Novel Stellate Ganglia Chemo-ablation Approach to Treat Cardiac Arrhythmia and Cardiac Remodeling in Heart Failure

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Project Summary Chronic heart failure (CHF) has become epidemic in developed nations accounting for about 6.5 million patients in the US alone. Although the use of β-adrenergic blocking agents, ACE inhibitors and Angiotensin II receptor blockers have been highly effective in slowing the progression of the disease and reducing mortality, there remains an extremely high mortality and morbidity rate for patients diagnosed with CHF. In about half of patients with CHF, complex ventricular arrhythmias, including non-sustained ventricular tachycardia, are present and sudden cardiac death (SCD) is common. Abnormalities and alteration in cardiac sympathetic control of the heart are linked to life threatening arrhythmias, CHF and SCD. Current methods for chemical treatment of sympathetically mediated arrhythmias offer only short-term (i.e., lasting a few hours to one day) effect by temporarily blocking stellate ganglion (SG) neuronal activity with local anesthetics (i.e., SG blockade). Recurrent drug-resistant cardiac arrhythmia patients may be offered surgical stellate ganglionectomy to permanently remove part of the SG. Although this surgery is effective for removing cardiac arrhythmias, it is not the first choice of treatment recommended by cardiologists because of the invasive nature of this procedure. Here, we propose an innovative strategy to chemically ablate the SG function by blocking its surrounding vascular supply, thereby inducing sympathetic neuronal apoptosis and cell death. In our preliminary study, we developed an injectable hydrogel delivery system based on FDA approved biopolymers with encapsulating sunitinib (SU) loaded microspheres. SU is an FDA approved small molecule that has anti-VEGF receptor and other tyrosine kinase activities for patients with neuroendocrine tumors. We demonstrated that SU could be sustained released from our delivery system and the released SU could disrupt the in vitro angiogenesis and in vivo vascular bed after injection into the rat SG. We thus hypothesize that sustained released SU disables the SG function by disrupting its vascular supply and subsequently reverses the CHF-associated cardiac arrhythmia (Aim 1) and regulates cardiac remodeling (Aim 2). This application will use highly integrative techniques to evaluate the therapeutic efficacy of SU loaded delivery system, including novel Rosa-tdTomato flox/flox::Tie2 Cre reporter mouse model, tissue clearance technique, molecular biological techniques and whole animal experiments (in vivo conscious electrocardiogram telemetry recording, cardiac electrical mapping, pressure-volume loop analysis). We believe that this proposed research will lay a solid scientific and technological foundation for developing a new therapy for the patients with CHF and other cardiomyopathy and improve the quality of life of these patients.