Importance of Systematic Diagnostic Testing in Idiopathic Ventricular Fibrillation: Results From the Dutch iVF Registry.

BACKGROUND: Idiopathic ventricular fibrillation (iVF) is a diagnosis of exclusion. Systematic diagnostic testing is important to exclude alternative causes for VF. The early use of "high yield" testing, including cardiac magnetic resonance (CMR), exercise testing, and sodium channel blocker provocation, has been increasingly recognized. OBJECTIVES: The purpose of this study was to investigate the importance and consistency of systematic diagnostic testing in iVF. METHODS: This study included 423 iVF patients from 11 large secondary and tertiary hospitals in the Netherlands. Clinical characteristics and diagnostic testing data were ascertained. RESULTS: IVF patients experienced the index event at a median age of 40 years (IQR: 28-52 years), and 61% were men. The median follow-up time was 6 years (IQR: 2-12 years). Over the years, "high yield" diagnostic tests were increasingly performed (mean 68% in 2000-2010 vs 75% in 2011-2021; P < 0.001). During follow-up, 38 patients (9%) originally labeled as iVF received an alternative diagnosis. Patients in whom "high-yield" diagnostic tests were consistently performed during the initial work-up received an alternative diagnosis less frequently during follow-up (HR: 0.439; 95% CI: 0.219-0.878; P = 0.020). Patients who received an alternative diagnosis during follow-up had a worse prognosis in terms of cardiac death (P = 0.012) with a trend toward more implantable cardioverter-defibrillator therapy (P = 0.055). CONCLUSIONS: Although adherence to (near) complete diagnostic testing in this population of iVF patients increased over the years, patients with iVF still undergo varying levels of diagnostic evaluation. The latter leads to initial underdiagnosis of alternative conditions and is associated with a worse prognosis. Our results underscore the importance of early systematic diagnostic assessment in patients with apparent iVF.

Variant Location Is a Novel Risk Factor for Individuals With Arrhythmogenic Cardiomyopathy Due to a Desmoplakin (DSP) Truncating Variant.

BACKGROUND: Truncating variants in desmoplakin (DSPtv) are an important cause of arrhythmogenic cardiomyopathy; however the genetic architecture and genotype-specific risk factors are incompletely understood. We evaluated phenotype, risk factors for ventricular arrhythmias, and underlying genetics of DSPtv cardiomyopathy. METHODS: Individuals with DSPtv and any cardiac phenotype, and their gene-positive family members were included from multiple international centers. Clinical data and family history information were collected. Event-free survival from ventricular arrhythmia was assessed. Variant location was compared between cases and controls, and literature review of reported DSPtv performed. RESULTS: There were 98 probands and 72 family members (mean age at diagnosis 43±8 years, 59% women) with a DSPtv, of which 146 were considered clinically affected. Ventricular arrhythmia (sudden cardiac arrest, sustained ventricular tachycardia, appropriate implantable cardioverter defibrillator therapy) occurred in 56 (33%) individuals. DSPtv location and proband status were independent risk factors for ventricular arrhythmia. Further, gene region was important with variants in cases (cohort n=98; Clinvar n=167) more likely to occur in the regions resulting in nonsense mediated decay of both major DSP isoforms, compared with n=124 genome aggregation database control variants (148 [83.6%] versus 29 [16.4%]; P<0.0001). CONCLUSIONS: In the largest series of individuals with DSPtv, we demonstrate that variant location is a novel risk factor for ventricular arrhythmia, can inform variant interpretation, and provide critical insights to allow for precision-based clinical management.

Reclassification of a likely pathogenic Dutch founder variant in KCNH2; implications of reduced penetrance.

BACKGROUND: Variants in KCNH2, encoding the human ether a-go-go (hERG) channel that is responsible for the rapid component of the cardiac delayed rectifier K+ current (IKr), are causal to long QT syndrome type 2 (LQTS2). We identified eight index patients with a new variant of unknown significance (VUS), KCNH2:c.2717C > T:p.(Ser906Leu). We aimed to elucidate the biophysiological effect of this variant, to enable reclassification and consequent clinical decision-making. METHODS: A genotype-phenotype overview of the patients and relatives was created. The biophysiological effects were assessed independently by manual-, and automated calibrated patch clamp. HEK293a cells expressing (i) wild-type (WT) KCNH2, (ii) KCNH2-p.S906L alone (homozygous, Hm) or (iii) KCNH2-p.S906L in combination with WT (1:1) (heterozygous, Hz) were used for manual patching. Automated patch clamp measured the variants function against known benign and pathogenic variants, using Flp-In T-rex HEK293 KCNH2-variant cell lines. RESULTS: Incomplete penetrance of LQTS2 in KCNH2:p.(Ser906Leu) carriers was observed. In addition, some patients were heterozygous for other VUSs in CACNA1C, PKP2, RYR2 or AKAP9. The phenotype of carriers of KCNH2:p.(Ser906Leu) ranged from asymptomatic to life-threatening arrhythmic events. Manual patch clamp showed a reduced current density by 69.8 and 60.4% in KCNH2-p.S906L-Hm and KCNH2-p.S906L-Hz, respectively. The time constant of activation was significantly increased with 80.1% in KCNH2-p.S906L-Hm compared with KCNH2-WT. Assessment of KCNH2-p.S906L-Hz by calibrated automatic patch clamp assay showed a reduction in current density by 35.6%. CONCLUSION: The reduced current density in the KCNH2-p.S906L-Hz indicates a moderate loss-of-function. Combined with the reduced penetrance and variable phenotype, we conclude that KCNH2:p.(Ser906Leu) is a low penetrant likely pathogenic variant for LQTS2.

Comparative analysis of right ventricular strain in Fabry cardiomyopathy and sarcomeric hypertrophic cardiomyopathy.

AIMS: To perform a comparative analysis of right ventricle (RV) myocardial mechanics, assessed by 2D speckle-tracking echocardiography (2D-STE), between patients with Fabry disease and patients with sarcomeric disease. METHODS AND RESULTS: Patients with Fabry cardiomyopathy (FC) (n = 28) were compared with patients with sarcomeric hypertrophic cardiomyopathy (HCM), matched for degree of left ventricle hypertrophy (LVH) and demographic characteristics (n = 112). In addition, patients with Fabry disease and no LVH [phenotype-negative carriers of pathogenic α-galactosidase gene mutations (GLA LVH-)] (n = 28) were compared with age and sex-matched carriers of sarcomeric gene mutations without LVH [Phenotype-negative carriers of pathogenic sarcomeric gene mutations (Sarc LVH-)] (n = 56). Standard echocardiography and 2D-STE were performed in all participants. Despite a subtle impairment of RV global longitudinal strain (RV-GLS) was common in both groups, patients with FC showed a more prominent reduction of RV free wall longitudinal strain (RV-FWS) and lower values of difference between RV-FWS and RV-GLS (ΔRV strain), in comparison to individuals with HCM (P < 0.001 and P = 0.002, respectively). RV-FWS and ΔRV strain demonstrated an independent and additive value in discriminating FC from HCM, over the presence of symmetric LVH, systolic anterior motion of the mitral valve and RV hypertrophy. Similar results were found in GLA LVH- patients: they had worse RV-FWS and lower values of ΔRV strain as compared to Sarc LVH- patients (both P < 0.001). CONCLUSION: Patients with FC show a specific pattern of RV myocardial mechanics, characterized by a larger impairment of RV-FWS and lower ΔRV strain in comparison to patients with HCM, which may be helpful in the differential diagnosis between these two diseases.

Sacral abnormalities including caudal appendage, skeletal dysplasia, and prenatal cardiomyopathy associated with a pathogenic TAB2 variant in a 3-generation family.

Haplo-insufficiency of the TGFß-activated kinase 1 binding protein 2 (TAB2) gene is associated with short stature, facial dysmorphisms, connective tissue abnormalities, hearing loss, and cardiac disease. Skeletal dysplasia and sacral dimples are also found in a minority of patients. Here, we describe a 3-generation family with caudal appendage, other sacral anomalies, and skeletal abnormalities including hypoplasia of the iliac wings and scapulae, fusion of the carpal bones and stenosis of the spinal canal, as well as a remarkable course of prenatally-detected cardiomyopathy with characteristics changing over time. Genetic analysis showed a heterozygous nonsense variant in the TAB2 gene.

Lamin A/C-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 LMNA c.992G>A (p.(Arg331Gln)) variant. Therefore, to evaluate the effect of this variant, we combined an evaluation of clinical data with functional experiments and morphological studies. METHODS AND RESULTS: Clinical data of 23 probands and 35 family members carrying this variant were retrospectively collected. A time-to-event analysis was performed to compare the course of the disease with carriers of other LMNA mutations. Myocardial biopsies were studied with electron microscopy and by measuring force development of the sarcomeres. Morphology of the nuclear envelope was assessed with immunofluorescence on cultured fibroblasts. The phenotype in probands and family members was characterized by atrioventricular conduction disturbances (61% and 44%, respectively), supraventricular arrhythmias (69% and 52%, respectively), and dilated cardiomyopathy (74% and 14%, respectively). LMNA p.(Arg331Gln) carriers had a significantly better outcome regarding the composite end point (malignant ventricular arrhythmias, end-stage heart failure, or death) compared with carriers of other pathogenic LMNA mutations. A shared haplotype of 1 Mb around LMNA suggested a common founder. The combined logarithm of the odds score was 3.46. Force development in membrane-permeabilized cardiomyocytes was reduced because of decreased myofibril density. Structural nuclear LMNA-associated envelope abnormalities, that is, blebs, were confirmed by electron microscopy and immunofluorescence microscopy. CONCLUSIONS: Clinical, morphological, functional, haplotype, and segregation data all indicate that LMNA p.(Arg331Gln) is a pathogenic founder mutation with a phenotype reminiscent of other LMNA mutations but with a more benign course.

Temporal Relationship of Asystole to Onset of Transient Loss of Consciousness in Tilt-Induced Reflex Syncope.

OBJECTIVES: The purpose of this study was to investigate the relationship between the onset of asystole and transient loss of consciousness (TLOC) in tilt-induced reflex syncope and estimate how often asystole was the principal cause of TLOC. BACKGROUND: The presence of asystole in vasovagal syncope (VVS) may prompt physicians to consider pacemaker therapy for syncope prevention, but the benefit of pacing is limited in VVS. METHODS: We evaluated electrocardiography, electroencephalography, blood pressure, and clinical findings during tilt-table tests. Inclusion required TLOC (video), electroencephalographic slowing, accelerating blood pressure decrease, and an RR interval ≥3 s. We excluded cases with nitroglycerin provocation. Asystole after onset of TLOC (group A) or within 3 s before TLOC (group B) was unlikely to cause TLOC, but an earlier start of asystole (group C) could be the cause of TLOC. RESULTS: In one-third of 35 cases (groups A [n = 9] and B [n = 3]), asystole was unlikely to be the primary cause of TLOC. The median of the mean arterial pressure at the onset of asystole was higher when asystole occurred early (45.5 mm Hg, group C) than when it occurred late (32.0 mm Hg, groups A and B), which suggests that vasodepression was not prominent at the start of asystole in early asystole, further suggesting that early asystole was the prime mechanism of syncope. CONCLUSIONS: In one-third of cases of tilt-induced asystolic reflex syncope, asystole occurred too late to have been the primary cause of TLOC. Reliance on electrocardiography data only is likely to overestimate the importance of asystole.

Patients with scar-related right ventricular tachycardia: determinants of long-term outcome.

INTRODUCTION: Patients with established arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) based on task force (TF) criteria and ventricular tachycardia (VT) are at risk of VT recurrence and sudden death. Data on patients with VT due to right ventricular (RV) scar not fulfilling TF criteria are lacking. The purpose of this study was to assess the long-term arrhythmia recurrence rate and outcome in patients with scar-related right VT with and without a diagnosis of ARVC/D. METHODS: Sixty-four patients (age 43.5 +/- 15 years, 49 males) presenting with nonischemic scar-related VT of RV origin were studied. Scar was identified by electroanatomical mapping, contrast echocardiography, and/or magnetic resonance imaging (MRI). Patients were evaluated and treated according to a standard institute protocol. RESULTS: Twenty-nine (45%) patients were diagnosed with ARVC/D according to TF criteria (TF+) and 35 (55%) with RV scar of undetermined origin (TF-) at the end of follow-up (64 +/- 42 months). Patients were treated with antiarrhythmic drugs, radiofrequency catheter ablation, and/or implantable cardioverter-defibrillator (ICD) implantation. VT recurrence-free survival for TF+ and TF- was 76% versus 74% at 1 year and 45% versus 50% at 4 years (P = ns). Patients with fast index VT (cycle length [CL]< or = 250 ms, n = 31) were more likely to experience a fast VT during follow-up than patients with a slow index VT (CL > 250 ms, n = 33) (61% vs 3%, P < 0.001). CONCLUSIONS: Scar-related RV VTs have a high recurrence rate in TF+ and TF- patients. Patients presenting with a fast index VT are at high risk for fast VT recurrence and may benefit most from ICD therapy.

Sirolimus-eluting stents versus bare-metal stents in patients with ST-segment elevation myocardial infarction: 9-month angiographic and intravascular ultrasound results and 12-month clinical outcome results from the MISSION! Intervention Study.

OBJECTIVES: Our purpose was to evaluate the efficacy and safety of drug-eluting stents in the setting of primary percutaneous coronary intervention for ST-segment elevation myocardial infarction (STEMI). BACKGROUND: There is inconsistent and limited evidence about the efficacy and safety of drug-eluting stents in STEMI patients. METHODS: A single-blind, single-center, randomized study was performed to compare bare-metal stents (BMS) with sirolimus-eluting stents (SES) in 310 STEMI patients. The primary end point was in-segment late luminal loss (LLL) at 9 months. Secondary end points included late stent malapposition (LSM) at 9 months as determined by intravascular ultrasound imaging and clinical events at 12 months. RESULTS: In-segment LLL was 0.68 +/- 0.57 mm in the BMS group and 0.12 +/- 0.43 mm in the SES group with a mean difference of 0.56 mm, 95% confidence interval 0.43 to 0.68 mm (p < 0.001). Late stent malapposition at 9 months was present in 12.5% BMS patients and in 37.5% SES patients (p < 0.001). Event-free survival at 12 months was 73.6% in BMS patients and 86.0% in SES patients (p = 0.01). The target-vessel-failure-free survival was 84.7% in the BMS group and 93.0% in the SES group (p = 0.02), mainly because of a higher target lesion revascularization rate in BMS patients (11.3% vs. 3.2%; p = 0.006). Rates of death, myocardial infarction, and stent thrombosis were not different. CONCLUSIONS: Sirolimus-eluting stent implantation in STEMI patients is associated with a favorable midterm clinical and angiographic outcome compared with treatment with BMS. However, LSM raises concern about the long-term safety of SES in STEMI patients.

Benefit of combined resynchronization and defibrillator therapy in heart failure patients with and without ventricular arrhythmias.

OBJECTIVES: We attempted to assess the efficacy of combined cardiac resynchronization therapy-implantable cardioverter-defibrillator (CRT-ICD) in heart failure patients with and without ventricular arrhythmias. BACKGROUND: Because CRT and ICDs both lower all-cause mortality in patients with advanced heart failure, combination of both therapies in a single device is challenging. METHODS: A total of 191 consecutive patients with advanced heart failure, left ventricular ejection fraction <35%, and a QRS duration >120 ms received CRT-ICD. Seventy-one patients had a history of ventricular arrhythmias (secondary prevention); 120 patients did not have prior ventricular arrhythmias (primary prevention). During follow-up, ICD therapy rate, clinical improvement after 6 months, and mortality rate were evaluated. RESULTS: During follow-up (18 +/- 4 months), primary prevention patients experienced less appropriate ICD therapies than secondary prevention patients (21% vs. 35%, p < 0.05). Multivariate analysis revealed, however, no predictors of ICD therapy. Furthermore, a similar, significant, improvement in clinical parameters was observed at 6 months in both groups. Also, the mortality rate in the primary prevention group was lower than in the secondary prevention group (3% vs. 18%, p < 0.05). CONCLUSIONS: As 21% of the primary prevention patients and 35% of the secondary prevention patients experienced appropriate ICD therapy within 2 years after implant, and no predictors of ICD therapy could be identified, implantation of a CRT-ICD device should be considered in all patients eligible for CRT.

Serial reevaluation for ARVD/C is indicated in patients presenting with left bundle branch block ventricular tachycardia and minor ECG abnormalities.

INTRODUCTION: Diagnosis of arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is based on a set of criteria proposed by the International Task Force (TF) for Cardiomyopathies in 1994. To fulfill these criteria, presence of both electrocardiographic and anatomical abnormalities must be assessed with ECG and imaging techniques, respectively. This may be difficult in patients with early/mild forms of the disease as detectable structural abnormalities may still be absent. We evaluated in which patients presenting with right ventricular tachycardia (VT) serial reevaluation for ARVD/C is indicated. METHODS AND RESULTS: Sixty consecutive patients (41 men, mean age 40+/-15 years) were evaluated by the TF criteria for possible ARVD/C because of presentation with a left bundle branch block (LBBB) VT, representing 1 minor criterion. The presence on the ECG of a T-wave inversion beyond lead V2 (1 minor), right precordial QRS prolongation (1 major), or an epsilon wave (1 major) was assessed together with the visualization of severe regional/global right ventricle dysfunction (1 major) or mild segmental dilatation/regional hypokinesia (1 minor) by standard imaging techniques. Initially, 22 (37%) patients were diagnosed as having ARVD/C. After 47+/-39 (range 6-146) months, 23 initially TF-negative patients were reevaluated because of recurrent symptoms, with 12 (52%) additional patients now meeting the TF criteria. Eleven of these 12 (92%) patients presented initially with ECG abnormalities only, but developed structural abnormalities on imaging at follow-up. CONCLUSION: ECG abnormalities may precede structural abnormalities warranting serial reevaluation for ARVD/C in initially TF-negative patients presenting with LBBB VT with only ECG abnormalities.

Arrhythmogenic right ventricular dysplasia/cardiomyopathy: screening, diagnosis, and treatment.

Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is a heart muscle disorder characterized pathologically by fatty or fibrofatty replacement and electrical instability of the right ventricular myocardium. Clinical manifestations include structural and functional malformations (fatty infiltration, dilatation, aneurysms) of the right ventricle, ECG abnormalities, and presentation with ventricular tachycardias with left bundle branch block pattern or sudden death. The disease often is familial with an autosomal inheritance. The typical hallmarks of ARVD/C are distributed in the so-called "triangle of dysplasia." The functional and morphologic characteristics are relevant to clinical imaging approaches such as contrast angiography, echocardiography, radionuclide angiography, ultrafast computed tomography, and cardiovascular magnetic resonance imaging. Evident forms of the disease are straightforward to diagnose based on a series of diagnostic criteria proposed by the International Task Force for Cardiomyopathy. However, the diagnosis of early and mild forms of the disease often is difficult. Treatment is directed toward preventing life-threatening ventricular arrhythmias in which radiofrequency ablation and implantable defibrillators play an increasing role. Despite new diagnostic and therapeutic approaches in ARVD/C, uncertainties about the etiology of the disease, the genetic basis, the appropriate diagnosis and therapy, and the clinical course of patients with ARVD/C have resulted in several registries to increase our knowledge of this intriguing disease.

Standardized screening and treatment of patients with life-threatening arrhythmias: the Leiden out-of-hospital cardiac arrest evaluation study.

OBJECTIVES: The aim of this study was to evaluate the effect of a systematic screening/treatment protocol on outcome in patients after aborted sudden death. BACKGROUND: Patients after aborted sudden death are at high risk for recurrent events. In this regard, systematic screening is mandatory to reveal the underlying etiology, to detect and subsequently treat reversible causes, and to establish patient-tailored antiarrhythmic treatment. METHODS: A total of 417 consecutive patients after aborted sudden death due to ventricular arrhythmias underwent echocardiography and coronary angiography. In the presence of coronary artery disease and myocardial ischemia, using stress-rest myocardial perfusion imaging/exercise testing, subsequent revascularization was performed. Patients without ischemic heart disease were further evaluated with magnetic resonance imaging, contrast echocardiography, right ventricular angiography and/or flecainide/ergonovine testing. After these diagnostic steps, final antiarrhythmic therapy was based on the outcome of electrophysiologic testing. RESULTS: The majority of patients had ischemic heart disease (n = 300, 72%). After screening, 78 (78 of 300, 26%) patients underwent revascularization. In 69% of patients, ventricular arrhythmias were inducible during electrophysiologic testing. Therapy consisted of implantable defibrillators in 301 (72%) patients, antiarrhythmic drugs in 239 (57%) patients, and catheter ablation in 58 (14%) patients. During 5-year follow-up, only 3 (<1%) patients died suddenly. The 5-year survival rate was 82%; of 39 deaths, 10 (26%) patients died due to non-cardiac disease and 26 (67%) due to heart failure. CONCLUSIONS: Screening and treatment of patients after aborted sudden death according to a standardized protocol resulted in <1% arrhythmic deaths during 5-year follow-up. The majority of patients died of heart failure, stressing the importance of optimizing medical and surgical therapy and screening.

Impact of percutaneous coronary intervention or coronary artery bypass grafting on outcome after nonfatal cardiac arrest outside the hospital.

Survivors of cardiac arrest due to ventricular arrhythmias are at risk for recurrent events. The role of revascularization in secondary prevention for survivors of cardiac arrest has been addressed in various studies with conflicting results. A total of 142 survivors of cardiac arrest with coronary artery disease were evaluated according to a standardized protocol, including 2-dimensional echocardiography, myocardial perfusion scintigraphy, coronary angiography, and electrophysiologic testing. Revascularization of scintigraphically documented ischemic myocardial regions was performed in 44 patients (31%). Final therapy was based on the results of electrophysiologic testing. Four-year survival rates were 100% for revascularized noninducible patients, 84% for revascularized inducible patients, 91% for nonrevascularized noninducible patients, and 72% for nonrevascularized inducible patients. Only 1 patient (<1% of study population) died suddenly. Recurrences were much more frequent in patients without revascularization (38% vs 7%, p <0.001) and the recurrence rate was 0% in the revascularized noninducible patients. Thus, revascularization of ischemically jeopardized myocardium in survivors of cardiac arrest resulted in excellent survival; moreover, in absence of inducible ventricular arrhythmias, the recurrence rate was 0%. Systematic evaluation of survivors of cardiac arrest due to ventricular arrhythmias allows risk stratification and guidance of subsequent antiarrhythmic therapy.