min; p < 0.001) and missing releases (confined: 27.09 ± 5.55 vs. 46.64 ± 9.66 number/10 minutes and open space: 27.09 ± 2.44 vs. 43.36 ± 6.4 number/10minutes; p < 0.001). A confined space significantly elevated no-flow-time in the two-rescuer-method vs. the one-rescuer-method (24.24 ± 1.06 s/2min vs. 21.26 ± 0.44 s/2min; p < 0.001), whereas compression frequency and compression depth were different but still within the current recommendations of ERC/AHA in both methods per condition. Limited space in an airliner cabin has significant impact on no-flow-time in a two-rescuer-method. In case of CPR and limited access to the patient, we recommend a one-rescuer-method as first approach to ensure early and high-quality CPR for experienced personnel.

During focal ischemia, neurons can use lactate as an alternative source of energy through its oxidation into pyruvate by the lactate dehydrogenase (LDH). After cardiac arrest, the neurological consequences of this phenomenon are unknown. Experimental study. Experimental laboratory. Male New-Zealand rabbits. Animals were surgically instrumented and randomly divided into five groups receiving short infusion duration of either lactate or pyruvate or a pre-cardiac arrest infusion of oxamate (an inhibitor of the lactate dehydrogenase) or injection of fluorocitrate (an inhibitor of astrocytic tricarboxylic acid), or Saline (lactate, pyruvate, Oxa, FC and Control groups, respectively). After randomization, animals were submitted to 10 min of ventricular fibrillation and subsequent resuscitation. All animals were then either followed during 4 h, for the evaluation of the cerebral net uptake and concentrations of metabolites by microdialysis (n = 6 in each experimental group, n = 12 in control group), or during 48 h for the evaluation of their neurological outcome (n = 7 in each groups and n = 14 in control group). Cardiac arrest was associated with a dramatic increase in cerebral net uptake of lactate during 120 min after resuscitation, which was increased by lactate or pyruvate administration. This was associated with an increase in the mean neurological dysfunction score (66.7 ± 4.7, 79.0 ± 4.5 vs 57.7 ± 1.5 in Lactate, Pyruvate and Control group respectively) at 48 h after cardiac arrest. Oxamate and FC administration were associated with a lower lactate cerebral uptake after cardiac arrest and with an improvement of the neurological recovery (28.85 ± 9.4, 23.86 ± 6.2 vs 57.7 ± 1.5 in Oxa, FC and Control group respectively). After cardiac arrest, immediate isotonic lactate or pyruvate administration is deleterious. Pre-cardiac arrest LDH inhibition was potently neuroprotective in this setting.