Abstract 428: Epicardial Application of Resiniferatoxin During Coronary Ligation Prevents Cardiac Remodeling and Improves Cardiovascular Dysfunction in Rats With Heart Failure
Sympatho-excitation is a hallmark of the chronic heart failure (CHF) state and is positively related to the morbidity and prognosis of patients with CHF. Previous studies from this laboratory have shown that the enhanced cardiac sympathetic afferent reflex (CSAR), a sympatho-excitatory reflex originating in the heart, contributes to the elevated sympathetic tone in CHF. Therefore, a therapeutic strategy for abolishing the contribution of the CSAR to this sympatho-excitation may be beneficial in CHF patients. Here, we applied Resiniferatoxin (RTX, 50 μg/ml), an ultra-potent agonist of transient receptor potential vanilloid 1 (TRPV1), to the surface of the rat heart during myocardium infarction (MI) surgery in order to selectively delete the TRPV1 receptor from contributing to activation of the CSAR. This procedure largely abolished the enhanced CSAR in CHF rats (blood pressure change in response to cardiac application of capsaicin and bradykinin (10 μg/ml): capsaicin, 33±2 vs. 5±1 mmHg; bradykinin, 37±3 vs. 11±2 mmHg; CHF+Vehicle vs. CHF+RTX 9-11 weeks after MI). Compared to CHF+Vehicle rats (n=7), there was significantly decreased sympathetic tone (50±6 vs. 22±2 % of Max, P<0.05) and improved baroreflex sensitivity (gain: 2.1±0.1 vs. 3.1±0.3, P<0.05) in CHF+RTX rats (n=9). Importantly, we found that compared to CHF+ Vehicle rats, CHF+RTX rats had normal left ventricular end diastolic pressure (LVEDP: 24±2 vs. 6±1 mmHg, P<0.05) even with similar infarcted size (39±5 vs. 32±2 %) and similar ejection fraction (36±4% vs. 39±2%). Cardiac hypertrophy and lung edma in CHF rats were prevented by RTX treatment. The latter was highly consistent with lowered LVEDP in CHF+RTX rats. Molecular evidence showed that RTX treatment significantly attenuated the left ventricular expressions of the fibrosis marker, smooth muscle actin alpha/GAPDH: (0.77±0.02 vs. 0.55±0.02, n=6, P<0.05). Given that reduced cardiac fibrosis may increase cardiac compliance, this molecular evidence may provide a potential explanation for the lower LVEDP in CHF+RTX rats. In summary, these are the first data to our knowledge to show that selective cardiac sympathetic deafferentation may be a potential clinical therapy for improving cardiac and autonomic function in the CHF state.
- © 2013 by American Heart Association, Inc.