An Innovative Therapeutic Approach to Treat Cardiomyopathy

This application addresses the topic area of Cardiomyopathy. Cardiovascular diseases are the leading cause of death in the United States and the incidence of cardiomyopathies are rising. As many as 1 in 500 adults may have cardiomyopathy, and is a leading cause of heart failure, with cost of care in the Veterans Affairs system exceeding $3.5 billion. Cardiomyopathies can be broadly classified into two groups, acquired and inherited. This reflects the varied initiating events for cardiomyopathy. Acquired cardiomyopathies refer to primary effects outside to the heart itself; a common cause is chronic high blood pressure (hypertension). Inherited cardiomyopathies are typically initiated by a mutated gene encoding a protein that functions within the heart. Regardless of the origin of the cardiomyopathy, it results in damage to the muscle tone of the heart and reduces its ability to pump blood to the rest of the body. A major goal of this proposal targets a novel mechanism that safely increases the ability of the heart to circulate blood. Thus, a major long-term benefit of successful completion of the proposed studies is the establishment of a new, effective broad-spectrum treatment for the diseased heart. Our laboratory discovered that a key molecule called Rad dynamically controls the activity of a class of proteins called calcium channels. Calcium channels are present in a wide variety of tissues. The core function of calcium channels is to open in response to an electrical stimulus to allow calcium ions to pass into the interior of a cell. In the heart calcium channels play key roles in contributing to electrical function of the heart (visible as the signal on an electrocardiogram), and in contributing to the force of contraction of the heart. The stronger the heart contracts, the more blood can be distributed into the lungs and oxygenated blood away from the heart to the rest of the body. During exercise, in battle, in any stressful situation our hearts adapt to an increased need for more activity by pumping more blood. The key transmitter for this response is commonly referred to as adrenaline, and the physiological response is colloquially called the ‘fight or flight’ response. To increase cardiac output, calcium channels become more active. We discovered that the protein Rad interacts within the calcium channel to limit activity. When we genetically eliminate Rad from the heart, there is a profound increase of calcium current, heart force production, and cardiac output. These findings suggest that a major physiological function of Rad is to mediate the ‘fight or flight’ response. A major shortcoming in the field is our absence of knowledge of which specific proteins Rad interacts with. In our proposed work we will determine Rad protein partners and we will determine how Rad itself is modified by ‘fight or flight’ signaling. A key research tool that we developed that motivates this proposal is a genetically modified animal that allows us to delete the Rad gene in only the muscle tissue of the heart (myocardium). Within 7 days of deleting myocardial Rad we discovered that heart function dramatically increased and in pilot studies we discovered that Rad-deleted animals show enhanced heart function into old age. When we experimentally imposed an equivalent of chronic high blood pressure to these animals, we discovered that Rad-deleted prevented the usual onset of pathological heart failure. These exciting findings motivated the present proposal. We will now use a spectrum of heart disease models to test our idea that deleting Rad can treat heart disease – specifically some of the most common cardiomyopathies such as that stimulated by chronic high blood pressure (hypertension) and resulting from stretching and thinning of the pumping chambers of the heart (dilated cardiomyopathy). The work is divided into two complementary aims. The first aim will establish a system to permit development of Rad-reduction therapeutics. The second aim will identify patient populations that stand to gain the most from Rad-reduction therapy. We envision that at the completion of these studies we can move from laboratory experiments to the development and application of new drugs to treat Veterans and the general population from the degradation in quality of life and premature death caused by cardiomyopathy