Chronic heart failure (CHF) is a growing epidemic in western societies. In the United States alone, approximately 6 million people live with CHF. In late stage CHF, renal failure is a complication that results in worsening heart failure. Patients exhibiting the cardio-renal syndrome have an extremely poor prognosis. Medical therapy for this syndrome has been ineffective. A new way of thinking about the mechanisms responsible for worsening renal function in CHF is necessary. During the previous cycle of this grant we elucidated an important neural pathway that not only mediates cardiac remodeling but also drives a massive increase in cardiac, renal and global sympathetic nerve activity in CHF. Ablation of this pathway markedly improves survival in the post MI-CHF rodent model. The Cardiac Sympathetic Afferent Reflex (CSAR) is mediated, in large part, by epicardial, TRPV1 receptor-expressing sensory endings whose cell bodies reside in the thoracic dorsal root ganglia. Here, we propose to build on our previous work by demonstrating an important role for cardiac spinal afferents in mediating renal dysfunction in severe CHF. Based on our preliminary data and using a novel TRPV1 Cre rat coupled with chemogenetic excitation and inhibition we will demonstrate the important role that these afferents play in the pathogenesis of the cardio-renal syndrome. We will furthermore utilize the ultrapotent neurotoxin resiniferatoxin (RTX; TRPV1 specific) to therapeutically salvage renal function in CHF. These studies are highly relevant to the clinical situation and will pave the way for a novel and innovative alternative to conventional therapy.
Cardiovascular diseases are leading causes of morbidity and mortality worldwide. Kidney failure is a major complication of chronic heart failure. The so-called cardio-renal syndrome is extremely difficult to treat and predicts a poor prognosis. We will study the role of cardiac reflex pathways on the development of the cardio- renal syndrome in a rodent model of heart failure. We will use novel techniques to show that altering cardiac reflex activity is beneficial to the kidney in heart failure These data will be important in developing therapies for reducing cardiovascular and renal morbidity and ultimately mortality.
