Investigating Developmental Differences in Cardiac Physiology
Open Access DepositedImplications for Pediatric and Adult Therapies
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Congenital heart disease (CHD) is the most prevalent congenital disability, affecting approximately 1 out of 10 births worldwide. More than 20% of CHD patients cannot survive without surgical intervention, and subsequent stabilizing agents, including inotropes, must be utilized during the perioperative period and postoperative recovery to increase cardiac output. However, clinical trial data on the pediatric population are extremely limited, and the safety and efficacy of these medications have not been formally studied in this population. Studies suggest the human myocardium undergoes significant developmental adaptations in the perinatal period, however the extent of our knowledge regarding changes in ionic currents, intracellular Ca2+ handling, and contractile function remains limited. Accordingly, it remains unclear how cardiomyocyte maturity may influence inotropic pharmacodynamics. This dissertation investigated the driving factors of postnatal cardiomyocyte maturation, the physiological effects on electrophysiology and contractility, and the impact on myocardial response to inotropic agents. Specifically, Aim 1 identified age-specific differences in drug response on cardiac electrophysiology and excitation-contraction coupling. We utilized a neonatal-juvenile guinea pig model to measure electrophysiology, excitation-contraction coupling, and left ventricular pressure during baseline conditions and following inotropic treatment. Aim 2 investigates the postnatal development of human cardiomyocytes. We utilized human cardiac tissue samples from neonates, infants, and children undergoing corrective heart surgery to identify the timing of developmental transitions in the human myocardium after birth. Lastly, we identified similarities in gene expression profiles between human and guinea pig cardiac tissue samples throughout postnatal development, which will aid in the translation of our animal studies. Collectively, this dissertation provides data on the age- and dose-specific physiological response to inotropes that is influenced by genomic and structural developmental adaptations. Notably, we identify developmental shifts in the expression of genes involved in electrical, mechanical, and calcium signaling. These findings can prompt the implementation of age-specific strategies for pharmacological interventions, improve our understanding of human postnatal cardiomyocyte development, and ultimately lead to informed clinical decisions to improve clinical outcomes for CHD patients.
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