Grant: Project Grant

Each and every heartbeat is initiated by a natural pacemaker in our hearts called the sinoatrial node. Normal sinus node function leads to proper activation of the atria (the upper chambers of the heart). This sequence of events ensures that heart rate is normal and that the heart is properly able to pump blood to our bodies. Common forms of cardiovascular disease, including hypertension (high blood pressure) result in serious damage to the sinoatrial node and the atria leading to arrhythmias (irregular, abnormal patterns in the heartbeat) such as sinoatrial node arrhythmias and atrial fibrillation. Although sinoatrial node disease and atrial fibrillation are very common in hypertension very little is known about why this happens our how they can be treated. Currently, people with sinoatrial node disease have to get an artificial pacemaker, which is costly and has a number of limitations. Similarly, current atrial fibrillation treatments are often not effective. My laboratory has developed substantial expertise in the study of sinoatrial node disease and atrial fibrillation including at the cellular and molecular level. We have discovered that a hormone, called C-type natriuretic peptide (CNP), can protect against sinoatrial node disease and atrial fibrillation in mouse models of hypertension. We have also discovered that an enzyme called phosphodiesterase 9 constrains the effects of CNP and that PDE9 inhibition can enhance the protective effects of CNP in the sinoatrial node and atria. Our proposed experiments will build on these novel discoveries and determine how CNP and phosphodiesterase 9 can each be used or targeted to treat or prevent the development of sinoatrial node disease and atrial fibrillation in hypertension. Our ultimate goal is to use this information to generate new therapeutic approaches to enhance the beneficial effects of CNP in the heart.