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Journal of the American College of Cardiology 04/2013; · 14.16 Impact Factor
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ABSTRACT: AIMS: Long QT syndrome (LQTS) type 3 is characterized by prolonged ventricular repolarization due to persistent sodium inward current secondary to a mutation in SCN5a, the gene encoding for the α-subunit of the sodium channel. We speculated that by disrupting calcium homeostasis the persistent inward sodium current in patients with LQTS type 3 might cause derangement of diastolic function. We aimed to identify functional myocardial alterations in a family with a sodium channelopathy with a phenotype of both LQTS type 3 and Brugada syndrome.METHODS AND RESULTS: The study group comprised 12 SCN5a mutation carriers (SCN5a-1795insD), 9 females and 3 males, mean age 35.7 ± 7.3 years, and 12 healthy controls. In addition to conventional echocardiographic measurements, two-dimensional speckle tracking was performed to assess tissue properties. Mean e' was lower in the patients compared with the controls (5.6 ± 0.75 vs. 6.7 ± 0.98 cm/s, P = 0.006). Onset QRS to maximum s' was longer in the patients than in the controls (0.20 ± 0.04 vs. 0.15 ± 0.05 s, P = 0.007), and the number of segments with post-systolic shortening was higher (6.58 ± 2.54 vs. 1.83 ± 1.64, P < 0.001).CONCLUSION: Patients in this family with LQTS type 3 showed post-systolic shortening, as well as both left and right ventricular diastolic dysfunction. The underlying mechanism remains to be elucidated but the persistent sodium inward current leading to calcium overload might play a role, in particular regarding diastolic dysfunction.
Europace 04/2013; · 1.98 Impact Factor
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ABSTRACT: BACKGROUND: Changes in P wave duration (PWD) and P wave area (PWA) have been described following catheter ablation for atrial fibrillation (AF). We hypothesize that video-assisted thoracoscopic pulmonary vein isolation (VATS-PVI) for AF results in decrease of PWD, PWA and P wave dispersion, which may resemble reverse electrical remodeling of the atrium after restoration of sinus rhythm. METHODS: VATS-PVI consisted of PVI and ganglionic plexus ablation in 29 patients (mean age, 59 ± 7 years; 23 males; 17 paroxysmal AF) and additional left atrial lesions in patients with persistent AF. PWD and PWA were measured in ECG lead II, aVF and V2 of ECGs during sinus rhythm before, directly after, and 6 months postprocedure. P wave dispersion was derived from the 12 lead ECG. RESULTS: Prior to VATS-PVI, PWD did not correlate with left atrial size and no difference in left atrial size was found between patients with paroxysmal or persistent AF (p = 0.27). Following VATS-PVI, PWD initially prolonged in all patients from 115 ± 4.6 ms to 131 ± 3.6 ms (p < 0.01) but shortened to 99 ± 3.2 ms after 6 months (p < 0.01). PWA was 5.60 ± 0.32 mV*ms at baseline, 6.44 ± 0.32 mV*ms post-VATS-PVI (P = NS), and 5.40 ± 0.28 mV*ms after 6 months (p = NS vs. baseline, p < 0.05 vs. post-VATS-PVI). P wave dispersion decreased in the persistent AF group from baseline 67 ± 3.3 to 64 ± 2.5 ms post-VATS-PVI (p = 0.30) and to 61 ± 3.4 ms after 6 months (p < 0.05). CONCLUSIONS: PWD increases significantly directly after successful VATS-PVI in both groups. There was significant decrease in PWD after 6 months. Similarly, P wave dispersion decreased in the persistent group. These changes suggest an immediate procedure related effect, but the later changes may represent reverse electrical atrial remodeling following cessation of AF.
Journal of Interventional Cardiac Electrophysiology 04/2013; · 1.17 Impact Factor
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Sami Viskin, Arthur A M Wilde,
Milton E Guevara-Valdivia,
Amin Daoulah,
Andrew Krahn,
Douglas P Zipes,
Amir Halkin,
Kalyanam Shivkumar,
Noel G Boyle,
Arnon Adler,
Bernard Belhassen,
Edgardo Schapachnik,
Farhan Asrar,
Raphael Rosso
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ABSTRACT: OBJECTIVES: To determine the availability of quinidine in the world. BACKGROUND: Quinidine is the only oral medication that is effective for preventing life-threatening ventricular arrhythmias due to Brugada syndrome and idiopathic ventricular fibrillation. However, because of its low price and restricted indication, this medication is not marketed in many countries. METHODS: We conducted a world survey of quinidine availability by contacting professional medical societies and arrhythmia specialists worldwide. Physicians were e-mailed questionnaires requesting information concerning the quinidine preparation available at their hospital. We also requested information concerning cases of adverse arrhythmic events resulting from quinidine unavailability. RESULTS: A total of 273 physicians from 131 countries provided information regarding quinidine availability: Quinidine is readily available in only 19 (14%) countries. In contrast, this medication is not accessible in 99 (76%) countries and is available but only through specific regulatory processes that require 4-30 days for completion in 13 (10%) countries. We were able to gather information concerning 22 patients who had serious arrhythmias probably related (10 cases) or possibility related (12 cases) to the absence of quinidine, including 2 fatalities possibly due to quinidine unavailability. CONCLUSIONS: The lack of quinidine accessibility is a serious medical hazard at the global level.
Journal of the American College of Cardiology 04/2013; · 14.16 Impact Factor
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ABSTRACT: Sudden cardiac death (SCD) from ventricular fibrillation during myocardial infarction is a leading cause of total and cardiovascular mortality. It has a multifactorial, complex nature and aggregates in families, implicating the involvement of heritable factors in the determination of risk. During the last few years, genome-wide association studies have uncovered common genetic variants modulating risk of SCD. We here review the current insight on genetic determinants of SCD in the community and describe the genome-wide association approaches undertaken thus far in uncovering genetic determinants of SCD risk.
Current pharmaceutical design 04/2013; · 4.41 Impact Factor
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Mayo Clinic Proceedings 04/2013; 88(4):309-11. · 5.70 Impact Factor
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Circulation Cardiovascular Genetics 04/2013; 6(2):141-143. · 6.11 Impact Factor
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Ling Xiao,
Tamara T Koopmann,
Balazs Ordog,
Pieter G Postema,
Arie O Verkerk,
Vivek Iyer,
Kevin J Sampson,
Gerard J J Boink,
Maya A Mamarbachi,
Andras Varro,
Luc Jordaens,
Jan Res,
Robert S Kass, Arthur A M Wilde,
Connie Bezzina,
Stanley Nattel
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ABSTRACT: Rationale: A chromosomal-haplotype producing cardiac overexpression of dipeptidyl peptidase-like protein-6 (DPP6) causes familial idiopathic ventricular fibrillation (IVF). The molecular basis of transient-outward current (Ito) in Purkinje fibers (PFs) is poorly understood. We hypothesized that DPP6 contributes to PF Ito and that its overexpression might specifically alter PF Ito-properties and repolarization. Objective: To assess the potential role of DPP6 in PF-Ito. Methods and Results: Clinical data in 5 IVF-patients suggested arrhythmia-origin in the PF conducting-system. PF and ventricular-muscle (VM) Ito had similar density, but PF Ito differed from VM in having tetraethylammonium-sensitivity and slower recovery. DPP6-overexpression significantly increased, whereas DPP6-kockdown reduced, Ito-density and tetraethylammonium-sensitivity in canine PF, but not VM-cells. The K(+)-channel interacting β-subunit KChIP2, essential for normal expression of transient outward current (Ito) in VM, was weakly-expressed in human PFs, whereas DPP6 and frequenin (NCS-1) were enriched. Heterologous expression of Kv4.3 in Chinese hamster ovary (CHO)-cells produced very small Ito; Ito-amplitude was greatly enhanced by co-expression with KChIP2 or DPP6. Co expression of DPP6 with Kv4.3 and KChIP2 failed to alter Ito versus Kv4.3/KChIP2 alone, but DPP6 expression with Kv4.3 and NCS-1 (to mimic PF Ito-composition), greatly enhanced Ito versus Kv4.3/NCS-1 and recapitulated characteristic PF kinetic/pharmacological properties. A mathematical model of cardiac PF action potentials showed that Ito-enhancement can greatly accelerate PF repolarization. Conclusions: These results point to a previously-unknown central role of DPP6 in PF Ito, with DPP6 gain-of-function selectively enhancing PF-current, and suggest that a DPP6-mediated PF early repolarization syndrome might be a novel molecular paradigm for some forms of IVF.
Circulation Research 03/2013; · 9.49 Impact Factor
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ABSTRACT: AIMS: We sought to obtain insights into the efficacy of two websites, www.QTdrugs.org and www.BrugadaDrugs.org, that have the intention to prevent fatal arrhythmias due to unsafe drug use in Long QT syndrome and Brugada syndrome.METHODS AND RESULTS: Prospective web-use statistical analysis combined with online surveys were employed. Our main outcome measure was the percentage of Long QT syndrome patients and Brugada syndrome patients reporting refraining or discontinuation of possible unsafe drugs. QTdrugs.org has received >3 100 000 visitors from 180 countries. Most visitors originated from the Americas (87%), as compared with Europe (7%), Asia (3%), Oceania (2%), and Africa (1%). The QTdrugs.org survey yielded 340 respondents: 34% were patients and 50% medical professionals. Of the patients, 79% reported that they refrained from, and 61% reported discontinuing drugs due to the website. The website was very much appreciated by 65% of the respondents and 30% found it rather helpful. The BrugadaDrugs.org received >48 000 visitors from 154 countries. Most visitors originated from Europe (46%) and the Americas (39%), but less from Asia (10%), Oceania (4%), and Africa (<1%). The BrugadaDrugs.org survey yielded 178 respondents: 68% were patients and 21% medical professionals. Of the patients, 72% reported refraining from, and 48% discontinuing drugs due to the website. The website was very much appreciated by 72% of the respondents and 25% found it rather helpful.CONCLUSION: These websites are extensively used, they promote drug awareness, and they help patients to avoid possible pro-arrhythmic drugs. Visitors find the websites valuable but should note their limitations.
Europace 03/2013; · 1.98 Impact Factor
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European journal of human genetics: EJHG 03/2013; · 3.56 Impact Factor
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Heart (British Cardiac Society) 02/2013; · 4.22 Impact Factor
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Andrew Mathias,
Arthur J Moss,
Coeli M Lopes,
Alon Barsheshet,
Scott McNitt,
Wojciech Zareba,
Jennifer L Robinson,
Emanuela H Locati,
Michael J Ackerman,
Jesaia Benhorin,
Elizabeth S Kaufman,
Pyotr G Platonov,
Ming Qi,
Wataru Shimizu,
Jeffrey A Towbin,
G Michael Vincent, Arthur A M Wilde,
Li Zhang,
Ilan Goldenberg
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ABSTRACT: BACKGROUND: Individual QTc may vary widely among carriers of the same LQTS mutation. Currently, neither the mechanism nor the implications of this variable penetrance are well understood. OBJECTIVES: We hypothesized that assessment of QTc variance in patients with congenital long QT syndrome (LQTS) who carry the same mutation provides incremental prognostic information to the patient-specific QTc. METHODS: The study population comprised 1206 LQTS patients with 95 different mutations and ≥5 individuals per mutation. Multivariate Cox proportional hazards regression modeling was used to assess the effect of mutation-specific standard deviation of QTc (QTcSD) on the risk of cardiac events (comprising syncope, aborted cardiac arrest, and sudden cardiac death) from birth through age 40 years in the total population and by genotype. RESULTS: Assessment of mutation-specific QTcSD showed large differences among carriers of the same mutations (median QTcSD = 45 msec). Multivariate analysis showed that each 20 msec increment in QTcSD was associated with a significant 33% (p=0.002) increase in the risk for cardiac events after adjustment for the patient-specific QTc duration and the family effect on QTc. The risk associated with QTcSD was pronounced among LQT1 patients (HR=1.55 per 20 msec increment [p<0.001]), whereas among LQT2 patients the risk associated with QTcSD was not statistically significant (HR=0.99 [p=0.95]; p-value for QTcSD-by-genotype interaction = 0.002). CONCLUSIONS: Our findings suggest that mutations with a wider variation in QTc duration are associated with increased risk for cardiac events. These findings appear to be genotype-specific, with a pronounced effect among patients with the LQT1 genotype.
Heart rhythm: the official journal of the Heart Rhythm Society 01/2013; · 4.56 Impact Factor
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Karin Y van Spaendonck-Zwarts,
Ingrid A W van Rijsingen,
Maarten P van den Berg,
Ronald H Lekanne Deprez,
Jan G Post,
Anneke M van Mil,
Folkert W Asselbergs,
Imke Christiaans,
Irene M van Langen, Arthur A M Wilde,
Rudolf A de Boer,
Jan D H Jongbloed,
Yigal M Pinto,
J Peter van Tintelen
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ABSTRACT: AIMS: With more than 40 dilated cardiomyopathy (DCM)-related genes known, genetic analysis of patients with idiopathic DCM is costly and time-consuming. We describe the yield from genetic analysis in DCM patients in a large Dutch cohort. METHODS AND RESULTS: We collected cardiological and neurological evaluations, family screenings, and genetic analyses for 418 index patients with idiopathic DCM. We identified 35 (putative) pathogenic mutations in 82 index patients (20%). The type of DCM influenced the yield, with mutations found in 25% of familial DCM cases, compared with 8% of sporadic DCM cases and 62% of cases where DCM was accompanied by neuromuscular disease. A PLN founder mutation (43 cases) and LMNA mutations (19 cases, 16 different mutations) were most prevalent and often demonstrated a specific phenotype. Other mutations were found in: MYH7, DES, TNNT2, DMD, TPM1, DMPK, SCN5A, SGCB (homozygous), and TNNI3. After a median follow-up of 40 months, the combined outcome of death from any cause, heart transplantation, or malignant ventricular arrhythmias in patients with a mutation was worse than in those without an identified mutation (hazard ratio 2.0, 95% confidence interval 1.4-3.0). This seems to be mainly attributable to a high prevalence of malignant ventricular arrhythmias and end-stage heart failure in LMNA and PLN mutation carriers. CONCLUSION: The yield of identified mutations in DCM index patients with clinical clues, such as associated neuromuscular disease or familial occurrence, is higher compared with those without these clues. For sporadic DCM, specific clinical characteristics may be used to select cases for DNA analysis.
European Journal of Heart Failure 01/2013; · 4.90 Impact Factor
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ABSTRACT: Rationale: Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is caused by mutations in cardiac ryanodine receptor (RyR2) or calsequestrin (Casq2) genes. Sinoatrial node dysfunction associated with CPVT may increase the risk for ventricular arrhythmia. Objective: To test the hypothesis that CPVT is suppressed by supraventricular overdrive stimulation. Methods and Results: Using CPVT mouse models (Casq2-/- and RyR2(R4496C)+/- mice), the effect of increasing sinus heart rate was tested by pretreatment with atropine and by atrial overdrive pacing. Increasing intrinsic sinus rate with atropine before catecholamine challenge suppressed ventricular tachycardia (VT) in 86% of Casq2-/- mice (6/7) and significantly reduced the ventricular arrhythmia (VA) score (atropine: 0.6±0.2 vs. vehicle: 1.7±0.3, p<0.05). Atrial overdrive pacing completely prevented VA in 16/19 (84%) Casq2-/- and in 7/8 (88%) RyR2(R4496C)+/- mice and significantly reduced ventricular premature beats in both CPVT models (p<0.05). Rapid pacing also prevented spontaneous calcium waves and triggered beats in isolated CPVT myocytes. In humans, heart-rate dependence of CPVT was evaluated by screening a CPVT patient registry for antiarrhythmic drug-naïve individuals that reached >85% of their maximum predicted heart rate during exercise testing. All 18 CPVT patients who fulfilled the inclusion criteria exhibited VA before reaching 87% of maximum heart rate. In six CPVT patients (33%), VA were paradoxically suppressed as sinus heart rates increased further with continued exercise. Conclusions: Accelerated supraventricular rates suppress VAs in two CPVT mouse models and in a subset of CPVT patients. Hypothetically, atrial overdrive pacing may be a therapy for preventing exercise-induced VT in treatment-refractory CPVT patients.
Circulation Research 01/2013; · 9.49 Impact Factor
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ABSTRACT: The late sodium current has been increasingly recognized for its mechanistic role in various cardiovascular pathologies, including angina pectoris, myocardial ischemia, atrial fibrillation, heart failure and congenital long QT syndrome. Although relatively small in magnitude, the late sodium current (I(NaL)) represents a functionally relevant contributor to cardiomyocyte (electro)physiology. Many aspects of I(NaL) itself are as yet still unresolved, including its distribution and function in different cell types throughout the heart, and its regulation by sodium channel accessory proteins and intracellular signalling pathways. Its complexity is further increased by a close interrelationship with the peak sodium current and other ion currents, hindering the development of inhibitors with selective and specific properties. Thus, increased knowledge of the intricacies of the complex nature of I(NaL) during distinct cardiovascular conditions and its potential as a pharmacological target is essential. Here, we provide an overview of the functional and electrophysiological effects of late sodium current inhibition on the level of the ventricular myocyte, and its potential cardioprotective and anti-arrhythmic efficacy in the setting of acquired and inherited ventricular dysfunction and arrhythmias.
Cardiovascular Drugs and Therapy 01/2013; · 3.13 Impact Factor
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ABSTRACT: Ventricular fibrillation (VF) in the setting of acute ST elevation myocardial infarction (STEMI) is a leading cause of mortality. Although the risk of VF has a genetic component, the underlying genetic factors are largely unknown. Since heart rate and ECG intervals of conduction and repolarization during acute STEMI differ between patients who do and patients who do not develop VF, we investigated whether SNPs known to modulate these ECG indices in the general population also impact on the respective ECG indices during STEMI and on the risk of VF.
The study population consisted of participants of the Arrhythmia Genetics in the NEtherlandS (AGNES) study, which enrols patients with a first STEMI that develop VF (cases) and patients that do not develop VF (controls). SNPs known to impact on RR interval, PR interval, QRS duration or QTc interval in the general population were tested for effects on the respective STEMI ECG indices (stage 1). Only those showing a (suggestive) significant association were tested for association with VF (stage 2). On average, VF cases had a shorter RR and a longer QTc interval compared to non-VF controls. Eight SNPs showed a trend for association with the respective STEMI ECG indices. Of these, three were also suggestively associated with VF.
RR interval and ECG indices of conduction and repolarization during acute STEMI differ between patients who develop VF and patients who do not. Although the effects of the SNPs on ECG indices during an acute STEMI seem to be similar in magnitude and direction as those found in the general population, the effects, at least in isolation, are too small to explain the differences in ECGs between cases and controls and to determine risk of VF.
PLoS ONE 01/2013; 8(2):e57216. · 4.09 Impact Factor
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Hiroshi Watanabe,
Christian van der Werf,
Ferran Roses-Noguer,
Arnon Adler,
Naokata Sumitomo,
Christian Veltmann,
Raphael Rosso,
Zahurul A Bhuiyan,
Hennie Bikker,
Prince J Kannankeril,
Minoru Horie,
Tohru Minamino,
Sami Viskin,
Björn C Knollmann,
Jan Till, Arthur A M Wilde
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ABSTRACT: BACKGROUND: Conventional therapy with β-blockers is incompletely effective in preventing arrhythmic events in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT). We have previously discovered that flecainide in addition to conventional drug therapy prevents ventricular arrhythmias in genotype-positive CPVT patients. OBJECTIVE: To study the efficacy of flecainide in genotype-negative CPVT patients. METHODS: We studied the efficacy of flecainide for reducing ventricular arrhythmias during exercise testing and preventing arrhythmia events during long-term follow-up. RESULTS: Twelve genotype-negative CPVT patients were treated with flecainide. Conventional therapy failed to control ventricular arrhythmias in all patients. Flecainide was initiated because of significant ventricular arrhythmias (n=8), syncope (n=3), or cardiac arrest (n=1). At the baseline exercise test before flecainide, 6 patients had ventricular tachycardia and 5 patients had bigeminal or frequent ventricular premature beats. Flecainide reduced ventricular arrhythmias at the exercise test in 8 patients compared to conventional therapy, similarly to genotype-positive patients in our previous report. Notably, flecainide completely prevented ventricular arrhythmias in 7 of the patients. Flecainide was continued in all patients except for one who had ventricular tachycardia at the exercise test on flecainide. During a follow-up of 48±94 months, arrhythmia events (sudden cardiac death and aborted cardiac arrest) associated with noncompliance occurred in two patients. Flecainide was not discontinued due to side effects in any of the patients. CONCLUSION: Flecainide was effective in genotype-negative CPVT patients, suggesting that spontaneous Ca(2+) release from ryanodine channels plays a role in arrhythmia susceptibility, similarly to genotype-positive patients.
Heart rhythm: the official journal of the Heart Rhythm Society 12/2012; · 4.56 Impact Factor
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ABSTRACT: BACKGROUND: -Indications for prophylactic implantable cardioverter-defibrillator (ICD) therapy in patients with inherited cardiac diseases stem from observational studies and are uncertain. This study evaluates the efficacy and harm rate of ICD implantations for primary prevention compared to secondary prevention in inherited cardiac diseases. METHODS AND RESULTS: -Between January 1(st) 1993 and April 1(st) 2011 354 patients with inherited cardiac diseases were treated with ICDs. Incidence rates of appropriate shocks in primary prevention patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) and hypertrophic cardiomyopathy (HCM) were 4.2-6.7/100 patient-years, while the risk for appropriate shocks in primary prevention patients with Brugada syndrome (BrS), long QT syndrome (LQTS) or carrying the DPP6 haplotype approached zero. Conversely, in secondary prevention patients there was a considerably higher incidence rate of appropriate shocks. None of the indications for primary prevention were associated with appropriate shock therapy. 123 patients (35%) experienced ICD-related adverse events. CONCLUSIONS: -For BrS, LQTS and DPP6 the efficacy of an ICD for primary prevention contrasts with the amount of harm, and that the factors that formed the indication for ICD implantation do not relate to the occurrence of appropriate shocks. The higher appropriate discharge rates in ARVC and HCM compared to primary electrical diseases might result from a more advanced risk stratification scheme in these inherited cardiomyopathies.
Circulation Arrhythmia and Electrophysiology 12/2012; · 6.46 Impact Factor
