Mitral annular disjunction in idiopathic ventricular fibrillation patients: just a bystander or a potential cause?

AIMS: Previously, we demonstrated that inferolateral mitral annular disjunction (MAD) is more prevalent in patients with idiopathic ventricular fibrillation (IVF) than in healthy controls. In the present study, we advanced the insights into the prevalence and ventricular arrhythmogenicity by inferolateral MAD in an even larger IVF cohort. METHODS AND RESULTS: This retrospective multi-centre study included 185 IVF patients [median age 39 (27, 52) years, 40% female]. Cardiac magnetic resonance images were analyzed for mitral valve and annular abnormalities and late gadolinium enhancement. Clinical characteristics were compared between patients with and without MAD. MAD in any of the 4 locations was present in 112 (61%) IVF patients and inferolateral MAD was identified in 24 (13%) IVF patients. Mitral valve prolapse (MVP) was found in 13 (7%) IVF patients. MVP was more prevalent in patients with inferolateral MAD compared with patients without inferolateral MAD (42 vs. 2%, P < 0.001). Pro-arrhythmic characteristics in terms of a high burden of premature ventricular complexes (PVCs) and non-sustained ventricular tachycardia (VT) were more prevalent in patients with inferolateral MAD compared to patients without inferolateral MAD (67 vs. 23%, P < 0.001 and 63 vs. 41%, P = 0.046, respectively). Appropriate implantable cardioverter defibrillator therapy during follow-up was comparable for IVF patients with or without inferolateral MAD (13 vs. 18%, P = 0.579). CONCLUSION: A high prevalence of inferolateral MAD and MVP is a consistent finding in this large IVF cohort. The presence of inferolateral MAD is associated with a higher PVC burden and non-sustained VTs. Further research is needed to explain this potential interplay.

Novel use of repolarization parameters in electrocardiographic imaging to uncover arrhythmogenic substrate.

BACKGROUND: Measuring repolarization characteristics is challenging and has been reserved for experienced physicians. In electrocardiographic imaging (ECGI), activation-recovery interval (ARI) is used as a measure of local cardiac repolarization duration. We hypothesized that repolarization characteristics, such as local electrogram morphology and local and global dispersion of repolarization timing and duration could be of significance in ECGI. OBJECTIVE: To further explore their potential in arrhythmic risk stratification we investigated the use of novel repolarization parameters in ECGI. MATERIALS AND METHODS: We developed and compared methods for T-peak and T-end detection in reconstructed potentials. All methods were validated on annotated reconstructed electrograms (EGMs). Characteristics of the reconstructed EGMs and epicardial substrate maps in IVF patients were analyzed by using data recorded during sinus rhythm. The ECGI data were analyzed for EGM morphology, conduction, and repolarization. RESULTS: We acquired ECGI data from 8 subjects for this study. In all patients we evaluated four repolarization parameters: Repolarization time, T-wave area, Tpeak-Tend interval, and T-wave alternans. Most prominent findings were steep repolarization time gradients in regions with flat EGMs. These regions were also characterized by low T-wave area and large differences in Tpeak-Tend interval. CONCLUSIONS: Measuring novel repolarization parameters in reconstructed electrograms acquired with ECGI is feasible, can be done in a fully automated manner and may provide additional information on underlying arrhythmogenic substrate for risk stratification. Further studies are needed to investigate their potential use and clinical application.

The Netherlands Arrhythmogenic Cardiomyopathy Registry: design and status update.

BACKGROUND: Clinical research on arrhythmogenic cardiomyopathy (ACM) is typically limited by small patient numbers, retrospective study designs, and inconsistent definitions. AIM: To create a large national ACM patient cohort with a vast amount of uniformly collected high-quality data that is readily available for future research. METHODS: This is a multicentre, longitudinal, observational cohort study that includes (1) patients with a definite ACM diagnosis, (2) at-risk relatives of ACM patients, and (3) ACM-associated mutation carriers. At baseline and every follow-up visit, a medical history as well information regarding (non-)invasive tests is collected (e. g. electrocardiograms, Holter recordings, imaging and electrophysiological studies, pathology reports, etc.). Outcome data include (non-)sustained ventricular and atrial arrhythmias, heart failure, and (cardiac) death. Data are collected on a research electronic data capture (REDCap) platform in which every participating centre has its own restricted data access group, thus empowering local studies while facilitating data sharing. DISCUSSION: The Netherlands ACM Registry is a national observational cohort study of ACM patients and relatives. Prospective and retrospective data are obtained at multiple time points, enabling both cross-sectional and longitudinal research in a hypothesis-generating approach that extends beyond one specific research question. In so doing, this registry aims to (1) increase the scientific knowledge base on disease mechanisms, genetics, and novel diagnostic and treatment strategies of ACM; and (2) provide education for physicians and patients concerning ACM, e. g. through our website ( www.acmregistry.nl ) and patient conferences.

Life-long tailoring of diagnosis and management of patients with idiopathic ventricular fibrillation-future perspectives in research.

The diagnosis and management of idiopathic ventricular fibrillation is challenging, as it requires extensive diagnostic testing and offers few curative options due to unknown underlying disease. The resulting population is a heterogeneous group of patients with a largely unknown natural history. Structural patient characterisation, follow-up and innovations in diagnostic testing can improve our understanding of the disease mechanisms of idiopathic ventricular fibrillation, detect underlying disease during follow-up and aid in therapeutic management. Recently, initiatives have been launched in the Netherlands to investigate the role of high-resolution non-invasive electrocardiographic imaging and genetic and familial screening in idiopathic ventricular fibrillation.

The role of the SCN5A-encoded channelopathy in irritable bowel syndrome and other gastrointestinal disorders.

BACKGROUND: Gastrointestinal functional and motility disorders, like irritable bowel syndrome (IBS), have a high prevalence in the Western population and cause significant morbidity and loss of quality of life leading to considerable costs for health care. A decade ago, it has been demonstrated that interstitial cells of Cajal and intestinal smooth muscle cells, cells important for gastrointestinal motility, express the sodium channel alpha subunit Nav 1.5. In the heart, aberrant variants in this sodium channel, encoded by SCN5A, are linked to inherited arrhythmia syndromes, like the long-QT syndrome type 3 and Brugada syndrome. Mounting data show a possible contribution of SCN5A mutants to gastrointestinal functional and motility disorders. Two percent of IBS patients harbor SCN5A mutations with electrophysiological evidence of loss- and gain-of-function. In addition, gastrointestinal symptoms are more prevalent in cardiac SCN5A-mutation positive patients. PURPOSE: This review firstly describes the Nav 1.5 channel and its physiological role in ventricular cardiomyocytes and gastrointestinal cells, then we focus on the involvement of mutant Nav 1.5 in gastrointestinal functional and motility disorders. Future research might uncover novel mutation-specific treatment strategies for SCN5A-encoded gastrointestinal channelopathies.

Noninvasive reconstruction of cardiac electrical activity: update on current methods, applications and challenges.

Electrical activity at the level of the heart muscle can be noninvasively reconstructed from body-surface electrocardiograms (ECGs) and patient-specific torso-heart geometry. This modality, coined electrocardiographic imaging, could fill the gap between the noninvasive (low-resolution) 12-lead ECG and invasive (high-resolution) electrophysiology studies. Much progress has been made to establish electrocardiographic imaging, and clinical studies appear with increasing frequency. However, many assumptions and model choices are involved in its execution, and only limited validation has been performed. In this article, we will discuss the technical details, clinical applications and current limitations of commonly used methods in electrocardiographic imaging. It is important for clinicians to realise the influence of certain assumptions and model choices for correct and careful interpretation of the results. This, in combination with more extensive validation, will allow for exploitation of the full potential of noninvasive electrocardiographic imaging as a powerful clinical tool to expedite diagnosis, guide therapy and improve risk stratification.

Founder mutations in the Netherlands: familial idiopathic ventricular fibrillation and DPP6.

In this part of a series on founder mutations in the Netherlands, we review familial idiopathic ventricular fibrillation linked to the DPP6 gene. Familial idiopathic ventricular fibrillation determines an intriguing subset of the inheritable arrhythmia syndromes as there is no recognisable phenotype during cardiological investigation other than ventricular arrhythmias highly associated with sudden cardiac death. Until recently, it was impossible to identify presymptomatic family members at risk for fatal events. We uncovered several genealogically linked families affected by numerous sudden cardiac deaths over the past centuries, attributed to familial idiopathic ventricular fibrillation. Notably, ventricular fibrillation in these families was provoked by very short coupled monomorphic extrasystoles. We were able to associate their phenotype of lethal arrhythmic events with a haplotype harbouring the DPP6 gene. While this gene has not earlier been related to cardiac arrhythmias, we are now able, for the first time, to identify and to offer timely treatment to presymptomatic family members at risk for future fatal events solely by genetic analysis. Therefore, when there is a familial history of unexplained sudden cardiac deaths, a link to the DPP6 gene may be explored as it may enable risk evaluation of the remaining family members. In addition, when closely coupled extrasystoles initiate ventricular fibrillation in the absence of other identifiable causes, a link to the DPP6 gene should be suspected.

End-diastolic myofiber stress and ejection strain increase with ventricular volume overload--Serial in-vivo analyses in dogs with complete atrioventricular block.

BACKGROUND: Myocardial stress and strain are considered primary mechanical stimuli for hypertrophic remodeling. Their values and significance in the intact beating heart during chronic overload remain poorly characterized. METHODS AND RESULTS: Left-ventricular (LV) dimensions (echocardiography) and pressure (invasive) were simultaneously recorded in anesthetized dogs at sinus rhythm (SR), acute and 1, 2, 6, 12 weeks of atrioventricular block (AVB), leading to structural, electrical and contractile remodeling. Mechanical load of the myocardium was quantified as myofiber stress (sigma(f)), being force along myofiber orientation per cross-sectional area, and natural myofiber strain (e(f)), being change in natural logarithm of myofiber length (l) divided by its reference length: e(f) = ln(l/l(ref)). Time courses of sigma(f) and e(f) were calculated from LV pressure and dimensions, using a validated mathematical model of cardiac mechanics. End-diastolic sigmaf increased from 2.0 +/- 0.1 kPa at SR to 3.4 +/- 0.3 kPa at acute AVB, remaining elevated for > 6 weeks. Systolic sigma(f) was not affected by AVB. Ejection strain rose instantly upon AVB, reaching a maximum at 2 weeks: 0.24 +/- 0.02 vs. 0.10 +/- 0.01 at SR. The increase of myofiber stroke work (sigma(f)-e(f) loop area) from 3.1 +/- 0.3 at SR to 6.0 +/- 0.5 kJ/m(3)/beat at 1 week AVB was attributed mainly to an increase of strain during ejection. Stroke work and ejection strain remained elevated up to 12 weeks. The rate of LV-mass increase was maximal (2.2 +/- 0.4 g/day) at 1 week AVB. CONCLUSIONS: Serial mechanical phenotyping is feasible in the intact anesthetized dog with chronic ventricular overload. Our new approach yields values of mechanical load that are comparable to those found in isolated myocardium by others. In chronic AVB, both end-diastolic myofiber stress and ejection strain are increased. Early increases of both parameters coincide with peak hypertrophic growth, suggesting their important role for mechanotransduction. Peak systolic sigmaf is likely not important for hypertrophy in this model, since it does not change throughout the experiment.

Giant negative T waves after treatment of severe hyperkalaemia.

We present the case of a 79-year-old female with severe hyperkalaemia and severe prerenal insufficiency due to dehydration and nephrotoxic medications, including spironolactone. The ECG showed AV nodal rhythm and tented T waves. After treatment with fluids, insulin, polystyrene sulphonate and sodium bicarbonate, the serum potassium level and kidney function normalised. Several days later, she developed QT prolongation with giant negative T waves without signs of ischaemia. In this report, we review the effect of hyperkalaemia on cardiac ion channel function and the associated changes on the ECG. In addition, the causes and mechanisms of giant negative T waves are discussed.