A Controlled Septal Ablation for Inoperable Hypertrophic Cardiomyopathy

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Project Summary Hypertrophic cardiomyopathy (HCM) is a genetic disease that results in abnormal thickening of ventricular heart muscle, particularly the septum, causing left ventricular outflow tract (LVOT) obstruction. When medication alone is not sufficient to relieve symptoms, the current gold standard, septal myectomy, is performed to surgically remove excess muscle with an open heart surgery. Unfortunately, many patients are poor surgical candidates and require less invasive treatment options. In these cases, cardiologists treat the patients with a minimally invasive catheterization technique called alcohol septal ablation (ASA), in which 1-4 mL of pure alcohol is injected into the septum via a septal perforator (artery) to destroy part of the septal muscle by triggering necrosis. However, the diffusive nature of pure alcohol causes dangerous uncontrollable necrosis and a very high complication profile for a minimally invasive technique. Risky complications of ASA, with a periprocedural mortality rate of ~2%, include atrioventricular block, ventricular fibrillation/tachycardia, and complete heart block due to lack of control of alcohol localization and indiscriminate tissue destruction. To answer the unmet clinical need, recently cyanoacrylate (super glue) was investigated as a replacement for pure alcohol but experienced challenges in efficacy and long-term safety. To overcome those limitations, our goal is to design a novel ablation system to replace the pure alcohol in ASA and achieve a controllable, localized septal tissue shrinkage and hence a safer ablation. Based on our preliminary data, we hypothesize that the delivery of a collagenase-coated, doxorubicin-loaded, degradable nanoparticles (NPs) will allow for localized doxorubicin-induced destruction of the hypertrophic cardiomyocytes, and this single dosage delivery will lead to regression of the overgrown HCM septal tissue. Doxorubicin was recently found to be responsible for the clearance of unwanted hypertrophic cardiac tissue, and the proposed single dosage delivery can avoid cardiac toxicity often caused by repeat exposure. Three aims will thus be pursued to better understand HCM septal tissue and develop this novel treatment approach: (1) Determine the biomechanical and microstructural abnormalities of human HCM septal tissues and develop a biomimicking in vitro 3D HCM model; (2) Develop a collagenase-coated, doxorubicin- loaded, biodegradable nanoparticle ablation system and optimize the ablation system using the in vitro 3D HCM model; (3) Validate the safety and efficacy of the newly developed ablation system in an HCM mouse model. The proposed research paves a new avenue to improve the safety and efficacy of septal ablation in inoperable HCM patients. The impacts are (i) the innovative concept and design of a controllable, localized ablation to replace the unpredictable, diffusive pure alcohol ablation, and (ii) the promising translational potential. This AREA project will also provide valuable NIH-funded research opportunities to our underrepresented undergraduate students at UT Arlington, a Hispanic-Serving Institute in Northern Texas.