Arrhythmogenic Cardiomyopathy in 2018–2019: ARVC/ALVC or Both?

Bennett, Richard G.; Haqqani, Haris M.; Berruezo, Antonio; Bella, Paolo Della; Marchlinski, Francis E.; Hsu, C.; Kumar, Saurabh

doi:10.1016/j.hlc.2018.10.013

Cited by 61 publications

(63 citation statements)

References 48 publications

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“…Besides ventricular arrhythmias is ACM characterized by fibrofatty replacement of the ventricular myocardium (Bennett et al, 2019). Fibroblasts can become activated upon injury or environmental stress, triggering their differentiation into myofibroblasts, the primary collagen-producing cell (Nguyen et al, 2014).…”

Section: Mitochondrial Related Fibrosis Formation In Acmmentioning

confidence: 99%

“…The prevalence of ACM in the general population ranges from 1:2000 to 1:5000, meaning that this disease is listed among the rare cardiovascular diseases (Basso et al, 2018). Age at time of diagnosis varies widely, with most patients being first diagnosed between 20 and 50 years of age (Bennett et al, 2019). ACM is characterized by progressive replacement of the myocardium with fatty and fibrous tissue, ending in impairment of the ventricular systolic function and ventricular dilatation (Corrado et al, 2017a).…”

Section: Introductionmentioning

confidence: 99%

“…ACM is characterized by progressive replacement of the myocardium with fatty and fibrous tissue, ending in impairment of the ventricular systolic function and ventricular dilatation (Corrado et al, 2017a). Cardiac remodeling in ACM patients is of right ventricular predominance, though left-ventricular or biventricular involvement has been recognized (Bennett et al, 2019). The fibrofatty substitution likely contributes to the development of ventricular arrhythmias by creating an anatomic substrate (Corrado et al, 2017b) though cellular mechanisms of initiation have been invoked.…”

Section: Introductionmentioning

confidence: 99%

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Mitochondrial Dysfunction as Substrate for Arrhythmogenic Cardiomyopathy: A Search for New Disease Mechanisms

et al. 2019

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Arrhythmogenic cardiomyopathy (ACM) is a familial heart disease, associated with ventricular arrhythmias, fibrofatty replacement of the myocardial mass and an increased risk of sudden cardiac death (SCD). Malignant ventricular arrhythmias and SCD largely occur in the pre-clinical phase of the disease, before overt structural changes occur. To prevent or interfere with ACM disease progression, more insight in mechanisms related to electrical instability are needed. Currently, numerous studies are focused on the link between cardiac arrhythmias and metabolic disease. In line with that, a potential role of mitochondrial dysfunction in ACM pathology is unclear and mitochondrial biology in the ACM heart remains understudied. In this review, we explore mitochondrial dysfunction in relation to arrhythmogenesis, and postulate a link to typical hallmarks of ACM. Mitochondrial dysfunction depletes adenosine triphosphate (ATP) production and increases levels of reactive oxygen species in the heart. Both metabolic changes affect cardiac ion channel gating, electrical conduction, intracellular calcium handling, and fibrosis formation; all well-known aspects of ACM pathophysiology. ATP-mediated structural remodeling, apoptosis, and mitochondria-related alterations have already been shown in models of PKP2 dysfunction. Yet, the limited amount of experimental evidence in ACM models makes it difficult to determine whether mitochondrial dysfunction indeed precedes and/or accompanies ACM pathogenesis. Nevertheless, current experimental ACM models can be very useful in unraveling ACM-related mitochondrial biology and in testing potential therapeutic interventions.

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Section: Mitochondrial Related Fibrosis Formation In Acmmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mitochondrial Dysfunction as Substrate for Arrhythmogenic Cardiomyopathy: A Search for New Disease Mechanisms

et al. 2019

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“…To better explore the association between arrhythmias and cardiomyopathy SCD, we set ARVC as an independent subgroup. ARVC is a familial cardiac disease characterized by ventricular arrhythmias and SCD, and it is the most common cause of SCD in young people [40]. As the sudden death is often the first symptom of this disease, it is urgent to explore the cause and mechanism of the disease in clinic.…”

Section: Discussionmentioning

confidence: 99%

Investigation on susceptible variants to arrhythmia in forensic autopsy cases of SCDs caused by cardiomyopathy: assessment with the candidate SNPs

Tian¹,

Jia²,

Zhao³

et al. 2019

Preprint

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Background: Fatal arrhythmia is a common cause of sudden cardiac death (SCD) in patients with cardiomyopathies. Nowadays, associations of many genetic variants with cardiomyopathy have gradually been highlighted, however, whether the arrhythmia-related single nucleotide polymorphisms (SNPs) are associated with SCDs caused by cardiomyopathies is elusive. To identify the genetic susceptible factors in cardiomyopathy, a retrospective study was conducted from the autopsy cases. Methods: The present study was composed of 223 forensic autopsy cases including 51 SCDs caused by cardiomyopathies and 172 controls. The cardiomyopathy cases were made up of arrhythmogenic right ventricular cardiomyopathy (ARVC, n = 27) and Non-ARVC [n = 24, including hypertrophic cardiomyopathy, dilated cardiomyopathy, restrictive cardiomyopathy, and unclassified cardiomyopathy]. Four arrhythmia-related candidate SNPs: rs4687718, rs7366407, rs4292933, and rs2824292) were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Association between genotypes and the risk of SCD was assessed by stratification of the cardiomyopathy (ARVC cases vs. Non-ARVC cases). Results: The A-allele and dominant model (AA + AG vs. GG) of rs4687718 on transketolase gene (TKT) were significantly associated with cardiomyopathies (ORA allele = 2.481, 95% CIA allele: 1.262 - 4.876, PA allele = 0.007; ORAA+AG genotype = 2.580, 95% CIAA+AG genotype: 1.206 - 5.519, PAA+AG genotype value = 0.012). After stratification by cardiomyopathy subtypes, the allelic and genotypic frequencies of rs4687718 in Non-ARVC group were significantly different compared to controls, and between ARVC group and controls the difference was only duplicated in genotypic frequency. In the light of analyses of the different genetic models, however, there were no significant differences between Non-ARVC group and controls, but the AA + AG vs. GG model was associated with ARVC group. No significant differences were detected for other three SNPs. Conclusion: Our results revealed an association between TKT rs4687718 and SCDs caused by cardiomyopathy in Chinese autopsy cases. These findings highlighted the important role of molecular testing and may play in propensity toward in clinical prediction and forensic identification of cardiomyopathy SCDs. It also provided the basis for the classification of different types of cardiomyopathy at the genetic level.

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“…ARVC is characterized by structural abnormalities in the right ventricle (RV) and ventricular arrhythmia at early stages. Left ventricular (LV) involvement becomes common with disease progression, and the biventricular involvement prompted recent recommendation of using a broader term, arrhythmogenic ventricular cardiomyopathy (ACM), for this disease 5, 6 . Current management of ARVC is mostly palliative and focuses on delaying disease progression and preventing SCD.…”

Section: Introductionmentioning

confidence: 99%

SORBS2is a susceptibility gene to arrhythmogenic right ventricular cardiomyopathy

Ding

Yang

Chen

et al. 2019

Preprint

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BACKGROUND: Arrhythogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy characterized by right ventricular remodeling and ventricular arrhythmia. To date, 16 ARVC causative genes have been identified from human genetic studies, accounting for about 60% of ARVC probands. Genetic basis for the remaining 40% ARVC probands remain elusive. METHODS:Prompted by a zebrafish mutagenesis screen that suggested the Sorbin and SH3 domain-containing 2 (SORBS2) ortholog as a candidate cardiomyopathy gene, we conducted detailed expressionl analysis of Sorbs2 in mice, as well as phenotypic characterization in the Sorbs2 knock-out (KO) mice. The intercalated disc (ICD) expression pattern and ARVC-like phenotypes further prompted us to conduct targeted sequencing of human patients with ARVC to search for rare variants in the SORBS2 gene. RESULTS:Sorbs2 is robustly expressed in the mouse heart, encoding an adhesion junction/desmosome protein that is mainly localized to the ICD. A mutation with near complete depletion of the Sorbs2 protein in mouse results in phenotypes characteristic of human ARVC, such as dilated right ventricle (RV), RV dysfunction, spontaneous ventricular tachycardia (VT), and premature death. Sorbs2 is required to maintain the structural integrity of ICD. Its absence resulted in profound cardiac electrical remodeling with impaired impulse conduction and action potential derangements. Five rare variants were identified from a cohort of 59 ARVC patients, among which two variants affect splicing. CONCLUSIONS:Sorbs2 KO mouse is an ARVC model and SORBS2 is a new ARVC susceptibility gene.

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Arrhythmogenic Cardiomyopathy in 2018–2019: ARVC/ALVC or Both?

Cited by 61 publications

References 48 publications

Mitochondrial Dysfunction as Substrate for Arrhythmogenic Cardiomyopathy: A Search for New Disease Mechanisms

Mitochondrial Dysfunction as Substrate for Arrhythmogenic Cardiomyopathy: A Search for New Disease Mechanisms

Investigation on susceptible variants to arrhythmia in forensic autopsy cases of SCDs caused by cardiomyopathy: assessment with the candidate SNPs

SORBS2is a susceptibility gene to arrhythmogenic right ventricular cardiomyopathy

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