Evidence for reduced susceptibility to cardiac bradycardias in South Asians compared with Caucasians.

OBJECTIVES: To investigate ethnic differences in susceptibility to bradycardias in South Asian and white European patients in the UK by determining rates of permanent pacemaker (PPM) implantation for sinus node dysfunction (SND) and atrioventricular block (AVB) in each ethnic group. METHODS: We carried out a retrospective cohort study into new PPM implantation during the period from 1 May 2006 to 31 March 2014, in patients of South Asian and Caucasian ethnicity resident in Leicestershire, UK. Numbers of individuals at risk in each ethnic group were derived from UK National Census data of 2011. Crude, and age-standardised incidence rates and risk ratios per 1000 population of PPM implantation were calculated for Caucasians and South Asians. RESULTS: During the study period, 4883 individuals from the Leicestershire population of 980 328 underwent PPM implantation, a cumulative implantation rate of 4.98/1000 population. The population cumulative PPM implantation rate for SND was 1.74/1000, AVB 2.83/1000 and other indications 0.38/1000 population. The crude incidence in Caucasians (6.15/1000 population) was higher than in South Asians (1.07/1000 population) and remained higher after age standardisation (5.60/1000 vs 2.03/1000, P<0.001). The age-standardised cumulative PPM implantation rates were lower in South Asians for both SND (0.53/1000 in South Asians; 1.97/1000 in Caucasians, P<0.001) and AVB (1.30/1000 in South Asians; 3.17/1000 in Caucasians, P<0.001). Standardised risk ratios (95% CI) for PPM implantation in South Asians compared with Caucasians for all pacing indications, SND and AVB were 0.36 (95% CI 0.36 to 0.37), 0.27 (95% CI 0.27 to 0.28) and 0.41 (95% CI 0.41 to 0.42), respectively. CONCLUSIONS: Rates of PPM implantation are lower in South Asians residing in the UK, compared with Caucasians. This observation raises the possibility of lower inherent susceptibility to bradycardias in South Asians compared with Caucasians. Studies aimed at identifying underlying mechanisms, including possible genetic differences, are warranted.

A frameshift deletion in the sarcomere gene MYL4 causes early-onset familial atrial fibrillation.

AIMS: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in man, causing substantial morbidity and mortality with a major worldwide public health impact. It is increasingly recognized as a highly heritable condition. This study aimed to determine genetic risk factors for early-onset AF. METHODS AND RESULTS: We sequenced the whole genomes of 8453 Icelanders and imputed genotypes of the 25.5 million sequence variants we discovered into 1799 Icelanders with early-onset AF (diagnosed before 60 years of age) and 337 453 controls. Each sequence variant was tested for association based on multiplicative and recessive inheritance models. We discovered a rare frameshift deletion in the myosin MYL4 gene (c.234delC) that associates with early-onset AF under a recessive mode of inheritance (allelic frequency = 0.58%). We found eight homozygous carriers of the mutation, all of whom had early-onset AF. Six of the homozygotes were diagnosed by the age of 30 and the remaining two in their 50s. Three of the homozygotes had received pacemaker implantations due to sick sinus syndrome, three had suffered an ischemic stroke, and one suffered sudden cardiac death. CONCLUSIONS: Through a population approach we found a loss of function mutation in the myosin gene MYL4 that, in the homozygous state, is completely penetrant for early-onset AF. The finding may provide novel mechanistic insight into the pathophysiology of this complex arrhythmia.

Incidence of and risk factors for sick sinus syndrome in the general population.

BACKGROUND: Little is known about the incidence of and risk factors for sick sinus syndrome (SSS), a common indication for pacemaker implantation. OBJECTIVES: This study sought to describe the epidemiology of SSS. METHODS: This analysis included 20,572 participants (mean baseline age 59 years, 43% male) in the ARIC (Atherosclerosis Risk In Communities) study and the CHS (Cardiovascular Health Study), who at baseline were free of prevalent atrial fibrillation and pacemaker therapy, had a heart rate of ≥ 50 beats/min unless using beta blockers, and were identified as of white or black race. Incident SSS cases were identified by hospital discharge International Classification of Disease-revision 9-Clinical Modification code 427.81 and validated by medical record review. RESULTS: During an average 17 years of follow-up, 291 incident SSS cases were identified (unadjusted rate 0.8 per 1,000 person-years). Incidence increased with age (hazard ratio [HR]: 1.73; 95% confidence interval [CI]: 1.47 to 2.05 per 5-year increment), and blacks had a 41% lower risk of SSS than whites (HR: 0.59; 95% CI: 0.37 to 0.98). Incident SSS was associated with greater baseline body mass index, height, N-terminal pro-B-type natriuretic peptide, and cystatin C, with longer QRS interval, with lower heart rate, and with prevalent hypertension, right bundle branch block, and cardiovascular disease. We project that the annual number of new SSS cases in the United States will increase from 78,000 in 2012 to 172,000 in 2060. CONCLUSIONS: Blacks have a lower risk of SSS than whites, and several cardiovascular risk factors were associated with incident SSS. With the aging of the population, the number of Americans with SSS will increase dramatically over the next 50 years.