The Serotonin Transporter in Pulmonary Arterial Hypertension

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DESCRIPTION (provided by applicant): Candidate: Kelly Chin, MD, is an Assistant Professor in Pulmonary and Critical Care at the University of Texas Southwestern Medical Center in Dallas, TX. She seeks support for career development to emerge as an independent investigator in the area of pulmonary arterial hypertension. Environment: Mentorship will be provided by Dr. Milton Packer, an expert in cardiovascular clinical trials, with additional mentorship from Drs. Lewis Rubin, an expert in pulmonary hypertension, and Lance Terada, an expert on cell signaling. Research and Career Development: Dr. Chin proposes two studies that will focus on the role for the serotonin transporter in pulmonary arterial hypertension (PAH). These two studies will test the hypothesis that the serotonin transporter is a key contributor to the development and persistence of elevated pulmonary pressures in patients with pulmonary arterial hypertension (PAH). The first study will be a randomized double-blind placebo controlled trial evaluating whether blockade of the serotonin transporter with fluoxetine, a selective serotonin reuptake inhibitor, will reduce pulmonary vascular resistance in patients with PAH. In her preliminary work involving open label use of fluoxetine, Dr. Chin found that three months treatment led to improvement in cardiac index (p<0.05) and pulmonary vascular resistance (p=NS) compared with baseline. In the proposed clinical trial, 34 patients will be randomized to placebo or fluoxetine for six months. The primary endpoint will be change in pulmonary vascular resistance, and secondary endpoints will include other hemodynamic changes, exercise capacity, quality of life and safety. Dr. Chin's second study will evaluate whether use of stimulants and other medications that act as serotonin transporter substrates is associated with idiopathic PAH. This will be studied using a case-control design with 70 cases and 140 controls, and medication use will be determined by in-person survey. Dr. Chin has previously shown that idiopathic PAH may be associated with use of methamphetamine, a stimulant with serotonin transporter substrate activity. Dr. Chin proposes to supplement this practical training in clinical research with formal coursework in statistics, pharmacology and pulmonary vascular biology. This work addresses several National Heart Lung and Blood Institute strategic objectives, including (1) Improving the understanding of the molecular and physiological basis of health and disease, and (2) Improving the understanding of the clinical mechanisms of disease and thereby enabling better prevention, diagnosis, and treatment.