Dilated Cardiomyopathy

McNally, Elizabeth M.; Mestroni, Luisa

doi:10.1161/circresaha.116.309396

Cited by 537 publications

(325 citation statements)

References 172 publications

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“…Additionally, recent reports have identified SCN5A mutations in a small percentage of ARVC patients 7. Overlap between ARVC and dilated cardiomyopathy has been well described, and pathogenic variants in sarcomere genes have been associated with DCM 8. Little data exists, however, on the prevalence of other cardiomyopathy‐associated genes in the ARVC population 9.…”

Section: Introductionmentioning

confidence: 99%

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: Introductionmentioning

confidence: 99%

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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“…The phenotype of dilated cardiomyopathy, characterized by left ventricular or biventricular dilatation, reduced systolic function and progressive heart failure, is, in general, genetically heterogeneous, dependant on genes encoding cytoskeletal, sarcomeric, mitochondrial, desmosomal, nuclear membrane, and RNA-binding proteins [45]. Lamin A/C mutations are found in around 5% of patients with non-familial idiopathic dilated cardiomyopathy, in 5%–10% of patients with idiopathic familial dilated cardiomyopathy and in 33% of cases of familial dilated cardiomyopathy with conduction defects [3,45].…”

Section: Dilated Cardiomyopathymentioning

confidence: 99%

“…Lamin A/C mutations are found in around 5% of patients with non-familial idiopathic dilated cardiomyopathy, in 5%–10% of patients with idiopathic familial dilated cardiomyopathy and in 33% of cases of familial dilated cardiomyopathy with conduction defects [3,45]. …”

Section: Dilated Cardiomyopathymentioning

confidence: 99%

Cardiolaminopathies from bench to bedside: challenges in clinical decision-making with focus on arrhythmia-related outcomes

Boriani

Biagini

Ziacchi

et al. 2018

Nucleus

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Lamin A/C gene mutations can be associated with cardiac diseases, usually referred to as ‘cardiolaminopathies’ characterized by arrhythmic disorders and/or left ventricular or biventricular dysfunction up to an overt picture of heart failure. The phenotypic cardiac manifestations of laminopathies are frequently mixed in complex clinical patterns and specifically may include bradyarrhythmias (sinus node disease or atrioventricular blocks), atrial arrhythmias (atrial fibrillation, atrial flutter, atrial standstill), ventricular tachyarrhythmias and heart failure of variable degrees of severity. Family history, physical examination, laboratory findings (specifically serum creatine phosphokinase values) and ECG findings are often important ‘red flags’ in diagnosing a ‘cardiolaminopathy’. Sudden arrhythmic death, thromboembolic events or stroke and severe heart failure requiring heart transplantation are the most dramatic complications of the evolution of cardiolaminopathies and appropriate risk stratification is clinically needed combined with clinical follow-up. Treatment with cardiac electrical implantable devices is indicated in case of bradyarrhythmias (implant of a device with pacemaker functions), risk of life-threatening ventricular tachyarrhythmias (implant of an ICD) or in case of heart failure with wide QRS interval (implant of a device for cardiac resynchronization). New technologies introduced in the last 5 years can help physicians to reduce device-related complications, thanks to the extension of device longevity and availability of leadless pacemakers or defibrillators, to be implanted in appropriately selected patients. An improved knowledge of the complex pathophysiological pathways involved in cardiolaminopathies and in the determinants of their progression to more severe forms will help to improve clinical management and to better target pharmacological and non-pharmacological treatments.

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“…Since the discovery of Myosin Heavy Chain 7 (MYH7) as the first causative gene of inherited hypertrophic cardiomyopathy (3,4), nearly 100 genes have been identified that either cause or predispose the development of cardiomyopathies (5), launching the era of molecular genetic studies to discover therapeutic strategies. Traditionally, the search of a therapeutic gene target needs to be guided by meticulous mechanistic studies on corresponding disease model, which can be a prolonged and inefficient process (6). In contrast, the phenotype-based genetic screening can be a powerful method to rapidly reveal new gene targets of therapeutic potential, as evidenced by those genetic suppressor screens in lower animal models (7)(8)(9)(10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

Retinoid X receptor alpha is a spatiotemporally-specific therapeutic target for doxorubicin-induced cardiomyopathy in adult zebrafish

Ding

Zhang

et al. 2018

Preprint

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While the genetic suppressor screen is efficient in suggesting therapeutic genes, this strategy has yet to be successful for cardiomyopathies in vertebrates. To develop such a strategy, we recently established a mutagenesis screen platform in zebrafish for systematic discovery of genetic modifiers of doxorubicin-induced cardiomyopathy (DIC). Here, we further revealed both molecular and cellular insights of the first salutary modifier emerged from the screen, i.e. gene-breaking transposon (GBT) 0419 that affects the retinoid X receptor alpha a (rxraa) gene.First, by rescuing the mutation in tissue-specific manner with multiple Cre-loxP systems, we demonstrated that the endothelial, but not myocardial or epicardial, function of rxraa is primary to this cardioprotective effects. Next, we showed that the rxraa-associated salutary effects on DIC were conferred partially by the activation of retinoid acid (RA) signaling. Finally, we identified isotretinoin and bexarotene, 2 US Food and Drug Administration-approved RXRA agonists that are effective in treating adult zebrafish DIC when administered during the early, but not the late, phase of DIC progression. Collectively, we provided the first in vivo genetic evidence in supporting RXRA as the therapeutic target for DIC, and uncovered a previously unrecognized spatiotemporally-restricted mechanism for this gene-based therapeutic strategy. Our study also justified that searching salutary modifiers via zebrafish mutagenesis screen can be effective in discovering new therapeutic targets for cardiomyopathies.

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Dilated Cardiomyopathy

Cited by 537 publications

References 172 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)

Cardiolaminopathies from bench to bedside: challenges in clinical decision-making with focus on arrhythmia-related outcomes

Retinoid X receptor alpha is a spatiotemporally-specific therapeutic target for doxorubicin-induced cardiomyopathy in adult zebrafish

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