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Magnesium (Mg) is a crucial element for cardiovascular system and its deficiency results in a variety of cardiac arrhythmias. The aim of this study is to determine the effect of oral Mg supplementation on the frequency of ventricular extrasystoles (VES) in children. Magnesium supplementation was given to 42 children who had VES without structural heart disease. Clinical, electrocardiographic, and Holter monitoring studies were reviewed. The mean baseline 24 h VES burden on Holter monitoring was 10.26% ± 4.13% and it was decreased to 6.62% ± 3.88% after. There was no significant difference between the pre-treatment serum Mg levels and the decrease in the frequency of VES. In conclusion, oral Mg therapy was found to be effective at suppressing VES in children regardless of serum Mg levels. Large and randomized studies are needed to demonstrate the effect of magnesium on VES suppression. [ABSTRACT FROM AUTHOR]

Systemic acid-base imbalances significantly influence the heart, both clinically and experimentally. Extensive knowledge exists regarding the impact of pH on cardiac function, yet the role of organic anions accumulating in acidosis is less explored. In severe metabolic acidosis cases, such as hereditary organic acidemias, these organic compounds can reach millimolar concentrations in blood and other body fluids, exerting significant physiological effects on the heart. Cardiomyopathies and arrhythmias are common in patients with organic acidemia, although the underlying pathophysiological processes remain unclear. Research into organic anion physiology, particularly concerning propionate -- which accumulates in propionic acidemia (PA), a form of organic acidemia commonly associated with cardiac illness -- has increased substantially in recent years. The purpose of this review is to provide an overview of the cardiac sequelae observed in PA patients who suffer from cardiac diseases. [ABSTRACT FROM AUTHOR]

Intranasal (IN) administration has emerged as a novel approach for rapid systemic absorption, with potential applicability in the management of acute cardiovascular events. This review explores the evolution of IN cardiovascular pharmacotherapy, emphasizing its potential in achieving systemic effects and bypassing the first-pass metabolism associated with oral administration. The extensive vascularization of nasal mucosa and a porous endothelial basement membrane facilitate efficient drug absorption into the bloodstream. The IN route ensures a critical swift onset of action, which allows self-administration in at-home settings. For instance, etripamil nasal spray, a first-in-class formulation, exemplifies the therapeutic potential of this approach in the treatment of spontaneous supraventricular tachycardia. The review critically assesses studies on IN formulations for angina, acute myocardial infarction, hypertensive episodes, and cardiac arrhythmias. Preclinical evaluations of beta-blockers, calcium-channel blockers, and antianginal drugs demonstrate the feasibility of IN administration for acute cardiovascular events. A small number of clinical trials have revealed promising results, emphasizing the superiority of IN drug delivery over oral administration in terms of bioavailability and onset of action. Unambiguously, the limited clinical trials and patient enrollment pose challenges in generalizing experimental outcomes. However, the nose-to-heart approach has clinical potential. [ABSTRACT FROM AUTHOR]

Hypertensive heart disease (HHD) remains a major global public health concern despite the implementation of new approaches for the management of hypertensive patients. The pathological changes occurring during HHD are complex and involve the development of structural and functional cardiac abnormalities. HHD describes a broad spectrum ranging from uncontrolled hypertension and asymptomatic left ventricular hypertrophy (LVH), either a concentric or an eccentric pattern, to the final development of clinical heart failure. Pressure-overload-induced LVH is recognised as the most important predictor of heart failure and sudden death and is associated with an increased risk of cardiac arrhythmias. Cardiac arrhythmias are considered to be one of the most important comorbidities affecting hypertensive patients. This is the second part of a three-part set of review articles. Here, we focus on the macrostructural and functional abnormalities associated with chronic high pressure, their involvement in HHD pathophysiology, and their role in the progression and prognosis of HHD. [ABSTRACT FROM AUTHOR]

Hypertrophic cardiomyopathy (HCM) is a cardiac muscle disorder characterized by generally asymmetric abnormal hypertrophy of the left ventricle without abnormal loading conditions (such as hypertension or valvular heart disease) accounting for the left ventricular wall thickness or mass. The incidence of sudden cardiac death (SCD) in HCM patients is about 1% yearly in adults, but it is far higher in adolescence. HCM is the most frequent cause of death in athletes in the Unites States of America. HCM is an autosomal-dominant genetic cardiomyopathy, and mutations in the genes encoding sarcomeric proteins are identified in 30–60% of cases. The presence of this genetic mutation carries more than 2-fold increased risk for all outcomes, including ventricular arrhythmias. Genetic and myocardial substrate, including fibrosis and intraventricular dispersion of conduction, ventricular hypertrophy and microvascular ischemia, increased myofilament calcium sensitivity and abnormal calcium handling, all play a role as arrhythmogenic determinants. Cardiac imaging studies provide important information for risk stratification. Transthoracic echocardiography can be helpful to evaluate left ventricular (LV) wall thickness, LV outflow-tract gradient and left atrial size. Additionally, cardiac magnetic resonance can evaluate the prevalence of late gadolinium enhancement, which when higher than 15% of LV mass is a prognostic maker of SCD. Age, family history of SCD, syncope and non-sustained ventricular tachycardia at Holter ECG have also been validated as independent prognostic markers of SCD. Arrhythmic risk stratification in HCM requires careful evaluation of several clinical aspects. Symptoms combined with electrocardiogram, cardiac imaging tools and genetic counselling are the modern cornerstone for proper risk stratification. [ABSTRACT FROM AUTHOR]

T‐wave alternans (TWA) has been used for predicting the risk of malignant cardiac arrhythmias and sudden cardiac death (SCD) in multiple clinical settings; however, possible mechanism(s) underlying the spontaneous transition from cellular alternans reflected by TWA to arrhythmias in impaired repolarization remains unclear. The healthy guinea pig ventricular myocytes under E‐4031 blocking IKr (0.1 μM, N = 12; 0.3 μM, N = 10; 1 μM, N = 10) were evaluated using whole‐cell patch‐clamp. The electrophysiological properties of isolated perfused guinea pig hearts under E‐4031 (0.1 μM, N = 5; 0.3 μM, N = 5; 1 μM, N = 5) were evaluated using dual‐ optical mapping. The amplitude/threshold/restitution curves of action potential duration (APD) alternans and potential mechanism(s) underlying the spontaneous transition of cellular alternans to ventricular fibrillation (VF) were examined. There were longer APD80 and increased amplitude and threshold of APD alternans in E‐4031 group compared with baseline group, which was reflected by more pronounced arrhythmogenesis at the tissue level, and were associated with steep restitution curves of the APD and the conduction velocity (CV). Conduction of AP alternans augmented tissue's functional spatiotemporal heterogeneity of regional AP/Ca alternans, as well as the AP/Ca dispersion, leading to localized uni‐directional conduction block that spontaneous facilitated the formation of reentrant excitation waves without the need for additional premature stimulus. Our results provide a possible mechanism for the spontaneous transition from cardiac electrical alternans in cellular action potentials and intercellular conduction without the involvement of premature excitations, and explain the increased susceptibility to ventricular arrhythmias in impaired repolarization. In this study, we implemented voltage‐clamp and dual‐optical mapping approaches to investigate the underlying mechanism(s) for the arrhythmogenesis of cardiac alternans in the guinea pig heart at cellular and tissue levels. Our results demonstrated a spontaneous development of reentry from cellular alternans, arising from a combined actions of restitution properties of action potential duration, conduction velocity of excitation wave and interplay between alternants of action potential and the intracellular Ca handling. We believe this study provides new insights into underlying the mechanism, by which cellular cardiac alternans spontaneously evolves into cardiac arrhythmias. [ABSTRACT FROM AUTHOR]

The adaptation lag of the QT interval after heart rate (HR) has been proposed as an arrhythmic risk marker. Most studies have quantified the QT adaptation lag in response to abrupt, step-like changes in HR induced by atrial pacing, in response to tilt test or during ambulatory recordings. Recent studies have introduced novel methods to quantify the QT adaptation lag to gradual, ramp-like HR changes in stress tests by evaluating the differences between the measured QT series and an estimated, memoryless QT series obtained from the instantaneous HR. These studies have observed the QT adaptation lag to progressively reduce when approaching the stress peak, with the underlying mechanisms being still unclear. This study analyzes the contribution of β-adrenergic stimulation to QT interval rate adaptation in response to gradual, ramp-like HR changes. We first quantify the QT adaptation lag in Coronary Artery Disease (CAD) patients undergoing stress test. To uncover the involved mechanisms, we use biophysically detailed computational models coupling descriptions of human ventricular electrophysiology and β-adrenergic signaling, from which we simulate ventricular action potentials and ECG signals. We characterize the adaptation of the simulated QT interval in response to the HR time series measured from each of the analyzed CAD patients. We show that, when the simulated ventricular tissue is subjected to a time-varying β-adrenergic stimulation pattern, with higher stimulation levels close to the stress peak, the simulated QT interval presents adaptation lags during exercise that are more similar to those measured from the patients than when subjected to constant β-adrenergic stimulation. During stress test recovery, constant and time-varying β-adrenergic stimulation patterns render similar adaptation lags, which are generally shorter than during exercise, in agreement with results from the patients. In conclusion, our findings support the role of time-varying β-adrenergic stimulation in contributing to QT interval adaptation to gradually increasing HR changes as those seen during the exercise phase of a stress test. [ABSTRACT FROM AUTHOR]

Lipid-lowering drugs have been shown to have cardioprotective effects but may have hidden cardiotoxic properties. Therefore, here we aimed to investigate if chronic treatment with the novel lipid-lowering drug bempedoic acid (BA) exerts hidden cardiotoxic and/or cardioprotective effects in a rat model of acute myocardial infarction (AMI). Wistar rats were orally treated with BA or its vehicle for 28 days, anesthetized and randomized to three different groups (vehicle + ischemia/reperfusion (I/R), BA + I/R, and positive control vehicle + ischemic preconditioning (IPC)) and subjected to cardiac 30 min ischemia and 120 min reperfusion. IPC was performed by 3 × 5 min I/R cycles before ischemia. Myocardial function, area at risk, infarct size and arrhythmias were analyzed. Chronic BA pretreatment did not influence cardiac function or infarct size as compared to the vehicle group, while the positive control IPC significantly reduced the infarct size. The incidence of reperfusion-induced arrhythmias was significantly reduced by BA and IPC. This is the first demonstration that BA treatment does not show cardioprotective effect although moderately reduces the incidence of reperfusion-induced arrhythmias. Furthermore, BA does not show hidden cardiotoxic effect in rats with AMI, showing its safety in the ischemic/reperfused heart. [ABSTRACT FROM AUTHOR]

Gitelman syndrome (GS), or congenital hypokalemic hypomagnesemia hypocalciuria with metabolic alkalosis, is a congenital inherited tubulopathy. This tubulopathy is associated with disorders of water-electrolyte homeostasis, such as metabolic alkalosis, hypokalemia, hyponatremia, hypomagnesemia and hypocalciuria. GS has an autosomal recessive inheritance. The loss-of-function mutation involves the gene that codifies for thiazide-sensitive sodium-chloride co-transporter located in the distal convoluted tubule. The physiopathology of the syndrome is characterized by activation of the renin-angiotensin-aldosterone system (RAAS) with a low plasmatic concentration of angiotensin-II. Despite hyper-activation of RAAS, average or low blood pressure is detected in association with low peripheral resistance and reduced response to vasopressors. Clinical findings are brief episodes of fatigue, syncope, vertigo, ataxia and blurred vision; sudden cardiac death might occur. This review aims to give insight into cardiovascular implications and management of GS. [ABSTRACT FROM AUTHOR]

Long QT syndrome (LQTS) is an inherited cardiac rhythm disorder associated with increased incidence of cardiac arrhythmias and sudden death. LQTS type 5 (LQT5) is caused by dominant mutant variants of KCNE1, a regulatory subunit of the voltage-gated ion channels generating the cardiac potassium current IKs. While mutant LQT5 KCNE1 variants are known to inhibit IKs amplitudes in heterologous expression systems, cardiomyocytes from a transgenic rabbit LQT5 model displayed unchanged IKs amplitudes, pointing towards the critical role of additional factors in the development of the LQT5 phenotype in vivo. In this study, we demonstrate that KCNE3, a candidate regulatory subunit of IKs channels minimizes the inhibitory effects of LQT5 KCNE1 variants on IKs amplitudes, while current deactivation is accelerated. Such changes recapitulate IKs properties observed in LQT5 transgenic rabbits. We show that KCNE3 accomplishes this by displacing the KCNE1 subunit within the IKs ion channel complex, as evidenced by a dedicated biophysical assay. These findings depict KCNE3 as an integral part of the IKs channel complex that regulates IKs function in cardiomyocytes and modifies the development of the LQT5 phenotype. [ABSTRACT FROM AUTHOR]

Aims: While mexiletine has been used for over 40 years for prevention of (recurrent) ventricular arrhythmias and for myotonia, patient access has recently been critically endangered. Here we aim to demonstrate the effectiveness and safety of mexiletine in the treatment of patients with (recurrent) ventricular arrhythmias, emphasizing the absolute necessity of its accessibility.Methods and Results: Studies were included in this systematic review (PROSPERO, CRD42020213434) if the efficacy or safety of mexiletine in any dose was evaluated in patients at risk for (recurrent) ventricular arrhythmias with or without comparison with alternative treatments (e.g. placebo). A systematic search was performed in Ovid MEDLINE, Embase, and in the clinical trial registry databases ClinicalTrials.gov and ICTRP. Risk of bias were assessed and tailored to the different study designs. Large heterogeneity in study designs and outcome measures prompted a narrative synthesis approach. In total, 221 studies were included reporting on 8970 patients treated with mexiletine. Age ranged from 0 to 88 years. A decrease in ventricular arrhythmias of >50% was observed in 72% of the studies for pre-mature ventricular complexes, 64% for ventricular tachycardia, and 33% for ventricular fibrillation. Electrocardiographic effects of mexiletine were small; only in a subset of patients with primary arrhythmia syndromes, a relative (desired) QTc decrease was reproducibly observed. As for adverse events, gastrointestinal complaints were most frequently observed (33% of the patients).Conclusions: In this systematic review, we present all the currently available knowledge of mexiletine in patients at risk for (recurrent) ventricular arrhythmias and show that mexiletine is both effective and safe. [ABSTRACT FROM AUTHOR]

Regular physical activity is important for cardiovascular health. However, high-volume endurance exercise has been associated with increased number of electrocardiogram (ECG) abnormalities, including disturbances in cardiac rhythm (arrhythmias) and abnormalities in ECG pattern. The aim of this study was to assess if heart rate variability (HRV) is associated with ECG abnormalities. Fifteen participants with previous cycling experience completed a 21-day high-volume endurance exercise cycle over 3,515 km. Participants wore a 5-lead Holter monitor for 24 h pre- and post-exercise, which was used to quantify ECG abnormalities and export sinus R-to-R intervals (NN) used to calculate HRV characteristics. As noise is prevalent in 24-h HRV recordings, both 24-h and heart rate collected during stable periods of time (i.e., deep sleep) were examined. Participants experienced significantly more arrhythmias post high-volume endurance exercise (median = 35) compared to pre (median = 12; p = 0.041). All 24-h and deep sleep HRV outcomes were not different pre-to-post high-volume endurance exercise (p > 0.05). Strong and significant associations with arrhythmia number post-exercise were found for total arrhythmia (total arrhythmia number pre-exercise, ρ = 0.79; age, ρ = 0.73), supraventricular arrhythmia (supraventricular arrhythmia number pre-exercise: ρ = 0.74; age: ρ = 0.66), and ventricular arrhythmia (age: ρ = 0.54). As a result, age and arrhythmia number pre-exercise were controlled for in hierarchical regression, which revealed that only deep sleep derived low frequency to high frequency (LF/HF) ratio post high-volume endurance exercise predicted post total arrhythmia number (B = 0.63, R 2Δ = 34%, p = 0.013) and supraventricular arrhythmia number (B = 0.77, R 2Δ = 69%, p < 0.001). In this study of recreationally active people, only deep sleep derived LF/HF ratio was associated with more total and supraventricular arrhythmias after high-volume endurance exercise. This finding suggests that measurement of sympathovagal balance during deep sleep might be useful to monitor arrhythmia risk after prolonged high-volume endurance exercise performance. [ABSTRACT FROM AUTHOR]

Objective: The exact biological mechanism whereby exposure to ambient ozone (O3) may contribute to clinical onset of cardiovascular events remains unclear. In this study, we aim to examine the impacts of O3 exposure on cardiac arrhythmias and potential pathways involved through autonomic dysfunction and myocardial injury. Methods: Seventy-three non-smoking healthy adults were followed with 4 repeated measurements of 24-hour ambulatory arrhythmias, heart rate variability, ST-segment deviation, and blood pressure (BP) in Beijing, China, 2014 ‒2016. Generalized additive mixed models coupled with distributed lag nonlinear models were constructed to evaluate the associations and potential interlinks between O3 exposure and outcome measurements. Results: During the study period, 24-hour average concentrations of ambient O3 were 47.4 μg/m³ (ranging from 1.0 to 165.9 μg/m³). Increased risks of premature ventricular contraction and ventricular tachycardia were associated with interquartile range increases in O3 exposure during the last 5 days before each participant's clinic visit, with relative risks of 2.14 (95% confidence interval [CI]: 1.95 to 2.32) and 5.47 (95% CI: 3.51 to 7.43), respectively. Mediation analyses further showed that sympathetic activation, parasympathetic inhibition, and elevated BP levels, as well as heightened risks of ST-segment depression could mediate up to 47.74% of the risks of arrhythmias attributable to O3 exposure. Conclusion: Our results suggest that short-term exposure to ambient O3 could prompt the genesis of arrhythmias partially through worsening autonomic function and myocardial burden. [ABSTRACT FROM AUTHOR]

Google Scholar PubMed OpenURL Placeholder Text WorldCat 7 Liu MB, Vandersickel N, Panfilov AV, Qu Z. R-From-T as a common mechanism of arrhythmia initiation in long QT syndromes. This editorial refers to 'Initiation of ventricular arrhythmia in the acquired long QT syndrome', by C. Alexander I et al i . https://doi.org/10.1093/cvr/cvac103. [Extracted from the article]

Chagas disease is a major health concern in Latin America. Ventricular arrhythmia (VA) is a hallmark of Chagas cardiomyopathy (CCM), associated with worse prognosis. The present study aimed to verify the association between myocardial mechanical dispersion (MD) and ventricular arrhythmogenicity in CCM. In a cross-sectional study, 77 patients (55.8 ± 10.4 years) with CCM were evaluated. Global longitudinal strain (GLS) and MD were assessed by echocardiography, derived from the speckle tracking technique. Myocardial MD was measured from the onset of the Q/R wave on electrocardiogram to the peak longitudinal strain in 16 segments of the left ventricle. Frequency and complexity of ventricular extrasystoles (VES) were assessed by dynamic electrocardiography. The density and complexity of VES and the presence of non-sustained ventricular tachycardias (NSVTs) increase as MD increases. In logistic regression, MD was the only variable associated with the presence of paired VES and ventricular bigeminy. In addition, both MD and GLS were associated with the presence of NSVT (both, p < 0.01), and MD was independently associated with NSVT (OR 1.04, 95% CI 1.004–1.201, p = 0.031). In CCM, MD is associated with a higher density and complexity of VES, including NSVT. [ABSTRACT FROM AUTHOR]

Cardiac arrhythmias are among the leading causes of mortality. They often arise from alterations in the electrophysiological properties of cardiac cells and their underlying ionic mechanisms. It is therefore critical to further unravel the pathophysiology of the ionic basis of human cardiac electrophysiology in health and disease. In the first part of this review, current knowledge on the differences in ion channel expression and properties of the ionic processes that determine the morphology and properties of cardiac action potentials and calcium dynamics from cardiomyocytes in different regions of the heart are described. Then the cellular mechanisms promoting arrhythmias in congenital or acquired conditions of ion channel function (electrical remodeling) are discussed. The focus is on human-relevant findings obtained with clinical, experimental, and computational studies, given that interspecies differences make the extrapolation from animal experiments to human clinical settings difficult. Deepening the understanding of the diverse pathophysiology of human cellular electrophysiology will help in developing novel and effective antiarrhythmic strategies for specific subpopulations and disease conditions. [ABSTRACT FROM AUTHOR]

Introduction of anti‐tachycardia pacing (ATP) therapy and longer detection intervals delivery have allowed to safely reduce unnecessary shocks, improving survival and quality of life in implantable cardioverter defibrillator (ICD) patients. However, there are still outstanding issues, especially regarding the mode of arrhythmias termination after ATP or shock delivery. Regardless of ICD therapy efficacy, the arrhythmia interruption does not always occur abruptly, indeed both nonsustained tachy‐ or bradyarrhythmias have been described after ICD therapy delivery, being the former classified as type 2 interruption. Several physiopathological mechanisms have been suggested to be responsible for this phenomenon. Our aim is to review current data on postshock and post‐ATP arrhythmias and to give insights on their possible mechanisms. [ABSTRACT FROM AUTHOR]

Plasmalogens (Pls) are a class of membrane phospholipids which serve a number of essential biological functions. Deficiency of Pls is associated with common disorders such as Alzheimer's disease or ischemic heart disease. A complete lack of Pls due to genetically determined defective biosynthesis gives rise to rhizomelic chondrodysplasia punctata (RCDP), characterized by a number of severe disabling pathologic features and death in early childhood. Frequent cardiac manifestations of RCDP include septal defects, mitral valve prolapse, and patent ductus arteriosus. In a mouse model of RCDP, reduced nerve conduction velocity was partially rescued by dietary oral supplementation of the Pls precursor batyl alcohol (BA). Here, we examine the impact of Pls deficiency on cardiac impulse conduction in a similar mouse model (Gnpat KO). In‐vivo electrocardiographic recordings showed that the duration of the QRS complex was significantly longer in Gnpat KO mice than in age‐ and sex‐matched wild‐type animals, indicative of reduced cardiac conduction velocity. Oral supplementation of BA for 2 months resulted in normalization of cardiac Pls levels and of the QRS duration in Gnpat KO mice but not in untreated animals. BA treatment had no effect on the QRS duration in age‐matched wild‐type mice. These data suggest that Pls deficiency is associated with increased ventricular conduction time which can be rescued by oral BA supplementation. [ABSTRACT FROM AUTHOR]

Background and Purpose: Reliable prediction of pro-arrhythmic side effects of novel drug candidates is still a major challenge. Although drug-induced pro-arrhythmia occurs primarily in patients with pre-existing repolarisation disturbances, healthy animals are employed for pro-arrhythmia testing. To improve current safety screening, transgenic long QT (LQTS) rabbit models with impaired repolarisation reserve were generated by overexpressing loss-of-function mutations of human HERG (HERG-G628S, loss of IKr ; LQT2), KCNE1 (KCNE1-G52R, decreased IKs ; LQT5), or both transgenes (LQT2-5) in the heart.Experimental Approach: Effects of K+ channel blockers on cardiac repolarisation and arrhythmia susceptibility were assessed in healthy wild-type (WT) and LQTS rabbits using in vivo ECG and ex vivo monophasic action potential and ECG recordings in Langendorff-perfused hearts.Key Results: LQTS models reflect patients with clinically "silent" (LQT5) or "manifest" (LQT2 and LQT2-5) impairment in cardiac repolarisation reserve: they were more sensitive in detecting IKr -blocking (LQT5) or IK1 /IKs -blocking (LQT2 and LQT2-5) properties of drugs compared to healthy WT animals. Impaired QT-shortening capacity at fast heart rates was observed due to disturbed IKs function in LQT5 and LQT2-5. Importantly, LQTS models exhibited higher incidence, longer duration, and more malignant types of ex vivo arrhythmias than WT.Conclusion and Implications: LQTS models represent patients with reduced repolarisation reserve due to different pathomechanisms. As they demonstrate increased sensitivity to different specific ion channel blockers (IKr blockade in LQT5 and IK1 and IKs blockade in LQT2 and LQT2-5), their combined use could provide more reliable and more thorough prediction of (multichannel-based) pro-arrhythmic potential of novel drug candidates. [ABSTRACT FROM AUTHOR]

Cardiomyocytes express a surprisingly large number of potassium channel types. The primary physiological functions of the currents conducted by these channels are to maintain the resting membrane potential and mediate action potential repolarization under basal conditions and in response to changes in the concentrations of intracellular sodium, calcium, and ATP/ADP. Here, we review the diversity and functional roles of cardiac potassium channels under normal conditions and how heritable mutations in the genes encoding these channels can lead to distinct arrhythmias. We briefly review atrial fibrillation and J-wave syndromes. For long and short QT syndromes, we describe their genetic basis, clinical manifestation, risk stratification, traditional and novel therapeutic approaches, as well as insights into disease mechanisms provided by animal and cellular models. [ABSTRACT FROM AUTHOR]

Objectives: This study investigated the relationship between the timing of ventricular tachycardia or ventricular fibrillation (VT or VF) and prognosis in patients undergoing primary percutaneous coronary intervention (PCI) for acute myocardial infarction (AMI).Background: It is unknown whether the timing of VT/VF occurrence affects the prognosis of patients with AMI.Methods: From January 2004 to December 2014, 1004 patients with AMI underwent primary PCI. Of these patients, 888 did not have VT/VF (non-VT/VF group) and 116 had sustained VT/VF during prehospitalization or hospitalization. Patients with VT/VF were divided into two groups: early VT/VF (VT/VF occurrence before and within 2 days of admission, 92 patients) and late VT/VF (VT/VF occurrence >2 days after admission; 24 patients) groups.Results: The frequency of VT/VF occurrence was high between the day of admission and the 2nd day and between days 6 and 10 of hospitalization. The late VT/VF group had a significantly longer onset-to-balloon time, lower ejection fraction, poorer renal function, and higher creatine phosphokinase (CK)-MB level on admission (p< 0.001). They also had a lower 30-day cardiac survival rate than the early VT/VF and non-VT/VF groups (42% vs. 76% vs. 96%, p < 0.001). Moreover, independent predictors of in-hospital cardiac mortality among patients with AMI who had sustained VT/VF were higher peak CK-MB [Odds ratio (OR: 1.001, 95%confidence interval (CI): 1.000-1.002, p= 0.03)], higher Killip class (OR: 1.484, 95%CI 1.017-2.165, p= 0.04), and late VT/VF (OR: 3.436, 95%CI 1.115-10.59, p= 0.03).Conclusions: The timing of VT/VF occurrences had a bimodal peak. Although late VT/VF occurrence after primary PCI was less frequent than early VT/VF occurrence, patients with late VT/VF had a very poor prognosis. [ABSTRACT FROM AUTHOR]

View large Download slide View large Download slide Aims Short-QT syndrome 1 (SQT1) is an inherited channelopathy with accelerated repolarization due to gain-of-function in HERG/ I Kr. Patients develop atrial fibrillation, ventricular tachycardia (VT), and sudden cardiac death with pronounced inter-individual variability in phenotype. We generated and characterized transgenic SQT1 rabbits and investigated electrical remodelling. Methods and results Transgenic rabbits were generated by oocyte-microinjection of β-myosin-heavy-chain-promoter-KCNH2/HERG-N588K constructs. Short-QT syndrome 1 and wild type (WT) littermates were subjected to in vivo ECG, electrophysiological studies, magnetic resonance imaging, and ex vivo action potential (AP) measurements. Electrical remodelling was assessed using patch clamp, real-time PCR, and western blot. We generated three SQT1 founders. QT interval was shorter and QT/RR slope was shallower in SQT1 than in WT (QT, 147.8 ± 2 ms vs. 166.4 ± 3, P < 0.0001). Atrial and ventricular refractoriness and AP duration were shortened in SQT1 (vAPD90, 118.6 ± 5 ms vs. 154.4 ± 2, P < 0.0001). Ventricular tachycardia/fibrillation (VT/VF) inducibility was increased in SQT1. Systolic function was unaltered but diastolic relaxation was enhanced in SQT1. I Kr-steady was increased with impaired inactivation in SQT1, while I Kr-tail was reduced. Quinidine prolonged/normalized QT and action potential duration (APD) in SQT1 rabbits by reducing I Kr. Diverse electrical remodelling was observed: in SQT1, I K1 was decreased—partially reversing the phenotype—while a small increase in I Ks may partly contribute to an accentuation of the phenotype. Conclusion Short-QT syndrome 1 rabbits mimic the human disease phenotype on all levels with shortened QT/APD and increased VT/VF-inducibility and show similar beneficial responses to quinidine, indicating their value for elucidation of arrhythmogenic mechanisms and identification of novel anti-arrhythmic strategies. [ABSTRACT FROM AUTHOR]

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The tetany in children represents a state of pathological hyperexcitability of the central and peripheral nervous system. The aim of this study is to present aspects of the benign extrasystolic arrhythmia in the children and teenagers with tetany, starting from the assumption that electrolyte imbalances of calcium and magnesium ions might be the cause of these dysrhythmias. The patients with hypocalcemic and hypomagnesemic tetany had the greatest share, followed by the patients with normocalcemic and normomagnesemic tetany, with no statistically significant difference between the atrial, respectively ventricular extrasystoles in any of the forms of tetany. The percentage of the occurrence of extrasystoles in the patients with latent tetany was higher than in the patients with manifest tetany, with a significant statistical difference between the types of extrasystoles, in both types of tetany. [ABSTRACT FROM AUTHOR]

Pulmonary embolism (PE) is a common, potentially fatal thrombotic disease. Atrial fibrillation (AF), the most common arrhythmia, may also lead to thromboembolic complications. Although initially appearing as distinct entities, PE and AF may coexist. The direction and extent of this association has not been well characterized. We performed a search of PubMed, Scopus, and the Cochrane Database of Systematic Reviews for publications that reported coexisting AF in patients with PE, or vice versa, to provide a systematic overview of pathophysiological and epidemiological aspects of this association (last search: October 13, 2016). We screened 650 articles following the PubMed search, and 697 through Scopus. PE and AF share many common risk factors, including old age, obesity, heart failure, and inflammatory states. In addition, PE may lead to AF through right-sided pressure overload or inflammatory cytokines. AF, in turn, might lead to right atrial appendage clot formation and thereby PE. Epidemiological studies indicate that AF can be seen as a presenting sign, during the early phase, or later in the course of recovery from PE. Patients with AF are also at increased risk of developing PE, a risk that correlates with the CHA2DS2-VASc score. For the choice of antithrombotic therapy, PE-related factors (provoked or unproved, active cancer, and prior recurrence) and AF-related factors (CHA2DS2-VASc score), risk of bleeding, and patient preferences should be considered. In conclusion, PE and AF may coexist, with an understudied bidirectional association. Prognostication and choice of antithrombotic therapy in patients with both PE and AF might be different compared with those who present with only one of the two and warrants further investigation. [ABSTRACT FROM AUTHOR]

In cardiac patients, life-threatening tachyarrhythmia is often precipitated by abnormal changes in ventricular repolarization and refractoriness. Repolarization abnormalities typically evolve as a consequence of impaired function of outward K+ currents in cardiac myocytes, which may be caused by genetic defects or result from various acquired pathophysiological conditions, including electrical remodelling in cardiac disease, ion channel modulation by clinically used pharmacological agents, and systemic electrolyte disorders seen in heart failure, such as hypokalaemia. Cardiac electrical instability attributed to abnormal repolarization relies on the complex interplay between a provocative arrhythmic trigger and vulnerable arrhythmic substrate, with a central role played by the excessive prolongation of ventricular action potential duration, impaired intracellular Ca2+ handling, and slowed impulse conduction. This review outlines the electrical activity of ventricular myocytes in normal conditions and cardiac disease, describes classical electrophysiological mechanisms of cardiac arrhythmia, and provides an update on repolarization-related surrogates currently used to assess arrhythmic propensity, including spatial dispersion of repolarization, activation-repolarization coupling, electrical restitution, TRIaD (triangulation, reverse use dependence, instability, and dispersion), and the electromechanical window. This is followed by a discussion of the mechanisms that account for the dependence of arrhythmic vulnerability on the location of the ventricular pacing site. Finally, the review clarifies the electrophysiological basis for cardiac arrhythmia produced by hypokalaemia, and gives insight into the clinical importance and pathophysiology of drug-induced arrhythmia, with particular focus on class Ia (quinidine, procainamide) and Ic (flecainide) Na+ channel blockers, and class III antiarrhythmic agents that block the delayed rectifier K+ channel (dofetilide). [ABSTRACT FROM AUTHOR]

This paper is the outcome of the fourth UC Davis Systems Approach to Understanding Cardiac Excitation-Contraction Coupling and Arrhythmias Symposium, a biannual event that aims to bring together leading experts in subfields of cardiovascular biomedicine to focus on topics of importance to the field. The theme of the 2016 symposium was 'K+ Channels and Regulation'. Experts in the field contributed their experimental and mathematical modelling perspectives and discussed emerging questions, controversies and challenges on the topic of cardiac K+ channels. This paper summarizes the topics of formal presentations and informal discussions from the symposium on the structural basis of voltage-gated K+ channel function, as well as the mechanisms involved in regulation of K+ channel gating, expression and membrane localization. Given the critical role for K+ channels in determining the rate of cardiac repolarization, it is hardly surprising that essentially every aspect of K+ channel function is exquisitely regulated in cardiac myocytes. This regulation is complex and highly interrelated to other aspects of myocardial function. K+ channel regulatory mechanisms alter, and are altered by, physiological challenges, pathophysiological conditions, and pharmacological agents. An accompanying paper focuses on the integrative role of K+ channels in cardiac electrophysiology, i.e. how K+ currents shape the cardiac action potential, and how their dysfunction can lead to arrhythmias, and discusses K+ channel-based therapeutics. A fundamental understanding of K+ channel regulatory mechanisms and disease processes is fundamental to reveal new targets for human therapy. [ABSTRACT FROM AUTHOR]

Cardiac arrhythmias can follow disruption of the normal cellular electrophysiological processes underlying excitable activity and their tissue propagation as coherent wavefronts from the primary sinoatrial node pacemaker, through the atria, conducting structures and ventricular myocardium. These physiological events are driven by interacting, voltage-dependent, processes of activation, inactivation, and recovery in the ion channels present in cardiomyocyte membranes. Generation and conduction of these events are further modulated by intracellular Ca2+ homeostasis, and metabolic and structural change. This review describes experimental studies on murine models for known clinical arrhythmic conditions in which these mechanisms were modified by genetic, physiological, or pharmacological manipulation. These exemplars yielded molecular, physiological, and structural phenotypes often directly translatable to their corresponding clinical conditions, which could be investigated at the molecular, cellular, tissue, organ, and whole animal levels. Arrhythmogenesis could be explored during normal pacing activity, regular stimulation, following imposed extra-stimuli, or during progressively incremented steady pacing frequencies. Arrhythmic substrate was identified with temporal and spatial functional heterogeneities predisposing to reentrant excitation phenomena. These could arise from abnormalities in cardiac pacing function, tissue electrical connectivity, and cellular excitation and recovery. Triggering events during or following recovery from action potential excitation could thereby lead to sustained arrhythmia. These surface membrane processes were modified by alterations in cellular Ca2+ homeostasis and energetics, as well as cellular and tissue structural change. Study of murine systems thus offers major insights into both our understanding of normal cardiac activity and its propagation, and their relationship to mechanisms generating clinical arrhythmias. [ABSTRACT FROM AUTHOR]

Over the last decade, the state-of-the-art in cardiac computational modelling has progressed rapidly. The electrophysiological function of the heart can now be simulated with a high degree of detail and accuracy, opening the doors for simulation-guided approaches to anti-arrhythmic drug development and patient-specific therapeutic interventions. In this review, we outline the basic methodology for cardiac modelling, which has been developed and validated over decades of research. In addition, we present several recent examples of how computational models of the human heart have been used to address current clinical problems in cardiac electrophysiology. We will explore the use of simulations to improve anti-arrhythmic pacing and defibrillation interventions; to predict optimal sites for clinical ablation procedures; and to aid in the understanding and selection of arrhythmia risk markers. Together, these studies illustrate how the tremendous advances in cardiac modelling are poised to revolutionize medical treatment and prevention of arrhythmia. [ABSTRACT FROM AUTHOR]

Seizure-related cardiac arrhythmias are frequently reported and have been implicated as potential pathomechanisms of Sudden Unexpected Death in Epilepsy (SUDEP). We attempted to identify clinical profiles associated with various (post)ictal cardiac arrhythmias. We conducted a systematic search from the first date available to July 2013 on the combination of two terms: 'cardiac arrhythmias' and 'epilepsy'. The databases searched were PubMed, Embase (OVID version), Web of Science and COCHRANE Library. We attempted to identify all case reports and case series. We identified seven distinct patterns of (post)ictal cardiac arrhythmias: ictal asystole (103 cases), postictal asystole (13 cases), ictal bradycardia (25 cases), ictal atrioventricular (AV)-conduction block (11 cases), postictal AV-conduction block (2 cases), (post)ictal atrial flutter/atrial fibrillation (14 cases) and postictal ventricular fibrillation (3 cases). Ictal asystole had a mean prevalence of 0.318% (95% CI 0.316% to 0.320%) in people with refractory epilepsy who underwent video-EEG monitoring. Ictal asystole, bradycardia and AV-conduction block were self-limiting in all but one of the cases and seen during focal dyscognitive seizures. Seizure onset was mostly temporal (91%) without consistent lateralisation. Postictal arrhythmias were mostly found following convulsive seizures and often associated with (near) SUDEP. The contrasting clinical profiles of ictal and postictal arrhythmias suggest different pathomechanisms. Postictal rather than ictal arrhythmias seem of greater importance to the pathophysiology of SUDEP. [ABSTRACT FROM AUTHOR]

Substantial differences in the risk of common arrhythmia syndromes exist between men and women, as well as in varying ethnic/racial groups. For example, despite an overall lower risk of sudden death and atrial fibrillation in women compared with men, women have longer QT intervals and a higher risk of torsades de pointes due to antiarrhythmic drugs and worse outcomes associated with atrial fibrillation. An ethnicity-related paradox in atrial fibrillation epidemiology is apparent; despite a higher prevalence of medical comorbidities such as hypertension, diabetes, and prolonged PR interval, blacks, Hispanics, and Asians have a lower risk of atrial fibrillation than whites. In this promising era of genomic medicine, an improved understanding of epidemiology and phenotype holds the potential for revealing novel therapeutic targets and preventing disease. [ABSTRACT FROM AUTHOR]

Anesthesia in the Methoxamine-Sensitized Rabbit Introduction The methoxamine-sensitized rabbit model is widely used to screen drugs for proarrhythmic properties, especially repolarization-dependent TdP arrhythmias. With the change of anesthesia and/or sensitizing agent, conduction disturbances have been reported as well. Therefore, we compared currently available in-house anesthetics in order to preserve arrhythmia sensitivity and preclude conduction disturbances. Methods and Results Rabbits were randomly assigned to 3 groups: (1) 35 mg/kg ketamine + 5 mg/kg xylazine; (2) 0.5 mL/kg hypnorm + 3 mg/kg midazolam; (3) 35 mg/kg ketamine + 20 mg/kg propofol. Anesthesia was maintained by 1.5% isoflurane. Concomitant infusion of methoxamine (17 μg/kg/min for 40 minutes) and dofetilide (10 μg/kg/min for 30 minutes) was used to induce arrhythmias. Sole methoxamine infusion exclusively decreased HR in groups 1 and 3. Dofetilide lengthened repolarization, followed in time by PQ/QRS prolongation, second-degree AV block, and subsequently TdP arrhythmias. TdP was seen in 80%, 0%, and 33% of the rabbits in groups 1, 2, and 3, respectively. Decreasing the dose of dofetilide to 5 μg/kg/min in ketamine/xylazine anesthetized rabbits resulted in a drop in TdP incidence (25%) while conduction disturbances persisted. Flunarizine (n = 6) suppressed all TdP arrhythmias while conduction disturbances remained present. Conclusion TdP incidence in the methoxamine-sensitized rabbit could be dramatically influenced by anesthesia, drug dose, and flunarizine, while conduction slowing remained present. Thus, conduction slowing seems to be the integral outcome in this model. [ABSTRACT FROM AUTHOR]

The authors comment on the thesis which offered an overview of the basic electrophysiological characteristics in single cardiomyocytes and the whole heart. Topics covered include the potential of electrical restitution and transmural and right-left chamber heterogeneity as markers for proarrhythmic risk stratification, the drugs chosen for validating the markers of proarrhythmic risk, and findings on the spatial and temporal heterogeneities within the heart.

Under diseased conditions, remodeling of the cardiac tissue properties ("passive properties") takes place; these are aspects of electrophysiological behavior that are not associated with active ion transport across cell membranes. Remodeling of the passive electrophysiological properties most often results from structural remodeling, such as gap junction down-regulation and lateralization, fibrotic growth infiltrating the myocardium, or the development of an infarct scar. Such structural remodeling renders atrial or ventricular tissue as a major substrate for arrhythmias. The current review focuses on these aspects of cardiac arrhythmogenesis. Due to the inherent complexity of cardiac arrhythmias, computer simulations have provided means to elucidate interactions pertinent to this spatial scale. Here we review the current state-of-the-art in modeling atrial and ventricular arrhythmogenesis as arising from the disease-induced changes in the passive tissue properties, as well as the contributions these modeling studies have made to our understanding of the mechanisms of arrhythmias in the heart. Because of the rapid advance of structural imaging methodologies in cardiac electrophysiology, we chose to present studies that have used such imaging methodologies to construct geometrically realistic models of cardiac tissue, or the organ itself, where the regional remodeling properties of the myocardium can be represented in a realistic way. We emphasize how the acquired knowledge can be used to pave the way for clinical applications of cardiac organ modeling under the conditions of structural remodeling. [ABSTRACT FROM AUTHOR]

Aims Atrial anti-arrhythmic effects of β-adrenoceptor antagonists (β-blockers) may involve both a suppression of pro-arrhythmic effects of catecholamines, and an adaptational electrophysiological response to chronic β-blocker use; so-called ‘pharmacological remodelling’. In human atrium, such remodelling decreases the transient outward (Ito) and inward rectifier (IK1) K+ currents, and increases the cellular action potential duration (APD) and effective refractory period (ERP). However, the consequences of these changes on mechanisms of genesis and maintenance of atrial fibrillation (AF) are unknown. Using mathematical modelling, we tested the hypothesis that the long-term adaptational decrease in human atrial Ito and IK1 caused by chronic β-blocker therapy, i.e. independent of acute electrophysiological effects of β-blockers, in an otherwise un-remodelled atrium, could suppress AF. Methods and results Contemporarily, biophysically detailed human atrial cell and tissue models were used to investigate effects of the β-blocker-based pharmacological remodelling. Chronic β-blockade remodelling prolonged atrial cell APD and ERP. The incidence of small amplitude APD alternans in the CRN model was reduced. At the 1D tissue level, β-blocker remodelling decreased the maximum pacing rate at which APs could be conducted. At the three-dimensional organ level, β-blocker remodelling reduced the life span of re-entry scroll waves. Conclusion This study improves our understanding of the electrophysiological mechanisms of AF suppression by chronic β-blocker therapy. Atrial fibrillation suppression may involve a reduced propensity for maintenance of re-entrant excitation waves, as a consequence of increased APD and ERP. [ABSTRACT FROM PUBLISHER]

Aims We aimed to investigate the association of number of completed races and finishing time with risk of arrhythmias among participants of Vasaloppet, a 90 km cross-country skiing event. Methods and results All the participants without cardiovascular disease who completed Vasaloppet during 1989–98 were followed through national registries until December 2005. Primary outcome was hospitalization for any arrhythmia and secondary outcomes were atrial fibrillation/flutter (AF), bradyarrhythmias, other supraventricular tachycardias (SVT), and ventricular tachycardia/ventricular fibrillation/cardiac arrest (VT/VF/CA). Among 52 755 participants, 919 experienced arrhythmia during follow-up. Adjusting for age, education, and occupational status, those who completed the highest number of races during the period had higher risk of any arrhythmias [hazard ratio (HR)1.30; 95% CI 1.08–1.58; for ≥5 vs. 1 completed race], AF (HR 1.29; 95% CI 1.04–1.61), and bradyarrhythmias (HR 2.10; 95% CI 1.28–3.47). Those who had the fastest relative finishing time also had higher risk of any arrhythmias (HR 1.30; 95% CI 1.04–1.62; for 100–160% vs. >240% of winning time), AF (1.20; 95% CI 0.93–1.55), and bradyarrhythmias (HR 1.85; 95% CI 0.97–3.54). SVT or VT/VF/CA was not associated with finishing time or number of completed races. Conclusions Among male participants of a 90 km cross-country skiing event, a faster finishing time and a high number of completed races were associated with higher risk of arrhythmias. This was mainly driven by a higher incidence of AF and bradyarrhythmias. No association with SVT or VT/VF/CA was found. [ABSTRACT FROM PUBLISHER]

Key points Ageing is associated with increased risk of sudden cardiac death due to malignant arrhythmias., Shortened refractoriness of Ca2+ release due to increased activity of Ca2+ release channels (RyRs) is recognized as an important contributor to cardiac-triggered arrhythmias. However, molecular mechanisms of RyR dysfunction and its contribution to arrhythmias in ageing remain to be examined., Using ventricular myocytes isolated from old rabbit hearts we demonstrate that age-associated increase in rate of production of reactive oxygen species (ROS) by mitochondria leads to the thiol-oxidation of RyRs, which underlies the hyperactivity of the channels and thus shortened refractoriness of Ca2+ release in cardiomyocytes from the ageing heart. Mitochondria-specific scavenging of ROS in old myocytes restored the redox status of RyRs, reducing SR Ca2+ leak and arrhythmogenic spontaneous Ca2+ waves., We conclude that increased ROS production by mitochondria contributes to age-associated increased risk of stress-induced arrhythmia and sudden cardiac death through thiol-modifications of RyRs., Abstract Ageing is associated with a blunted response to sympathetic stimulation and an increased risk of arrhythmia and sudden cardiac death. Aberrant calcium (Ca2+) handling is an important contributor to the electrical and contractile dysfunction associated with ageing. Yet, the specific molecular mechanisms underlying abnormal Ca2+ handling in ageing heart remain poorly understood. In this study, we used ventricular myocytes isolated from young (5-9 months) and old (4-6 years) rabbit hearts to test the hypothesis that changes in Ca2+ homeostasis are caused by post-translational modification of ryanodine receptors (RyRs) by mitochondria-derived reactive oxygen species (ROS) generated in the ageing heart. Changes in parameters of Ca2+ handling were determined by measuring cytosolic and intra-sarcoplasmic reticulum (SR) Ca2+ dynamics in intact and permeabilized ventricular myocytes using confocal microscopy. We also measured age-related changes in ROS production and mitochondria membrane potential using a ROS-sensitive dye and a mitochondrial voltage-sensitive fluorescent indicator, respectively. In permeablized myocytes, ageing did not change SERCA activity and spark frequency but decreased spark amplitude and SR Ca2+ load suggesting increased RyR activity. Treatment with the antioxidant dithiothreitol reduced RyR-mediated SR Ca2+ leak in permeabilized myocytes from old rabbit hearts to the level comparable to young. Moreover, myocytes from old rabbits had more depolarized mitochondria membrane potential and increased rate of ROS production. Under β-adrenergic stimulation, Ca2+ transient amplitude, SR Ca2+ load, and latency of pro-arrhythmic spontaneous Ca2+ waves (SCWs) were decreased while RyR-mediated SR Ca2+ leak was increased in cardiomyocytes from old rabbits. Additionally, with β-adrenergic stimulation, scavenging of mitochondrial ROS in myocytes from old rabbit hearts restored redox status of RyRs, which reduced SR Ca2+ leak, ablated most SCWs, and increased latency to levels comparable to young. These data indicate that an age-associated increase of ROS production by mitochondria leads to the thiol-oxidation of RyRs, which underlies the hyperactivity of RyRs and thereby shortened refractoriness of Ca2+ release in cardiomyocytes from the ageing heart. This mechanism probably plays an important role in the increased incidence of arrhythmia and sudden death in the ageing population. [ABSTRACT FROM AUTHOR]

Long QT syndrome is the prototypical disorder of ventricular repolarization (VR), and a genotype- phenotype relation is postulated. Furthermore, although increased VR heterogeneity (dispersion) may be important in the arrhythmogenicity in long QT syndrome, this hypothesis has not been evaluated in humans and cannot be tested by conventional electrocardiography. In contrast, vectorcardiography allows assessment of VR heterogeneity and is more sensitive to VR alterations than electrocardiography. Therefore, vectorcardiography was used to compare the electrophysiological phenotypes of two mutations in the LQT1 gene with different in vitro biophysical properties, and with LQT2 mutation carriers and healthy control subjects. We included 99 LQT1 gene mutation carriers (57 Y111C, 42 R518X) and 19 LQT2 gene mutation carriers. Potassium channel function is in vitro most severely impaired in Y111C. The control group consisted of 121 healthy subjects. QRS, QT, and T-peak to T-end (Tp-e) intervals, measures of the QRS vector and T vector and their relationship, and T-loop morphology parameters were compared at rest. Apart from a longer heart rate-corrected QT interval (QT heart rate corrected according to Bazett) in Y111C mutation carriers, there were no significant differences between the two LQT1 mutations. No signs of increased VR heterogeneity were observed among the LQT1 and LQT2 mutation carriers. QT heart rate corrected according to Bazett and Tp-e were longer, and the Tp-eto- QT ratio greater in LQT2 than in LQT1 and the control group. In conclusion, there was a marked discrepancy between in vitro potassium channel function and in vivo electrophysiological properties in these two LQT1 mutations. Together with previous observations of the relatively low risk for clinical events in Y111C mutation carriers, our results indicate need for cautiousness in predicting in vivo electrophysiological properties and the propensity for clinical events based on in vitro assessment of ion channel function alone. [ABSTRACT FROM AUTHOR]

The implantable cardioverter-defibrillator significantly improves survival in patients with malignant ventricular arrhythmias but does not target the underlying pathological substrate responsible for arrhythmic events. A significant proportion of defibrillator recipients experience multiple ventricular tachycardia/fibrillation episodes over a short period of time, termed electrical storm (ES). The current therapeutic strategy for ES is complex and unsatisfactory because simultaneous administration of several medications and additional invasive procedures are often required to control ES. Moreover, this treatment does not favorably influence the long-term outcome. Clearly, improved ES therapies are necessary and desirable, but a lack of understanding of the pathophysiological mechanisms underlying ES has hindered the development of more effective, rationally based therapeutic approaches. This paper reviews emerging experimental and clinical findings that provide insights into the pathophysiology of ES and discusses mechanism-based innovative therapeutic strategies. [ABSTRACT FROM AUTHOR]

Objective - To assess the efficacy of IV lidocaine in decreasing complication rate and improving the outcome in dogs with gastric dilatation volvulus (GDV). Design - Prospective non-controlled study of S3 lidocaine-treated dogs with GDV compared to 47 untreated historical controls with GDV. Setting - University veterinary teaching hospital. Animals - One hundred and thirty client-owned dogs with naturally occurring GDV. Interventions - Study group dogs were treated at presentation with lidocaine (2 mg/kg, IV bolus) followed by constant rate infusion (CRI) of 0.05 mg/kg/min for 24 h. Historical control dogs did not receive any lidocaine. Measurements and Main Results - There were no group differences in age, body weight, time lag from onset of clinical signs to presentation, rectal temperature and pulse rate at presentation, and proportion of gastric wall necrosis. The proportions of cardiac arrhythmias and acute kidney injury (AKI) were significantly (P< 0.001 and P = 0.045, respectively) lower in the lidocaine group (10/83 [12%] versus 18/47 [38,3%] and 3/83 [3.6] versus 0/47). Median hospitalization time period was shorter (P = 0.05) in the lidocaine group compared to the controls (median 48 h; range 24-360 h versus median 72 h; range 24-144 h, respectively). Conclusion and Clinical Relevance - Early treatment with IV lidocaine bolus, followed by CRI of lidocaine for 24 h post presentation decreased the occurrence of cardiac arrhythmias, AKI and hospitalization time period significantly in lidocaine-treated dogs with GDV compared to untreated historical controls. Due to the nonblinded, placebo-uncontroHed, nonrandomized nature of the current study, further evaluation of the efficacy of lidocaine in dogs with GDV is warranted. [ABSTRACT FROM AUTHOR]

Human ether a go-go-related gene type 1 (hERG1) K+ channels conduct the rapid delayed rectifier K+ current and mediate action potential repolarization in the heart. Mutations in KCNH2 (the gene that encodes hERG1) causes LQT2, one of the most common forms of long QT syndrome, a disorder of cardiac repolarization that predisposes affected subjects to ventricular arrhythmia and increases the risk of sudden cardiac death. Hundreds of LQT2-associated mutations have been described, and most cause a loss of function by disrupting subunit folding, assembly, or trafficking of the channel to the cell surface. Loss-of-function mutations in hERG1 channels have also recently been implicated in epilepsy. A single gain-of-function mutation has been described that causes short QT syndrome and cardiac arrhythmia. In addition, up-regulation of hERG1 channel expression has been demonstrated in specific tumors and has been associated with skeletal muscle atrophy in mice. [ABSTRACT FROM AUTHOR]

Protracted QT interval (QTI) adaptation to abrupt heart rate (HR) changes has been identified as a clinical arrhythmic risk marker. This study investigates the ionic mechanisms of QTI rate adaptation and its relationship to arrhythmic risk. Computer simulations and experimental recordings in human and canine ventricular tissue were used to investigate the ionic basis of QTI and action potential duration (APD) to abrupt changes in HR with a protocol commonly used in clinical studies. The time for 90% QTI adaptation is 3.5 mm in simulations, in agreement with experimental and clinical data in humans. APD adaptation follows similar dynamics, being faster in midmyocardial cells (2.5 mm) than in endocardial and epicardial cells (3.5 mm). Both QTI and APD adapt in two phases following an abrupt HR change: a fast initial phase with time constant < 30 s, mainly related to L-type calcium and slow-delayed rectifier potassium current, and a second slow phase of >2 mm driven by intracellular sodium concentration ([Na+]i) dynamics. Alterations in [Na+]i dynamics due to [Na+/K+ pump current inhibition result in protracted rate adaptation and are associated with increased proarrhythmic risk, as indicated by action potential triangulation and faster L-type calcium current recovery from inactivation, leading to the formation of early afterdepolarizations. In conclusion, this study suggests that protracted QTI adaptation could be an indicator of altered [Na+]i dynamics following [Na+/K+ pump inhibition as it occurs in patients with ischemia or heart failure. An increased risk of cardiac arrhythmias in patients with protracted rate adaptation may be due to an increased risk of early afterdepolarization formation. [ABSTRACT FROM AUTHOR]

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KCNE1 associates with the poreforming a-subunit KCNQI to generate the slow (/Ks) current in cardiac myocytes. Mutations in either KCNQ1 or KCNEI can alter the biophysical properties of `K. and mutations in KCNE1 underlie cases of long QT syndrome type 5 (LQT5). We previously investigated a mutation in KCNE 1, T58P1L59P, which causes severe attenuation of /Ks. However, how T58P/L59P acts to disrupt /Ks has not been determined. In this study, we investigate and compare the effects of T58PfL59P with three other LQT5 mutations (G52R, S74L, and R98W) on the biophysical properties of the current, trafficking of KCNQ1, and assembly of the /Ks channel. G52R and T58P/L59P produce currents that lack the kinetic behavior of /Ks. In contrast, S74L and R98W both produce 1K5-like currents but with rightward shifted voltage dependence of activation. All of the LQT5 mutants express protein robustly, and T58P1L59P and R98W cause modest, but significant, defects in the trafficking of KCNQ 1. Despite defects in trafficking, in the presence of KCNQ1, T58P/L59P and the other LQT5 mutants are present at the plasma membrane. Interestingly, in comparison to KCNEI and the other LQT5 mutants, T58P/L59P associates only weakly with KCNQ1. In conclusion, we identify the disease mechanisms for each mutation and reveal that T58P/L59P causes disease through a novel mechanism that involves defective /Ks complex assembly. [ABSTRACT FROM AUTHOR]

Although numerous studies have reported the effects of genetic alterations on murine electrophysiology, the range of normal values for ventricular activation, repolarization, and arrhythmias in mouse hearts is not known. We analyzed right ventricular (RV), left ventricular (LV), and septal activation times, monophasic action potential durations (APD), and right ventricular effective refractory periods during spontaneous rhythm, induced AV nodal block, right ventricular pacing (100–300 ms paced cycle length), and programmed stimulation in 410 beating, Langendorff-perfused, wild-type mouse hearts of CD1, DBAC3H, FVBN, C57/Bl6, and hybrid backgrounds (age 203 ± 132 days). Action potential duration was longer at longer cycle lengths. LV-APD prolonged more than RV-APD, resulting in an increased heterogeneity of APD at longer pacing cycle lengths. Higher heart weight/body weight ratio and DBAC3H and FVB/N backgrounds were associated with long APD, C57Bl/6 background was associated with short APD. Activation times were longer in older hearts. There were no clear-cut sex-dependent APD differences. Sustained spontaneous arrhythmias occurred in 1% of hearts, non-sustained arrhythmias in 18%. Induction of AV block and C57Bl/6 genetic background were associated with spontaneous arrhythmias. Programmed stimulation induced arrhythmias in 51% of hearts. Inducible arrhythmias were associated with advanced age and shorter refractory periods. Ventricular APD in beating mouse hearts show rate- and site-dependent changes comparable to man and large animals. Bradycardia provokes spontaneous arrhythmias in mouse heart, while age-dependent conduction slowing and short refractory periods predispose to induced arrhythmias. Genetic background influences repolarization and arrhythmogenesis. These findings provide systematic data for the design and interpretation of arrhythmia studies in murine disease models. [ABSTRACT FROM AUTHOR]

The beat-to-beat dynamicity of the QT-RR interval relationship is difficult to assess with the use of traditional correction factors (QTc) and changes in QTc do not accurately reflect or quantify arrhythmogenic risk. Further, the interpretation of arrhythmogenic risk is influenced by autonomic state. To visualize the QT-RR interval dynamics under varying conditions of autonomic state from impaired repolarization, we have developed a system to sequentially plot the beat-to-beat confluence of ECG data or 'clouds' obtained from conscious dogs and humans. To represent the non-uniformity of the clouds, a bootstrap sampling method that computes the mathematical centre of the uncorrected beat-to-beat QT value (QTbtb) and defines the upper and lower 95% confidence bounds is used. The same method can also be used to examine heterogeneity, hysteresis (both acceleration and deceleration) and restitution (beat-to-beat QT-TQ interval relationship). Impaired repolarization with the combination of E-4031 and L-768,673 (inhibitor of IKs current) increased heterogeneity of restitution at rest 55-91%; increased hysteresis during heart rate acceleration after isoproterenol challenge by approximately 40-60%; and dramatically diminished the minimum TQ boundary by 72% to only 28 ms. Impaired repolarization alters restitution during normal sinus rhythm and increases hysteresis/heterogeneity during heart rate acceleration following sympathetic stimulation. These findings are supported by similar clinical observations in LQT1 and LQT2 syndromes. Therefore, the assessment of the dynamic QT-RR and QT-TQ interval relationships through quantification of heterogeneity, hysteresis and restitution may allow a more accurate non-invasive evaluation of the conditions leading to cardiac arrhythmia. [ABSTRACT FROM AUTHOR]

Arrhythmias are frequent complication in patients with acute myocardial infarction (MI). The importance of accelerated idioventricular rhythm (AIVR), ventricular fibrillation or tachycardia (VF, VT), atrial fibrillation or flutter (AF) and bradycardias is considered and discussed in this review article. The value of the presence of AIVR as a marker of reperfusion is small, but in combination with other non-invasive markers (ST-segment resolution), its presence is connected with a high probability of successful reperfusion. Early ventricular arrhythmias are a serious complication of MI. However, if they are revealed and treated in time, they apparently do not represent a negative prognostic factor. Later occurred VF or VT are more a symptom of larger MI. AF, which is not directly life-threatening for the patients, frequently occurs in patients with larger MI and it is an independent predictor of a poor long-term prognosis of these patients. The early and successful reperfusion therapy is the best anti-arrhythmic therapeutic method in patients with MI. [ABSTRACT FROM AUTHOR]

Background: To evaluate the role of nonsustained ventricular tachycardias (NSVT) for the prediction of major ventricular arrhythmias (MVA) in patients with idiopathic dilated cardiomyopathy (DCM) after optimization of medical treatment. Methods and Results: Three hundred nineteen consecutive DCM patients were evaluated after adequate stabilization on optimal angiotensin-converting enzyme (ACE) inhibitor (88%) and β-blocker (82%) therapy. Frequency, length, and rate of NSVT at 24-hour Holter monitoring were analyzed to assess their values in predicting MVA (unexpected sudden death, SVT, ventricular fibrillation, and appropriate implantable cardioverter defibrillator interventions). During follow-up (median 96 months, 1st–3rd interquartile range 52–130), MVA incidence was low, and not statistically different between patients with and without NSVT (3 and 2 per 100 patient-years, respectively, P = nonsignificant [NS] at log-rank analysis). At multivariable analysis, the number of NSVT was predictive of MVA only if left ventricular ejection fraction (LVEF) was >0.35 (two NSVT/day vs no NSVT/day: hazard ratio [HR] 5.3, 95% confidence interval [CI] 1.59–17.85 in LVEF >0.35 vs HR 0.93, 95% CI 0.3–2.81 in LVEF ≤0.35). Consequently, in patients with LVEF ≤0.35, MVA incidence rates were similar regardless of NSVT (3.6 and 4.1 patient-years, respectively, in those with and without NSVT, P = NS), while in patients with LVEF >0.35, MVA incidence (3.1 per 100 patient-years vs 0.9 per 100 patient-years, P = 0.003) was significantly higher when NSVT were present. Conclusions: After medical stabilization, NSVT did not increase the risk of MVA in patients with DCM and LVEF ≤0.35. Conversely, the number and length of NSVT runs were significantly related to the occurrence of MVA in the patients with LVEF >0.35. [ABSTRACT FROM AUTHOR]

Atrial fibrillation is the most common arrhythmia occurring after heart surgery. Its prevalence after coronary artery bypass surgery is 17 - 33%. Atrial fibrillation requires additional treatment, lengthens hospitalization and increases the overall expenses of cardiac surgery. Atrial fibrillation can cause hemodynamic problems, predispose to congestive heart failure and increase the risk of stroke. Beta-blockers have been shown to effectively prevent atrial fibrillation, and beta-blockers should be a part of the medication of every patient undergoing cardiac surgery, if there are no contraindications. Amiodarone therapy can also be considered for especially high-risk patients. [ABSTRACT FROM AUTHOR]