Cardiogenetics, Volume 11, Issue 2 (June 2021) – 5 articles

Background. Each year, approximately 5000 New Zealanders are admitted to hospital with first-time acute coronary syndrome (ACS). The Multi-Ethnic New Zealand Study of Acute Coronary Syndromes (MENZACS) is a prospective longitudinal cohort study embedded within the All New Zealand Acute Coronary Syndrome Quality Improvement (ANZACS-QI) registry in six hospitals. The objective of MENZACS is to examine the relationship between clinical, genomic, and cardiometabolic markers in relation to presentation and outcomes post-ACS. Methods. Patients with first-time ACS are enrolled and study-specific research data is collected alongside the ANZACS-QI registry. The research blood samples are stored for future genetic/biomarker assays. Dietary information is collected with a food frequency questionnaire and information about physical activity, smoking, and stress is also collected via questionnaire. Detailed family history, ancestry, and ethnicity data are recorded on all participants. Results. During the period between 2015 and 2019, there were 2015 patients enrolled. The mean age was 61 years, with 60% of patients aged <65 years and 21% were female. Ethnicity and cardiovascular (CV) risk factor distribution was similar to ANZACS-QI: 13% Māori, 5% Pacific, 5% Indian, and 74% NZ European. In terms of CV risk factors, 56% were ex-/current smokers, 42% had hypertension, and 19% had diabetes. ACS subtype was ST elevation myocardial infarction (STEMI) in 41%, non-ST elevation myocardial infarction (NSTEM) in 54%, and unstable angina in 5%. Ninety-nine percent of MENZACS participants underwent coronary angiography and 90% had revascularization; there were high rates of prescription of secondary prevention medications upon discharge from hospital. Conclusion. MENZACS represents a cohort with optimal contemporary management and will be a significant epidemiological bioresource for the study of environmental and genetic factors contributing to ACS in New Zealand’s multi-ethnic environment. The study will utilise clinical, nutritional, lifestyle, genomic, and biomarker analyses to explore factors influencing the progression of coronary disease and develop risk prediction models for health outcomes. Full article

Genetic variants in MYBPC3 are one of the most common causes of hypertrophic cardiomyopathy (HCM). While variants in MYBPC3 affecting canonical splice site dinucleotides are a well-characterised cause of HCM, only recently has work begun to investigate the pathogenicity of more deeply intronic variants. Here, we present three patients with HCM and intronic splice-affecting MYBPC3 variants and analyse the impact of variants on splicing using in vitro minigene assays. We show that the three variants, a novel c.927-8G>A variant and the previously reported c.1624+4A>T and c.3815-10T>G variants, result in MYBPC3 splicing errors. Analysis of blood-derived patient RNA for the c.3815-10T>G variant revealed only wild type spliced product, indicating that mis-spliced transcripts from the mutant allele are degraded. These data indicate that the c.927-8G>A variant of uncertain significance and likely benign c.3815-10T>G should be reclassified as likely pathogenic. Furthermore, we find shortcomings in commonly applied bioinformatics strategies to prioritise variants impacting MYBPC3 splicing and re-emphasise the need for functional assessment of variants of uncertain significance in diagnostic testing. Full article

Sudden death, especially at a young age, may be caused by an underlying genetic cause. Hereditary conditions with an increased risk of sudden death at a young age include cardiomyopathies, arrhythmia syndromes, and hereditary thoracic aortic aneurysms and dissections. The identification of a genetic cause allows for genetic testing and cardiological surveillance in at-risk relatives. Three sudden death cases from our hospital illustrate the value of autopsy, genetic, and cardiological screening in relatives following a sudden death. On autopsy, histology consistent with hereditary cardiomyopathy is a reason for the referral of relatives. In addition, in the absence of an identifiable cause of death by autopsy in young sudden death patients, arrhythmia syndrome should be considered as a potential genetic cause. Full article

Systems biology is established as an integrative computational analysis methodology with practical and theoretical applications in clinical cardiology. The integration of genetic and molecular components of a disease produces interacting networks, modules and phenotypes with clinical applications in complex cardiovascular entities. With the holistic principle of systems biology, some of the features of complexity and natural progression of cardiac diseases are approached and explained. Two important interrelated holistic concepts of systems biology are described; the emerging field of personalized medicine and the constraint-based thinking with downward causation. Constraints in cardiovascular diseases embrace three scientific fields related to clinical cardiology: biological and medical constraints; constraints due to limitations of current technology; and constraints of general resources for better medical coverage. Systems healthcare and personalized medicine are connected to the related scientific fields of: ethics and legal status; data integration; taxonomic revisions; policy decisions; and organization of human genomic data. Full article

Cardiovascular disorders are the main complication in autosomal dominant polycystic kidney disease (ADPKD). contributing to both morbidity and mortality. This review considers clinical studies unveiling cardiovascular features in patients with ADPKD. Additionally, it focuses on basic science studies addressing the dysfunction of the polycystin proteins located in the cardiovascular system as a contributing factor to cardiovascular abnormalities. In particular, the effects of polycystin proteins’ deficiency on the cardiomyocyte function have been considered. Full article