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Background Cardiovascular events (CEs) remain the leading cause of death in patients with tetanus. We examined the incidence, patterns, and associated predictors of CEs among patients with tetanus in Vietnam. Methods An ambidirectional cohort study was conducted on hospitalized adult patients with tetanus at the Hospital for Tropical Diseases between 2019 and 2020. Information on demographics, tetanus disease, CEs and outcomes were collected. Results Among all 572 included patients, CEs accounted for 10.8% (95%CI 8.6–13.7%) and included Takotsubo cardiomyopathy (40.3%, 95%CI 29.0–52.8%), arrhythmia (19.4%, 95%CI 11.4–30.9%), sudden cardiac arrest (16.1%, 95%CI 9.0–27.2%), myocardial infarction (11.3%, 95%CI 5.6–21.5%), heart failure (6.5%, 95%CI 2.5–15.4%) and pulmonary embolism (6.5%, 95%CI 2.5–15.4%). CEs occurred from day 5 to 20 of illness. Among 62 CE patients, 21% (95%CI 12.7–32.6%) died and 61.3% (95%CI 48.9–72.4%) developed autonomic nervous system dysfunction (ANSD). Three-fourths (24/32) of patients with Takotsubo cardiomyopathy or myocardial infarction had ANSD. CEs were significantly associated with modified Ablett scores (AOR = 2.42, 95%CI 1.1–5.6, P =.04), underlying diseases (AOR = 2.7, 95%CI 1.1–6.8, P =.04) and overweight (AOR = 0.18, 95%CI.04–.8, P =.02). Conclusions CEs are not rare and associated with high mortality. The most common CE is Takotsubo cardiomyopathy. CEs can occur at any stage of illness, with or without ANSD. To prevent mortality, it is pivotal to screen CEs in patients with tetanus, especially those with underlying diseases, high modified Ablett scores, and a normal or low BMI. More studies are needed to fully elucidate the impact of ANSD on the cardiovascular function and the CE associated mortality in tetanus. [ABSTRACT FROM AUTHOR]

Anomalous left coronary artery originating from the pulmonary artery (ALCAPA) is an infrequent congenital anomaly. Presentation of this syndrome is rare in adults. Nevertheless, adult patients are at risk of ischaemia, arrhythmias or sudden cardiac death and always require surgical intervention. At our institution, a specific technique of interposition of the right internal iliac artery as a free-graft for left coronary artery reimplantation was used in adult ALCAPA patients. The aim of this report is to determine long-term results and experiences with this surgical technique. [ABSTRACT FROM AUTHOR]

The article discusses unconventional methods of cardioversion, which involve using mechanical, pharmacological, or electrical techniques to convert cardiac arrhythmias into normal sinus rhythm. The authors present a case study where a rectal thermometer inadvertently cardioverted a patient with stable atrioventricular nodal re-entrant tachycardia. They explain that this unconventional method stimulates parasympathetic nerve fibers in the rectum, leading to non-random and reproducible cardioversion. The article also mentions other unusual cases of cardioversion, such as digital rectal examination and collisions with objects. The authors emphasize the importance of keeping an open mind and exploring unconventional approaches in medical practice. [Extracted from the article]

Iatrogenic coronary artery dissection is a rare complication seen in 0.07% of coronary procedures. Presentations of this condition vary, ranging from signs of myocardial ischemia to rarer presentations of ventricular arrhythmias. We present a rare case of a 55-year-old patient with native aortic valve endocarditis who developed right coronary artery dissection (RCAD) in the immediate post-op period presenting with refractory ventricular fibrillation (VF). Emergency coronary angiogram revealed an extensive RCAD extending from the ostium to the mid-vessel as the cause of VF. A consensus between the cardiologists and the cardiac surgeons led to an emergency right coronary artery bypass graft (CABG) that resolved the VF. This case illustrates a rare presentation of iatrogenic RCAD and the successful management of the same. We highlight the importance of prompt detection via angiography in patients suspected of having coronary artery dissection and showcase the successful implementation of emergency CABG in a patient with unstable haemodynamics. [ABSTRACT FROM AUTHOR]

Electronic cigarette use has grown exponentially in recent years, and while their popularity has increased, the long-term effects on the heart are yet to be fully studied and understood. Originally designed as devices to assist with those trying to quit traditional combustible cigarette use, their popularity has attracted use by teens and adolescents who traditionally have not smoked combustible cigarettes. Acute effects on the heart have been shown to be similar to traditional combustible cigarettes, including increased heart rate and blood pressure. The main components of electronic cigarettes that contribute to these arrhythmic effects are found in the e-liquid that is aerosolized and inhaled, comprised of nicotine, flavourings, and a combination of vegetable glycerin (VG) and propylene glycol (PG). Nicotine can potentially induce both ventricular and atrial arrhythmogenesis, with both the atrial and ventricular effects resulting from the interactions of nicotine and the catecholamines they release via potassium channels. Atrial arrhythmogenesis, more specifically atrial fibrillation, can also occur due to structural alterations, which happens because of nicotine downregulating microRNAs 133 and 590, both post-transcriptional growth factor repressors. Liquid flavourings and the combination of PG and VG can possibly lead to arrhythmic events by exposing users to acrolein, an aldehyde that stimulates TRPA1 that in turn causes a change towards sympathetic activation and autonomic imbalance. The design of these electronic delivery devices is constantly changing; therefore, it has proven extremely difficult to study the long-term effects on the heart caused by electronic cigarettes but will be important to understand given their rising popularity. The arrhythmic effects of electronic cigarettes appear similar to traditional cigarettes as well; however, a comprehensive review has not been compiled and is the focus of this article. [ABSTRACT FROM AUTHOR]

The cardiac sodium channel NaV1.5 is an essential modulator of cardiac excitability, with decreased NaV1.5 levels at the plasma membrane and consequent reduction in sodium current (I Na) leading to potentially lethal cardiac arrhythmias. NaV1.5 is distributed in a specific pattern at the plasma membrane of cardiomyocytes, with localization at the crests, grooves, and T-tubules of the lateral membrane and particularly high levels at the intercalated disc region. NaV1.5 forms a large macromolecular complex with and is regulated by interacting proteins, some of which are specifically localized at either the lateral membrane or intercalated disc. One of the NaV1.5 trafficking routes is via microtubules (MTs), which are regulated by MT plus-end tracking proteins (+TIPs). In our search for mechanisms involved in targeted delivery of NaV1.5, we here provide an overview of previously demonstrated interactions between NaV1.5 interacting proteins and +TIPs, which potentially (in)directly impact on NaV1.5 trafficking. Strikingly, +TIPs interact extensively with several intercalated disc- and lateral membrane-specific NaV1.5 interacting proteins. Recent work indicates that this interplay of +TIPs and NaV1.5 interacting proteins mediates the targeted delivery of NaV1.5 at specific cardiomyocyte subcellular domains, while also being potentially relevant for the trafficking of other ion channels. These observations are especially relevant for diseases associated with loss of NaV1.5 specifically at the lateral membrane (such as Duchenne muscular dystrophy), or at the intercalated disc (for example, arrhythmogenic cardiomyopathy), and open up potential avenues for development of new anti-arrhythmic therapies. [ABSTRACT FROM AUTHOR]

Current understanding of arrhythmia mechanisms and design of anti-arrhythmic drug therapies hinges on the assumption that myocytes from the same region of a single heart have similar, if not identical, action potential waveforms and drug responses. On the contrary, recent experiments reveal significant heterogeneity in uncoupled healthy myocytes both from different hearts as well as from identical regions within a single heart. In this work, a methodology is developed for quantifying the individual electrophysiological properties of large numbers of uncoupled cardiomyocytes under ion channel block in terms of the parameters values of a conceptual fast-slow model of electrical excitability. The approach is applied to a population of nearly 500 rabbit ventricular myocytes for which action potential duration (APD) before and after the application of the drug nifedipine was experimentally measured (Lachaud et al. 2022, Cardiovasc. Res.). To this end, drug action is represented by a multiplicative factor to an effective ion conductance, a closed form asymptotic expression for APD is derived and inverted to determine model parameters as functions of APD and |$\varDelta $| APD (drug-induced change in APD) for each myocyte. Two free protocol-related quantities are calibrated to experiment using an adaptive-domain procedure based on an original assumption of optimal excitability. The explicit APD expression and the resulting set of model parameter values allow (a) direct evaluation of conditions necessary to maintain fixed APD or |$\varDelta $| APD, (b) predictions of the proportion of cells remaining excitable after drug application, (c) predictions of stimulus period dependency and (d) predictions of dose-response curves, the latter being in agreement with additional experimental data. [ABSTRACT FROM AUTHOR]

Cardiac conduction disease is a major cause of morbidity and mortality worldwide. There is considerable clinical significance and an emerging need of early detection of these diseases for preventive treatment success before more severe arrhythmias occur. However, developing such early screening tools is challenging due to the lack of early electrocardiograms (ECGs) before symptoms occur in patients. Mouse models are widely used in cardiac arrhythmia research. The goal of this paper is to develop deep learning models to predict cardiac conduction diseases in mice using their early ECGs. We hypothesize that mutant mice present subtle abnormalities in their early ECGs before severe arrhythmias present. These subtle patterns can be detected by deep learning though they are hard to be identified by human eyes. We propose a deep transfer learning model, DeepMiceTL, which leverages knowledge from human ECGs to learn mouse ECG patterns. We further apply the Bayesian optimization and |$k$| -fold cross validation methods to tune the hyperparameters of the DeepMiceTL. Our results show that DeepMiceTL achieves a promising performance (F1-score: 83.8%, accuracy: 84.8%) in predicting the occurrence of cardiac conduction diseases using early mouse ECGs. This study is among the first efforts that use state-of-the-art deep transfer learning to identify ECG patterns during the early course of cardiac conduction disease in mice. Our approach not only could help in cardiac conduction disease research in mice, but also suggest a feasibility for early clinical diagnosis of human cardiac conduction diseases and other types of cardiac arrythmias using deep transfer learning in the future. [ABSTRACT FROM AUTHOR]

Acute kidney injury (AKI) is defined by a rapid increase in serum creatinine levels, reduced urine output or both. Death may occur in 16–49% of patients admitted to an intensive care unit with severe AKI. Complex arrhythmias are a potentially serious complication in AKI patients with pre-existing or AKI-induced heart damage and myocardial dysfunction, with fluid overload, especially electrolyte and acid–base disorders, representing the pathogenetic mechanisms of arrhythmogenesis. Cardiac arrhythmias, in turn, increase the risk of poor renal outcomes, including AKI. Arrhythmic risk in AKI patients receiving kidney replacement treatment may be reduced by modifying dialysis/replacement fluid composition. The most common arrhythmia observed in AKI patients is atrial fibrillation. Severe hyperkalaemia, sometimes combined with hypocalcaemia, causes severe bradyarrhythmias in this clinical setting. Although the likelihood of life-threatening ventricular arrhythmias is reportedly low, the combination of cardiac ischaemia and specific electrolyte or acid–base abnormalities may increase this risk, particularly in AKI patients who require kidney replacement treatment. The purpose of this review is to summarize the available epidemiological, pathophysiological and prognostic evidence aiming to clarify the complex relationships between AKI and cardiac arrhythmias. [ABSTRACT FROM AUTHOR]

Andersen-Tawil syndrome (ATS) is a rare inheritable disease associated with loss-of-function mutations in KCNJ2, the gene coding the strong inward rectifier potassium channel Kir2.1, which forms an essential membrane protein controlling cardiac excitability. ATS is usually marked by a triad of periodic paralysis, life-threatening cardiac arrhythmias and dysmorphic features, but its expression is variable and not all patients with a phenotype linked to ATS have a known genetic alteration. The mechanisms underlying this arrhythmogenic syndrome are poorly understood. Knowing such mechanisms would be essential to distinguish ATS from other channelopathies with overlapping phenotypes and to develop individualized therapies. For example, the recently suggested role of Kir2.1 as a countercurrent to sarcoplasmic calcium reuptake might explain the arrhythmogenic mechanisms of ATS and its overlap with catecholaminergic polymorphic ventricular tachycardia. Here we summarize current knowledge on the mechanisms of arrhythmias leading to sudden cardiac death in ATS. We first provide an overview of the syndrome and its pathophysiology, from the patient's bedside to the protein and discuss the role of essential regulators and interactors that could play a role in cases of ATS. The review highlights novel ideas related to some post-translational channel interactions with partner proteins that might help define the molecular bases of the arrhythmia phenotype. We then propose a new all-embracing classification of the currently known ATS loss-of-function mutations according to their position in the Kir2.1 channel structure and their functional implications. We also discuss specific ATS pathogenic variants, their clinical manifestations, and treatment stratification. The goal is to provide a deeper mechanistic understanding of the syndrome toward the development of novel targets and personalized treatment strategies. [ABSTRACT FROM AUTHOR]

This article discusses the interactions between KCNQ1 and KCNH2 in relation to the long QT type 1 (LQT1) phenotype. LQT1 and LQT2 are two major forms of the inherited channelopathy long QT syndrome (LQTS). Loss-of-function mutations in KCNQ1 or KCNH2 cause a reduction in the cardiac repolarizing currents IKs or IKr, respectively, leading to a prolonged cardiac action potential duration (APD) and QT interval. The article presents evidence that the reduction of IKs in LQT1 patients may also result in a concomitant down-regulation of IKr, which further increases the risk of arrhythmias. The findings suggest that a more comprehensive assessment of repolarization reserve is necessary to accurately evaluate the arrhythmic risk in LQTS patients. [Extracted from the article]

Microtubules (MTs) are a crucial part of the cytoskeleton that help maintain cellular balance under mechanical stress. Excessive post-translational modifications (PTMs) of MTs, such as detyrosination, have been linked to impaired cardiac contractility. In a study on mice with Duchenne muscular dystrophy (DMD), researchers found that increased detyrosination of MTs was associated with decreased expression of the cardiac Na+ channel Nav1.5. By reducing detyrosinated tubulin, the researchers were able to restore Nav1.5 expression and improve sodium current. This finding suggests that targeting detyrosinated MTs could be a promising strategy for addressing cardiac arrhythmias. [Extracted from the article]

His serum K SP + sp was 4.4 mmol/l and Mg SP 2+ sp was 1.3 mmol/l. Intravenous amiodarone therapy was initiated, and after 72 h of drug exposure (total dose of 4.5 g amiodarone), sinus rhythm was successfully restored. Learning points for clinicians Macroscopic T-wave alternans (TWA) signifies significant vulnerability during repolarization and may be a harbinger of impending electrical instability. Introduction This case study presents the electrocardiographic (ECG) findings of a 70-year-old male with chronic heart failure caused by atrial fibrillation, who developed macrovolt T-wave alternans (TWA) and subsequent malignant arrhythmia after amiodarone treatment. [Extracted from the article]

Aims Long QT syndrome (LQTS) carries a risk of life-threatening polymorphic ventricular tachycardia (Torsades de Pointes, TdP) and is a major cause of premature sudden cardiac death. TdP is induced by R-on-T premature ventricular complexes (PVCs), thought to be generated by cellular early-afterdepolarisations (EADs). However, EADs in tissue require cellular synchronisation, and their role in TdP induction remains unclear. We aimed to determine the mechanism of TdP induction in rabbit hearts with acquired LQTS (aLQTS). Methods and results Optical mapping of action potentials (APs) and intracellular Ca2+ was performed in Langendorff-perfused rabbit hearts (n = 17). TdP induced by R-on-T PVCs was observed during aLQTS (50% K+/Mg++ & E4031) conditions in all hearts (P < 0.0001 vs. control). Islands of AP prolongation bounded by steep voltage gradients (VGs) were consistently observed before arrhythmia and peak VGs were more closely related to the PVC upstroke than EADs, both temporally (7 ± 5 ms vs. 44 ± 27 ms, P < 0.0001) and spatially (1.0 ± 0.7 vs. 3.6 ± 0.9 mm, P < 0.0001). PVCs were initiated at estimated voltages of ∼ −40 mV and had upstroke dF/dtmax and Vm-Ca2+ dynamics compatible with I CaL activation. Computational simulations demonstrated that PVCs could arise directly from VGs, through electrotonic triggering of I CaL. In experiments and the model, sub-maximal L-type Ca2+ channel (LTCC) block (200 nM nifedipine and 90% gCaL, respectively) abolished both PVCs and TdP in the continued presence of aLQTS. Conclusion These data demonstrate that I CaL activation at sites displaying steep VGs generates the PVCs which induce TdP, providing a mechanism and rationale for LTCC blockers as a novel therapeutic approach in LQTS. [ABSTRACT FROM AUTHOR]

Aims Human-induced pluripotent stem cell-cardiomyocytes (hiPSC-CMs) are widely used to study arrhythmia-associated mutations in ion channels. Among these, the cardiac sodium channel SCN5A undergoes foetal-to-adult isoform switching around birth. Conventional hiPSC-CM cultures, which are phenotypically foetal, have thus far been unable to capture mutations in adult gene isoforms. Here, we investigated whether tri-cellular cross-talk in a three-dimensional (3D) cardiac microtissue (MT) promoted post-natal SCN5A maturation in hiPSC-CMs. Methods and results We derived patient hiPSC-CMs carrying compound mutations in the adult SCN5A exon 6B and exon 4. Electrophysiological properties of patient hiPSC-CMs in monolayer were not altered by the exon 6B mutation compared with isogenic controls since it is not expressed; further, CRISPR/Cas9-mediated excision of the foetal exon 6A did not promote adult SCN5A expression. However, when hiPSC-CMs were matured in 3D cardiac MTs, SCN5A underwent isoform switch and the functional consequences of the mutation located in exon 6B were revealed. Up-regulation of the splicing factor muscleblind-like protein 1 (MBNL1) drove SCN5A post-natal maturation in microtissues since its overexpression in hiPSC-CMs was sufficient to promote exon 6B inclusion, whilst knocking-out MBNL1 failed to foster isoform switch. Conclusions Our study shows that (i) the tri-cellular cardiac microtissues promote post-natal SCN5A isoform switch in hiPSC-CMs, (ii) adult splicing of SCN5A is driven by MBNL1 in these tissues, and (iii) this model can be used for examining post-natal cardiac arrhythmias due to mutations in the exon 6B. Translational perspective The cardiac sodium channel is essential for conducting the electrical impulse in the heart. Postnatal alternative splicing regulation causes mutual exclusive inclusion of fetal or adult exons of the corresponding gene, SCN5A. Typically, immature hiPSCCMs fall short in studying the effect of mutations located in the adult exon. We describe here that an innovative tri-cellular three-dimensional cardiac microtissue culture promotes hiPSC-CMs maturation through upregulation of MBNL1, thus revealing the effect of a pathogenic genetic variant located in the SCN5A adult exon. These results help advancing the use of hiPSC-CMs in studying adult heart disease and for developing personalized medicine applications. [ABSTRACT FROM AUTHOR]

Aims Systematic use of patient-reported outcomes (PROs) have the potential to improve quality of care and reduce costs of health care services. We aimed to describe whether PROs in patients diagnosed with heart disease are directly associated with health care costs. Methods and results A national cross-sectional survey including PROs at discharge from a heart centre with 1-year follow-up using data from national registers. We included patients with either ischaemic heart disease (IHD), arrhythmia, heart failure (HF), or valvular heart disease (VHD). The Hospital Anxiety and Depression Scale, the heart-specific quality of life, the EuroQol five-dimensional questionnaire, and the Edmonton Symptom Assessment Scale were used. The economic analysis was based on direct costs including primary, secondary health care, and medical treatment. Patient-reported outcomes were available from 13 463 eligible patients out of 25.241 [IHD (n = 7179), arrhythmia (n = 4322), HF (n = 987), or VHD (n = 975)]. Mean annual total direct costs in all patients were €23 228 (patients with IHD: €19 479, patients with arrhythmia: €21 076, patients with HF: €34 747, patients with VDH: €48 677). Hospitalizations contributed overall to the highest part of direct costs. For patients discharged with IHD or arrhythmia, symptoms of anxiety or depression, worst heart-specific quality of life or health status, and the highest symptom burden were associated with increased economic expenditure. We found no associations in patients with HF or VHD. Conclusion Patient-reported outcomes at discharge from a heart centre were associated with direct health care costs in patients with IHD and arrhythmia. Registration ClinicalTrials.gov: NCT01926145. [ABSTRACT FROM AUTHOR]

Recent epidemiological findings link asthma to adverse cardiovascular responses. Yet, the precise cardiovascular impacts of asthma have been challenging to disentangle from the potential cardiovascular effects caused by asthma medication. The purpose of this study was to determine the impacts of allergic airways disease alone on cardiovascular function in an experimental model. Female Wistar rats were intranasally sensitized and then challenged once per week for 5 weeks with saline vehicle or a mixture of environmental allergens (ragweed, house dust mite, and Aspergillus fumigatus). Ventilatory and cardiovascular function, measured using double-chamber plethysmography and implantable blood pressure (BP) telemetry and cardiovascular ultrasound, respectively, were assessed before sensitization and after single and final allergen challenge. Responses to a single 0.5 ppm ozone exposure and to the cardiac arrhythmogenic agent aconitine were also assessed after final challenge. A single allergen challenge in sensitized rats increased tidal volume and specific airways resistance in response to provocation with methacholine and increased bronchoalveolar lavage fluid (BALF) eosinophils, neutrophils, lymphocytes, cytokines interleukin (IL)-4, IL-5, IL-10, IL-1β, tumor necrosis factor-α, and keratinocyte chemoattract-growth-related oncogene characteristic of allergic airways responses. Lung responses after final allergen challenge in sensitized rats were diminished, although ozone exposure increased BALF IL-6, IL-13, IL-1 β, and interferon-γ and modified ventilatory responses only in the allergen group. Final allergen challenge also increased systolic and mean arterial BP, stroke volume, cardiac output, end-diastolic volume, sensitivity to aconitine-induced cardiac arrhythmia, and cardiac gene expression with lesser effects after a single challenge. These findings demonstrate that allergic airways responses may increase cardiovascular risk in part by altering BP and myocardial function and by causing cardiac electrical instability. [ABSTRACT FROM AUTHOR]

Bidirectional ventricular tachycardia (VT) is a rare ventricular dysrhythmia with a limited differential diagnosis that includes digitalis toxicity, catecholaminergic polymorphic VT, aconite poisoning, and genetic channelopathy syndromes, specifically, Andersen–Tawil syndrome (ATS). We present a case of a young female with palpitations found to have bidirectional VT on cardiac event monitor and strong family history of cardiac dysrhythmias. Her physical examination findings included minor dysmorphic features of mandibular hypoplasia, hypertelorism, and clinodactyly. The patient was clinically diagnosed with ATS and started on a beta-blocker for control of ectopy. A second Holter review demonstrated markedly decreased burden of ventricular ectopy compared to the initial monitoring. She was referred for genetic testing, which revealed a KCNJ2 mutation. Bidirectional VT is an uncommon ventricular dysrhythmia that has a limited differential diagnosis, one of which is ATS—a rare genetic disorder that results from mutations in the KCNJ2 gene. The condition is frequently associated with developmental, skeletal, and cardiac abnormalities. Although there are no strong recommendations that exist for treatment of ventricular dysrhythmias associated with this genetic disorder, we demonstrate a case of clinical improvement in a patient with ATS by using the beta-blocker metoprolol succinate. Furthermore, we propose that ATS patients may not need exercise restrictions as overall ventricular ectopy burden decreased with exercise and there was no prolongation of the QT interval. This patient will continue to follow up in our clinic to reassess symptom burden and for continued monitoring for the development of any new features. [ABSTRACT FROM AUTHOR]

Pathogenic variants in the voltage-gated sodium channel gene family (SCNs) lead to early onset epilepsies, neurodevelopmental disorders, skeletal muscle channelopathies, peripheral neuropathies and cardiac arrhythmias. Disease-associated variants have diverse functional effects ranging from complete loss-of-function to marked gain-of-function. Therapeutic strategy is likely to depend on functional effect. Experimental studies offer important insights into channel function, but are resource intensive and only performed in a minority of cases. Given the evolutionarily conserved nature of the sodium channel genes we investigated whether similarities in biophysical properties between different voltage-gated sodium channels can predict function and inform precision treatment across sodium channelopathies. We performed a systematic literature search identifying functionally assessed variants in any of the nine voltage-gated sodium channel genes until 28 April 2021. We included missense variants that had been electrophysiologically characterised in mammalian cells in whole-cell patch-clamp recordings. We performed an alignment of linear protein sequences of all sodium channel genes and correlated variants by their overall functional effect on biophysical properties. Of 951 identified records, 437 sodium channel-variants met our inclusion criteria and were reviewed for functional properties. Of these, 141 variants were epilepsy-associated (SCN1/2/3/8A), 79 had a neuromuscular phenotype (SCN4/9/10/11A), 149 were associated with a cardiac phenotype (SCN5/10A) and 68 (16%) were considered benign. We detected 38 missense variant pairs with an identical disease-associated variant in a different sodium channel gene. 35 out of 38 of those pairs resulted in similar functional consequences indicating up to 92% biophysical agreement between corresponding sodium channel variants (odds ratio = 11.3; 95% CI = 2.8 to 66.9; P < 0.001). Pathogenic missense variants were clustered in specific functional domains, whereas population variants were significantly more frequent across non conserved domains (odds ratio = 18.6; 95% CI = 10.9 to 34.4; P < 0.001). Pore-loop regions were frequently associated with loss-of-function (LoF) variants, whereas inactivation sites were associated with gain-of-function (GoF; odds ratio = 42.1, 95% CI = 14.5 to 122.4; P < 0.001), whilst variants occurring in voltage-sensing regions comprised a range of gain- and loss-of-function effects. Our findings suggest that biophysical characterisation of variants in one SCN-gene can predict channel function across different SCN-genes where experimental data are not available. The collected data represent the first GoF versus LoF topological map of SCN proteins indicating shared patterns of biophysical effects aiding variant analysis and guiding precision therapy. We integrated our findings into a free online webtool to facilitate functional sodium channel gene variant interpretation (http://SCN-viewer.broadinstitute.org). [ABSTRACT FROM AUTHOR]

The monitoring of physiological function and dysfunction is an important principle in modern medicine. Heart rate is a basic example of this type of observation, particularly assessing the neurocardiac system, which entails the autonomic nervous system and intracardiac processes. The neurocardiac axis is an underappreciated and often overlooked system which, if measured appropriately in the clinical setting, may allow identification of patients at risk of disease progression and even mortality. While heart rate itself is a simplistic tool, more information may be gathered through assessing heart rate variability and heart rate recovery time. Studies have demonstrated an association of slow heart rate recovery and lower heart rate variability as markers of elevated sympathetic and lower parasympathetic tone. These parameters have additionally been shown to relate to development of arrhythmia, heart failure, systemic inflammatory processes, ischaemic heart disease and an increased rate of mortality. The aim of this review is to detail how heart rate is homeostatically controlled by the autonomic nervous system, how heart rate can impact on pathophysiological processes, and how heart rate variability and heart rate recovery time may be used in the clinical setting to allow the neurocardiac system to be assessed. [ABSTRACT FROM AUTHOR]

Aims A mutation in the phospholamban (PLN) gene, leading to deletion of Arg14 (R14del), has been associated with malignant arrhythmias and ventricular dilation. Identifying pre-symptomatic carriers with vulnerable myocardium is crucial because arrhythmia can result in sudden cardiac death, especially in young adults with PLN-R14del mutation. This study aimed at assessing the efficiency and efficacy of in vivo genome editing, using CRISPR/Cas9 and a cardiotropic adeno-associated virus-9 (AAV9), in improving cardiac function in young adult mice expressing the human PLN-R14del. Methods and results Humanized mice were generated expressing human wild-type (hPLN-WT) or mutant (hPLN-R14del) PLN in the heterozygous state, mimicking human carriers. Cardiac magnetic resonance imaging at 12 weeks of age showed bi-ventricular dilation and increased stroke volume in mutant vs. WT mice, with no deficit in ejection fraction or cardiac output. Challenge of ex vivo hearts with isoproterenol and rapid pacing unmasked higher propensity for sustained ventricular tachycardia (VT) in hPLN-R14del relative to hPLN-WT. Specifically, the VT threshold was significantly reduced (20.3 ± 1.2 Hz in hPLN-R14del vs. 25.7 ± 1.3 Hz in WT, P < 0.01) reflecting higher arrhythmia burden. To inactivate the R14del allele, mice were tail-vein-injected with AAV9.CRISPR/Cas9/gRNA or AAV9 empty capsid (controls). CRISPR-Cas9 efficiency was evaluated by droplet digital polymerase chain reaction and NGS-based amplicon sequencing. In vivo gene editing significantly reduced end-diastolic and stroke volumes in hPLN-R14del CRISPR-treated mice compared to controls. Susceptibility to VT was also reduced, as the VT threshold was significantly increased relative to controls (30.9 ± 2.3 Hz vs. 21.3 ± 1.5 Hz; P < 0.01). Conclusions This study is the first to show that disruption of hPLN-R14del allele by AAV9-CRISPR/Cas9 improves cardiac function and reduces VT susceptibility in humanized PLN-R14del mice, offering preclinical evidence for translatable approaches to therapeutically suppress the arrhythmogenic phenotype in human patients with PLN-R14del disease. [ABSTRACT FROM AUTHOR]

Objectives Cardiac complications of SSc are a leading cause of SSc-associated death. Cardiac imaging for identifying substrate abnormality may be useful in predicting risk of cardiac arrhythmias or future cardiac failure. The aim of this study was to quantify the burden of asymptomatic fibro-inflammatory myocardial disease using cardiac magnetic resonance imaging (CMR) and assess the relationship between asymptomatic myocardial fibrosis and cardiac arrhythmias in SSc. Methods Thirty-two patients with SSc with no documented history of pulmonary vascular or heart disease underwent CMR with gadolinium and 24-h ambulatory ECG. Focal myocardial fibrosis was assessed using post-gadolinium imaging and diffuse fibro-inflammatory myocardial disease quantified using T1- and T2-mapping. CMR results were compared with an age- and sex-matched control group. Results Post-gadolinium focal fibrosis was prevalent in SSc but not controls (30% vs 0%, p  < 0.01).. T1-mapping values (as a marker of diffuse fibrosis) were greater in SSc than controls [saturated recovery single-shot acquisition (SASHA): 1584 ms vs 1515 ms, P  < 0.001; shortened Modified look locker sequence (ShMOLLI): 1218 ms vs 1138 ms, p  < 0.001]. More than one-fifth (22.6%) of the participants had ventricular arrhythmias on ambulatory ECG, but no associations between focal or diffuse myocardial fibrosis and arrhythmias were evident. Conclusion In SSc patients without evidence of overt cardiac disease, a high burden of myocardial fibrosis and arrhythmias was identified. However, there was no clear association between focal or diffuse myocardial fibrosis and arrhythmias, suggesting CMR may have limited use as a screening tool to identify SSc patients at risk of future significant arrhythmias. [ABSTRACT FROM AUTHOR]

Life-threatening complications (LTCs) and negative results of surgical treatments often go unreported. Minimally invasive repair of pectus excavatum (MIRPE) represents a procedure with a low incidence of adverse outcomes. However, 15 potentially fatal cases of MIRPE-related heart injury have been published. We report a case of cardiac perforation (CP) during MIRPE. A 12-year-old female was admitted for elective repair of a severe asymmetric pectus excavatum. Preoperative computed tomography showed a Haller index of 4.9. MIRPE was performed under bilateral video-assisted thoracoscopy. After the placement of the pectus bar, cardiac arrhythmias, hypotension and bilateral hemothorax occurred. Emergency thoracotomy without pectus bar removal showed CP. The wound sites were repaired and the pectus bar was eventually successfully implanted. The patient was discharged on postoperative day 11. After 10 months, she remains asymptomatic. Reporting rare complications is essential for accurate calculations of the true prevalence of LTCs, maintaining high alertness in pediatric surgeons. [ABSTRACT FROM AUTHOR]

In this case report, we present 31-year-old twin sisters diagnosed with severe Barlow mitral valve prolapse, mitral annular disjunction and presence of lateral mid-wall fibrosis diagnosed on MRI as well as ventricular arrhythmias, and a very rare variant of Loeys-Dietz syndrome, being referred to our center for surgical repair. Genetic testing detected pathogenic variants of clinical significance in SMAD3 and KCNH2 genes that are associated with autosomal dominant disease of Loeys-Dietz syndrome. Due to the presence of severe mitral valve regurgitation, the first patient was referred for minimally invasive mitral valve repair that was performed successfully. Before discharge, a subcutaneous ICD implantation was performed as primary prevention against malignant ventricular arrhythmias and sudden cardiac death. Her twin sister presented with the identical diagnosis and underwent the same surgical procedure with S-ICD implantation a few months later. [ABSTRACT FROM AUTHOR]

This article discusses a case study of a man in his 30s with acute promyelocytic leukemia (APL) who was treated with arsenic trioxide and experienced recurrent loss of consciousness. The patient's electrocardiogram (ECG) showed a prolonged QTc interval and a distinct beat-to-beat alternating of opposite T-wave polarity, known as macrovolt T-wave alternans (TWA). The patient later developed torsades de pointes (TdP), a life-threatening ventricular arrhythmia. The article concludes that the treatment of relapsed APL with arsenic trioxide can prolong the QTc interval and increase the spacial heterogeneity of repolarization, leading to the occurrence of ventricular tachyarrhythmias. [Extracted from the article]

This letter to the editor discusses the role of artificial intelligence (AI) and imaging techniques in the management of arrhythmias, with a focus on atrial fibrillation (AF). The authors highlight the potential of AI and imaging to detect, prevent, and treat arrhythmias, as well as improve efficiency for clinicians. They discuss the use of deep learning and MRI scans to estimate atrial wall thickness and predict recurrence following catheter ablation. The authors also mention the value of radiological imaging, such as late gadolinium enhancement cardiac MRI and automated CT scans, in supporting the management of arrhythmias. They acknowledge the limitations of AI, including challenges in image interpretation and the risk of exacerbating bias and prejudice. Overall, the authors believe that further research in this field could redefine and improve the quality of life for individuals with arrhythmias. [Extracted from the article]

This article discusses the mechanisms and potential treatment options for atrial fibrillation (AF). The authors highlight the interplay between initiating triggers and sustaining mechanisms of AF, with triggers often originating from the pulmonary veins and other sites. They present evidence for the existence of localized drivers of AF, referred to as "electrically isolated conduction pathways (EICPs)," which can be detected and targeted during AF ablation procedures. The authors suggest that further research is needed to validate these findings in clinical settings and explore potential methods for preventing the escape of localized reentrant sources. [Extracted from the article]

Introduction: It is well established that hyperthyroidism is a strong independent risk factor for atrial fibrillation (AF). However, the relationship between hypothyroidism and AF is complex and not fully understood. The abnormal thyroid hormone levels can disrupt the electrical signals that regulate heart rhythm, potentially leading to AF. Some symptoms of hypothyroidism, such as fatigue, weakness, and shortness of breath, can mimic the symptoms of AF. This can make it challenging to diagnose AF in individuals with underlying thyroid issues. Meanwhile the treatment of hypothyroidism in A patient with AF can significantly improve the symptoms. Clinical Case: A 54 years old female was referred to the Therapy department with fatigue and palpitations. She was diagnosed one year ago with paroxysmal tachysystolic atrial fibrillation. CHADSVASK-1, EHRA-3. She experienced paroxysmal episodes four to five times a month for which she took propafenone. At presentation echocardiography (ECHO) showed LVEDD-50, LVEDS-35, IVS-12, LVPW-11, LA-42, EF-57%. The blood sample revealed TSH-8.41 (reference range 0.3-4 mIU/l), free T4-1.15 (reference range 10-25 pmol/l), free T3-3.76 (reference range 2.5-5.8 pmol/l), AbTPO-1040 (reference range 2.5-30 IU/ml). On thyroid ultrasound examination dimensions of right lobe were 18 *23 * 39 mm, left lobe were 22*20*38 mm, isthmus 3.8 mm, and no nodules were present. Total thyroid volume was 19.5 mL. The gland had heterogeneous echotexture and normal vascularity. Treatment with levothyroxine 50 mcg was started. After 6 weeks of treatment with levothyroxine TSH improved to 3.8 mIU/l and patient's fatigue and palpitation symptoms significantly improved, and no new paroxysms were detected. Conclusion: Managing hypothyroidism through thyroid hormone replacement therapy can often help control and sometimes even reverse AF if the arrhythmia was related to thyroid dysfunction. However, some individuals, as in this case, may continue to have AF even after their thyroid levels are normalized. In this case we emphasize the importance of understanding the effect of hypothyroidism on AF. [ABSTRACT FROM AUTHOR]

Here, we review the highlights of cardiovascular basic science published in 2021 and early 2022 on behalf of the European Society of Cardiology Council for Basic Cardiovascular Science. We begin with non-coding RNAs which have emerged as central regulators cardiovascular biology, and then discuss how technological developments in single-cell 'omics are providing new insights into cardiovascular development, inflammation, and disease. We also review recent discoveries on the biology of extracellular vesicles in driving either protective or pathogenic responses. The Nobel Prize in Physiology or Medicine 2021 recognized the importance of the molecular basis of mechanosensing and here we review breakthroughs in cardiovascular sensing of mechanical force. We also summarize discoveries in the field of atherosclerosis including the role of clonal haematopoiesis of indeterminate potential, and new mechanisms of crosstalk between hyperglycaemia, lipid mediators, and inflammation. The past 12 months also witnessed major advances in the field of cardiac arrhythmia including new mechanisms of fibrillation. We also focus on inducible pluripotent stem cell technology which has demonstrated disease causality for several genetic polymorphisms in long-QT syndrome and aortic valve disease, paving the way for personalized medicine approaches. Finally, the cardiovascular community has continued to better understand COVID-19 with significant advancement in our knowledge of cardiovascular tropism, molecular markers, the mechanism of vaccine-induced thrombotic complications and new anti-viral therapies that protect the cardiovascular system. [ABSTRACT FROM AUTHOR]

Aims Abnormal intracellular calcium (Ca2+) handling contributes to the progressive nature of atrial fibrillation (AF), the most common sustained cardiac arrhythmia. Evidence in mouse models suggests that activation of the nuclear factor of activated T-cell (NFAT) signalling pathway contributes to atrial remodelling. Our aim was to determine the role of NFATc2 in AF in humans and mouse models. Methods and results Expression levels of NFATc1–c4 isoforms were assessed by quantitative reverse transcription–polymerase chain reaction in right atrial appendages from patients with chronic AF (cAF). NFATc1 and NFATc2 mRNA levels were elevated in cAF patients compared with those in normal sinus rhythm (NSR). Western blotting revealed increased cytosolic and nuclear levels of NFATc2 in AF patients. Similar findings were obtained in CREM-IbΔC-X transgenic (CREM) mice, a model of progressive AF. Telemetry ECG recordings revealed age-dependent spontaneous AF in CREM mice, which was prevented by NFATc2 knockout in CREM:NFATc2–/– mice. Programmed electrical stimulation revealed that CREM:NFATc2–/– mice lacked an AF substrate. Morphometric analysis and histology revealed increased atrial weight and atrial fibrosis in CREM mice compared with wild-type controls, which was reversed in CREM:NFATc2–/– mice. Confocal microscopy showed an increased Ca2+ spark frequency despite a reduced sarcoplasmic reticulum (SR) Ca2+ load in CREM mice compared with controls, whereas these abnormalities were normalized in CREM:NFATc2–/– mice. Western blotting revealed that genetic inhibition of Ca2+/calmodulin-dependent protein kinase II-mediated phosphorylation of S2814 on ryanodine receptor type 2 (RyR2) in CREM:RyR2-S2814A mice suppressed NFATc2 activation observed in CREM mice, suggesting that NFATc2 is activated by excessive SR Ca2+ leak via RyR2. Finally, chromatin immunoprecipitation sequencing from AF patients identified Ras and EF-hand domain-containing protein (Rasef) as a direct target of NFATc2-mediated transcription. Conclusion Our findings reveal activation of the NFAT signalling pathway in patients of Chinese and European descent. NFATc2 knockout prevents the progression of AF in the CREM mouse model. [ABSTRACT FROM AUTHOR]

Aims Diastolic Ca release (DCR) from sarcoplasmic reticulum (SR) Ca release channel ryanodine receptor (RyR2) has been linked to multiple cardiac pathologies, but its exact role in shaping divergent cardiac pathologies remains unclear. We hypothesize that the SR-mitochondria interplay contributes to disease phenotypes by shaping Ca signalling. Methods and results A genetic model of catecholaminergic polymorphic ventricular tachycardia (CPVT2 model of CASQ2 knockout) and a pre-diabetic cardiomyopathy model of fructose-fed mice (FFD), both marked by DCR, are employed in this study. Mitochondria Ca (mCa) is modulated by pharmacologically targeting mitochondria Ca uniporter (MCU) or permeability transition pore (mPTP), mCa uptake, and extrusion mechanisms, respectively. An MCU activator abolished Ca waves in CPVT2 but exacerbated waves in FFD cells. Mechanistically this is ascribed to mitochondria's function as a Ca buffer or source of reactive oxygen species (mtROS) to exacerbate RyR2 functionality, respectively. Enhancing mCa uptake reduced and elevated mtROS production in CPVT2 and FFD, respectively. In CPVT2, mitochondria took up more Ca in permeabilized cells, and had higher level of mCa content in intact cells vs. FFD. Conditional ablation of MCU in the CPVT2 model caused lethality and cardiac remodelling, but reduced arrhythmias in the FFD model. In parallel, CPVT2 mitochondria also employ up-regulated mPTP-mediated Ca efflux to avoid mCa overload, as seen by elevated incidence of MitoWinks (an indicator of mPTP-mediated Ca efflux) vs. FFD. Both pharmacological and genetic inhibition of mPTP promoted mtROS production and exacerbation of myocyte Ca handling in CPVT2. Further, genetic inhibition of mPTP exacerbated arrhythmias in CPVT2. Conclusion In contrast to FFD, which is more susceptible to mtROS-dependent RyR2 leak, in CPVT2 mitochondria buffer SR-derived DCR to mitigate Ca-dependent pathological remodelling and rely on mPTP-mediated Ca efflux to avoid mCa overload. SR-mitochondria interplay contributes to the divergent pathologies by disparately shaping intracellular Ca signalling. [ABSTRACT FROM AUTHOR]

The electrocardiogram (ECG) is a vital diagnostic tool for identifying a variety of cardiac disorders, including cardiac arrhythmia (ARR), sinus rhythms and heart failure. However, rapid interpretation of ECG recordings is quite important in the diagnosis of heart-related diseases. Many patients can be saved using the systems developed for the rapid and accurate analysis of ECG signals. A novel ensemble method based on shifted one-dimensional local binary patterns (S-1D-LBP) and long short-term memory (LSTM) is presented for the prognosis of ARR, normal sinus rhythm (NSR) and congestive heart failure (CHF) in this study. The ECG signals were first subjected to the S-1D-LBP method. Depending on the R and L parameters of this method, nine different signals are generated. Each of the histograms of these signals is given to LSTM models with the same hyperparameters. ECG signals are classified according to the common decisions of LSTM models with nine different input signals. The suggested method was tested using ECG signals (ARR, NSR and CHF) from the MIT-BIH and BIDMC datasets. Considering the results obtained in the applications carried out with various scenarios, it was observed that a high (99.6%) success rate was attained by the proposed approach. The suggested S-1D-LBP + ELSTM (Ensemble LSTM) model is expected to be safe to employ in the classification of various signals. [ABSTRACT FROM AUTHOR]