Abstract Arrhythmogenic right ventricular cardiomyopathy (ARVC) is characterized by degeneration of the right ventricle and ventricular tachycardia originating from the right ventricle. Additionally, ...the disease is an inherited cardiomyopathy that mainly follows the autosomal dominant pattern. More than 10 genes have been reported as causative genes for ARVC, and more than half of ARVC patients carry mutations in desmosome related genes. The desmosome is one of the structures involved in cell adhesion and its disruption leads to various diseases, including a skin disease called pemphigus. Among desmosome genes, mutations in PKP2 are most frequently identified in ARVC patients. Although the genotype–phenotype correlations remain to be fully studied, many studies have reported clinical manifestations of, prognosis for, and appropriate therapies for ARVC from the perspective of gene mutations. A collective review of these reports would enhance the understanding of ARVC pathogenesis and clinical manifestation. This review discusses the clinical issues of ARVC from the genetic background.
Skeletal muscle is composed of heterogeneous populations of myofibers classified as slow‐ and fast‐twitch fibers. Myofiber size and composition are drastically changed in response to physiological ...demands. We previously showed that transcriptional cofactor vestigial‐like (Vgll) 2 is a pivotal regulator of slow muscle gene programming under sedentary conditions. However, whether Vgll2 is required for skeletal muscle adaptations after chronic overload is unclear. Therefore, we investigated the role of Vgll2 in chronic overload‐inducing skeletal muscle adaptations using synergist ablation (SA) on plantaris. We found that Vgll2 is an essential regulator of the switch towards a slow‐contractile phenotype and oxidative metabolism during chronic overload. Mice lacking Vgll2 exhibited limited fiber type transition and downregulation of genes related to lactate metabolism and their regulator peroxisome proliferator‐activated receptor gamma coactivator 1α1, after SA, was augmented in Vgll2‐deficient mice compared with in wild‐type mice. Mechanistically, increased muscle usage elevated Vgll2 levels and promoted the interaction between Vgll2 and its transcription partners such as TEA domain1 (TEAD1), MEF2c, and NFATc1. Calcium ionophore treatment promoted nuclear translocation of Vgll2 and increased TEAD‐dependent MYH7 promotor activity in a Vgll2‐dependent manner. Taken together, these data demonstrate that Vgll2 plays an important role for functional adaptation of skeletal muscle to chronic overload.
Transcriptional activity mediated vestigial‐like (Vgll) 2 is elevated by chronic overload stimulation and is required for fiber type remodeling of skeletal muscle. Chronic overload promotes interaction between Vgll2 and transcriptional partners such as TEA domain transcription factors, MEF2c, and NFATc1. our data suggest that Vgll2‐ transcription factor complex regulates slow muscle gene programming.
Abstract
Aims
Calmodulinopathies are rare life-threatening arrhythmia syndromes which affect mostly young individuals and are, caused by mutations in any of the three genes (CALM 1–3) that encode ...identical calmodulin proteins. We established the International Calmodulinopathy Registry (ICalmR) to understand the natural history, clinical features, and response to therapy of patients with a CALM-mediated arrhythmia syndrome.
Methods and results
A dedicated Case Report File was created to collect demographic, clinical, and genetic information. ICalmR has enrolled 74 subjects, with a variant in the CALM1 (n = 36), CALM2 (n = 23), or CALM3 (n = 15) genes. Sixty-four (86.5%) were symptomatic and the 10-year cumulative mortality was 27%. The two prevalent phenotypes are long QT syndrome (LQTS; CALM-LQTS, n = 36, 49%) and catecholaminergic polymorphic ventricular tachycardia (CPVT; CALM-CPVT, n = 21, 28%). CALM-LQTS patients have extremely prolonged QTc intervals (594 ± 73 ms), high prevalence (78%) of life-threatening arrhythmias with median age at onset of 1.5 years interquartile range (IQR) 0.1–5.5 years and poor response to therapies. Most electrocardiograms (ECGs) show late onset peaked T waves. All CALM-CPVT patients were symptomatic with median age of onset of 6.0 years (IQR 3.0–8.5 years). Basal ECG frequently shows prominent U waves. Other CALM-related phenotypes are idiopathic ventricular fibrillation (IVF, n = 7), sudden unexplained death (SUD, n = 4), overlapping features of CPVT/LQTS (n = 3), and predominant neurological phenotype (n = 1). Cardiac structural abnormalities and neurological features were present in 18 and 13 patients, respectively.
Conclusion
Calmodulinopathies are largely characterized by adrenergically-induced life-threatening arrhythmias. Available therapies are disquietingly insufficient, especially in CALM-LQTS. Combination therapy with drugs, sympathectomy, and devices should be considered.
Background: Catecholaminergic polymorphic ventricular tachycardia (CPVT) has been often misdiagnosed as long QT syndrome (LQTS) type 1 (LQT1), which phenotypically mimics CPVT but has a relatively ...better prognosis. Methods and Results: The derivation and validation cohorts consisted of 146 and 21 patients, respectively, all of whom had exercise- or emotional stress-induced cardiac events. In the derivation cohort, 42 and 104 patients were first clinically diagnosed with CPVT and LQTS, respectively. Nine of 104 patient who had initial diagnosis of LQTS were found to carry RYR2 mutations. They were misdiagnosed due to 4 different reasons: (1) transient QT prolongation after cardiopulmonary arrest; (2) QT prolongation after epinephrine test; (3) absence of ventricular arrhythmia after the exercise stress test (EST); and (4) assumption of LQTS without evidence. Based on genetic results, we constructed a composite scoring system by modifying the Schwartz score: replacing the corrected QT interval (QTc) at 4 min recovery time after EST >480 ms with that at 2 min, or with ∆QTc (QTc at 2 min of recovery−QTc before exercise) >40 ms and assigning a score of −1 for ∆QTc <10 ms or documented polymorphic ventricular arrhythmias. This composite scoring yielded 100% sensitivity and specificity for the clinical differential diagnosis between LQT1 and CPVT when applied to the validation cohort. Conclusions: The modified Schwartz score facilitated the differential diagnosis between LQT1 and CPVT.
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is one of the causes of sudden cardiac death in young people and results from RYR2 mutations in ~60% of CPVT patients. The inheritance of ...the RYR2 mutations follows an autosomal dominant trait, however, de novo mutations are often identified during familial analysis. In 36 symptomatic CPVT probands with RYR2 mutations, we genotyped their parents and confirmed the origin of the respective mutation. In 26 sets of proband and both parents (trio), we identified 17 de novo mutations (65.4%), seven from their mothers and only two mutations were inherited from their fathers. Among nine sets of proband and mother, five mutations were inherited from mothers. Four other mutations were of unknown origin. The inheritance of RYR2 mutations was significantly more frequent from mothers (n = 12, 34.3%) than fathers (n = 2, 5.7%) (P = 0.013). The mean ages of onset were not significantly different in probands between de novo mutations and those from mothers. Thus, half of the RYR2 mutations in our cohort were de novo, and most of the remaining mutations were inherited from mothers. These data would be useful for family analysis and risk stratification of the disease.
Acquired long QT syndrome (aLQTS) exhibits QT prolongation and Torsades de Pointes ventricular tachycardia triggered by drugs, hypokalaemia, or bradycardia. Sometimes, QTc remains prolonged despite ...elimination of triggers, suggesting the presence of an underlying genetic substrate. In aLQTS subjects, we assessed the prevalence of mutations in major LQTS genes and their probability of being carriers of a disease-causing genetic variant based on clinical factors.
We screened for the five major LQTS genes among 188 aLQTS probands (55 ± 20 years, 140 females) from Japan, France, and Italy. Based on control QTc (without triggers), subjects were designated 'true aLQTS' (QTc within normal limits) or 'unmasked cLQTS' (all others) and compared for QTc and genetics with 2379 members of 1010 genotyped congenital long QT syndrome (cLQTS) families. Cardiac symptoms were present in 86% of aLQTS subjects. Control QTc of aLQTS was 453 ± 39 ms, shorter than in cLQTS (478 ± 46 ms, P < 0.001) and longer than in non-carriers (406 ± 26 ms, P < 0.001). In 53 (28%) aLQTS subjects, 47 disease-causing mutations were identified. Compared with cLQTS, in 'true aLQTS', KCNQ1 mutations were much less frequent than KCNH2 (20% 95% CI 7-41% vs. 64% 95% CI 43-82%, P < 0.01). A clinical score based on control QTc, age, and symptoms allowed identification of patients more likely to carry LQTS mutations.
A third of aLQTS patients carry cLQTS mutations, those on KCNH2 being more common. The probability of being a carrier of cLQTS disease-causing mutations can be predicted by simple clinical parameters, thus allowing possibly cost-effective genetic testing leading to cascade screening for identification of additional at-risk family members.
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