The relationship between clinical phenotypes and desmosomal gene mutations in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) is poorly characterized. Therefore, we performed a meta-analysis to explore the genotype-phenotype relationship in patients with ARVC. Any studies reporting this genotype-phenotype relationship were included. In total, 11 studies involving 1,113 patients were included. The presence of desmosomal gene mutations was associated with a younger onset age of ARVC (32.7 ± 15.2 versus 43.2 ± 13.3 years; P = 0.001), a higher incidence of T wave inversion in V1–3 leads (78.5% versus 51.6%; P = 0.0002) or a family history of ARVC (39.5% versus 27.1%; P = 0.03). There was no difference in the proportion of males between desmosomal-positive and desmosomal-negative patients (68.3% versus 68.9%; P = 0.60). The presence of desmosomal gene mutations was not associated with global or regional structural and functional alterations (63.5% versus 60.5%; P = 0.37), epsilon wave (29.4% versus 26.2%; P = 0.51) or ventricular tachycardia of left bundle-branch morphology (62.6% versus 57.2%; P = 0.30). Overall, patients with desmosomal gene mutations are characterized by an earlier onset age, a higher incidence of T wave inversion in V1–3 leads and a strong family history of ARVC.

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Several studies investigated the role of physical activity in atrial fibrillation (AF), but the results remain controversial. We aimed to estimate the association between physical activity and incident AF, as well as to determine whether a sex difference existed. We systematically retrieved relevant studies from Cochrane Library, PubMed, and ScienceDirect through December 1, 2015. Data were abstracted from eligible studies and effect estimates pooled using a random-effects model. Thirteen prospective studies fulfilled inclusion criteria. For primary analysis, neither total physical activity exposure (relative risk [RR]: 0.98, 95% confidence interval [CI]: 0.90-1.06, P = 0.62) nor intensive physical activity (RR: 1.07, 95% CI: 0.93-1.25, P = 0.41) was associated with a significant increased risk of AF. In the country-stratified analysis, the pooled results were not significantly changed. However, in the sex-stratified analysis, total physical activity exposure was associated with an increased risk of AF in men (RR: 1.18, 95% CI: 1.02-1.37), especially at age <50 years (RR: 1.58, 95% CI: 1.28-1.95), with a significantly reduced risk of AF in women (RR: 0.92, 95% CI: 0.87-0.97). Additionally, male individuals with intensive physical activity had a slightly higher (although statistically nonsignificant) risk of developing AF (RR: 1.12, 95% CI: 0.99-1.28), but there was a significantly reduced risk of incident AF in women (RR: 0.92, 95% CI: 0.86-0.98). Published literature supports a sex difference in the association between physical activity and incident AF. Increasing physical activity is probably associated with an increased risk of AF in men and a decreased risk in women.

Several studies have investigated the role of physical fitness in atrial fibrillation (AF), but the results remain controversial. We aimed to estimate the association between physical fitness and risk of AF. We comprehensively retrieved data from the Cochrane Library, PubMed, and Embase databases until February 29, 2016, for studies evaluating the association of physical fitness with the risk of AF. Data were abstracted from included studies, and effect estimates were pooled using a random-effects model. Six studies with a total of 205 094 participants and 15 919 AF cases fulfilled the inclusion criteria. When physical fitness was assessed as a continuous variable, per incremental increase of physical fitness was associated with a 9% reduced risk of AF (risk ratio [RR]: 0.91, 95% confidence interval [CI]: 0.84-1.00, P = 0.05). When physical fitness was assessed as a categorical variable, the risk of AF was significantly reduced (RR: 0.51, 95% CI: 0.28-0.91, P = 0.02) in individuals with the highest level of physical fitness compared with those with the lowest level. The intermediate vs the lowest level of physical fitness was associated with a 28% reduced risk of AF (RR: 0.72, 95% CI: 0.56-0.93, P = 0.01). The sensitivity analysis indicated that these results were stable. Notably, there was evidence of statistical heterogeneity across studies; therefore, we should interpret the results cautiously. In conclusion, published literature supports that a higher level of physical fitness is associated with a lower risk of AF. Further studies should be performed to confirm these findings.

BackgroundEarly repolarization syndrome (ERS) may be a near-Mendelian or an oligogenic disease; however, no direct evidence has been provided to support this theory.Methods and resultsWe described a large Chinese family with nocturnal sudden cardiac death induced by ERS in most of the young male adults. One missense mutation (p.Q1916R) was found in the major subunit of the L-type calcium channel gene CACNA1C by the direct sequencing of candidate genes. A concomitant gain-of-function variant in the sodium channel gene SCN5A (p.R1193Q) was found to rescue the phenotype of the female CACNA1C-Q1916R mutation carriers, which led to the incomplete penetrance. The functional studies, via the exogenous expression approach, revealed that the CACNA1C-Q1916R mutation led to a decreasing L-type calcium current and the protein expression defect. The decreased calcium current produced by the mutant channel was improved by isoproterenol but exacerbated by testosterone. The effects of CACNA1C-Q1916R mutation and testosterone on cellular electrophysiology were further confirmed by the human ventricular action potential simulation.ConclusionsOur results demonstrated that the loss-of-function CACNA1C-Q1916R mutation contributed to ERS-related sudden cardiac death, and the phenotypic incomplete penetrance was modified by the SCN5A-R1193Q variant and sex. These findings suggest that phenotypes of ERS are modified by multiple genetic factors, which supports the theory that ERS may be an oligogenic disease.