-Related Cardiac Disease: Late Onset With a Variable and Mild Phenotype in a Large Cohort of Patients With the Lamin A/C p.(Arg331Gln) Founder Mutation.

Background: Interpretation of missense variants can be especially difficult when the variant is also found in control populations. This is what we encountered for the c.992G>A (p.

QT interval variability in body surface ECG: measurement, physiological basis, and clinical value: position statement and consensus guidance endorsed by the European Heart Rhythm Association jointly with the ESC Working Group on Cardiac Cellular Electrophysiology.

This consensus guideline discusses the electrocardiographic phenomenon of beat-to-beat QT interval variability (QTV) on surface electrocardiograms. The text covers measurement principles, physiological basis, and clinical value of QTV. Technical considerations include QT interval measurement and the relation between QTV and heart rate variability.

Myokit: A simple interface to cardiac cellular electrophysiology.

Myokit is a new powerful and versatile software tool for modeling and simulation of cardiac cellular electrophysiology. Myokit consists of an easy-to-read modeling language, a graphical user interface, single and multi-cell simulation engines and a library of advanced analysis tools accessible through a Python interface. Models can be loaded from Myokit's native file format or imported from CellML.

Detailed characterization of familial idiopathic ventricular fibrillation linked to the DPP6 locus.

Background: Familial idiopathic ventricular fibrillation (IVF) is a severe disease entity and is notoriously difficult to manage because there are no clinical risk indicators for premature cardiac arrest. Previously, we identified a link between familial IVF and a risk haplotype on chromosome 7q36 (involving the arrhythmia gene DPP6).

Objective: The purpose of this study was to expand our knowledge of familial IVF and to discuss its (extended) clinical characteristics.

Hypertrophic remodelling in cardiac regulatory myosin light chain (MYL2) founder mutation carriers.

Aims: Phenotypic heterogeneity and incomplete penetrance are common in patients with hypertrophic cardiomyopathy (HCM). We aim to improve the understanding in genotype-phenotype correlations in HCM, particularly the contribution of an MYL2 founder mutation and risk factors to left ventricular hypertrophic remodelling.

Methods And Results: We analysed 14 HCM families of whom 38 family members share the MYL2 c.

Clinical Presentation, Long-Term Follow-Up, and Outcomes of 1001 Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy Patients and Family Members.

Background: Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is a progressive cardiomyopathy. We aimed to define long-term outcome in a transatlantic cohort of 1001 individuals.

Methods And Results: Clinical and genetic characteristics and follow-up data of ARVD/C index-patients (n=439, fulfilling of 2010 criteria in all) and family members (n=562) were assessed.

Opportunities and challenges of current electrophysiology research: a plea to establish 'translational electrophysiology' curricula.

Cardiac electrophysiology has evolved into an important subspecialty in cardiovascular medicine. This is in part due to the significant advances made in our understanding and treatment of heart rhythm disorders following more than a century of scientific discoveries and research. More recently, the rapid development of technology in cellular electrophysiology, molecular biology, genetics, computer modelling, and imaging have led to the exponential growth of knowledge in basic cardiac electrophysiology.

Electromechanical window negativity in genotyped long-QT syndrome patients: relation to arrhythmia risk.

Aim: Prolonged and dispersed left-ventricular (LV) contraction is present in patients with long-QT syndrome (LQTS). Electrical and mechanical abnormalities appear most pronounced in symptomatic individuals. We focus on the 'electromechanical window' (EMW; duration of LV-mechanical systole minus QT interval) in patients with genotyped LQTS.

Long-QT mutation p.K557E-Kv7.1: dominant-negative suppression of IKs, but preserved cAMP-dependent up-regulation.

Aims: Mutations in KCNQ1, encoding for Kv7.1, the α-subunit of the IKs channel, cause long-QT syndrome type 1, potentially predisposing patients to ventricular tachyarrhythmias and sudden cardiac death, in particular, during elevated sympathetic tone. Here, we aim at characterizing the p.

Interventricular differences in β-adrenergic responses in the canine heart: role of phosphodiesterases.

Background: RV and LV have different embryologic, structural, metabolic, and electrophysiologic characteristics, but whether interventricular differences exist in β-adrenergic (β-AR) responsiveness is unknown. In this study, we examine whether β-AR response and signaling differ in right (RV) versus left (LV) ventricles.

Methods And Results: Sarcomere shortening, Ca(2+) transients, ICa,L and IKs currents were recorded in isolated dog LV and RV midmyocytes.

Right-ventricular enlargement in arrhythmogenic right-ventricular cardiomyopathy is associated with decreased QRS amplitudes and T-wave negativity.

Background: Arrhythmogenic right-ventricular cardiomyopathy (ARVC) can lead to RV dilatation. We hypothesized that electrocardiographic characteristics including QRS amplitudes in the extremity- and precordial leads, the S amplitude in lead V1 , and extent of T-wave negativity over the precordial leads are related to RV dilatation in this condition.

Methods: In 42 ARVC patients and 42 controls, we correlated total QRS amplitude in the extremity leads (∑QRSext ), precordial leads (∑QRSprec ) and in all leads (∑QRStot : summation of ∑QRSext and ∑QRSprec ), S amplitude in lead V1 and the extent of T-wave inversion in the precordial leads (V1 vs.

Nfat and miR-25 cooperate to reactivate the transcription factor Hand2 in heart failure.

Although aberrant reactivation of embryonic gene programs is intricately linked to pathological heart disease, the transcription factors driving these gene programs remain ill-defined. Here we report that increased calcineurin/Nfat signalling and decreased miR-25 expression integrate to re-express the basic helix-loop-helix (bHLH) transcription factor dHAND (also known as Hand2) in the diseased human and mouse myocardium. In line, mutant mice overexpressing Hand2 in otherwise healthy heart muscle cells developed a phenotype of pathological hypertrophy.

Wavelet-sparsity based regularization over time in the inverse problem of electrocardiography.

Noninvasive, detailed assessment of electrical cardiac activity at the level of the heart surface has the potential to revolutionize diagnostics and therapy of cardiac pathologies. Due to the requirement of noninvasiveness, body-surface potentials are measured and have to be projected back to the heart surface, yielding an ill-posed inverse problem. Ill-posedness ensures that there are non-unique solutions to this problem, resulting in a problem of choice.

Determinants of beat-to-beat variability of repolarization duration in the canine ventricular myocyte: a computational analysis.

Beat-to-beat variability of repolarization duration (BVR) is an intrinsic characteristic of cardiac function and a better marker of proarrhythmia than repolarization prolongation alone. The ionic mechanisms underlying baseline BVR in physiological conditions, its rate dependence, and the factors contributing to increased BVR in pathologies remain incompletely understood. Here, we employed computer modeling to provide novel insights into the subcellular mechanisms of BVR under physiological conditions and during simulated drug-induced repolarization prolongation, mimicking long-QT syndromes type 1, 2, and 3.

Realistic training data improve noninvasive reconstruction of heart-surface potentials.

The inverse problem of electrocardiography is to noninvasively reconstruct electrical heart activity from body-surface electrocardiograms. Solving this problem is beneficial to clinical practice. However, reconstructions cannot be obtained straightforwardly due to the ill-posed nature of this problem.

Diastolic spontaneous calcium release from the sarcoplasmic reticulum increases beat-to-beat variability of repolarization in canine ventricular myocytes after β-adrenergic stimulation.

Rationale: Spontaneous Ca(2+) release (SCR) from the sarcoplasmic reticulum can cause delayed afterdepolarizations and triggered activity, contributing to arrhythmogenesis during β-adrenergic stimulation. Excessive beat-to-beat variability of repolarization duration (BVR) is a proarrhythmic marker. Previous research has shown that BVR is increased during intense β-adrenergic stimulation, leading to SCR.

Arrhythmogenic mechano-electric heterogeneity in the long-QT syndrome.

Since the first linkage of the long-QT syndrome to the Harvey ras-1 gene in 1991 ample research has been performed to decipher the molecular-biophysical basis of congenital repolarization defects and the electrophysiological mechanisms of torsades-de-pointes arrhythmias in this condition. Mechanistic knowledge is mostly derived from cellular experiments (cardiac myocytes, cultured cells), ventricular tissue (including arterially-perfused wedge) preparations and Langendorff-perfused hearts, with relatively little information from in-vivo animal models, and even more scant intact human-heart investigations. Until now, much emphasis has been put on purely membrane-related pathways of arrhythmia initiation with a prominent role for spatiotemporal dispersion of repolarization, early afterdepolarizations and reentrant excitation.

Measurement of action potential generation in isolated canine left ventricular midmyocardial myocytes.

Proarrhythmic side effects are a major limitation during the drug development process for cardiac and non-cardiac compounds. Because changes in cardiac action potential (AP) are undesirable, the evaluation of the effects of test compounds on the AP is essential before advancing new compounds to clinical testing. However, an increase in repolarization duration alone is not always proarrhythmic, and newer surrogate markers have been suggested to better predict the occurrence of arrhythmia.

Dominant-negative control of cAMP-dependent IKs upregulation in human long-QT syndrome type 1.

Rationale: The mutation A341V in the S6 transmembrane segment of KCNQ1, the α-subunit of the slowly activating delayed-rectifier K(+) (I(Ks)) channel, predisposes to a severe long-QT1 syndrome with sympathetic-triggered ventricular tachyarrhythmias and sudden cardiac death.

Objective: Several genetic risk modifiers have been identified in A341V patients, but the molecular mechanisms underlying the pronounced repolarization phenotype, particularly during β-adrenergic receptor stimulation, remain unclear. We aimed to elucidate these mechanisms and provide new insights into control of cAMP-dependent modulation of I(Ks).