[Show abstract][Hide abstract] ABSTRACT: Analyzing a patient with progressive and severe cardiac conduction disorder combined with idiopathic ventricular fibrillation (IVF), we identified a splice site mutation in the sodium channel gene SCN5A. Due to the severe phenotype, we performed whole-exome sequencing (WES) and identified an additional mutation in the KCNK17 gene encoding the K2P potassium channel TASK-4. The heterozygous change (c.262G>A) resulted in the p.Gly88Arg mutation in the first extracellular pore loop. Mutant TASK-4 channels generated threefold increased currents, while surface expression was unchanged, indicating enhanced conductivity. When co-expressed with wild-type channels, the gain-of-function by G88R was conferred in a dominant-active manner. We demonstrate that KCNK17 is strongly expressed in human Purkinje cells and that overexpression of G88R leads to a hyperpolarization and strong slowing of the upstroke velocity of spontaneously beating HL-1 cells. Thus, we propose that a gain-of-function by TASK-4 in the conduction system might aggravate slowed conductivity by the loss of sodium channel function. Moreover, WES supports a second hit-hypothesis in severe arrhythmia cases and identified KCNK17 as a novel arrhythmia gene.
EMBO Molecular Medicine 06/2014; · 7.80 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is characterized by recurrent syncopes and sudden cardiac death triggered by sympathetic activation in young individuals without structural heart disease and a normal baseline electrocardiogram. There is reason to question whether the current expert consensus treatment recommendation, maximal tolerated β-blockade alone or in combination with low-dose flecainide, is the optimal antiarrhythmic treatment strategy in CPVT, as high doses of β-blockers may eventually lead to adverse side effects and β-blocker discontinuation. Indeed, β-blocker non-compliance accounts for around 5% of sudden cardiac deaths in CPVT patients.
Differing from the current recommendation, we present the first report of a CPVT patient successfully treated with high-dose flecainide and minimal β-blockade. This combination resulted in complete suppression of ventricular arrhythmias during exercise stress tests and Holter monitoring and was well tolerated without any side effects. We review the current literature on β-blocker non-compliance-related sudden cardiac death in CPVT, summarize the in vitro and in vivo data on flecainide therapy in CPVT, and discuss the rationale of our antiarrhythmic approach.
<Learning objective: This case illustrates typical features of CPVT including the therapeutic management of a young CPVT patient with poor β-blocker tolerance at normal dosages. In this setting, high-dose flecainide combined with minimal β-blockade may (1) result in complete antiarrhythmic response and may (2) improve the antiarrhythmic drug-compliance thereby reducing the risk of non-compliance-related sudden cardiac death.
[Show abstract][Hide abstract] ABSTRACT: The development of pharmacologic agents for the treatment of diseases is still challenging, especially in rare inherited arrhythmia syndromes like long and short QT syndrome, Brugada syndrome and catecholaminergic polymorphic ventricular tachycardia. The underling pathophysiologic mechanism of these inherited diseases is in most cases either a gain- or a loss-of-function due to mutations in ion channel genes. Although the biophysical properties of mutant channel subunits are well studied, little is known aboutthe targeting effect of specific pharmacologic agents. In this review, we focus on the therapeutic (in vivo) and the experimental (in vitro) approaches in the most common inherited forms.
Current Medicinal Chemistry 11/2013; · 3.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Brugada syndrome is a rare cardiac arrhythmia disorder, causally related to SCN5A mutations in around 20% of cases. Through a genome-wide association study of 312 individuals with Brugada syndrome and 1,115 controls, we detected 2 significant association signals at the SCN10A locus (rs10428132) and near the HEY2 gene (rs9388451). Independent replication confirmed both signals (meta-analyses: rs10428132, P = 1.0 × 10(-68); rs9388451, P = 5.1 × 10(-17)) and identified one additional signal in SCN5A (at 3p21; rs11708996, P = 1.0 × 10(-14)). The cumulative effect of the three loci on disease susceptibility was unexpectedly large (Ptrend = 6.1 × 10(-81)). The association signals at SCN5A-SCN10A demonstrate that genetic polymorphisms modulating cardiac conduction can also influence susceptibility to cardiac arrhythmia. The implication of association with HEY2, supported by new evidence that Hey2 regulates cardiac electrical activity, shows that Brugada syndrome may originate from altered transcriptional programming during cardiac development. Altogether, our findings indicate that common genetic variation can have a strong impact on the predisposition to rare diseases.
[Show abstract][Hide abstract] ABSTRACT: Andersen-Tawil syndrome (ATS) is characterized by dysmorphic features, periodic paralyses and abnormal ventricular repolarization. After genotyping a large set of patients with congenital long-QT syndrome, we identified two novel, heterozygous KCNJ2 mutations (p.N318S, p.W322C) located in the C-terminus of the Kir2.1 subunit. These mutations have a different localization than classical ATS mutations which are mostly located at a potential interaction face with the slide helix or at the interface between the C-termini. Mutation carriers were without the key features of ATS, causing an isolated cardiac phenotype. While the N318S mutants regularly reached the plasma membrane, W322C mutants primarily resided in late endosomes. Co-expression of N318S or W322C with wild-type Kir2.1 reduced current amplitudes only by 20-25 %. This mild loss-of-function for the heteromeric channels resulted from defective channel trafficking (W322C) or gating (N318S). Strikingly, and in contrast to the majority of ATS mutations, neither mutant caused a dominant-negative suppression of wild-type Kir2.1, Kir2.2 and Kir2.3 currents. Thus, a mild reduction of native Kir2.x currents by non dominant-negative mutants may cause ATS with an isolated cardiac phenotype.
Archiv für Kreislaufforschung 05/2013; 108(3):353. · 7.35 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Genetisch bedingte (monogene) Herzerkrankungen bedürfen einer sorgsamen klinischen, genetischen und familiären Diagnostik, da die Erkrankungen mit einem hohen kardiovaskulären Risiko in jungen Jahren assoziiert sein können. Es handelt sich zumeist um Erkrankungen durch Ionenkanalgenmutationen, die genetisch heterogen und von einer unterschiedlichen Sensitivität in der Mutationsdetektion (pro Erkrankung oder Ionenkanalgen) gekennzeichnet sind. In Analogie zu anderen Ionenkanalerkrankungen besteht oft ein episodisches Auftreten von Symptomen, das durch Trigger (meist erhöhte Herzfrequenz bei körperlicher und/oder physischer Belastung) gefördert werden kann. Bei diesen relativ seltenen Erkrankungen ist eine frühzeitige Diagnostik und interdisziplinäre Betreuung durch Kardiologen, Kinderkardiologen und Humangenetikern (und ggf. Psychologen) sinnvoll. Mittlerweile existieren erste internationale Empfehlungen, wann eine Genotypisierung aus diagnostischer, therapeutischer oder prognostischer Sicht durchzuführen ist.
Medizinische Genetik 01/2013; 25(4). · 0.09 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Marked prolongation of the QT interval on the electrocardiogram associated with the polymorphic ventricular tachycardia Torsades de Pointes is a serious adverse event during treatment with antiarrhythmic drugs and other culprit medications, and is a common cause for drug relabeling and withdrawal. Although clinical risk factors have been identified, the syndrome remains unpredictable in an individual patient. Here we used genome-wide association analysis to search for common predisposing genetic variants. Cases of drug-induced Torsades de Pointes (diTdP), treatment tolerant controls, and general population controls were ascertained across multiple sites using common definitions, and genotyped on the Illumina 610k or 1M-Duo BeadChips. Principal Components Analysis was used to select 216 Northwestern European diTdP cases and 771 ancestry-matched controls, including treatment-tolerant and general population subjects. With these sample sizes, there is 80% power to detect a variant at genome-wide significance with minor allele frequency of 10% and conferring an odds ratio of ≥2.7. Tests of association were carried out for each single nucleotide polymorphism (SNP) by logistic regression adjusting for gender and population structure. No SNP reached genome wide-significance; the variant with the lowest P value was rs2276314, a non-synonymous coding variant in C18orf21 (p = 3×10(-7), odds ratio = 2, 95% confidence intervals: 1.5-2.6). The haplotype formed by rs2276314 and a second SNP, rs767531, was significantly more frequent in controls than cases (p = 3×10(-9)). Expanding the number of controls and a gene-based analysis did not yield significant associations. This study argues that common genomic variants do not contribute importantly to risk for drug-induced Torsades de Pointes across multiple drugs.
PLoS ONE 01/2013; 8(11):e78511. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The SCN5A gene encodes for the α-subunit of the cardiac sodium channel NaV1.5, which is responsible for the rapid upstroke of the cardiac action potential. Mutations in this gene may lead to multiple life-threatening disorders of cardiac rhythm or are linked to structural cardiac defects. Here, we characterized a large family with a mutation in SCN5A presenting with an atrioventricular conduction disease and absence of Brugada syndrome.
In a large family with a high incidence of sudden cardiac deaths, a heterozygous SCN5A mutation (p.1493delK) with an autosomal dominant inheritance has been identified. Mutation carriers were devoid of any cardiac structural changes. Typical ECG findings were an increased P-wave duration, an AV-block I° and a prolonged QRS duration with an intraventricular conduction delay and no signs for Brugada syndrome. HEK293 cells transfected with 1493delK showed strongly (5-fold) reduced Na(+) currents with altered inactivation kinetics compared to wild-type channels. Immunocytochemical staining demonstrated strongly decreased expression of SCN5A 1493delK in the sarcolemma consistent with an intracellular trafficking defect and thereby a loss-of-function. In addition, SCN5A 1493delK channels that reached cell membrane showed gain-of-function aspects (slowing of the fast inactivation, reduction in the relative fraction of channels that fast inactivate, hastening of the recovery from inactivation).
In a large family, congregation of a heterozygous SCN5A gene mutation (p.1493delK) predisposes for conduction slowing without evidence for Brugada syndrome due to a predominantly trafficking defect that reduces Na(+) current and depolarization force.
PLoS ONE 01/2013; 8(6):e67963. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Inherited long QT syndrome (LQTS) is characterized by a prolonged ventricular repolarization (QTc interval) and symptoms (syncope, sudden cardiac arrest) due to polymorphic ventricular arrhythmias. As of today, 13 different cardiac ion channel genes have been associated with congenital LQTS. The most common ones are due to KCNQ1 (LQT-1), KCNH2 (LQT-2), and SCN5A (LQT-3) gene mutations and account for up to 75 % of cases. Typical clinical findings are an increased QT interval on the surface electrocardiogram, specifically altered T wave morphologies, polymorphic ventricular arrhythmias, or an indicative family history. Recently, in the HRS/EHRA expert consensus statement, comprehensive genetic testing of major LQTS genes was recommended for index patients for whom there is a strong clinical suspicion of LQTS. Overall, antiadrenergic therapy, in particular β-receptor blockers, has been the mainstay of therapy and has significantly reduced cardiac events. For high-risk patients, an implantable cardioverter defibrillator (ICD) is recommended. Importantly, lifestyle modification and avoidance of arrhythmia triggers are additional important approaches.
[Show abstract][Hide abstract] ABSTRACT: AIMS: The use of implantable cardioverter defibrillators (ICD) in patients with torsade de pointes (TdP) and ventricular fibrillation in the presence of acquired long QT syndrome (aLQTS) is under debate, partly due to the fact that aLQTS is potentially reversible and currently no long-term follow-up data are available. We aimed to evaluate the long-term follow-up of patients with acquired long QT syndrome (aLQTS) who had received an implantable cardioverter defibrillator (ICD) for secondary prevention of sudden cardiac arrest (SCA). METHOD AND RESULTS: Over a 10 year period, 43 patients with an ICD after survived cardiac arrest (SCA) due to an aLQTS were included [female n= 27 (63%); mean age 61 ± 16 years]. There was no clinical evidence for congenital LQTS (Schwartz score 1.25 ± 0.8). Structural heart disease was present in 29 patients (47%; ischaemic n= 13; dilated cardiomyopathy n= 9; mean EF 41%± 12). The most common proarrhythmic trigger happened to be antiarrhythmic drugs (n= 34; 79%). Other triggers included contrast agent (n= 1), haloperidol (n= 2), severe hypokalaemia (n= 2), drug abuse/alcohol (n= 2), and mere severe bradycardia (n= 2). Under trigger QTc interval measured 536 ± 58 vs. 438 ± 33 ms without trigger (P< 0.001). During a mean follow-up of 84 ± 55 months, appropriate shocks occurred in 19 patients (44%); inappropriate shocks in 13 patients (30%; only inappropriate n= 3). Appropriate shocks were almost as common in patients without as in those with structural heart disease (35 vs. 48%; P= 0.32). None of the patients were re-exposed to the initial trigger during the follow-up period. Beta-blocker medication did not prevent ICD shocks (12 of 19 vs. 11 of 24 on medication). ConcluSION: Appropriate ICD shocks are a common finding in patients with aLQTS and SCA irrespective of the underlying cause or structural heart disease. Thus, even in the presence of relevant acquired proarrhythmia ICD may be beneficial.
[Show abstract][Hide abstract] ABSTRACT: Cardiac action potential repolarisation is determined by K(+) currents including I(Ks). I(Ks) channels are heteromeric channels composed of KCNQ1 and KCNE E-subunits. Mutations in KCNQ1 are associated with sinus bradycardia, familial atrial fibrillation (fAF) and/or short QT syndrome as a result of gain-of-function, and long QT syndrome (LQTS) due to loss-of-function in the ventricles. Here, we report that the missense mutation R231C located in S4 voltage sensor domain is associated with a combined clinical phenotype of sinus bradycardia, fAF and LQTS. We aim to understand the molecular basis of the complex clinical phenotype.
We expressed and functionally analyzed the respective channels kinetics in Xenopus laevis oocytes. The molecular nature of the residue R231 was studied by homology modeling and molecular dynamics simulation.
As a result, the mutation reduced voltage sensitivity of channels, possibly due to neutralization of the positive charge of the arginine side chain substituted by cysteine. Modeling suggested that the charge carrying side chain of R231 is positioned suitably to transfer transmembrane voltages into conformational energy. Further, the mutation altered the functional interactions with KCNE subunits.
The mutation acted in a E-subunit dependent manner, suggesting I(Ks) function altered by the presence of different KCNE subunits in sinus node, atria and ventricles as the molecular basis of sinus bradycardia, fAF and LQTS in mutation carriers.
Cellular Physiology and Biochemistry 01/2012; 29(5-6):809-18. · 3.42 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Drug-induced long-QT syndrome (diLQTS) is an adverse drug effect that has an important impact on drug use, development, and regulation. We tested the hypothesis that common variants in key genes controlling cardiac electric properties modify the risk of diLQTS.
In a case-control setting, we included 176 patients of European descent from North America and Europe with diLQTS, defined as documented torsades de pointes during treatment with a QT-prolonging drug. Control samples were obtained from 207 patients of European ancestry who displayed <50 ms QT lengthening during initiation of therapy with a QT-prolonging drug and 837 control subjects from the population-based KORA study. Subjects were successfully genotyped at 1424 single-nucleotide polymorphisms (SNPs) in 18 candidate genes including 1386 SNPs tagging common haplotype blocks and 38 nonsynonymous ion channel gene SNPs. For validation, we used a set of cases (n=57) and population-based control subjects of European descent. The SNP KCNE1 D85N (rs1805128), known to modulate an important potassium current in the heart, predicted diLQTS with an odds ratio of 9.0 (95% confidence interval, 3.5-22.9). The variant allele was present in 8.6% of cases, 2.9% of drug-exposed control subjects, and 1.8% of population control subjects. In the validation cohort, the variant allele was present in 3.5% of cases and in 1.4% of control subjects.
This high-density candidate SNP approach identified a key potassium channel susceptibility allele that may be associated with the rare adverse drug reaction torsades de pointes.
[Show abstract][Hide abstract] ABSTRACT: The aim of the present study was to assess the feasibility and safety of target-directed sampling of right ventricular (RV) endomyocardial biopsies (EMB) in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC).
EMB is an integral part of the diagnostic evaluation of ARVC. Due to safety concerns, EMB are often obtained from the RV septum, which is usually spared from characteristic alterations. At our institution, EMB in ARVC patients were sampled target-directed from predilection areas and areas with abnormal contraction.
Under fluoroscopic guidance, 3,777 EMB samples from 6 different RV sites were obtained in 482 patients who were evaluated for unclear cardiomyopathy (n = 280; 58%), assumed myocarditis (n = 59; 12%), or unexplained ventricular tachyarrhythmias (n = 143; 30%). Complication rates were compared with those from exclusively septal EMB procedures (n = 2,321) in 271 patients after heart transplantation (HTx).
Overall, no procedure-related deaths or sustained ventricular tachyarrhythmias occurred. A pericardial effusion was reported in 6 of 161 patients with the final diagnosis of ARVC (3.7%) needing no further intervention in all but 1 patient (0.6%) who required pericardiocentesis. Among the non-ARVC patients (n = 321), the incidence of a minor pericardial effusion (3.9%) and cardiac tamponade (2.2%) was comparable to that in ARVC (p = NS) but was higher when compared with HTx (p < 0.001). A transient complete atrioventricular block occurred in 1 of 321 non-ARVC (0.3%) and 2 of 271 HTx patients (0.1%).
Multisite target-directed EMB sampling in ARVC is a safe procedure when performed by experienced interventionalists. The procedure-related complication rates were low and comparable to those in other cardiomyopathies.
[Show abstract][Hide abstract] ABSTRACT: The implantable cardioverter defibrillator (ICD) is an established therapy for patients at risk of sudden cardiac death. Nevertheless the endocardial electrode in conventional systems plays a major role in long-term complications (difficult removal, risk of endocarditis, etc.). The totally subcutaneous ICD (S-ICD®, Cameron Health, San Clemente, CA, USA) represents a new and particularly significant development in ICD therapy which, since it requires no electrode in or on the heart, results in significantly fewer perioperative and long-term complications (e.g., thromboembolism and endocarditis risk). Although we see an indication for primary and secondary prevention, patients need to be informed about the limited data from randomized trials with the S-ICD®. As there is no permanent pacing option, patients in whom a pacemaker is indicated are not appropriate candidates for S-ICD®. In addition, patients with ventricular tachycardias that can be terminated by antitachycardic pacing are not recommended for the device. In the present article, we report our initial experience with the 18 patients implanted with the S-ICD® to date, comment on the available studies and offer a critical perspective.
[Show abstract][Hide abstract] ABSTRACT: Very recently, mutations in the TRPM4 gene have been identified in four pedigrees as the cause of an autosomal dominant form of cardiac conduction disease. To determine the role of TRPM4 gene variations, the relative frequency of TRPM4 mutations and associated phenotypes was assessed in a cohort of 160 unrelated patients with various types of inherited cardiac arrhythmic syndromes. In eight probands with atrioventricular block or right bundle branch block--five familial cases and three sporadic cases--a total of six novel and two published TRPM4 mutations were identified. In patients with sinus node dysfunction, Brugada syndrome, or long-QT syndrome, no mutations were found. The novel mutations include six amino acid substitutions and appeared randomly distributed through predicted TRPM4 protein. In addition, eight polymorphic sites including two in-frame deletions were found. Mutations separated from polymorphisms by absence in control individuals and familial cosegregation in some families. In summary, TRPM4 gene mutations appear to play a major role in cardiac conduction disease but not for other related syndromes so far. The phenotypes are variable and clearly suggestive of additional factors modulating the disease phenotype in some patients.
Human Mutation 09/2011; 33(1):109-17. · 5.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The totally subcutaneous implantable cardioverter-defibrillator (S-ICD) is an entirely novel defibrillation device that avoids the direct contact of device electrodes with the heart and the cardiovascular system. Here, we present a particular case of a young woman with congenital long-QT syndrome in which we implanted the electrode alternatively, right parasternally. This decision was based on the thoracic anatomy of the patient and on findings of a model of S-ICD electrodes in an adult torso. In conclusion, in some patients an alternative subcutaneous electrode position may be carefully considered but should not be taken to outweigh the standard left-sided placement. (PACE 2012; 35:e254-e257).
Pacing and Clinical Electrophysiology 03/2011; 35(9):e254-7. · 1.75 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background: Myotonic dystrophy type 2 (DM2) is an autosomal dominant multisystem disorder caused by CCTG repeat expansions within intron 1 of the ZNF9 gene on chromosome 3q. Cardiac conduction disturbances, supraventricular arrhythmias, and cardiomyopathy are described in DM2 but Brugada-like features have not yet been reported. Brugada syndrome (BS) is a genetically heterogeneous cardiac conduction disorder which is characterized by a significant ST-segment elevation upon ECG evaluations and bears an increased risk for sudden cardiac death. Case reports: We report two unrelated patients with genetically confirmed DM2 who developed clinical relevant cardiac arrhythmias with syncopal events from 35 (patient 1) and 47 years (patient 2). Brugada-like ECG findings were present in both patients. Family history was negative for BS, but the mothers of both index patients were also affected by DM2 and had different ventricular rhythm disturbances. SCN5A gene sequencing revealed an unknown genetic variant c.4140 C > A, p.N1380K, in patient 1, while no mutation was detected in patient 2. Discussion: Our observations may suggest that Brugada-like cardiac arrhythmias can occur in DM2, as this seems also to be the case in DM1. The chance association of two independent inherited disorders has to be considered and cannot be excluded in one of our patients. However, on statistical grounds, this possibility cannot explain all observed cases of DM with Brugada-like cardiac disease.
European Journal of Neurology 05/2010; · 4.16 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Brugada syndrome (BrS) is a common heritable channelopathy. Mutations in the SCN5A-encoded sodium channel (BrS1) culminate in the most common genotype.
This study sought to perform a retrospective analysis of BrS databases from 9 centers that have each genotyped >100 unrelated cases of suspected BrS.
Mutational analysis of all 27 translated exons in SCN5A was performed. Mutation frequency, type, and localization were compared among cases and 1,300 ostensibly healthy volunteers including 649 white subjects and 651 nonwhite subjects (blacks, Asians, Hispanics, and others) that were genotyped previously.
A total of 2,111 unrelated patients (78% male, mean age 39 +/- 15 years) were referred for BrS genetic testing. Rare mutations/variants were more common among BrS cases than control subjects (438/2,111, 21% vs. 11/649, 1.7% white subjects and 31/651, 4.8% nonwhite subjects, respectively, P <10(-53)). The yield of BrS1 genetic testing ranged from 11% to 28% (P = .0017). Overall, 293 distinct mutations were identified in SCN5A: 193 missense, 32 nonsense, 38 frameshift, 21 splice-site, and 9 in-frame deletions/insertions. The 4 most frequent BrS1-associated mutations were E1784K (14x), F861WfsX90 (11x), D356N (8x), and G1408R (7x). Most mutations localized to the transmembrane-spanning regions.
This international consortium of BrS genetic testing centers has added 200 new BrS1-associated mutations to the public domain. Overall, 21% of BrS probands have mutations in SCN5A compared to the 2% to 5% background rate of rare variants reported in healthy control subjects. Additional studies drawing on the data presented here may help further distinguish pathogenic mutations from similarly rare but otherwise innocuous ones found in cases.
Heart rhythm: the official journal of the Heart Rhythm Society 01/2010; 7(1):33-46. · 4.56 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Cardiomyopathies (diseases of the heart muscle) are a relevant but heterogeneous group of cardiac diseases. The underlying structural myocardial alterations, detectable with contemporary cardiac imaging modalities and also on twelve-lead surface ECG, embody both linkage and differentiation of the respective clinical forms. Most of these are defined to the heart, however, cardiac involvement is also known in the presence of specific metabolic or muscular systemic diseases. In many of the known cardiomyopathies, a genetic background has been elucidated thus indicating a potential familial disease. This, in turn, also harbors the risk that more family members may be affected besides the index patient.
[Show abstract][Hide abstract] ABSTRACT: Brugada syndrome (BrS) is characterized by the presence of coved ST-segment elevations in the right precordial leads (so-called type I ECG) and additional clinical features. Caused by cardiac ion channel gene mutations, BrS may be associated with ventricular and atrial conduction disturbances as well as ventricular fibrillation. Recent studies have discussed whether BrS is merely a primary electric disorder or whether inflammatory or other histopathologic abnormalities in the right ventricle (RV) underlie the ECG phenotype.
We retrospectively analyzed BrS biopsy samples from 21 unrelated patients for histopathologic abnormalities (hypertrophy, fibrosis, inflammation, fatty tissue) together with the patients' clinical, genetic, and imaging data. Eleven patients (52%) had normal RV imaging (by angiography, echocardiography, or cardiac MRI). Results of myocardial biopsies were normal in 3 patients (14%) and revealed mostly moderate abnormalities in the others. Four patients (19%) had predominant fatty tissue in the RV myocardium. Using immunohistochemistry and conventional tissue staining, we could not detect inflammatory tissue changes, an observation compatible with the clinical absence of signs for myocarditis.
Imaging and histopathologic evaluation may detect moderate but uncharacteristic cardiac abnormalities in patients with BrS. None of the patients had arrhythmogenic RV cardiomyopathy or overt myocarditis. Only in a small subset did predominant histopathologic abnormalities in the biopsy samples of the RV outflow tract occur that could provide a link to the ECG phenotype. A variety of mechanisms, including genetic and structural RV alterations, may underlie the Brugada ECG phenotype.
Circulation Arrhythmia and Electrophysiology 02/2009; 2(1):16-23. · 5.95 Impact Factor