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Dr. Han-Jun Wang, Professor, Vice Chair of Research

Department of Anesthesiology, University of Nebraska Medical Center

Abstract:

Chronic heart failure (CHF) is a serious and debilitating condition with poor survival rates and an increasing level of prevalence in the aging population. The exaggerated sympatho-excitation that is a hallmark of CHF is a critical factor in the development and progression of the CHF state. The enhanced cardiac spinal afferent reflex (CSAR) critically contributes to the exaggerated global sympathetic tone in CHF. Our previous studies found that chronic ablation of CSAR by epicardial application of a selective afferent neurotoxin, resiniferatoxin (RTX), improves cardiac diastolic dysfunction, cardiac remodeling, venous congestion and renal dysfunction, ultimately enhancing long-term survival in CHF rats. Our recent unpublished findings further suggest that neural inflammation is a key driver of chronic cardiac afferent sensitization. Using a coronary ligation-induced myocardial infarction (MI) rat model, we observed a marked increase in Iba1-positive macrophages and the pro- inflammatory macrophage marker Interferon regulatory factor 8 (IRF8) in thoracic (T1-T4) dorsal root ganglia (DRGs) starting at four weeks post-MI and persisting for at least four weeks. These inflammatory changes were largely prevented by the anti-inflammatory drug minocycline (Mino), significantly depleted by clodronate liposomes and local thoracic epidural delivery of an anti-inflammatory ProGel Dexamethasone. All three treatments attenuated the exaggerated CSAR in CHF rats. These findings highlight neural inflammation as a promising therapeutic target for mitigating cardiac spinal afferent sensitization and improving cardiac function in CHF.