PacePDE

Despite the tremendous progress made in the prevention, diagnosis, and treatment of cardiovascular (CV) diseases, they continue to cause a large proportion of deaths and disability in Europe, and place a substantial burden on the health care systems and economies of Europe. Numerous epidemiological and clinical studies have revealed a positive correlation between heart rate (HR) and total and CV morbi-mortality. HR at rest is an important predictor of heart failure and coronary heart disease. Data now suggest that HR is a treatable risk factor in patients with CV disease, and not simply a prognostic marker. There is increasing evidence of improved outcomes following the reduction of raised HR. To date, molecules such as ß-blockers and Ca2+ channel antagonists reduce HR but have multiple additional effects on the CV system and their use may be limited by adverse reactions or contraindications. The identification of the cellular and molecular mechanisms specifically involved in the generation and regulation of cardiac automatism, also called pacemaker activity, is fundamental to understanding the role of rhythm in CV diseases. The autonomic nervous system is the major extracardiac determinant of the HR. An increase in cyclic AMP (cAMP) levels following a catecholamine release induces a chronotropic effect. Intracellular cAMP levels result from the balance between its synthesis by adenylyl cyclases and its degradation by phosphodiesterases (PDEs). PDEs represent the only known route for degrading the second messenger uniquely positioning them to provide a key regulatory role. Among the 5 PDE families (PDE1-4 and 8) degrading cAMP in the heart, PDE4 is critical for the regulation of cardiac excitation-contraction coupling in atrial and ventricular myocytes. The PDE4 family is encoded by 4 genes among which 3 are expressed in the heart (pde4a, pde4b and pde4d) and encode for multiple variants. Each PDE4 variant plays a unique and non-overlapping physiological role in the body. However, their respective contribution to the regulation of pacemaker activity remains illdefined. The overall aim of this project is to define the precise role of the distinct PDE4 isoforms in the control of cardiac pacemaker activity. Using genetically engineered mice, as well as a combination of molecular and physiological approaches will allow a unique and global characterization of the functional roles of the various PDE4 isoforms in the sinoatrial node (origin of pacemaker activity) and will refine our view of PDE participation in the regulation of pacemaker activity. The characterization of the PDE4 isoforms specifically involved in the control of cardiac automatism is important for basic science knowledge and has a clinical relevance. Lowering HR represents an important therapeutic approach for the treatment of heart failure and coronary heart disease. Therefore a selective activation of PDE4, whose expression is decreased in heart failure, to lower HR would be a promising strategy to treat numerous cardiac diseases.