Cao Tran, MD, PhD
Awards
Advance-CTR Pilot Projects Program (Cycle 7)
"Targeting mechanotransduction for atrial arythmias in pulmonary hypertension"
Multi-PI: Peter Bronk, PhD
The survival of patients with pulmonary arterial hypertension is confounded by the risk of cardiac arrhythmias which on their own increase the risk of mortality. This study aims to identify the mechanisms behind atrial arrhythmias induced by pulmonary arterial hypertension and identify drug targets to treat those arrhythmias.
Although recent progress in treating pulmonary arterial hypertension (PAH) has reduced mortality of PAH patients, atrial fibrillation is a major complication associated with PAH. Common therapies for atrial fibrillation often exacerbate PAH or are not effective at reducing arrhythmias under PAH conditions. The broad goals of this proposal are to determine the pathway linking PAH conditions to atrial arrhythmias and find target pathways to treat PAH induced atrial arrhythmias.
The hypothesis is that chronic stretch of the right atrium disrupts the mechanotransduction protein complexes at cell-cell and cell-matrix junctions of atrial myocytes resulting in altered expression or localization of key ion channels for action potential kinetics and conduction, leading to atrial arrhythmias.
The specific aims are:
Aim 1) to determine the expression levels of ion channels and mechanotransduction complex proteins in the right atrial tissue of PAH patients with atrial arrhythmias vs. control patients. Echocardiographic and electrocardiographic data from each patient will be used to correlate changes in the expression of these proteins with right atrial size, severity of hypertension, and atrial conduction anomalies.
Aim 2) to determine the functional link between mechanotransduction complex disruption and susceptibility to atrial arrhythmias using a rat model of PAH. Optical mapping of right atria from PAH rats will determine conduction velocity, and action potential parameters vs. control rats. Whole-cell patch clamp of isolated right atrial PAH rat myocytes will determine the ionic mechanisms of arrhythmogenicity seen in atrial tissue. Biochemistry and immunohistochemistry of right atrial PAH rat tissue will determine alteration in mechanotransduction protein complexes and anomalies in tissue and cellular physiology.
Finally, the tyrosine phosphatase inhibitor DPM-1001 will be used to test the concept of stabilizing junctional complexes to prevent structural and electrical remodeling and reduce the incidence of atrial arrhythmias. This project is important to identify new targets in the mechanotransduction pathway for therapies to reduce atrial arrhythmias in PAH patients.