In a significant discovery, a team of clinicians and basic science researchers at Brigham and Women’s Hospital (BWH) identified molecules responsible for the metabolic underpinnings of pulmonary hypertension (PH) and confirmed their hypothesis in a patient with previously undiagnosed exercise-induced PH.
“Currently, therapy for pulmonary hypertension is used to extend survival and palliate symptoms, with most of the focus at the end stages of disease,” said Stephen Y. Chan, MD, PhD, lead author of the study. “But, very little is known about the initiating molecular triggers for this disease. We believe that discoveries in this regard would constitute a major advance in our goals to design more effective methods to alter or prevent PH.”
For nearly a decade, BWH researchers have been investigating the complex molecular mechanisms related to hypoxic or ischemic injury of pulmonary and peripheral blood vessels. As a post-doctoral fellow working with Joseph Loscalzo, MD, PhD, Chairman of the Department of Medicine at BWH, Dr. Chan initially identified the hypoxia-induced microRNA-210 (miR-210) as a critical regulator of iron-sulfur cluster formation, mitochondrial metabolism, and acute cellular survival in the hypoxic pulmonary vasculature (Cell Metabolism. 10 (4); 273-84, 2009).
Using a variety of methods ranging from computational biology, biophysics, molecular biology, and in vivo physiology, the team established that miR-210 decreases expression of its target gene ISCU, which is critical to the production of iron-sulfur clusters. These clusters are essential for normal mitochondrial function and metabolism. In preclinical models, this metabolic shift results in vascular proliferation, remodeling, and the catastrophic consequences of PH (EMBO Molecular Medicine (2015) emmm.201404511).
To apply the theory in a study subject, Dr. Chan, Aaron B. Waxman, MD, PhD, Director of the Pulmonary Vascular Disease Program, David M. Systrom, MD, and others in the Heart & Vascular Center at BWH collaborated to study a 29-year-old Norwegian woman with known homozygous intronic ISCU mutations.
At rest, echocardiography showed normal right ventricular function and size. Pulmonary arterial catheterization revealed normal right and left heart filling pressure but with a mean pulmonary arterial pressure at the upper limits of normal (mPAP of 21 mmHg). Advanced cardiopulmonary exercise testing performed in the catheterization laboratory at BWH, however, revealed exertional dyspnea and abnormally increased pulmonary vascular resistance (PVR) during exercise (maximum PVR at exercise = 135 dynes s/cm5), accompanied by elevated mean pulmonary arterial pressure (maximal mPAP = 31 mmHg). Importantly, the patient’s symptoms improved significantly when she was placed on the PDE5 inhibitor tadalafil.
Improvement of 6-min walk test (6 MWT) in an ISCU mut/mut individual after initiation of pulmonary vasodilator therapy (PDE5 inhibitor)
“This is the first known observation of pulmonary vascular dysfunction in a person with ISCU deficiency,” said Dr. Chan. “This case helps to establish a definitive connection between ISCU and PH.”
The findings also highlight the potential of designing new therapeutic approaches to treat PH that focus on ISCU proteins, miR-210, and other genes known to be directly linked to iron-sulfur production. Dr. Chan and his colleagues are currently collaborating with companies that manufacture pharmacologic agents that inhibit microRNAs.
“There is still a lot of work to be done, but we feel that these findings represent a major advance in our ongoing efforts to fight this disease,” said Dr. Waxman.
The Pulmonary Vascular Disease Program at BWH, led by Aaron B. Waxman, MD, PhD, provides highly-specialized, multidisciplinary evaluation and care for patients with complex pulmonary vascular conditions, including unexplained dyspnea, pulmonary arterial hypertension, and pulmonary hypertension associated with heart disease, COPD, chronic thromboembolic disease, liver disease, and other conditions.
For more information, or to refer a patient to our Pulmonary Vascular Disease Program, please call our HVC Navigation Center access line at (857) 307-4000.
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