Lethal Ventricular Arrhythmias Research Articles

The anesthesiologist's guide to swine trauma physiology research: a report of two decades of experience from the experimental traumatology laboratory.

Swine are one of the major animal species used in translational research, with unique advantages given the similar anatomic and physiologic characteristics as man, but the investigator needs to be familiar with important differences. This article targets clinical anesthesiologists who are proficient in human monitoring. We summarize our experience during the last two decades, with the aim to facilitate for clinical and non-clinical researchers to improve in porcine research. This was a retrospective review of 337 swine with a mean (SD) weight 60 (4.2) kg at the Experimental Traumatology laboratory at Södersjukhuset (Stockholm south general hospital) between 2003 and 2023, including laboratory parameters and six CT-angiography examinations. Swine may be ventilated through the snout using a size 2 neonatal mask. Intubate using a 35cm miller laryngoscope and an intubating introducer. Swine are prone to alveolar atelectasis and often require alveolar recruitment. Insert PA-catheters through a cut-down technique in the internal jugular vein, and catheters in arteries and veins using combined cut-down and Seldinger techniques. Cardiopulmonary resuscitation is possible and lateral chest compressions are most effective. Swine are prone to lethal ventricular arrhythmias, which may be reversed by defibrillation. Most vital parameters are similar to man, with the exception of a higher core temperature, higher buffer bases and increased coagulation. Anesthesia methods are similar to man, but swine require five times the dose of ketamine. Swine share anatomical and physiological features with man, which allows for seamless utilization of clinical monitoring equipment, medication, and physiological considerations.

The Heart of Rett Syndrome: A Quantitative Analysis of Cardiac Repolarization.

Rett syndrome (RTT) is a developmental encephalopathy disorder that is associated with a high incidence of sudden death presumably from cardiorespiratory etiologies. Electrocardiogram (ECG) abnormalities, such as prolonged heart-rate corrected QT (QTc) interval, are markers of cardiac repolarization and are associated with potentially lethal ventricular arrhythmias. This study investigates the cardiac repolarization characteristics of RTT patients, including QTc and T-wave morphology characteristics. A retrospective quantitative analysis on 110 RTT patients and 124 age and sex-matched healthy controls was conducted. RTT patients had longer QTc, more abnormal T-wave morphology, and greater heterogeneity of cardiac repolarization parameters compared to controls. Even RTT patients without prolonged QTc had more abnormal ECG and T-wave characteristics than controls. Among RTT patients, MECP2 patients had prolonged QTc compared to CDKL5 and FOXG1 patients. A subset of five RTT patients who died had normal QTc, but more abnormal T-wave morphology than the remaining RTT patients. Cardiac repolarization abnormalities are present in RTT patients, even without long QTc. T-wave morphology is related to RTT genotype and may be predictive of mortality. These findings could be used to help the management and monitoring of RTT patients.

Homozygous or compound heterozygous variants in DSG2 are mainly causative of Japanese arrhythmogenic right ventricular cardiomyopathy

Abstract Background Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy mainly caused by desmosomal gene variants. Previously, we showed that the genetic backgrounds of ARVC in Japanese was different from those in Caucasian and that DSG2 was the most common causative gene. Purpose We aimed to confirm the inheritance mode of Japanese ARVC caused by pathogenic variants in DSG2. Furthermore, we reassessed the difference of phenotypes depending on the genotype. Methods and results Among 153 ARVC probands diagnosed with definite, borderline or possible by TFC2010 excluding the criteria of family history, 66 had one or more DSG2 variants (25 homozygous, 26 compound heterozygous, 11 multiple variants with unknown allele origin and 4 heterozygous). In the family screening, 62 relatives carried DSG2 variants (2 homozygous, 6 compound heterozygous, 54 heterozygous). All family members with a heterozygous DSG2 variant were not fulfilled ARVC diagnostic criteria. These results indicate that most of ARVC caused by DSG2 variants is an autosomal recessive disease. Therefore, 62 probands who have multiple DSG2 variants were included as pathogenic DSG2 variants carriers in following analysis. Figure A shows the genotypes in Japanese ARVC probands. We compared the clinical characteristics of the probands with DSG2 variants to those with PKP2 ones (N = 28). DSG2 variant carriers hospitalized for heart failure at younger age (42 ± 17 vs. 64 ± 13 years, P = 0.003) and had lower LVEF at diagnosis (51 [39 - 60] vs. 60 [55 - 65] %, P = 0.004). On the other hand, PKP2 variant carriers suffered atrial fibrillation more frequently (N = 7 (25%) vs. N = 5(8%), P = 0.04) and sustained VT at younger age though it was not statistically significant (38 ± 18 vs. 47 ± 15 years, P = 0.055). Finally, we analyzed the genotype effect on the incidence of lethal ventricular arrhythmia (LVA). The cumulative incidence in probands with each causative gene is shown in Figure B. Using multivariable analysis, we confirmed that PKP2 variant carriers had higher risk for LVA after adjusted by sex, medication, catheter ablation and device implantation (HR 2.904; 95% CI 1.530 – 5.513, P = 0.001). Conclusion DSG2 was the most common causative gene for ARVC in Japanese, and their mode of inheritance was mainly autosomal recessive. While DSG2 variants were associated with LV involvement and heart failure, PKP2 variants were risk for ventricular arrhythmia. Our findings would be helpful for diagnosis and prognosis for the ARVC patients.Genotype of Japanese ARVC probandsCumulative incidence of LVA

Perfomance of sudden cardiac death prediction strategies before and after Septal Reduction Strategies in patients with Hypertrophic Cardiomyopathy

Abstract Background Actual sudden death (SD) risk stratification strategies for Hypertrophic Cardiomyopathy have not been validated for patients after a septal reduction treatment (SRT). Therefore, it is largely unresolved the quantification of the ventricular arrhythmias (VA) burden after an SRT and how risk stratification should be performed in such patients. Purpose To evaluate the performance of ESC SD Risk stratification model and AHA ACC Risk Factors for SD in the identification of patients with lethal ventricular arrhythmias after SRT. Methods Data from 11 high-volume HCM specialty centers from the international SHaRe Registry were used to describe the natural history of patients with SRT. Patients were followed from SRT until last follow-up or meeting the composite outcome of ventricular arrhythmias (sudden cardiac death (SCD), resuscitated cardiac arrest, or appropriate implantable cardioverter-defibrillator (ICD) therapy). Cox proportional hazards models were used to identify predictors of prognosis and incident development. Calculation of SD score was performed before the SRT and at 1 year from the procedure. Results Of the 10385 patients part of the ShaRe Registry, 1835 (18%, 968 (53%) males) underwent a SRT during a median follow-up of 6.8 (IQR 3.4-9.8). A total of 455 (25%) had Alcohol Septal Ablation (ASA) and 1377 (75%) had myectomy. Patients who underwent myectomy were younger (49±18 vs 56±15 years, p<0.01), more frequent with a sarcomeric mutation (396 (29%) vs 111 (24%), p<0.01). Over 6.8 years after the procedure, 77 (4%) died because of HCM (0.6%/year) and 87 (5%) presented a composite VA outcome (0.7%/year). Development of the composite VA event was associated with younger age at procedure (38±20 vs 54±18 years, p<0.01), the development of a LV EF< 50% (29 (33%) vs 351 (20%), p<0.01), a more severely dilated LA (47±7 vs 43±11 years, p<0.01) and greater LV maximal wall thickness (24±6 vs 21±6 years, p<0.01). Significant predictor of the composite VA outcome was the presence of a LA diameter ³ 45 mm (HR, 2.6 [95% CI, 1.7–3.5]). Patients who presented the VA outocome were classified according to ESC SCD Risk pre and post SRT as: 40 (46%) as high risk, 31 (36%) as intermidiate risk, 16 (18%) as low risk pre intervention and 26 (46%) as high risk, 41 (47%) as intermidiate risk, 20 (18%) as low risk post procedure. AHA ACC SCD risk factors pre and post SRT classified patients as: 56 (64%) as class IIA 25 (29%) as Clas IIB, 6 (7%) as Class III and post SRT 42 (48%) as Class IIA, 31(36%) as Class IIB, 14 (16%) as Class III. Conclusions Current stratification strategies potentially underestimate the risk of SD pre and post SRT. Specifically, ESC SD risk strategies underperformed in the identification of intermidiate high risk patient, whereas AHA ACC were capable of identifying 84% of patients who had a malignant VA.

Roles of aldosterone on ventricular arrhythmias, and associated gap junction and ion channel remodeling in hypertrophic heart

Abstract Background Ventricular arrhythmias are critical causes of death in patients with chronic heart failure (CHF). Aldosterone (Ald) is an exacerbating factor of CHF and mineral corticoid receptor antagonist (MRA) is usual drug for the management of CHF. MRA also suppressed sudden cardiac death, however, mechanisms of these effects remain unknown. We investigated the effects of MRA on ventricular arrhythmias and arrhythmogenic factors using Dahl Salt sensitive (DS) rats. Methods (in vivo) DS rats were divided into three groups; low salt group (LS), high salt group (HS), and eplerenone-, an MRA, treated high salt group (HS+EPL). Low salt (0.3% NaCl) or high salt (8% NaCl) were administrated for 8 weeks and EPL was administrated in the last 4 weeks. Cardiac geometry and function were assessed by echocardiography. Susceptibility of ventricular arrhythmias were assessed using programmed stimulation. Myocyte hypertrophy and cardiac fibrosis were examined by Masson’s trichrome staining. Expression and distribution of connexin43 (Cx43) were examined by immunostaining and western blotting. mRNA expression of Ca transient-related factors, such as phospholamban, SERCA2a, and ryanosin 2, and potassium ion channel-related factors, such as KCNE1 and KCNQ1, was examined by RT-PCR. (in vitro) Ald (1-100 nM) was administrated to cultured rat neonatal cardiomyocytes. Expression of Cx43, Ca transient-related, and potassium ion channel-related factors are also examined as mentioned above. Effects of Src tyrosin kinase inhibitor, PP2, and ERK inhibitor, PD98059, on Ald-induced Cx43 reduction were examined by RT-PCR and immunostaining. Results Systolic blood pressure and Ald concentrations in cardiac tissue were higher in HS group than LS group, and EPL did not affect them. In HS group left ventricular hypertrophy, dilatation and systolic dysfunction were observed in association with myocyte hypertrophy and interstitial fibrosis. EPL significantly recovered cardiac function and histological impairments. In addition, elongation of QTc in ECG and susceptibility of ventricular tachycardia were remarkable in HS group rather than LS and EPL attenuated them. Distribution of Cx43 was scattered in HS group, and EPL attenuated these changes. Decrease in SERCA2a and increase in KCNE1/KCNQ1 mRNA expression were found in HS group, and these changes were attenuated by EPL. In cultured myocytes, Ald decreased Cx43 mRNA and protein expression in a dose dependent fashion. Ald-induced Cx43 reduction was inhibited by PP2 and PD98059. In addition, Ald (100 nM) also decreased SERCA2a and increased KCNE1/KCNQ1 mRNA expression. Conclusion These results indicate that Ald reduced and dispersed the Cx43 expression reduction and dispersion through Src tyrosin kinase and ERK signaling pathways, and also mediated SRECA2A and KCNE1/KCNQ1 expression, which induced QTc prolongation and susceptibility of lethal ventricular arrhythmias in hypertensive cardiac hypertrophy.

Arrhythmogenic Right Ventricular Cardiomyopathy - what do we know? A review of current knowledge state

Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is an inherited disorder that is responsible for a considerable number of sudden death cases in young athletes. Its pathological hallmark is a progressive loss of myocytes predominantly in the right ventricle and its simultaneous replacement by fibrous and fat tissue, which in turn leads to an increased risk of potentially lethal ventricular arrhythmias to occur. Over a dozen of mutations have been confirmed as genetic basis of ARVC with most of them affecting genes encoding desmosome proteins, however in up to half of all cases the exact etiology is still unknown. By number of studies, it is implied that physical activity is the most significant environmental factor that impacts the development and course of the disease. The main focus of treatment is to prevent sudden cardiac deaths and additionally to moderate arrhythmic events and heart failure.

Predicting lethal ventricular arrhythmias in hypertrophic cardiomyopathy using non-electrophysiologic methods: Invasive EGM vs. non-invasive ECG analysis of fragmentation.

Predicting lethal ventricular arrhythmias in hypertrophic cardiomyopathy using non-electrophysiologic methods: Invasive EGM vs. non-invasive ECG analysis of fragmentation.

Lethal ventricular arrhythmia due to entrectinib-induced Brugada syndrome: a case report and literature review.

Entrectinib, a multikinase inhibitor of ROS1 and tropomyosin receptor kinases, is recommended to treat ROS1-positive metastatic non-small cell lung cancer (NSCLC). In a previous study, entrectinib-related cardiotoxicity occurred in 2% of patients; however, lethal arrhythmias remain understudied. We encountered a case of fatal arrhythmia due to drug-induced Brugada syndrome caused by entrectinib. An 81-year-old Japanese male with lung adenocarcinoma harboring ROS1-fusion gene was treated with entrectinib. The patient developed lethal arrhythmias three days after drug initiation, including ventricular tachycardia with Brugada-like electrocardiogram changes. Echocardiography and coronary angiography revealed no evidence of acute coronary syndrome or myocarditis. Following the termination of entrectinib, the electrocardiogram abnormality improved within 12days. Hence, paying special attention to and monitoring electrocardiogram changes is necessary. In addition, it is also necessary to consider early therapeutic interventions and discontinuation of the drug in cases of drug-induced Brugada syndrome.

The plant-derived alkaloid aloperine prevents ischemia/reperfusion injury-induced sudden cardiac death.

Sudden cardiac death (SCD) remains a major cause of global mortality. In addition to modern interventions, botanical folk medicines have long been used to treat cardiovascular disease, although the efficacy and underlying mechanisms are often unresolved. Aloperine, a bioactive quinolizidine alkaloid isolated from Sophora alopecuroides plants, exhibits antioxidant, anti-inflammatory, antitumor, and vasorelaxant properties, but possible antiarrhythmic effects of aloperine in SCD are unclear. Here, we examined whether aloperine protects against ischemia and reperfusion injury-associated lethal ventricular arrhythmia and sudden cardiac death. Rats were divided into sham, control, and aloperine groups, and reperfusion-provoked ventricular arrhythmogenesis, cardiac damage markers, and signaling pathways quantified following left main coronary artery ischemia and reperfusion. In vitro studies of effects of aloperine on hERG and Kv4.3 cardiac voltage-gated potassium (Kv) channels were performed using two-electrode voltage clamp analysis of cloned channels expressed in Xenopus laevis oocytes. Aloperine pretreatment (10 mg/kg) did not affect baseline cardiac electrical stability; yet, it reduced ventricular arrhythmogenesis and susceptibility to SCD (mortality rate: control: 64.3%; aloperine: 0%) induced by reperfusion injury. Aloperine also reduced serum levels of LDH, CK-MB, α-HBDH, and cTnI post-I/R, and stimulated phosphorylation of ventricular ERK1/2 and STAT-3, which are key components of RISK and SAFE signaling pathways. Inhibition of either ERK1/2 (with U0126) or STAT-3 (with Ag490) abolished aloperine-induced anti-arrhythmic effects and ERK1/2 and STAT-3 phosphorylation. Interestingly, while aloperine (100 μM) had no effect on cloned Kv4.3 activity, aloperine (1 μM and up) negative-shifted the voltage dependence of hERG activation by ~10 mV and increased peak hERG current by 35%. Thus, aloperine exerts striking anti-arrhythmic effects against myocardial ischemia and reperfusion injury-induced severe lethal ventricular arrhythmia and sudden cardiac death via the ERK1/2/STAT-3 signaling pathway, with potential additional contribution from increased cardiac myocyte repolarization capacity via augmented hERG activity.

Artificial Intelligence in Ventricular Arrhythmias and Sudden Death.

Sudden cardiac arrest due to lethal ventricular arrhythmias is a major cause of mortality worldwide and results in more years of potential life lost than any individual cancer. Most of these sudden cardiac arrest events occur unexpectedly in individuals who have not been identified as high-risk due to the inadequacy of current risk stratification tools. Artificial intelligence tools are increasingly being used to solve complex problems and are poised to help with this major unmet need in the field of clinical electrophysiology. By leveraging large and detailed datasets, artificial intelligence-based prediction models have the potential to enhance the risk stratification of lethal ventricular arrhythmias. This review presents a synthesis of the published literature and a discussion of future directions in this field.

Electropharmacological Characterization of Licorice Using the Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes Sheets and the Chronic Atrioventricular Block Dogs.

Licorice has been traditionally prescribed for palpitation, whereas its overdose has caused lethal arrhythmias including torsade de pointes. Licorice contains glycyrrhizic acid of ≥ 2% (w/w), which is hydrolyzed to glycyrrhetinic acid (GRA) in the intestine. Since their cardiac electropharmacological properties are not fully understood, we assessed them to ask mechanism of licorice-induced torsade de pointes. GRA at 0.1, 1 and 10μg/mL was cumulatively applied to the human induced pluripotent stem cell-derived cardiomyocytes sheets (n = 6). GRA shortened spontaneous activation interval and repolarization period, and decreased maximum contraction velocity, indicating Ca2+ channel blockade. It prolonged effective refractory period and post-repolarization refractoriness with a steep frequency-dependency, whereas it delayed conduction with a modest use-dependency, resembling lidocaine in the mode of Na+ channel-blocking action. Meanwhile, Kanzoto containing a decoction of licorice alone in a dose of 2 or 6g/body/day was orally administered to the conscious chronic atrioventricular block dogs for 3days (n = 4). Kanzoto prolonged QT interval with increasing its temporal dispersion, suggesting K+ channel suppression, and slightly decreased the plasma K+ concentration without inducing torsade de pointes. Moreover, it significantly suppressed atrial and idioventricular rates, leading to sinus arrest along with the onset of ventricular fibrillation in one animal, possibly due to Na+ channel blockade. These results indicate that electropharmacological profile of licorice can be explained by Na+, Ca2+ and K+ channels blockade, which may be associated with low torsadogenic risk, but might contribute to the onset of other types of lethal ventricular arrhythmias.

LB-456090-4 NEAR-TERM PREDICTION OF LIFE-THREATENING VENTRICULAR ARRHYTHMIAS USING ARTIFICIAL INTELLIGENCE-ENABLED SINGLE LEAD AMBULATORY ECG

Identifying patients at high-risk of sudden cardiac death (SCD) in the mid to long-term remains particularly challenging. Accurate prediction of lethal ventricular arrhythmias in the near-term would enable preemptive actions to eventually prevent SCD. We hypothesized that artificial intelligence could be leveraged to identify a dynamic electrical profile on Holter ECG data heralding the near-term occurrence of sustained ventricular tachycardia (VT).

PO-01-217 FUNCTIONAL CHARACTERIZATION OF CALCIUM HANDLING KINETICS IN RE-ENGINEERED CARDIOMYOCYTES FROM A PATIENT WITH TYPE 2 LONG QT SYNDROME

Type 2 long QT syndrome (LQT2) is caused by pathogenic variants in the KCNH2-encoded Kv11.1 K+ channel resulting in prolongation of the action potential duration (APD) at the cellular level and QT prolongation in the patient, predisposing LQT2 patients to potentially lethal ventricular arrhythmias. Limited evidence, namely prolonged Ca2+ transient in human induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs) and enhanced Ca2+ leak in transgenic LQT2 rabbit model, suggests that KCNH2 pathogenic variants may be associated with perturbations in intracellular Ca2+ handling. To characterize the APD and Ca2+ handling properties of an iPSC-CM model of LQT2. iPSC-CMs were generated from a patient with a pathogenic KCNH2 frame-shift variant (p.Q901fs/71) and an unrelated healthy control. Confocal imaging of FluoVolt voltage dye was used to measure the APD at 90% repolarization (APD90) in iPSC-CMs. Ca2+ kinetics was characterized using Ca2+ sensing dye Fluo4-AM before and after treatment with 100 nM isoproterenol (ISO). Q901fs/71-iPSC-CMs had a significantly prolonged APD90 compared to wild-type (WT) iPSC-CMs (444 ±9 ms vs 631±8 ms, p<0.001). Q901fs/71-iPSC-CMs had a higher Ca2+ amplitude (DF/F0) before (0.423±0.043 vs 0.97±0.07, p=0.001) and after ISO treatment (0.602±0.051 vs 1.056 ±0.06, p<0.001) compared to WT. The Ca2+ transient duration (CTD90) was longer in Q901fs/71-iPSC-CMs than in WT before (1.062±0.041 s vs 1.306±0.038 s, p=0.01), but not after ISO (1.071±0.062 s vs 1.092±0.044 s, p=0.96). Peak to 90% Ca2+ decay time was increased in Q901fs/71-iPSC-CMs before (0.785±0.04 s vs 0.942±0.033 s, p=0.028), but not after ISO (0.748±0.054 s vs 0.767±0.038 s, p=0.95). Upstroke time was longer in Q901fs/71-iPSC-CMs compared to WT before (0.281±0.006 s vs 0.364±0.014 s; p=0.002) but not after ISO (0.327±0.014 s vs 0.344±0.025 s; p=0.88). Upstroke velocity (DF/F0/t) was increased in Q901fs/71-iPSC-CMs before (1.092±0.122 vs 2.278±0.278, p<0.001) and after ISO (1.310±0.117 vs 2.2±0.139, p=0.005). Ca2+ leak from sarcoplasmic reticulum was higher in Q901fs/71-iPSC-CMs before (16% vs 38%) and after ISO (16% vs 55%). We show that iPSC-CMs derived from the patient with a truncating LQT2-causative variant (yielding likely Kv11.1 channel haploinsufficiency) have prolonged APD90 and display abnormal Ca2+ handling properties such as higher amplitude, increase in Ca2+ leak, prolonged transient duration, Ca2+ decay time, and upstroke velocity compared to WT iPSC-CMs.

PO-04-143 CARDIOVASCULAR OUTCOMES IN LMNA-MEDIATED CARDIAC LAMINOPATHY: THE MAYO CLINIC EXPERIENCE

Pathogenic loss-of-function variants in LMNA-encoding lamin A/C cause a range of phenotypes, including lipodystrophy, premature aging, muscular dystrophy, and cardiomyopathy. LMNA-mediated cardiac laminopathy is viewed as a particularly malignant form of arrhythmogenic dilated cardiomyopathy (DCM). However, a paucity of data exists comparing the cardiovascular outcomes in cardiac laminopathy to other DCM genotypes. Therefore, we sought to ascertain whether the prevalence of advanced heart failure (AHF), ventricular arrhythmia (VA), and stroke events differ between patients with either LMNA-mediated DCM or TTN-mediated DCM who were evaluated in a single tertiary medical center. All patients with either a pathogenic (P) or likely pathogenic (LP) variant in either LMNA or TTN in the Mayo Clinic Genetic ACM Registry (n=389) were included. A VA event was defined as sudden cardiac death (SCD), sudden cardiac arrest (SCA), sustained VA, or an appropriate ICD shock while an AHF event was defined as ventricular assist device implantation or heart transplantation. Overall, 88 patients with a P/LP variant in LMNA (61% female) and 72 patients with a P/LP variant in TTN (42% female) were identified. LMNA-positive patients were more likely to have a family history of SCA/SCD (56% vs 35%; p=0.008) and more likely to receive an ICD (60% versus 33%; p=0.001). Interestingly, the prevalence of atrial fibrillation (51% vs. 40%; p=0.2), stroke (8% vs. 8%; p=0.9), and AHF events (12% vs 8%; p=0.4) was similar between LMNA- and TTN-positive patients. However, LMNA-positive patients trended towards more VA events (32% vs 20%; p=0.08). Independent of sex, time-to-event analysis showed LMNA patients had an earlier time (p=0.0009) to a composite endpoint (AHF event or VA event) and remained significant when separating the endpoints: AHF event (p=0.008) and VA event (p=0.0009). LMNA-mediated cardiac laminopathy is a highly arrhythmogenic form of DCM with nearly one-third experiencing a SCA and/or appropriate ICD therapy and half with a history of atrial fibrillation. Although the overall rate of ventricular arrhythmic and AHF events was similar between LMNA and TTN P/LP variant-positive patients, cardiac laminopathy results in earlier end stage heart failure and potentially lethal ventricular arrhythmias.

Electrocardiogram in arrhytmogenic cardiomyopathy.

Criteria for diagnosis of arrhythmogenic cardiomyopathy (ACM) were first proposed in 1994 and subsequently revised in 2010 and in 2020 by an international task force. According to the last consensus of 2020, ACM is defined as a heart muscle disease affecting right ventricle, left ventricle or both, whose principal pathologic feature is fibrofatty myocardial replacement that impairs systolic ventricular function and predisposes to lethal ventricular arrhythmias. ECG findings not only could help to early recognize affected patients but also could identify the ones with maximum risk of ventricular arrhythmias and sudden cardiac death.

Scarring/arrhythmogenic cardiomyopathy.

The designation of 'arrhythmogenic cardiomyopathy' reflects the evolving concept of a heart muscle disease affecting not only the right ventricle (ARVC) but also the left ventricle (LV), with phenotypic variants characterized by a biventricular (BIV) or predominant LV involvement (ALVC). Herein, we use the term 'scarring/arrhythmogenic cardiomyopathy (S/ACM)' to emphasize that the disease phenotype is distinctively characterized by loss of ventricular myocardium due to myocyte death with subsequent fibrous or fibro-fatty scar tissue replacement. The myocardial scarring predisposes to potentially lethal ventricular arrhythmias and underlies the impairment of systolic ventricular function. S/ACM is an 'umbrella term' which includes a variety of conditions, either genetic or acquired (mostly post-inflammatory), sharing the typical 'scarring' phenotypic features of the disease. Differential diagnoses include 'non-scarring' heart diseases leading to either RV dilatation from left-to-right shunt or LV dilatation/dysfunction from a dilated cardiomyopathy. The development of 2020 upgraded criteria ('Padua criteria') for diagnosis of S/ACM reflected the evolving clinical experience with the expanding spectrum of S/ACM phenotypes and the advances in cardiac magnetic resonance (CMR) imaging. The Padua criteria aimed to improve the diagnosis of S/ACM by incorporation of CMR myocardial tissue characterization findings. Risk stratification of S/ACM patients is mostly based on arrhythmic burden and ventricular dysfunction severity, although other ECG or imaging parameters may have a role. Medical therapy is crucial for treatment of ventricular arrhythmias and heart failure. Implantable cardioverter defibrillator (ICD) is the only proven life-saving treatment, despite its significant morbidity because of device-related complications and inappropriate shocks. Selection of patients who can benefit the most from ICD therapy is one of the most challenging issues in clinical practice.

LRP6-mediated phosphorylation of connexin43 in myocardial infarction.

Ventricular tachycardia (VT) and ventricular fibrillation are most causes of early death in patients with acute myocardial infarction (AMI). Conditional cardiac-specific low-density lipoprotein receptor-related protein 6 (LRP6)-knockout mice with connexin 43 (Cx43) reduction triggered the lethal ventricular arrhythmias. Thus, it is necessary for exploring whether LRP6 and its upstream genes circRNA1615 mediate the phosphorylation of Cx43 in VT of AMI. Here, we showed that circRNA1615 regulated the expression of LRP6 mRNA through sponge adsorption of miR-152-3p. Importantly, LRP6 interference fragments aggravated hypoxia injury of Cx43, while overexpression of LRP6 improved the phosphorylation of Cx43. Subsequently, interference with G-protein alpha subunit (Gαs) downstream of LRP6 further inhibited the phosphorylation of Cx43, along with increasing VT. Our results demonstrated that LRP6 upstream genes circRNA1615 controlled the damage effect and VT in AMI, and LRP6 mediated the phosphorylation of Cx43 via Gαs which played a role in VT of AMI.

The mechanisms of potassium loss in acute myocardial ischemia: New insights from computational simulations.

Acute myocardial ischemia induces hyperkalemia (accumulation of extracellular potassium), a major perpetrator of lethal reentrant ventricular arrhythmias. Despite considerable experimental efforts to explain this pathology in the last decades, the intimate mechanisms behind hyperkalemia remain partially unknown. In order to investigate these mechanisms, we developed a novel computational model of acute myocardial ischemia which couples a) an electrophysiologically detailed human cardiomyocyte model that incorporates modifications to account for ischemia-induced changes in transmembrane currents, with b) a model of cardiac tissue and extracellular K + transport. The resulting model is able to reproduce and explain the triphasic time course of extracellular K + concentration within the ischemic zone, with values of close to 14mmol/L in the central ischemic zone after 30min. In addition, the formation of a border zone of approximately 1.2cm 15minafter the onset of ischemia is predicted by the model. Our results indicate that the primary rising phase of is mainly due to the imbalance between K + efflux, that increases slightly, and K + influx, that follows a reduction of the NaK pump activity by more than 50%. The onset of the plateau phase is caused by the appearance of electrical alternans (a novel mechanism identified by the model), which cause an abrupt reduction in the K + efflux. After the plateau, the secondary rising phase of is caused by a subsequent imbalance between the K + influx, which continues to decrease slowly, and the K + efflux, which remains almost constant. Further, the study shows that the modulation of these mechanisms by the electrotonic coupling is the main responsible for the formation of the ischemic border zone in tissue, with K + transport playing only a minor role. Finally, the results of the model indicate that the injury current established between the healthy and the altered tissue is not sufficient to depolarize non-ischemic cells within the healthy tissue.

Cardiac Alternans: From Bedside to Bench and Back

Cardiac alternans arises from dynamical instabilities in the electrical and calcium cycling systems of the heart, and often precedes ventricular arrhythmias and sudden cardiac death. In this review, we integrate clinical observations with theory and experiment to paint a holistic portrait of cardiac alternans: the underlying mechanisms, arrhythmic manifestations and electrocardiographic signatures. We first summarize the cellular and tissue mechanisms of alternans that have been demonstrated both theoretically and experimentally, including 3 voltage-driven and 2 calcium-driven alternans mechanisms. Based on experimental and simulation results, we describe their relevance to mechanisms of arrhythmogenesis under different disease conditions, and their link to electrocardiographic characteristics of alternans observed in patients. Our major conclusion is that alternans is not only a predictor, but also a causal mechanism of potentially lethal ventricular and atrial arrhythmias across the full spectrum of arrhythmia mechanisms that culminate in functional reentry, although less important for anatomic reentry and focal arrhythmias.

Reengineering Mexiletine by chemical synthesis to decrease toxicity and improve pharmacological properties with patient-derived iPSC cardiomyocytes.

Heart disease is one of the top causes of healthcare expenses in the United States. Lethal ventricular cardiac arrhythmia can arise in acquired or congenital heart disease. Long QT syndrome type 3 (LQT3) is a congenital form of ventricular arrhythmia caused by mutations in the cardiac sodium channel SCN5A.