Cardiac failure is a major cause of morbidity and mortality in the US with about 5.7 million affected and resulting in 300,000 deaths each year (NHLBI statistics). Although there are a number of treatments available, prevention and treatment of heart failure remain major clinical problems. Cardiac remodeling, which includes cardiomyocyte hypertrophy, fibrotic responses and changes in function, can be a detrimental pathologic process that leads to cardiac failure. Aldosterone antagonists are a major improvement in heart failure treatment that results in 30% decrease in mortality when added to previously optimized therapy. These beneficial effects have led to recognition of the mineralocorticoid receptor (MR) and aldosterone as major independent cardiovascular disease mediator. Our long-term goal is to understand how inflammatory processes and immune cells subtypes participate in cardiac remodeling and how these processes can be altered therapeutically particularly by MR and other myeloid modifiers. Our recent data show that MR in myeloid cells can act as a """"""""Myeloid Modifier"""""""" altering the phenotype of myeloid cells. Myeloid MR has a critical function in the cardiac inflammatory, hypertrophic and fibrotic response in response to angiotensin II. By understanding the role of MR in these myeloid cells and how the altered myeloid phenotype in myeloid MR knockouts is beneficial, we will be able to define the mechanisms and then be able to manipulate these myeloid cells for further therapeutic benefit. To accomplish these goals, we will 1) determine the precise alterations in the pathophysiology of cardiac remodeling by MR inactivation in physiologic and genetic models of cardiac remodeling. These studies will include the progression and functional evaluation of the disease models. Physiological relevant models include a model for MI (LAD ligation), chronic hypertension (aortic banding), and a genetic model of hypertrophic cardiomyopathy, 2) define the alteration in immune myeloid cells during the remodeling and how they participate in the mechanisms of remodeling. This will also involve further testing of the target immune cell type and alteration of the myeloid phenotype by genetic manipulation. 3) test the hypothesis that other myeloid modifiers can alter remodeling in predicted ways based on their ability to alter the inflammatory phenotypes thus supporting the role of these cells and potentially pointing the way to targets for therapeutic intervention.
Cardiac failure is a major cause of morbidity and mortality in the US with about 5.7 million affected and resulting in 300,000 deaths each year (NHLBI statistics). Although there are a number of treatments available, prevention and treatment of heart failure remain major clinical problems. These studies will determine the role of immune cells in the progression of this disease and potentially lead to new treatments.
