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The aim of this study was to explore the prevalence of likely pathogenic or pathogenic variants and assess the diagnostic yield from genetic testing for cardiac arrhythmias in Norway since 2003. Data from 1991 probands and 2782 relatives were retrospectively collected from the laboratory information management system at Unit for Cardiac and Cardiovascular Genetics, Oslo University hospital. Of 1991 probands, 57.4% were females, age at genetic testing was 33.1 (±22.7) years, and 32.5% were under the age of 18. A likely pathogenic or pathogenic variant (including 14 novel) was detected in 15.4% in total. Of the 2782 relatives, 53.7% were females, age at genetic testing was 35.6 (±22.5) years, 27.3% were under the age of 18, and 45.3% carried the family variant. Probands and relatives combined, 1/3356 persons in the Norwegian population were heterozygous for an arrhythmia‐causing variant. The founder variant p.Q530X (NM_000218.2: c.1588C>T) in KCNQ1 accounted for 34% of all variants in Norway. In conclusion, genetic testing provided a genetic basis of the arrhythmia in 15.4% of the probands. Familial cascade screening identified four times as many variant‐positive relatives, allowing early detection and prompt stratification of arrhythmic risk of those variant carriers. [ABSTRACT FROM AUTHOR]

Aims Gene therapy with cardiac phosphodiesterases (PDEs), such as phosphodiesterase 4B (PDE4B), has recently been described to effectively prevent heart failure (HF) in mice. However, exact molecular mechanisms of its beneficial effects, apart from general lowering of cardiomyocyte cyclic adenosine monophosphate (cAMP) levels, have not been elucidated. Here, we studied whether gene therapy with two types of PDEs, namely PDE2A and PDE4B, can prevent pressure-overload-induced HF in mice by acting on and restoring altered cAMP compartmentation in distinct subcellular microdomains. Methods and results HF was induced by transverse aortic constriction followed by tail-vein injection of adeno-associated-virus type 9 vectors to overexpress PDE2A3, PDE4B3, or luciferase for 8 weeks. Heart morphology and function was assessed by echocardiography and histology which showed that PDE2A and especially PDE4B gene therapy could attenuate cardiac hypertrophy, fibrosis, and decline of contractile function. Live cell imaging using targeted cAMP biosensors showed that PDE overexpression restored altered cAMP compartmentation in microdomains associated with ryanodine receptor type 2 (RyR2) and caveolin-rich plasma membrane. This was accompanied by ameliorated caveolin-3 decline after PDE2A3 overexpression, reduced RyR2 phosphorylation in PDE4B3 overexpressing hearts, and antiarrhythmic effects of both PDEs measured under isoproterenol stimulation in single cells. Strong association of overexpressed PDE4B but not PDE2A with RyR2 microdomain could prevent calcium leak and arrhythmias in human-induced pluripotent stem-derived cardiomyocytes with the A2254V mutation in RyR2 causing catecholaminergic polymorphic ventricular tachycardia. Conclusion Our data indicate that gene therapy with phosphodiesterases can prevent HF including associated cardiac remodelling and arrhythmias by restoring altered cAMP compartmentation in functionally relevant subcellular microdomains. [ABSTRACT FROM AUTHOR]

Bidirectional ventricular tachycardia is a unique arrhythmia that can herald lethal arrhythmia syndromes. Using cases based on real patient stories, this article examines 3 different presentations to help clinicians learn the differential diagnosis associated with this condition. Each associated genetic disorder will be briefly discussed, and valuable tips for distinguishing them from each other will be provided. [ABSTRACT FROM AUTHOR]

Genome-wide association studies have identified several hundred loci associated with type 2 diabetes mellitus (T2DM). Additionally, pathogenic variants in several genes are known to cause monogenic diabetes that overlaps clinically with T2DM. Whole-exome sequencing of related individuals with T2DM is a powerful approach to identify novel high-penetrance disease variants in coding regions of the genome. We performed whole-exome sequencing on four related individuals with T2DM - including one individual diagnosed at the age of 33 years. The individuals were negative for mutations in monogenic diabetes genes, had a strong family history of T2DM, and presented with several characteristics of metabolic syndrome. A missense variant (p.N2291D) in the type 2 ryanodine receptor (RyR2) gene was one of eight rare coding variants shared by all individuals. The variant was absent in large population databases and affects a highly conserved amino acid located in a mutational hotspot for pathogenic variants in Catecholaminergic polymorphic ventricular tachycardia (CPVT). Electrocardiogram data did not reveal any cardiac abnormalities except a lower-than-normal resting heart rate (< 60 bpm) in two individuals - a phenotype observed in CPVT individuals with RyR2 mutations. RyR2-mediated Ca2+ release contributes to glucose-mediated insulin secretion and pathogenic RyR2 mutations cause glucose intolerance in humans and mice. Analysis of glucose tolerance testing data revealed that missense mutations in a CPVT mutation hotspot region - overlapping the p.N2291D variant - are associated with complete penetrance for glucose intolerance. In conclusion, we have identified an atypical missense variant in the RyR2 gene that co-segregates with diabetes in the absence of overt CPVT. [ABSTRACT FROM AUTHOR]

Primary electrical heart diseases, often considered channelopathies, are inherited genetic abnormalities of cardiomyocyte electrical behavior carrying the risk of malignant arrhythmias leading to sudden cardiac death (SCD). Approximately 54% of sudden, unexpected deaths in individuals under the age of 35 do not exhibit signs of structural heart disease during autopsy, suggesting the potential significance of channelopathies in this group of age. Channelopathies constitute a highly heterogenous group comprising various diseases such as long QT syndrome (LQTS), short QT syndrome (SQTS), idiopathic ventricular fibrillation (IVF), Brugada syndrome (BrS), catecholaminergic polymorphic ventricular tachycardia (CPVT), and early repolarization syndromes (ERS). Although new advances in the diagnostic process of channelopathies have been made, the link between a disease and sudden cardiac death remains not fully explained. Evolving data in electrophysiology and genetic testing suggest previously described diseases as complex with multiple underlying genes and a high variety of factors associated with SCD in channelopathies. This review summarizes available, well-established information about channelopathy pathogenesis, genetic basics, and molecular aspects relative to principles of the pathophysiology of arrhythmia. In addition, general information about diagnostic approaches and management is presented. Analyzing principles of channelopathies and their underlying causes improves the understanding of genetic and molecular basics that may assist general research and improve SCD prevention. [ABSTRACT FROM AUTHOR]

A 10-year-old female patient experienced syncope while swimming, and electrocardiography revealed polymorphic ventricular tachycardia, leading to a diagnosis of catecholaminergic polymorphic ventricular tachycardia. No pathogenic variant was identified in RYR2. Additional comprehensive genetic testing revealed novel compound heterozygous variants in trans-2,3-enoyl-coenzyme A reductase–like gene, which caused a recessive form of catecholaminergic polymorphic ventricular tachycardia.

This study presents a dynamic simulation of a combined cooling, heating, and power (CCHP) configuration powered by concentrating photovoltaic thermal (CPVT) collectors. The desired configuration comprises CPVT collectors, a phase change material (PCM) storage tank, an organic Rankine cycle (ORC), an absorption chiller, and heat exchangers. The evaluation has been carried out for a residential building using EES, MATLAB, and TRNSYS software. Moreover, an auxiliary heater has been used to provide the thermal energy of the desired configuration in case of low or no solar irradiation. The desired configuration has been evaluated from energy, exergy, and economic points of view during the warm months of the year (May to September). Also, the influences of key parameters of the desired system such as the CPVT area, CPVT flow rate, and PCM melting temperature on the performance of the desired configuration have been examined. The results indicate that the solar fraction enhances by about 161 % when the CPVT area changes from 100 m2 to 400 m2. Also, CPVT has found to be the main contributor to exergy destruction, accounting for 49% of the total. The maximum energy and exergy efficiencies of the desired configuration are obtained at the CPVT area of 400 m2 with values of 72.26 % and 79.03 % respectively. On the other hand, the lowest payback period occurs at 100 m2 with value of 11 years.

Background: In sudden cardiac arrest survivors without an immediately identifiable cause, additional extensive yet individualised testing is required. Methods: We describe 3 survivors of sudden cardiac arrest in whom exercise stress testing was not performed during the initial hospital admission. Results: All 3 patients were incorrectly diagnosed with long QT syndrome based on temporary sudden cardiac arrest–related heart rate–corrected QT interval prolongation, and exercise stress testing was not performed during the initial work-up. When they were subjected to exercise stress testing during follow-up, a delayed diagnosis of catecholaminergic polymorphic ventricular tachycardia (CPVT) was made. As a result, these patients were initially managed inappropriately, and their family members were initially not screened for CPVT. Conclusion: In sudden cardiac arrest survivors without an immediately identifiable cause, omission of exercise stress testing or erroneous interpretation of the results can lead to a delayed or missed diagnosis of CPVT, which may have considerable implications for survivors and their family. [ABSTRACT FROM AUTHOR]

Genome-wide association studies have identified several hundred loci associated with type 2 diabetes mellitus (T2DM). Additionally, pathogenic variants in several genes are known to cause monogenic diabetes that overlaps clinically with T2DM. Whole-exome sequencing of related individuals with T2DM is a powerful approach to identify novel high-penetrance disease variants in coding regions of the genome. We performed whole-exome sequencing on four related individuals with T2DM – including one individual diagnosed at the age of 33 years. The individuals were negative for mutations in monogenic diabetes genes, had a strong family history of T2DM, and presented with several characteristics of metabolic syndrome. A missense variant (p.N2291D) in the type 2 ryanodine receptor (RyR2) gene was one of eight rare coding variants shared by all individuals. The variant was absent in large population databases and affects a highly conserved amino acid located in a mutational hotspot for pathogenic variants in Catecholaminergic polymorphic ventricular tachycardia (CPVT). Electrocardiogram data did not reveal any cardiac abnormalities except a lower-than-normal resting heart rate (< 60 bpm) in two individuals – a phenotype observed in CPVT individuals with RyR2 mutations. RyR2-mediated Ca2+ release contributes to glucose-mediated insulin secretion and pathogenic RyR2 mutations cause glucose intolerance in humans and mice. Analysis of glucose tolerance testing data revealed that missense mutations in a CPVT mutation hotspot region – overlapping the p.N2291D variant – are associated with complete penetrance for glucose intolerance. In conclusion, we have identified an atypical missense variant in the RyR2 gene that co-segregates with diabetes in the absence of overt CPVT.

Introduction: We describe a unique case of TECRL‐CPVT presented with cardiac arrest. Methods: Post resuscitation, the patient developed regular ventricular tachycardia featuring a left purkinje system morphology. Results: There was clear suppression of arrhythmia with the addition of flecainide and isolated ventricular ectopy causing secondary T‐wave changes. Conclusion: A high index of suspicion was required to eventually make the diagnosis through whole exome sequencing. [ABSTRACT FROM AUTHOR]

Concentrating PV thermal (CPVT) collector with spectral splitting technology is a promising solution for heat and electricity production. To extend the use of this technology, a novel and cost-effective CPVT collector for harsh environments, such as those in Saudi Arabia, is presented and evaluated using theoretical energy, economy, and environmental analysis. Two questions are answered in this study, namely: which is the best operation strategy, and which is the best energy storage technology for CPVT. The potential of using a CPVT under the climate conditions of six cities in Saudi Arabia is also evaluated. It is found that a heat/electricity production strategy and a thermal energy storage are the most suitable for the CPVT technology. The economic assessment shows a levelized cost of electricity (LCOE) of $0.0847/kWh and a levelized cost of heat (LCOH) of $0.0536/kWh when water is used as a spectral filter, and a LCOE of $0.0906/kWh and a LCOH of $0.0462/kWh when ZnO nanoparticles are added. The CO2-equivalent emissions in a 20 MW CPVT plant are cut from 5675 tonnes to 7822 tonnes per year for Saudi Arabian weather and present power generation conditions. [ABSTRACT FROM AUTHOR]

BackgroundSarcoplasmic reticulum Ca2+ leak and post-translational modifications under stress have been implicated in catecholaminergic polymorphic ventricular tachycardia (CPVT), a highly lethal inherited arrhythmogenic disorder. Human induced pluripotent stem cells (hiPSCs) offer a unique opportunity for disease modeling.ObjectiveThe aims were to obtain functional hiPSC-derived cardiomyocytes from a CPVT patient harboring a novel ryanodine receptor (RyR2) mutation and model the syndrome, drug responses and investigate the molecular mechanisms associated to the CPVT syndrome.MethodsPatient-specific cardiomyocytes were generated from a young athletic female diagnosed with CPVT. The contractile, intracellular Ca2+ handling and electrophysiological properties as well as the RyR2 macromolecular remodeling were studied.ResultsExercise stress electrocardiography revealed polymorphic ventricular tachycardia when treated with metoprolol and marked improvement with flecainide alone. We found abnormal stress-induced contractile and electrophysiological properties associated with sarcoplasmic reticulum Ca2+ leak in CPVT hiPSC-derived cardiomyocytes. We found inadequate response to metoprolol and a potent response of flecainide. Stabilizing RyR2 with a Rycal compound prevents those abnormalities specifically in CPVT hiPSC-derived cardiomyocytes. The RyR2-D3638A mutation is located in the conformational change inducing-central core domain and leads to RyR2 macromolecular remodeling including depletion of PP2A and Calstabin2.ConclusionWe identified a novel RyR2-D3638A mutation causing 3D conformational defects and aberrant biophysical properties associated to RyR2 macromolecular complex post-translational remodeling. The molecular remodeling is for the first time revealed using patient-specific hiPSC-derived cardiomyocytes which may explain the CPVT proband's resistance. Our study promotes hiPSC-derived cardiomyocytes as a suitable model for disease modeling, testing new therapeutic compounds, personalized medicine and deciphering underlying molecular mechanisms.

The heat absorbed by the heat transfer fluid for cooling a concentrated photovoltaic thermal (CPVT) solar collector can be used for purposes such as residential heating and cooking. Because of the combined production of heat and power, these systems are proposed for individual or commercial use in rural areas. In this study, a hybrid system was proposed to increase the electrical efficiency of the system. Experiments were conducted in winter conditions. Two operational modes were compared, namely a CPVT system with HP (HP-CPVT) and without HP (CPVT). The evaporator of the heat pump was settled inside the triangular trough receiver. The effects of cooling the PV system with a heat pump in the bifacial CPVT system on the electrical and thermal energy efficiencies were investigated. The electricity and thermal energy efficiencies of the CPVT system were calculated as 12.54% and 38.37% in the HP-CPVT system, respectively, and 10.05% and 81.97% in the CPVT system, respectively. The electrical exergy efficiencies of the CPVT system with and without HP were 14.65% and 10.73%, respectively. The thermal exergy efficiencies of the CPVT system with and without HP were 82.47% and 85.63%, respectively. The thermal heat obtained from the HP-CPVT system can be used for heating needs. Thus, the bifacial HP-CPVT system was an example of the micro-CHP system. [ABSTRACT FROM AUTHOR]

The brief opening mode of the mitochondrial permeability transition pore (mPTP) serves as a calcium (Ca2+) release valve to prevent mitochondrial Ca2+ (mCa2+) overload. Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a stress-induced arrhythmic syndrome due to mutations in the Ca2+ release channel complex of ryanodine receptor 2 (RyR2). We hypothesize that inhibiting the mPTP opening in CPVT exacerbates the disease phenotype. By crossbreeding a CPVT model of CASQ2 knockout (KO) with a mouse missing CypD, an activator of mPTP, a double KO model (DKO) was generated. Echocardiography, cardiac histology, and live-cell imaging were employed to assess the severity of cardiac pathology. Western blot and RNAseq were performed to evaluate the contribution of various signaling pathways. Although exacerbated arrhythmias were reported, the DKO model did not exhibit pathological remodeling. Myocyte Ca2+ handling was similar to that of the CASQ2 KO mouse at a low pacing frequency. However, increased ROS production, activation of the CaMKII pathway, and hyperphosphorylation of RyR2 were detected in DKO. Transcriptome analysis identified altered gene expression profiles associated with electrical instability in DKO. Our study provides evidence that genetic inhibition of mPTP exacerbates RyR2 dysfunction in CPVT by increasing activation of the CaMKII pathway and subsequent hyperphosphorylation of RyR2. [ABSTRACT FROM AUTHOR]

Mutations in the calcium-sensing protein calmodulin (CaM) have been linked to two cardiac arrhythmia diseases, Long QT Syndrome 14 (LQT14) and Catecholaminergic Polymorphic Ventricular Tachycardia Type 4 (CPVT4), with varying degrees of severity. Functional characterization of the CaM mutants most strongly associated with LQT14 show a clear disruption of the calcium-dependent inactivation (CDI) of the L-Type calcium channel (LCC). CPVT4 mutants on the other hand are associated with changes in their affinity to the ryanodine receptor. In clinical studies, some variants have been associated with both CPVT4 and LQT15. This study uses simulations in a model for excitation–contraction coupling in the rat ventricular myocytes to understand how LQT14 variant might give the functional phenotype similar to CPVT4. Changing the CaM-dependent transition rate by a factor of 0.75 corresponding to the D96V variant and by a factor of 0.90 corresponding to the F142L or N98S variants, in a physiologically based stochastic model of the LCC prolonger, the action potential duration changed by a small amount in a cardiac myocyte but did not disrupt CICR at 1, 2, and 4 Hz. Under beta-adrenergic simulation abnormal excitation–contraction coupling was observed above 2 Hz pacing for the mutant CaM. The same conditions applied under beta-adrenergic stimulation led to the rapid onset of arrhythmia in the mutant CaM simulations. Simulations with the LQT14 mutations under the conditions of rapid pacing with beta-adrenergic stimulation drives the cardiac myocyte toward an arrhythmic state known as Ca2+ overload. These simulations provide a mechanistic link to a disease state for LQT14-associated mutations in CaM to yield a CPVT4 phenotype. The results show that small changes to the CaM-regulated inactivation of LCC promote arrhythmia and underscore the significance of CDI in proper heart function. [ABSTRACT FROM AUTHOR]

Background: This study examined the clinical characteristics, genetic basis, healthcare utilisation and costs of catecholaminergic ventricular tachycardia (CPVT) patients from a Chinese city. Methods: This was a territory-wide retrospective cohort study of consecutive CPVT patients at public hospitals or clinics in Hong Kong. Healthcare resource utilisation for accident and emergency (A&E), inpatient and outpatient attendances were analysed over 19 years (2001-2019) followed by calculations of annualised costs (in USD). Results: Sixteen patients with a median presentation age (interquartile range (IQR) of 11 (9-14) years old) were included. Fifteen patients (93.8%) were initially symptomatic. Ten patients had both premature ventricular complexes (PVCs) and ventricular tachycardia/fibrillation (VT/VF). One patient had PVCs without VT/VF. Genetic tests were performed on 14 patients (87.5%). Eight (57.1%) tested positive for the ryanodine receptor 2 (RyR2) gene. Seven variants have been described elsewhere (c.14848G>A, c.12475C>A, c.7420A>G, c.11836G>A, c.14159T>C, c.10046C>T and c.7202G>A). c.14861C>G is a novel RyR2 variant not been reported outside this cohort. Patients were treated with beta-blockers (n = 16), amiodarone (n = 3) and verapamil (n = 2). Sympathectomy (n = 8) and implantable-cardioverter defibrillator implantation (n = 3) were performed. Over a median follow-up of 13.3 years (IQR: 8.4-18.1) years, six patients exhibited incident VT/VF. At the patient level, the median (IQR) annualised costs for A&E, inpatient and outpatient attendances were $66 (40-95), $10521 (5240-66887) and $791 (546-1105), respectively. Conclusions: All patients presented before the age of 19. The yield of genetic testing was 57%. The most expensive attendance type was inpatient stays, followed by outpatients and A&E attendances. [ABSTRACT FROM AUTHOR]

Based on the different requirements of solar energy integrated with buildings, a hybrid photovoltaic and thermal solar energy collector with integrated phase change material (PVT-PCM) have been developed. The thermal system combines air-based and water-based conditions to meet the building heat demand in different seasons. In addition, PCM is used to absorb the heat that was not taken away by the thermal system. And the vessel is optimized to enhance its thermal conductivity. The results of cross-season test show that the overall efficiency of the system is 39.4%, and the energy-saving efficiency is 64.2%. The system controls the temperature and utilizes the heat through the thermal system. The economic analysis and energy saving potential of the system in low latitude areas are analyzed. The results show that the additional payback period of the system is 13.1 years. And based on the local energy structure, the maximum CO 2 emission can be reduced by 156.1 kg/year. The optimization systems BPVT and CPVT are proposed, and simulation and analysis results show that BPVT is more valuable for further exploration. Compared with the traditional PV system, PVT-PCM system improved the comprehensive utilization rate of solar energy and has a broader research and development prospect. • A new PVT system with switchable working status is designed. • ●The system has potential to reduce CO 2 emissions combined with energy structures. • ●The 13.1 years additional investment payback period show good application potential. • ●The optimization systems are proposed and predicted for further exploration. [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]

Introduction: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare inherited cardiac ion channelopathy. The present study aims to examine the clinical characteristics, genetic basis, and arrhythmic outcomes of CPVT patients from China to elucidate the difference between CPVT patients in Asia and Western countries. Methods: PubMed and Embase were systematically searched for case reports or series reporting on CPVT patients from China until 19 February 2022 using the keyword: "Catecholaminergic Polymorphic Ventricular Tachycardia" or "CPVT", with the location limited to: "China" or "Hong Kong" or "Macau" in Embase, with no language or publication-type restriction. Articles that did not state a definite diagnosis of CPVT and articles with duplicate cases found in larger cohorts were excluded. All the included publications in this review were critically appraised based on the Joanna Briggs Institute Critical Appraisal Checklist. Clinical characteristics, genetic findings, and the primary outcome of spontaneous ventricular tachycardia/ventricular fibrillation (VT/VF) were analyzed. Results: A total of 58 unique cases from 15 studies (median presentation age: 8 (5.0–11.8) years old) were included. All patients, except one, presented at or before 19 years of age. There were 56 patients (96.6%) who were initially symptomatic. Premature ventricular complexes (PVCs) were present in 44 out of 51 patients (86.3%) and VT in 52 out of 58 patients (89.7%). Genetic tests were performed on 54 patients (93.1%) with a yield of 87%. RyR2, CASQ2, TERCL, and SCN10A mutations were found in 35 (71.4%), 12 (24.5%), 1 (0.02%) patient, and 1 patient (0.02%), respectively. There were 54 patients who were treated with beta-blockers, 8 received flecainide, 5 received amiodarone, 2 received verapamil and 2 received propafenone. Sympathectomy (n = 10), implantable cardioverter-defibrillator implantation (n = 8) and ablation (n = 1) were performed. On follow-up, 13 patients developed VT/VF. Conclusion: This was the first systematic review of CPVT patients from China. Most patients had symptoms on initial presentation, with syncope as the presenting complaint. RyR2 mutation accounts for more than half of the CPVT cases, followed by CASQ2, TERCL and SCN10A mutations. [ABSTRACT FROM AUTHOR]

Concentrating PV thermal (CPVT) collector with spectral splitting technology is a promising solution for heat and electricity production. To extend the use of this technology, a novel and cost-effective CPVT collector for harsh environments, such as those in Saudi Arabia, is presented and evaluated using theoretical energy, economy, and environmental analysis. Two questions are answered in this study, namely: which is the best operation strategy, and which is the best energy storage technology for CPVT. The potential of using a CPVT under the climate conditions of six cities in Saudi Arabia is also evaluated. It is found that a heat/electricity production strategy and a thermal energy storage are the most suitable for the CPVT technology. The economic assessment shows a levelized cost of electricity (LCOE) of $0.0847/kWh and a levelized cost of heat (LCOH) of $0.0536/kWh when water is used as a spectral filter, and a LCOE of $0.0906/kWh and a LCOH of $0.0462/kWh when ZnO nanoparticles are added. The CO2-equivalent emissions in a 20 MW CPVT plant are cut from 5675 tonnes to 7822 tonnes per year for Saudi Arabian weather and present power generation conditions.

Refrigeration systems have a broad range of applications, playing a critical role in human life. Especially, vaccine preservation in rural regions has become more critical than in the past during the COVID19 era. In this sense, meeting the cooling process's energy need with renewable energy is critical, as the grid cannot support it. Thus, solar energy has been extensively studied for use in refrigeration cycles. Compression, absorption, adsorption, desiccant, and ejector refrigeration cycles are frequently used in this configuration. This article discusses multiple studies showing various attributes' impact on a system's overall efficiency. Most previous reviews did not cover PV with refrigeration cycles. So, this paper surveys the literature on PV-powered cooling cycles. For better classification, PV technologies are categorized into three types: PV, PVT, and CPVT. With this regard, CPVTs still have a way to progress due to a lack of studies compared to PV. The works are divided into three main sections as Exergy Studies, Experimental Studies, and Simulation and Numerical Studies. This review paper categorizes and rates refrigeration-assisted solar systems based on exergy destruction, exergy efficiency, and COP of cooling cycles. The results showed that PV panels have the highest exergy destruction in most of the systems. It is concluded that using PV technologies has a great potential to supply cooling demand, especially in a hot climate condition. Moreover, the study's findings are anticipated to aid designers in scaling up photovoltaic-based cooling systems, resulting in more efficient and sustainable designs. [ABSTRACT FROM AUTHOR]

Provide a brief summary of your article (100–150 words; no references or figures/tables). The synopsis appears only in the table of contents and is often used by indexing services such as PubMed. Genetic arrhythmia syndromes are rare, yet harbor the potential for highly consequential, often unpredictable arrhythmias or sudden death events. There has been historical uncertainty regarding the correct advice to offer to affected patients who are reasonably wanting to participate in sporting and athletic endeavors. In some cases, this had led to abundantly cautious disqualifications, depriving individuals from participation unnecessarily. Societal guidance and expert opinion has evolved significantly over the last decade or 2, along with our understanding of the genetics and natural history of these conditions, and the emphasis has switched toward shared decision making with respect to the decision to participate or not, with patients and families becoming better informed, and willing participants in the decision making process. This review aims to give a brief update of the salient issues for the busy physician concerning these syndromes and to provide a framework for approaching their management in the otherwise aspirational or keen sports participant. [ABSTRACT FROM AUTHOR]

Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is a rare electrical genetic disease characterized by ventricular polymorphic tachycardia and/or bidirectional ventricular tachycardia induced by the release of catecholamines caused by intense physical or emotional stress in structurally normal hearts. Mostly, it is caused by mutations in genes that are involved in calcium homeostasis, in particular in the gene encoding for cardiac ryanodine receptor (RyR2). Our observation is the first description of familial CPVT caused by mutation of the RyR2 gene, linked to the complete AV block.

Heterozygous missense variants of the cardiac ryanodine receptor gene (RYR2) cause catecholaminergic polymorphic ventricular tachycardia (CPVT). These missense variants of RYR2 result in a gain of function of the ryanodine receptors, characterized by increased sensitivity to activation by calcium that results in an increased propensity to develop calcium waves and delayed afterdepolarizations. We have recently detected a nonsense variant in RYR2 in a young patient who suffered an unexplained cardiac arrest. To understand the mechanism by which this variant in RYR2, p.(Arg4790Ter), leads to ventricular arrhythmias, human induced pluripotent stem cells (hiPSCs) harboring the novel nonsense variant in RYR2 were generated and differentiated into cardiomyocytes (RYR2‐hiPSC‐CMs) and molecular and calcium handling properties were studied. RYR2‐hiPSC‐CMs displayed significant calcium handling abnormalities at baseline and following treatment with isoproterenol. Treatment with carvedilol and nebivolol resulted in a significant reduction in calcium handling abnormalities in the RYR2‐hiPSC‐CMs. Expression of the mutant RYR2 allele was confirmed at the mRNA level and partial silencing of the mutant allele resulted in a reduction in calcium handling abnormalities at baseline. The nonsense variant behaves similarly to other gain of function variants in RYR2. Carvedilol and nebivolol may be suitable treatments for patients with gain of function RYR2 variants. [ABSTRACT FROM AUTHOR]

Cardiac diseases are the leading causes of death, with a growing number of cases worldwide, posing a challenge for both healthcare and research. Therefore, the most relevant aim of cardiac research is to unravel the molecular pathomechanisms and identify new therapeutic targets. Cardiac ryanodine receptor (RyR2), the Ca2+ release channel of the sarcoplasmic reticulum, is believed to be a good therapeutic target in a group of certain heart diseases, collectively called cardiac ryanopathies. Ryanopathies are associated with the impaired function of the RyR, leading to heart diseases such as congestive heart failure (CHF), catecholaminergic polymorphic ventricular tachycardia (CPVT), arrhythmogenic right ventricular dysplasia type 2 (ARVD2), and calcium release deficiency syndrome (CRDS). The aim of the current review is to provide a short insight into the pathological mechanisms of ryanopathies and discuss the pharmacological approaches targeting RyR2. [ABSTRACT FROM AUTHOR]

Human induced pluripotent stem cells (hiPSCs) can be used to generate various cell types in the human body. Hence, hiPSC-derived cardiomyocytes (hiPSC-CMs) represent a significant cell source for disease modeling, drug testing, and regenerative medicine. The immaturity of hiPSC-CMs in two-dimensional (2D) culture limit their applications. Cardiac tissue engineering provides a new promise for both basic and clinical research. Advanced bioengineered cardiac in vitro models can create contractile structures that serve as exquisite in vitro heart microtissues for drug testing and disease modeling, thereby promoting the identification of better treatments for cardiovascular disorders. In this review, we will introduce recent advances of bioengineering technologies to produce in vitro cardiac tissues derived from hiPSCs. [ABSTRACT FROM AUTHOR]

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited disturbance of the heart rhythm (arrhythmia) that is induced by stress or that occurs during exercise. Most mutations that have been linked to CPVT are found in two genes, i.e., ryanodine receptor 2 (RyR2) and calsequestrin 2 (CASQ2), two proteins fundamentally involved in the regulation of intracellular Ca2+ in cardiac myocytes. We inserted six CPVT-causing mutations via clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 into unc-68 and csq-1 , the Caenorhabditis elegans homologs of RyR and CASQ, respectively. We characterized those mutations via video-microscopy, electrophysiology, and calcium imaging in our previously established optogenetic arrhythmia model. In this study, we additionally enabled high(er) throughput recordings of intact animals by combining optogenetic stimulation with a microfluidic chip system. Whereas only minor/no pump deficiency of the pharynx was observed at baseline, three mutations of UNC-68 (S2378L, P2460S, Q4623R; RyR2-S2246L, -P2328S, -Q4201R) reduced the ability of the organ to follow 4 Hz optogenetic stimulation. One mutation (Q4623R) was accompanied by a strong reduction of maximal pump rate. In addition, S2378L and Q4623R evoked an altered calcium handling during optogenetic stimulation. The 1,4-benzothiazepine S107, which is suggested to stabilize RyR2 channels by enhancing the binding of calstabin2, reversed the reduction of pumping ability in a mutation-specific fashion. However, this depends on the presence of FKB-2, a C. elegans calstabin2 homolog, indicating the involvement of calstabin2 in the disease-causing mechanisms of the respective mutations. In conclusion, we showed for three CPVT-like mutations in C. elegans RyR a reduced pumping ability upon light stimulation, i.e., an arrhythmia-like phenotype, that can be reversed in two cases by the benzothiazepine S107 and that depends on stabilization via FKB-2. The genetically amenable nematode in combination with optogenetics and high(er) throughput recordings is a promising straightforward system for the investigation of RyR mutations and the selection of mutation-specific drugs. [ABSTRACT FROM AUTHOR]

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an arrhythmogenic syndrome characterized by life‐threatening arrhythmias, a normal resting electrocardiogram and the absence of overt structural heart abnormalities. Mutations in RyR2 gene account for the large part of CPVT cases. Less frequently, mutations in CASQ2 gene have been linked to the recessive form of the disease. Overall, approximately 35% of CPVT patients remain without a genetic etiology implying that other genes might be found causative of the disease. Here, we present a 6‐year‐old boy born to first‐degree related parents, with a typical phenotype of CPVT and a family history of sudden cardiac death of his brother at 7 years. A trio‐based whole exome sequencing was performed, and we identified a homozygous variant in AGRN gene and a heterozygous variant in RPL3L gene. We hypothesized that the presence of the homozygous variant in AGRN accounts for the CPVT phenotype in this family and the heterozygous variant in RPL3L gene may act as a modifier gene. Further studies are needed to determine the role of these genes in CPVT. [ABSTRACT FROM AUTHOR]

Abstract Heterozygous missense variants of the cardiac ryanodine receptor gene (RYR2) cause catecholaminergic polymorphic ventricular tachycardia (CPVT). These missense variants of RYR2 result in a gain of function of the ryanodine receptors, characterized by increased sensitivity to activation by calcium that results in an increased propensity to develop calcium waves and delayed afterdepolarizations. We have recently detected a nonsense variant in RYR2 in a young patient who suffered an unexplained cardiac arrest. To understand the mechanism by which this variant in RYR2, p.(Arg4790Ter), leads to ventricular arrhythmias, human induced pluripotent stem cells (hiPSCs) harboring the novel nonsense variant in RYR2 were generated and differentiated into cardiomyocytes (RYR2‐hiPSC‐CMs) and molecular and calcium handling properties were studied. RYR2‐hiPSC‐CMs displayed significant calcium handling abnormalities at baseline and following treatment with isoproterenol. Treatment with carvedilol and nebivolol resulted in a significant reduction in calcium handling abnormalities in the RYR2‐hiPSC‐CMs. Expression of the mutant RYR2 allele was confirmed at the mRNA level and partial silencing of the mutant allele resulted in a reduction in calcium handling abnormalities at baseline. The nonsense variant behaves similarly to other gain of function variants in RYR2. Carvedilol and nebivolol may be suitable treatments for patients with gain of function RYR2 variants.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited disturbance of the heart rhythm (arrhythmia) that is induced by stress or that occurs during exercise. Most mutations that have been linked to CPVT are found in two genes, i.e., ryanodine receptor 2 (RyR2) and calsequestrin 2 (CASQ2), two proteins fundamentally involved in the regulation of intracellular Ca2+ in cardiac myocytes. We inserted six CPVT-causing mutations via clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 into unc-68 and csq-1, the Caenorhabditis elegans homologs of RyR and CASQ, respectively. We characterized those mutations via video-microscopy, electrophysiology, and calcium imaging in our previously established optogenetic arrhythmia model. In this study, we additionally enabled high(er) throughput recordings of intact animals by combining optogenetic stimulation with a microfluidic chip system. Whereas only minor/no pump deficiency of the pharynx was observed at baseline, three mutations of UNC-68 (S2378L, P2460S, Q4623R; RyR2-S2246L, -P2328S, -Q4201R) reduced the ability of the organ to follow 4 Hz optogenetic stimulation. One mutation (Q4623R) was accompanied by a strong reduction of maximal pump rate. In addition, S2378L and Q4623R evoked an altered calcium handling during optogenetic stimulation. The 1,4-benzothiazepine S107, which is suggested to stabilize RyR2 channels by enhancing the binding of calstabin2, reversed the reduction of pumping ability in a mutation-specific fashion. However, this depends on the presence of FKB-2, a C. elegans calstabin2 homolog, indicating the involvement of calstabin2 in the disease-causing mechanisms of the respective mutations. In conclusion, we showed for three CPVT-like mutations in C. elegans RyR a reduced pumping ability upon light stimulation, i.e., an arrhythmia-like phenotype, that can be reversed in two cases by the benzothiazepine S107 and that depends on stabilization via FKB-2. The genetically amenable nematode in combination with optogenetics and high(er) throughput recordings is a promising straightforward system for the investigation of RyR mutations and the selection of mutation-specific drugs.

Abstract Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an arrhythmogenic syndrome characterized by life‐threatening arrhythmias, a normal resting electrocardiogram and the absence of overt structural heart abnormalities. Mutations in RyR2 gene account for the large part of CPVT cases. Less frequently, mutations in CASQ2 gene have been linked to the recessive form of the disease. Overall, approximately 35% of CPVT patients remain without a genetic etiology implying that other genes might be found causative of the disease. Here, we present a 6‐year‐old boy born to first‐degree related parents, with a typical phenotype of CPVT and a family history of sudden cardiac death of his brother at 7 years. A trio‐based whole exome sequencing was performed, and we identified a homozygous variant in AGRN gene and a heterozygous variant in RPL3L gene. We hypothesized that the presence of the homozygous variant in AGRN accounts for the CPVT phenotype in this family and the heterozygous variant in RPL3L gene may act as a modifier gene. Further studies are needed to determine the role of these genes in CPVT.

BackgroundCatecholaminergic polymorphic ventricular tachycardia (CPVT) is a lethal inherited arrhythmia syndrome characterized by adrenergically stimulated ventricular tachycardia. Mutations in the cardiac ryanodine receptor gene (RYR2) cause an autosomal dominant form of CPVT, while mutations in the cardiac calsequestrin 2 gene (CASQ2) cause an autosomal recessive form.ObjectiveThe aim of this study was to clinically and genetically evaluate a large family with severe autosomal dominant CPVT.MethodsClinical evaluation of family members was performed, including detailed history, physical examination, electrocardiogram, exercise stress test, and autopsy review of decedents. We performed genome-wide linkage analysis in 12 family members and exome sequencing in 2 affected family members. In silico models of mouse and rabbit myocyte electrophysiology were used to predict potential disease mechanisms.ResultsSevere CPVT with dominant inheritance in 6 members was diagnosed in a large family with 2 sudden deaths, 2 resuscitated cardiac arrests, and multiple appropriate implantable cardioverter-defibrillator shocks. A comprehensive analysis of cardiac arrhythmia genes did not reveal a pathogenic variant. Exome sequencing identified a novel heterozygous missense variant in CASQ2 (Lys180Arg) affecting a highly conserved residue, which cosegregated with disease and was absent in unaffected family members. Genome-wide linkage analysis confirmed a single linkage peak at the CASQ2 locus (logarithm of odds ratio score 3.01; θ = 0). Computer simulations predicted that haploinsufficiency was unlikely to cause the severe CPVT phenotype and suggested a dominant negative mechanism.ConclusionWe show for the first time that a variant in CASQ2 causes autosomal dominant CPVT. Genetic testing in dominant CPVT should include screening for heterozygous CASQ2 variants.

Background Differential diagnosis of recurrent syncope is a routine procedure in clinical practice. Most of these syncopes are benign reflex syncopes but identifying patients with cardiac syncope is crucial to prevent fatal outcomes. Case summary In this case report, we present the case of a young athlete with recurrent unexplained syncope referred to us for a second opinion. Despite normal resting-electrocardiography and echocardiography, he developed frequent polymorphic and bidirectional premature ventricular contractions during exercise. Genetic testing confirmed a mutation in the RyR2-gene and the diagnosis of catecholaminergic polymorphic ventricular tachycardia was made. A medical therapy with betablockers was initiated but poorly tolerated, so that an implantable cardioverter-defibrillator was implanted. Furthermore, family screening revealed his mother and his sister to be genetic carriers as well. Implantable cardioverter-defibrillator implantation was performed in both family members. The patient did not experience any syncope or arrhythmic episodes during the follow-up period. Discussion This case report highlights the importance of thorough diagnostic and potential pitfalls in patients with unexplained syncope. Sometimes, the diagnostic steps need to be extended or repeated to detect rare or potential malignant causes of syncope. [ABSTRACT FROM AUTHOR]

Background and Purpose: Treatment of cardiac arrhythmia remains challenging due to severe side effects of common anti-arrhythmic drugs. We previously demonstrated that mitochondrial Ca2+ uptake in cardiomyocytes represents a promising new candidate structure for safer drug therapy. However, druggable agonists of mitochondrial Ca2+ uptake suitable for preclinical and clinical studies are still missing.Experimental Approach: Herewe screened 727 compounds with a history of use in human clinical trials in a three-step screening approach. As a primary screening platform we used a permeabilized HeLa cell-based mitochondrial Ca2+ uptake assay. Hits were validated in cultured HL-1 cardiomyocytes and finally tested for anti-arrhythmic efficacy in three translational models: a Ca2+ overload zebrafish model and cardiomyocytes of both a mouse model for catecholaminergic polymorphic ventricular tachycardia (CPVT) and induced pluripotent stem cell derived cardiomyocytes from a CPVT patient.Key Results: We identifiedtwo candidate compounds, the clinically approved drugs ezetimibe and disulfiram, which stimulate SR-mitochondria Ca2+ transfer at nanomolar concentrations. This is significantly lower compared to the previously described mitochondrial Ca2+ uptake enhancers (MiCUps) efsevin, a gating modifier of the voltage-dependent anion channel 2, and kaempferol, an agonist of the mitochondrial Ca2+ uniporter. Both substances restored rhythmic cardiac contractions in a zebrafish cardiac arrhythmia model and significantly suppressed arrhythmogenesis in freshly isolated ventricular cardiomyocytes from a CPVT mouse model as well as induced pluripotent stem cell derived cardiomyocytes from a CPVT patient.Conclusion and Implications: Taken together we identified ezetimibe and disulfiram as novel MiCUps and efficient suppressors of arrhythmogenesis and as such as, promising candidates for future preclinical and clinical studies. [ABSTRACT FROM AUTHOR]

TRDN mutations cause catecholaminergic polymorphic ventricular tachycardia (CPVT) but may present with abnormal electrocardiogram (ECG) findings provoking a diagnosis of long QT syndrome (LQTS). We report two novel cases of sudden cardiac death in children due to mutations of TRDN, providing further insight into this rare and aggressive inherited arrhythmia syndrome. Whole exome sequencing (WES) was performed in two unrelated children who experienced cardiac arrest during exercise and were negative for targeted testing of LQTS. WES identified a novel homozygous splice‐site mutation in both patients, denoted c.22+1G>T, absent from gnomAD and suggesting a founder variant in the Iranian population. We now summarize the genetic architecture of all reported TRDN‐related patients, including 27 patients from 21 families. The average age‐onset was 30 months (range 1–10) for all cases. Adrenergic‐mediated cardiac events were common, occurring in 23 of 27 cases (85%). LQTS was diagnosed in 10 cases (37%), CPVT in 10 (37%) cases, and in 7 cases. No phenotypic diagnosis was provided. Five cases (15%) had evidence for associated skeletal myopathy. Four missense TRDN variants (24%) were observed in diseased cases, while the remaining variants reflect putative loss‐of‐function (LOF) mutations. No disease phenotype was reported in 26 heterozygous carriers. In conclusion, TRDN mutations cause a rare autosomal recessive arrhythmia syndrome presenting with adrenergic‐mediated arrhythmic events, but with ECG abnormalities leading to a diagnosis of LQTS in a proportion of cases. Heterozygous carriers are free of disease manifestations. [ABSTRACT FROM AUTHOR]

The brief opening mode of the mitochondrial permeability transition pore (mPTP) serves as a calcium (Ca2+) release valve to prevent mitochondrial Ca2+ (mCa2+) overload. Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a stress-induced arrhythmic syndrome due to mutations in the Ca2+ release channel complex of ryanodine receptor 2 (RyR2). We hypothesize that inhibiting the mPTP opening in CPVT exacerbates the disease phenotype. By crossbreeding a CPVT model of CASQ2 knockout (KO) with a mouse missing CypD, an activator of mPTP, a double KO model (DKO) was generated. Echocardiography, cardiac histology, and live-cell imaging were employed to assess the severity of cardiac pathology. Western blot and RNAseq were performed to evaluate the contribution of various signaling pathways. Although exacerbated arrhythmias were reported, the DKO model did not exhibit pathological remodeling. Myocyte Ca2+ handling was similar to that of the CASQ2 KO mouse at a low pacing frequency. However, increased ROS production, activation of the CaMKII pathway, and hyperphosphorylation of RyR2 were detected in DKO. Transcriptome analysis identified altered gene expression profiles associated with electrical instability in DKO. Our study provides evidence that genetic inhibition of mPTP exacerbates RyR2 dysfunction in CPVT by increasing activation of the CaMKII pathway and subsequent hyperphosphorylation of RyR2.

The heat absorbed by the heat transfer fluid for cooling a concentrated photovoltaic thermal (CPVT) solar collector can be used for purposes such as residential heating and cooking. Because of the combined production of heat and power, these systems are proposed for individual or commercial use in rural areas. In this study, a hybrid system was proposed to increase the electrical efficiency of the system. Experiments were conducted in winter conditions. Two operational modes were compared, namely a CPVT system with HP (HP-CPVT) and without HP (CPVT). The evaporator of the heat pump was settled inside the triangular trough receiver. The effects of cooling the PV system with a heat pump in the bifacial CPVT system on the electrical and thermal energy efficiencies were investigated. The electricity and thermal energy efficiencies of the CPVT system were calculated as 12.54% and 38.37% in the HP-CPVT system, respectively, and 10.05% and 81.97% in the CPVT system, respectively. The electrical exergy efficiencies of the CPVT system with and without HP were 14.65% and 10.73%, respectively. The thermal exergy efficiencies of the CPVT system with and without HP were 82.47% and 85.63%, respectively. The thermal heat obtained from the HP-CPVT system can be used for heating needs. Thus, the bifacial HP-CPVT system was an example of the micro-CHP system.

Catecholaminergic polymorphic ventricular tachycardia type 1 (CPVT1) is an inherited arrhythmogenic disorder caused by missense mutations in the cardiac ryanodine receptors (RyR2), that result in increased β‐adrenoceptor stimulation‐induced diastolic Ca2+ leak. We have previously shown that exercise training prevents arrhythmias in CPVT1, potentially by reducing the oxidation of Ca2+/calmodulin‐dependent protein kinase type II (CaMKII). Therefore, we tested whether an oxidation‐resistant form of CaMKII protects mice carrying the CPVT1‐causative mutation RyR2‐R2474S (RyR2‐RS) against arrhythmias. Antioxidant treatment (N‐acetyl‐L‐cysteine) reduced the frequency of β‐adrenoceptor stimulation‐induced arrhythmogenic Ca2+ waves in isolated cardiomyocytes from RyR2‐RS mice. To test whether the prevention of CaMKII oxidation exerts an antiarrhythmic effect, mice expressing the oxidation‐resistant CaMKII‐MM281/282VV variant (MMVV) were crossed with RyR2‐RS mice to create a double transgenic model (RyR2‐RS/MMVV). Wild‐type mice served as controls. Telemetric ECG surveillance revealed an increased incidence of ventricular tachycardia and an increased arrhythmia score in both RyR2‐RS and RyR2‐RS/MMVV compared to wild‐type mice, both following a β‐adrenoceptor challenge (isoprenaline i.p.), and following treadmill exercise combined with a β‐adrenoceptor challenge. There were no differences in the incidence of arrhythmias between RyR2‐RS and RyR2‐RS/MMVV mice. Furthermore, no differences were observed in β‐adrenoceptor stimulation‐induced Ca2+ waves in RyR2‐RS/MMVV compared to RyR2‐RS. In conclusion, antioxidant treatment reduces β‐adrenoceptor stimulation‐induced Ca2+ waves in RyR2‐RS cardiomyocytes. However, oxidation‐resistant CaMKII‐MM281/282VV does not protect RyR2‐RS mice from β‐adrenoceptor stimulation‐induced Ca2+ waves or arrhythmias. Hence, alternative oxidation‐sensitive targets need to be considered to explain the beneficial effect of antioxidant treatment on Ca2+ waves in cardiomyocytes from RyR2‐RS mice. [ABSTRACT FROM AUTHOR]

Abstract Catecholaminergic polymorphic ventricular tachycardia type 1 (CPVT1) is an inherited arrhythmogenic disorder caused by missense mutations in the cardiac ryanodine receptors (RyR2), that result in increased β‐adrenoceptor stimulation‐induced diastolic Ca2+ leak. We have previously shown that exercise training prevents arrhythmias in CPVT1, potentially by reducing the oxidation of Ca2+/calmodulin‐dependent protein kinase type II (CaMKII). Therefore, we tested whether an oxidation‐resistant form of CaMKII protects mice carrying the CPVT1‐causative mutation RyR2‐R2474S (RyR2‐RS) against arrhythmias. Antioxidant treatment (N‐acetyl‐L‐cysteine) reduced the frequency of β‐adrenoceptor stimulation‐induced arrhythmogenic Ca2+ waves in isolated cardiomyocytes from RyR2‐RS mice. To test whether the prevention of CaMKII oxidation exerts an antiarrhythmic effect, mice expressing the oxidation‐resistant CaMKII‐MM281/282VV variant (MMVV) were crossed with RyR2‐RS mice to create a double transgenic model (RyR2‐RS/MMVV). Wild‐type mice served as controls. Telemetric ECG surveillance revealed an increased incidence of ventricular tachycardia and an increased arrhythmia score in both RyR2‐RS and RyR2‐RS/MMVV compared to wild‐type mice, both following a β‐adrenoceptor challenge (isoprenaline i.p.), and following treadmill exercise combined with a β‐adrenoceptor challenge. There were no differences in the incidence of arrhythmias between RyR2‐RS and RyR2‐RS/MMVV mice. Furthermore, no differences were observed in β‐adrenoceptor stimulation‐induced Ca2+ waves in RyR2‐RS/MMVV compared to RyR2‐RS. In conclusion, antioxidant treatment reduces β‐adrenoceptor stimulation‐induced Ca2+ waves in RyR2‐RS cardiomyocytes. However, oxidation‐resistant CaMKII‐MM281/282VV does not protect RyR2‐RS mice from β‐adrenoceptor stimulation‐induced Ca2+ waves or arrhythmias. Hence, alternative oxidation‐sensitive targets need to be considered to explain the beneficial effect of antioxidant treatment on Ca2+ waves in cardiomyocytes from RyR2‐RS mice.

Cardiomyocytes are endowed with a complex repertoire of ion channels, responsible for the generation of action potentials (APs), travelling waves of electrical excitation, propagating throughout the heart and leading to cardiac contractions. Cardiac AP waveforms are shaped by a striking diversity of K+ channels. The pivotal role of K+ channels in cardiac health and disease is underscored by the dramatic impact that K+ channel dysfunction has on cardiac arrhythmias. The development of drugs targeted to specific K+ channels is expected to provide an optimized approach to antiarrhythmic therapy. Here, we review the functional roles of cardiac potassium channels under normal and diseased states. We survey current antiarrhythmic drugs (AADs) targeted to voltage-gated and Ca2+-activated K+ channels and highlight future research opportunities. K+ channel dysfunction resulting from genetic defects (channelopathies), can promote cardiac arrhythmias. Most long QT syndrome cases related to K+ channels are loss-of-function mutations, while short QT syndrome cases are gain-of-function mutations and include defects in channel gating, permeation, and channel trafficking. Mutations in the delayed rectifier channels I Ks , I Kr , and I Kur have been associated with atrial fibrillation and comprise both loss-of-function and gain-of-function mutations. For long QT syndrome, I Ks and I Kr channel openers are potentially interesting new drugs, while, for atrial fibrillation, Kv1.5 and SK channel blockers may be beneficial. However, these drugs need to prove their selectivity and safety in preclinical and clinical trials. [ABSTRACT FROM AUTHOR]