Dataset Information

Phenotypic expression and clinical outcomes in a South Asian PRKAG2 cardiomyopathy cohort.

ABSTRACT: The PRKAG2 syndrome is a rare autosomal dominant phenocopy of sarcomeric hypertrophic cardiomyopathy (HCM), characterized by ventricular pre-excitation, progressive conduction system disease and left ventricular hypertrophy. This study describes the phenotype, genotype and clinical outcomes of a South-Asian PRKAG2 cardiomyopathy cohort over a 7-year period. Clinical, electrocardiographic, echocardiographic, and cardiac MRI data from 22 individuals with PRKAG2 variants (68% men; mean age 39.5?±?18.1 years), identified at our HCM centre were studied prospectively. At initial evaluation, all of the patients were in NYHA functional class I or II. The maximum left ventricular wall thickness was 22.9?±?8.7 mm and left ventricular ejection fraction was 53.4?±?6.6%. Left ventricular hypertrophy was present in 19 individuals (86%) at baseline. 17 patients had an WPW pattern (77%). After a mean follow-up period of 7 years, 2 patients had undergone accessory pathway ablation, 8 patients (36%) underwent permanent pacemaker implantation (atrio-ventricular blocks-5; sinus node disease-2), 3 patients developed atrial fibrillation, 11 patients (50%) developed progressive worsening in NYHA functional class, and 6 patients (27%) experienced sudden cardiac death or equivalent. PRKAG2 cardiomyopathy must be considered in patients with HCM and progressive conduction system disease.

SUBMITTER: Ahamed H

PROVIDER: S-EPMC7691361 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Phenotypic expression and clinical outcomes in a South Asian PRKAG2 cardiomyopathy cohort.

Ahamed Hisham H Balegadde Aniketh Vijay AV Menon Shilpa S Menon Ramesh R Ramachandran Aishwarya A Mathew Navin N Natarajan K U KU Nair Indu Ramachandran IR Kannan Rajesh R Shankar Meghna M Mathew Oommen K OK Nguyen Thong T TT Gupta Ravi R Stawiski Eric W EW Ramprasad V L VL Seshagiri Somasekar S Phalke Sameer S

Scientific reports 20201126 1

The PRKAG2 syndrome is a rare autosomal dominant phenocopy of sarcomeric hypertrophic cardiomyopathy (HCM), characterized by ventricular pre-excitation, progressive conduction system disease and left ventricular hypertrophy. This study describes the phenotype, genotype and clinical outcomes of a South-Asian PRKAG2 cardiomyopathy cohort over a 7-year period. Clinical, electrocardiographic, echocardiographic, and cardiac MRI data from 22 individuals with PRKAG2 variants (68% men; mean age 39.5 ± 1 ...[more]

PMID: 33244021

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Project description:BackgroundHypertrophic cardiomyopathy (HCM) is caused by rare variants in sarcomere-encoding genes, but little is known about the clinical significance of these variants in the general population.ObjectivesThe goal of this study was to compare lifetime outcomes and cardiovascular phenotypes according to the presence of rare variants in sarcomere-encoding genes among middle-aged adults.MethodsThis study analyzed whole exome sequencing and cardiac magnetic resonance imaging in UK Biobank participants stratified according to sarcomere-encoding variant status.ResultsThe prevalence of rare variants (allele frequency <0.00004) in HCM-associated sarcomere-encoding genes in 200,584 participants was 2.9% (n = 5,712; 1 in 35), and the prevalence of variants pathogenic or likely pathogenic for HCM (SARC-HCM-P/LP) was 0.25% (n = 493; 1 in 407). SARC-HCM-P/LP variants were associated with an increased risk of death or major adverse cardiac events compared with controls (hazard ratio: 1.69; 95% confidence interval [CI]: 1.38-2.07; P < 0.001), mainly due to heart failure endpoints (hazard ratio: 4.23; 95% CI: 3.07-5.83; P < 0.001). In 21,322 participants with both cardiac magnetic resonance imaging and whole exome sequencing, SARC-HCM-P/LP variants were associated with an asymmetric increase in left ventricular maximum wall thickness (10.9 ± 2.7 mm vs 9.4 ± 1.6 mm; P < 0.001), but hypertrophy (≥13 mm) was only present in 18.4% (n = 9 of 49; 95% CI: 9%-32%). SARC-HCM-P/LP variants were still associated with heart failure after adjustment for wall thickness (hazard ratio: 6.74; 95% CI: 2.43-18.7; P < 0.001).ConclusionsIn this population of middle-aged adults, SARC-HCM-P/LP variants have low aggregate penetrance for overt HCM but are associated with an increased risk of adverse cardiovascular outcomes and an attenuated cardiomyopathic phenotype. Although absolute event rates are low, identification of these variants may enhance risk stratification beyond familial disease.

Project description:ObjectivesSuccessful treatment of acute coronary syndrome (ACS) relies on its rapid recognition. It is unclear whether the accepted presentation of chest pain applies to different ethnic groups. We thus examined potential ethnic variations in ACS symptoms and clinical care outcomes in white, South Asian and Chinese patients.DesignCross-sectional survey.SettingParticipants were hospitalised at 1 of 12 Canadian centres across four provinces.Participants1334 patients with ACS (630 white; 488 South Asian; 216 Chinese).Main outcome measuresACS presentation symptoms (classic/typical midsternal pain/discomfort with or without radiation to the left neck, shoulder or arm) were assessed by self-report. Clinical care outcomes (time to emergency room [ER] presentation, cardiac catheterisation; receipt of cardiac catheterisation, percutaneous coronary intervention [PCI] or coronary artery bypass grafting [CABG]) were obtained by health record audit.ResultsThe mean age of the sample was 62 years and 30% had ST-elevation myocardial infarction (STEMI). The most common presenting symptom was midsternal pain/discomfort of any intensity regardless of ethnic status. Yet, a substantial proportion of patients reported atypical symptoms (33% white, 19% South Asian, 20% Chinese; p<0.006). After adjustment for age, sex, education, current smoking, extent of coronary artery disease, presence of diabetes or chronic kidney disease and STEMI vs non-STEMI/unstable angina, South Asians were more likely to present with at least moderate intensity midsternal pain/discomfort (adjusted OR [AOR] 1.44; 95% CI 1.05 to 1.98), whereas Chinese were less likely to present with radiating symptoms (AOR 0.53; 95% CI 0.38 to 0.74) compared with whites. South Asians with atypical pain (relative to those with midsternal pain/discomfort) took significantly longer to present to the ER (p=0.037), and were less likely to receive PCI (p=0.008) or CABG (p=0.041).ConclusionsAtypical presentations were associated with greater delays in arrival to the emergency department and reduced invasive cardiovascular care in South Asians.

Project description:ImportanceThe genetic variant MYBPC3Δ25bp occurs in 4% of South Asian descendants, with an estimated 100 million carriers worldwide. MYBPC3 Δ25bp has been linked to cardiomyopathy and heart failure. However, the high prevalence of MYBPC3Δ25bp suggests that other stressors act in concert with MYBPC3Δ25bp.ObjectiveTo determine whether there are additional genetic factors that contribute to the cardiomyopathic expression of MYBPC3Δ25bp.Design, setting, andparticipantsSouth Asian individuals living in the United States were screened for MYBPC3Δ25bp, and a subgroup was clinically evaluated using electrocardiograms and echocardiograms at Loyola University, Chicago, Illinois, between January 2015 and July 2016.Main outcomes and measuresNext-generation sequencing of 174 cardiovascular disease genes was applied to identify additional modifying gene mutations and correlate genotype-phenotype parameters. Cardiomyocytes derived from human-induced pluripotent stem cells were established and examined to assess the role of MYBPC3Δ25bp.ResultsIn this genotype-phenotype study, individuals of South Asian descent living in the United States from both sexes (36.23% female) with a mean population age of 48.92 years (range, 18-84 years) were recruited. Genetic screening of 2401 US South Asian individuals found an MYBPC3Δ25bpcarrier frequency of 6%. A higher frequency of missense TTN variation was found in MYBPC3Δ25bp carriers compared with noncarriers, identifying distinct genetic backgrounds within the MYBPC3Δ25bp carrier group. Strikingly, 9.6% of MYBPC3Δ25bp carriers also had a novel MYBPC3 variant, D389V. Family studies documented D389V was in tandem on the same allele as MYBPC3Δ25bp, and D389V was only seen in the presence of MYBPC3Δ25bp. In contrast to MYBPC3Δ25bp, MYBPC3Δ25bp/D389V was associated with hyperdynamic left ventricular performance (mean [SEM] left ventricular ejection fraction, 66.7 [0.7%]; left ventricular fractional shortening, 36.6 [0.6%]; P < .03) and stem cell-derived cardiomyocytes exhibited cellular hypertrophy with abnormal Ca2+ transients.Conclusions and relevanceMYBPC3Δ25bp/D389V is associated with hyperdynamic features, which are an early finding in hypertrophic cardiomyopathy and thought to reflect an unfavorable energetic state. These findings support that a subset of MYBPC3Δ25bp carriers, those with D389V, account for the increased risk attributed to MYBPC3Δ25bp.

Dataset Information

Phenotypic expression and clinical outcomes in a South Asian PRKAG2 cardiomyopathy cohort.

Publications

Phenotypic expression and clinical outcomes in a South Asian PRKAG2 cardiomyopathy cohort.

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