Date of Award
Bachelor of Science (B.S.) in Public Health Studies: Clinical Health Sciences and University Honors
Heart failure -- Etiology, Cardiac arrest -- Genetic aspects, Cardiac arrest -- Young adults -- Pathophysiology
Long-chain 3-Hydroxyacyl CoA Dehydrogenase Deficiency (LCHADD) is an autosomal recessive defect in fatty acid oxidation that presents with hypoketotic hypoglycemia and/or hypertrophic cardiomyopathy in infancy, and recurrent rhabdomyolysis in adolescence, however, sudden cardiac death has not been a previously reported complication of LCHADD. We have conducted a case review study comparing young adult LCHADD patients who have experienced sudden cardiac arrest events (n=5) to similar patients who have not (n=5) for the purpose of evaluating associated cardiac risk factors. We reviewed medical records from ECG tests, hospitalization reports, acylcarnitine, and complete metabolic panels, clinic notes, and autopsy reports. Retrospective chart review has led to no certain etiology however, electrolyte derangements, low free carnitine and elevated total to free carnitine ratio have been noted upon hospitalization in sudden cardiac arrest cases. At the time of the sudden cardiac death event, only one subject was in a metabolic crisis with elevated creatine phosphokinase levels. Life-threatening ventricular arrhythmias appear to be a newly recognized life-threatening complication in the adolescent and young adult age groups of LCHADD patients. The exact mechanism underlying the sudden death events is not understood and there are no current therapies. Understanding the pathophysiology of inherited arrhythmias can be challenging due to the complexity of both the heart and LCHAD deficiency along with the lack of appropriate cellular and in vivo models. Recent advances in human-induced pluripotent stem cell (hiPSC) technology have provided extraordinary progress in understanding the mechanisms in generating human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). Future directions of this study seek to generate LCHAD deficient patient-derived iPSC-CMs in order to assess mitochondrial function, force of contraction, oxygen consumption rates, impacts of analytes, and calcium regulation. In a paper published in the Nature Methods Journal, Burridge and colleagues establish an easily reproducible protocol for the chemically defined generation of human cardiomyocytes (Burridge, Matsa, & Shukla, 2014) from skin fibroblast-derived induced pluripotent stem cells. Our research lab will establish this method which utilizes three crucial components of a chemically defined medium consisting of the basal medium RPMI 1640, L-ascorbic acid 2-phosphate along with recombinant human albumin to generate cardiomyocytes with an immature phenotype. This chemically defined medium will provide reproducible, scalable methods for deriving cardiomyocytes from iPSCs however, they do remain immature in nature and future directions of the study seek to adapt newly engineered maturation protocols. Assessing the disruption of bioenergetics and mitochondrial function in hiPSC-CMs will provide a meaningful in vitro model to examine the potential pathways and biochemical mechanisms that contribute to cardiac arrhythmias observed in affected LCHADD patients who have experienced sudden cardiac death events. Ultimately, clinical trials will be needed to further characterize the pathophysiology of these severe cardiac manifestations in young adult LHCADD populations.
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Saini, Ajesh, "Sudden Cardiac Death in Young Adults with Long-Chain 3-Hydroxyacyl Coa Dehydrogenase Deficiency (LCHADD)" (2020). University Honors Theses. Paper 862.