ABSTRACT
AIMS: The aim of this study was to determine the frequency of heterozygous truncating ALPK3 variants (ALPK3tv) in patients with hypertrophic cardiomyopathy (HCM) and confirm their pathogenicity using burden testing in independent cohorts and family co-segregation studies. METHODS AND RESULTS: In a discovery cohort of 770 index patients with HCM, 12 (1.56%) were heterozygous for ALPK3tv [odds ratio(OR) 16.11, 95% confidence interval (CI) 7.94-30.02, P = 8.05e-11] compared to the Genome Aggregation Database (gnomAD) population. In a validation cohort of 2047 HCM probands, 32 (1.56%) carried heterozygous ALPK3tv (OR 16.17, 95% CI 10.31-24.87, P < 2.2e-16, compared to gnomAD). Combined logarithm of odds score in seven families with ALPK3tv was 2.99. In comparison with a cohort of genotyped patients with HCM (n = 1679) with and without pathogenic sarcomere gene variants (SP+ and SP-), ALPK3tv carriers had a higher prevalence of apical/concentric patterns of hypertrophy (60%, P < 0.001) and of a short PR interval (10%, P = 0.009). Age at diagnosis and maximum left ventricular wall thickness were similar to SP- and left ventricular systolic impairment (6%) and non-sustained ventricular tachycardia (31%) at baseline similar to SP+. After 5.3 ± 5.7 years, 4 (9%) patients with ALPK3tv died of heart failure or had cardiac transplantation (log-rank P = 0.012 vs. SP- and P = 0.425 vs. SP+). Imaging and histopathology showed extensive myocardial fibrosis and myocyte vacuolation. CONCLUSIONS: Heterozygous ALPK3tv are pathogenic and segregate with a characteristic HCM phenotype.
Subject(s)
Cardiomyopathy, Hypertrophic , Muscle Proteins/genetics , Protein Kinases/genetics , Cardiomyopathy, Hypertrophic/genetics , Heterozygote , Humans , Mutation , SarcomeresABSTRACT
Heavily calcified lesions present a challenge for percutaneous coronary intervention. With rotational atherectomy, it is possible to treat these lesions and paclitaxel-eluting stents (PESs) reduce the risk of restenosis over the long term. This retrospective study investigated clinical outcomes with rotational atherectomy and PESs in 50 consecutive patients with heavily calcified lesions. Mortality and target lesion revascularization at 1 year (median, 14 months; interquartile range, 8.75-25.5 months) were recorded. Some 52% of patients were aged over 70 years, 68% were male, 52% had acute coronary syndrome, 80% had multivessel disease and 44% were receiving abciximab. Two patients died in hospital, three died during follow-up (one cardiac death) and 3 (6%) underwent target lesion revascularization. At 1 year, the survival rate free of cardiac death was 94% and the survival rate free of target lesion revascularization was 94%. These findings demonstrate that the combination of rotational atherectomy and PESs gives excellent results in heavily calcified lesions.
