Background Sudden cardiac death (SCD) is the most devastating complication of hypertrophic cardiomyopathy (HCM), but this can be prevented by an implantable cardioverter-defibrillator (ICD). The aim ...of this study is to evaluate HCM patients with ICDs for primary or secondary prevention of SCD. Methods The study population consisted of all HCM patients with an ICD in 2 tertiary referral clinics. End points during follow-up were total and cardiac mortality, appropriate and inappropriate ICD intervention, and device-related complications. Cox-regression analysis was performed to identify predictors of outcome. Results ICDs were implanted in 134 patients with HCM (mean age 44 ± 17 years, 34% women, 4.2 ± 4.8 years follow-up). Annualized cardiac mortality rate was 3.4% per year and associated with New York Heart Association class III or IV (HR 5.2 2.0-14, P = .002) and cardiac resynchronization therapy (HR 6.3 2.1-20, P = .02). Appropriate ICD interventions occurred in 38 patients (6.8%/year) and was associated with implantation for secondary prevention of SCD (HR 4.0 1.8-9.1, P = .001) and male gender (HR 3.3 1.2-9.0, P = .02). Inappropriate ICD intervention occurred in 21 patients (3.7%/year) and in 20 patients device related complications were documented (3.6%/year). Conclusion ICDs successfully abort life-threatening arrhythmias in HCM patients at increased risk of SCD with an annualized intervention rate of 6.8% per year. End-stage heart failure is the main cause of mortality in these patients. The annualized rate of inappropriate ICD intervention was 3.7% per year, whereas device-related complications occurred 3.6% per year.
Abstract Background Cardiomyopathies are usually inherited and predominantly affect adults, but they can also present in childhood. Although our understanding of the molecular basis of pediatric ...cardiomyopathy has improved, the underlying mechanism remains elusive in a substantial proportion of cases. Objectives This study aimed to identify new genes involved in pediatric cardiomyopathy. Methods The authors performed homozygosity mapping and whole-exome sequencing in 2 consanguineous families with idiopathic pediatric cardiomyopathy. Sixty unrelated patients with pediatric cardiomyopathy were subsequently screened for mutations in a candidate gene. First-degree relatives were submitted to cardiac screening and cascade genetic testing. Myocardial samples from 2 patients were processed for histological and immunohistochemical studies. Results We identified 5 patients from 3 unrelated families with pediatric cardiomyopathy caused by homozygous truncating mutations in ALPK3 , a gene encoding a nuclear kinase that plays an essential role in early differentiation of cardiomyocytes. All patients with biallelic mutations presented with severe hypertrophic and/or dilated cardiomyopathy in utero, at birth, or in early childhood. Three patients died from heart failure within the first week of life. Moreover, 2 of 10 (20%) heterozygous family members showed hypertrophic cardiomyopathy with an atypical distribution of hypertrophy. Deficiency of alpha-kinase 3 has previously been associated with features of both hypertrophic and dilated cardiomyopathy in mice. Consistent with studies in knockout mice, we provide microscopic evidence for intercalated disc remodeling. Conclusions Biallelic truncating mutations in the newly identified gene ALPK3 give rise to severe, early-onset cardiomyopathy in humans. Our findings highlight the importance of transcription factor pathways in the molecular mechanisms underlying human cardiomyopathies.
Pathogenic gene mutations are found in about 50% of patients with hypertrophic cardiomyopathy (HC). Previous studies have shown an association between sarcomere mutations and medium-term outcome. The ...association with long-term outcome has not been described. The aim of this cohort study was to assess the long-term outcomes of patients with genotype positive (G+) and genotype negative (G−) HC. The study population consisted of 626 patients with HC (512 probands and 114 relatives) who underwent phenotyping and genetic testing from 1985 to 2014. End points were all-cause mortality, cardiovascular (CV) mortality, heart failure (HF)–related mortality, and sudden cardiac death/aborted sudden cardiac death (SCD/aborted SCD). Kaplan–Meier and multivariate Cox regression analyses were performed. A pathogenic mutation was detected in 327 patients (52%). G+ probands were younger than G− probands (46 ± 15 vs 55 ± 15 years, p <0.001), had more non sustained ventricular tachycardia (34% vs 13%; p <0.001), more often a history of syncope (14% vs 7%; p = 0.016), and more extreme hypertrophy (maximal wall thickness ≥30 mm, 7% vs 1%; p <0.001). G− probands were more symptomatic (New York Heart Association ≥II, 73% vs 53%, p <0.001) and had higher left ventricular outflow tract gradients (42 ± 39 vs 29 ± 33 mm Hg, p = 0.001). During 12 ± 9 years of follow-up, G+ status was an independent risk factor for all-cause mortality (hazard ratio HR 1.90, 95% CI 1.14 to 3.15; p = 0.014), CV mortality (HR 2.82, 95% CI 1.49 to 5.36; p = 0.002), HF-related mortality (HR 6.33, 95% CI 1.79 to 22.41; p = 0.004), and SCD/aborted SCD (HR 2.88, 95% CI 1.23 to 6.71; p = 0.015). In conclusion, during long-term follow-up, patients with G+ HC are at increased risk of all-cause death, CV death, HF-related death, and SCD/aborted SCD.
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