BME Seminar Series: Madison Nowak & Kevin Blum, PhD Students

Madison Nowak: 

"Age-associated ion channel localization and expression changes regulate cardiac sodium gain-of-function"

Action potentials in the heart are initiated by sodium (Na⁺) ion influx via voltage-gated Na⁺ channels.  Na⁺ channel gain-of-function (GoF) mutations associated with the long QT type-3 (LQT3) syndrome can produce a late Na⁺ current, triggering pro-arrhythmic early after-depolarizations (EADs) that prolong the action potential duration (APD). Recently, we showed that preferential localization of Na+ channels at the intercalated disk and narrow intercellular clefts suppress EADs and APD prolongation in LQT3-associated models (Nowak, et al., Biophysical J, 2020). Clinically, LQT3-associated arrhythmias can present early in life but often do not manifest until adulthood, suggesting that the disease phenotype can be “concealed.”  We hypothesize that subcellular, cellular, and tissue changes associated with development can predict disease manifestation. We performed simulations to predict EAD regulation by key cellular and tissue properties that vary with age, specifically cell size, gap junctional coupling, and Na⁺ channel localization and density.  Models predict that age-associated increases of total Na⁺ current conductance, mediated by both increases in cell size and Na+ channel density, is a critical factor governing APD prolongation and EAD formation. Simulations predict normal APD (i.e., comparable to wild-type) for nominal parameters associated with neonatal and early development stages, but variability in cellular properties can lead to EAD formation for these early stages, consistent with the variability in symptom manifestation for LQT3 patients. In contrast, nominal adult parameters consistently predict the formation of EADs, which are suppressed by narrow cleft width. Our work predicts that intercellular cleft Na⁺ is a key regulator of cardiac arrhythmias in LQT3 that is modulated by complex interactions of age-associated factors.

Kevin Blum: 

"Translational Tissue Engineering for Congenital Heart Disease"

Tissue engineered vascular grafts (TEVGs) hold promise for the surgical treatment of congenital heart disease by the creation of vascular conduits made of the patient’s own cells. In a clinical trial evaluating our TEVG as an extracardiac Fontan procedure, several patients developed asymptomatic stenosis within the TEVG, leading to a halting of the clinical trial. Following these unexpected outcomes, we employed a computational-experimental approach to evaluate neotissue formation in the TEVG utilizing small and large animal models. Our small animal models demonstrated that the immune system, in particular macrophages, are critical to the development of neotissue, but must be held in a careful balance to prevent over- or under- development of neotissue. Computational modeling results showed that, unexpectedly, the stenosis in our clinical trial was not only mathematically predicted, but was also predicted to self-resolve without treatment. This finding was corroborated by our large animal models, which demonstrated spontaneous reversal of stenosis over six months. We then take this work further, using the large animal model to evaluate the long term remodeling of the TEVG into a neovessel. Our results, coupled with continued mathematical modeling, demonstrate that neotissue formation and remodeling are driven by inflammatory and mechanobiological processes which drive the development of a neovessel that demonstrates native-like architecture, biological function, and biological growth capacity.