Dichloroactate for Pulmonary Hypertension

In health, blood flows freely from the heart through the lungs at low pressure. In a disease called pulmonary arterial hypertension (PAH), the blood vessels are narrow and this causes a back pressure on the heart, leading to premature death from heart failure. Idiopathic pulmonary arterial hypertension (IPAH) has no known cause and typically affects women of child bearing age. The current treatments are unsatisfactory. This project will examine an entirely new approach. It will investigate a drug called dichloroacetate (DCA) that acts by changing energy production in dividing cells. The study will seek early evidence that DCA might reduce the resistance to the passage of blood through the lungs of patients and improve heart function and include specific tests to confirm its mechanism of action. The drug is inexpensive and already available for human use. If the results of this study are encouraging, it will offer a new dimension to the management of IPAH and stimulate a further study in a larger patient population.

Idiopathic pulmonary arterial hypertension (IPAH) is a devastating disease, characterised by increased pulmonary vascular resistance due to structural remodelling of pulmonary arterioles. The current treatment options are few and at best slow the course of the disease; annual mortality remains in excess of 10%. The prevailing view is that novel treatments are needed that are directed at preventing and reversing the proliferative vascular lesions. This project will investigate an entirely novel approach. A characteristic of proliferating cells is aerobic glycolysis, which appears to confer a survival advantage. Dicholoroacetate (DCA), a small molecule inhibitor of pyruvate dehydrogenase kinase, activates pyruvate dehydrogenase and promotes oxidative phosphorylation through entry of pyruvate into the Krebs cycle. Used for many years in the treatment of mitochondrial diseases, it is now undergoing clinical trials in cancer and preclinical data strongly support its clinical evaluation in IPAH. This study will seek evidence that DCA, 25mg/kg bid, reduces pulmonary vascular resistance and improves cardiac function in IPAH patients, together with proof-of-mechanism ? an increase in local tissue glucose oxidation ? and safety. The study is timely, from the view of clinical need, the preclinical data and existing experience with the drug in humans. The assembled investigators have the specific expertise and environment to conduct the study. An experimental medicine design is needed to capture the size of the effect on pulmonary and cardiac haemodynamics and maximise information gain while minimising exposure. It will provide appropriate training for a clinician scientist in experimental medicine and will inform the design of a larger definitive study. DCA is inexpensive and if effective would provide a novel and complementary treatment option for IPAH.