Impact of genotype on clinical course in arrhythmogenic right ventricular dysplasia/cardiomyopathy-associated mutation carriers

Bhonsale, Aditya; Groeneweg, Judith A.; James, Cynthia A.; Dooijes, Dennis; Tichnell, Crystal; Jongbloed, Jan D. H.; Murray, Brittney; Riele, Anneline S.J.M. te; Berg, Maarten P. van den; Bikker, Hennie; Atsma, Douwe E.; Groot, Natasja M. De; Houweling, Arjan C.; Heijden, Jeroen F. van der; Russell, Stuart D.; Doevendans, Pieter A.; Veen, Toon A.B. van; Tandri, Harikrishna; Wilde, Arthur A.M.; Judge, Daniel P.; Tintelen, J. Peter van; Calkins, Hugh; Hauer, Richard N.W.

doi:10.1093/eurheartj/ehu509

Cited by 366 publications

(346 citation statements)

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“…Compared to previously published ARVC patients carrying desmosomal mutations, individuals with sarcomere variants tended to be slightly older (36.8 years of age vs. 33.2 years of age), though not significant 2. Clinical characteristics of the study population were compared to previously published values2 in desmosomal mutations (definitions in Supplementary Table S2): gender, type of presentation, syncope, inducibility at electrophysiology study, premature ventricular contraction (PVC) count on 24‐hour ambulatory monitoring (Holter), ICD placement, appropriate ICD therapy, ventricular tachycardia (VT) storm, VT ablation, and left ventricular dysfunction (left ventricular ejection fraction below 50%), heart failure, and transplant. Individuals with ARVC carrying sarcomere variants were more likely to have undergone a VT ablation (P = 0.009), but otherwise had a similar disease presentation and course to desmosomal mutation carriers.…”

Section: Resultscontrasting

confidence: 82%

“…Indeed, these individuals with sarcomere variants meet TFC for ARVC, and do not have significant differences in structural disease than desmosomal variant carriers. The cohort reported here is less likely to have a reported family history of disease than previous reported prevalences in desmosomal mutation carriers 2. They have no significant differences in phenotype by TFC, do not meet HCM criteria, but also, importantly, they do not have any significant differences in clinical course (other than being more likely to undergo catheter ablation, which is by physician judgment) than previously described individuals with ARVC with desmosomal mutations 2.…”

Section: Discussioncontrasting

confidence: 50%

“…Pathogenic variants in five genes ( DSP , PKP2 , DSG2 , DSC2 , and JUP ) are classically thought to play a large role in ARVC pathogenesis 2, 3. In routine clinical practice, however, even in a well phenotyped population, up to 40% of ARVC cases still elude identification of a genetic root cause 2, 3. Because of the importance of identifying those at risk for sudden death, gene finding efforts have continued.…”

Section: Introductionmentioning

confidence: 99%

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Identification of sarcomeric variants in probands with a clinical diagnosis of arrhythmogenic right ventricular cardiomyopathy (ARVC)

Murray

Hoorntje

Riele

et al. 2018

Cardiovasc electrophysiol

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AimsArrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy characterized by ventricular arrhythmias and sudden death. Currently 60% of patients meeting Task Force Criteria (TFC) have an identifiable mutation in one of the desmosomal genes. As much overlap is described between other cardiomyopathies and ARVC, we examined the prevalence of rare, possibly pathogenic sarcomere variants in the ARVC population.MethodsOne hundred and thirty‐seven (137) individuals meeting 2010 TFC for a diagnosis of ARVC, negative for pathogenic desmosomal variants, TMEM43, SCN5A, and PLN were screened for variants in the sarcomere genes (ACTC1, MYBPC3, MYH7, MYL2, MYL3, TNNC1, TNNI3, TNNT2, and TPM1) through either clinical or research genetic testing.ResultsSix probands (6/137, 4%) were found to carry rare variants in the sarcomere genes. These variants have low prevalence in controls, are predicted damaging by Polyphen‐2, and some of the variants are known pathogenic hypertrophic cardiomyopathy mutations. Sarcomere variant carriers had a phenotype that did not differ significantly from desmosomal mutation carriers. As most of these probands were the only affected individuals in their families, however, segregation data are noninformative.ConclusionThese data show variants in the sarcomere can be identified in individuals with an ARVC phenotype. Although rare and predicted damaging, proven functional and segregational evidence that these variants can cause ARVC is lacking. Therefore, caution is warranted in interpreting these variants when identified on large next‐generation sequencing panels for cardiomyopathies.

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Section: Resultscontrasting

confidence: 82%

Section: Discussioncontrasting

confidence: 50%

Section: Introductionmentioning

confidence: 99%

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Identification of sarcomeric variants in probands with a clinical diagnosis of arrhythmogenic right ventricular cardiomyopathy (ARVC)

Murray

Hoorntje

Riele

et al. 2018

Cardiovasc electrophysiol

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“…Дальнейшие исследования подтвердили, что множественные мутации в генах десмосом ассоциированы с более тяжелым течением заболевания и являются дополнительным фактором риска ВСС, выявление которого, в сочетании с дру-гими факторами, расширяет показания к импланта-ции ИКД [19]. Описано, что у имеющих мутации в гене десмоплакина достоверно чаще развивается систолическая дисфункция ЛЖ (40%) и ХСН (13%), нежели у лиц с мутацией в гене плакофилина [22]. Кроме того, есть данные, что трансплантация сердца требуется достоверно чаще тем пациентам, у которых выявлено 2 и более мутации [22,23].…”

Section: материал и методыunclassified

A Case of Dna-Diagnostics Application for Arrhythmogenic Right Ventricle Cardiomyopathy

Shestak¹,

Lutokhina²,

Фролова³

et al. 2016

Russ J Cardiol

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Аритмогенная кардиомиопатия правого желу-дочка (АКПЖ, MIM*#107970) -генетически детер-минированное заболевание миокарда с высоким риском внезапной сердечной смерти (ВСС), характе-ризующееся фиброзным и/или жировым замеще-нием кардиомиоцитов преимущественно правого желудочка (ПЖ), частыми желудочковыми наруше-ниями ритма, ведущее к развитию сердечной недо-статочности. В ряде случаев жизнеугрожающие желу-дочковые аритмии могут возникнуть до развития явного структурного и функционального ремодели-рования миокарда (так называемая "скрытая" фаза АКПЖ), что значительно затрудняет раннюю диагно-стику заболевания. Нередко первым и единственным симптомом болезни является ВСС. Патоморфологи-ческая диагностика лиц, умерших внезапно в возрас-те до 35 лет показала, что на долю недиагностирован-ной АКПЖ приходится значительная часть случаев ВСС: 12,5-25% в Италии, 17% в США, 14,1% Шестак А. Г.* -н. с. лаборатории медицинской генетики, Благова О. В. -д. м.н., профессор кафедры факультетской терапии №1 лечебного факультета, Луто-хина Ю. А. -аспирант по специальности "Кардиология" кафедры факультет-ской терапии №1 лечебного факультета, Фролова Ю. В. -д. м.н., в. н.с. отделе-ния хирургического лечения дисфункций миокарда и сердечной недостаточно-сти, Дземешкевич С. Л. -д. м.н., профессор, зав. отделением хирургического лечения дисфункций миокарда и сердечной недостаточности, Заклязьмин-ская Е. В. -д. м.н., профессор, зав. лабораторией медицинской генетики. Aim. Analysis of the results of dnA-diagnostics in practice, for the two most common types of arrhythmogenic cardiomyopathies of the right ventricle (ACRV) in cardiovascular and surgery setting. Material and methods. Clinical and laboratory study performed, of the selection of 38 patients with a diagnosis at presentation -ACRV, with consequent genetic counseling and dnA-diagnostics for 2 most common types of ACRV. Results. Mutations in two genes responsible for the most common ACRV types, were found in 22,9% of patients. Analysis of occurrence rate was done for mutations in groups with definite, probable and possible diagnoses of ACRV, and of total impact of genetic data on diagnostics of the disease. Conclusion. data obtained on the Russian selection of patients shows similarity with the data on prevalence of two most common genetic forms of ACRV in other ethnicities. Russ

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“…Arrhythmogenic right ventricular cardiomyopathy (ARVC), also known as ‘Arrhythmogenic right ventricular dysplasia’, is a rare cardiovascular disease, often familial, that predisposes to ventricular arrhythmias (VA) potentially leading to sudden cardiac death (SCD) in young patients [1–4]. ARVC is more prevalent in young people and athletes [5–7].…”

Section: Introductionmentioning

confidence: 99%

Right ventricular dysplasia: management and treatment in light of current evidence

Idris

Shah

Park

2018

Journal of Community Hospital Internal Medicine Perspectives

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Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare cardiovascular disease that predisposes to ventricular arrhythmias potentially leading to sudden cardiac death (SCD). ARVC varies considerably with multiple clinical presentations, ranging from no symptoms to cardiac arrhythmias to SCD. ARVC prevalence is not well known, but the estimated prevalence in the general population is 1:5000. Diagnosis of ARVC can be made by using the Revised European Society of Cardiology criteria for ARVC that includes ventricular structural and functional changes, ECG abnormalities, arrhythmias, family and genetic factors. The management of ARVC is focused on prevention of lethal events such as SCD. Implantable cardioverter defibrillator placement is the only proven mortality benefit in treatment of ARVC. Other treatment strategies include medications such as beta blockers and antiarrhythmics, radiofrequency ablation, surgery, cardiac transplantation, and lifestyle changes. All these interventions help in symptomatic treatment but none of them have proved to decrease mortality rates. ARVC is a progressive disease that leads to SCD if not treated appropriately. Management of these diseases has been a challenge for physicians. With the advent of technology and many new drugs/devices under clinical investigation, this might change in the future. However, while advances in technologies have helped elucidate many aspects of these diseases, many mysteries still remain of this unique disease. With continued research, we can expect more cost-effective and patient-friendly drug therapies and ablation techniques to be developed in the near future.

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Impact of genotype on clinical course in arrhythmogenic right ventricular dysplasia/cardiomyopathy-associated mutation carriers

Abstract: Presentation with SCD/VF occurs at a significantly younger age when compared with sustained monomorphic VT. The genotype of ARVD/C mutation carriers impacts clinical course and disease expression. Male sex negatively modifies phenotypic expression.

Cited by 366 publications

References 29 publications

Identification of sarcomeric variants in probands with a clinical diagnosis of arrhythmogenic right ventricular cardiomyopathy (ARVC)

Identification of sarcomeric variants in probands with a clinical diagnosis of arrhythmogenic right ventricular cardiomyopathy (ARVC)

A Case of Dna-Diagnostics Application for Arrhythmogenic Right Ventricle Cardiomyopathy

Right ventricular dysplasia: management and treatment in light of current evidence

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