Targeting Acid-Sensing Ion Channel 3 in a Mouse Model of Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM) resulting from sarcomere gene mutations is the most prevalent genetic heart disorder, affecting approximately 1 in 500 individuals. HCM is marked by progressive myocardial hypertrophy, myocardial fibrosis, focal ischemia, myofiber disarray, and an elevated susceptibility to arrhythmias and sudden cardiac death. Human studies demonstrate a selective increase in cardiac norepinephrine signaling in HCM, and our lab has previously demonstrated that the cardiac spinal afferent reflex is sensitized in an alpha tropomyosin mutant mouse model of HCM. Acid-sensing ion channel 3 (ASIC3) is prominently expressed on cardiac spinal afferent nerves, yet its function and expression in HCM is unknown. We hypothesize that augmented activity and/or expression of ASIC3 on cardiac spinal afferents contributes to the increased cardiac sympathetic drive in HCM mice. We measured maximum systolic left ventricular pressure (MSLVP), dP/dt max, and heart rate (HR), in response to a single IV bolus infusion of the selective ASIC3 blocker, APETx2, in anesthetized (isoflurane 2% in O2) male and female HCM (n=12) and WT (n=11) mice. Statistical comparisons were performed with t-tests and results are expressed as mean±SE. As expected, baseline MSLVP (HCM 64.4±1.6 vs. WT 89.5±2.0 mmHg), dP/dt max (HCM 5910±179 vs. WT 7777±295 mmHg/s), and HR (HCM 409±8 vs. WT 522±5 beats/min) were significantly (p<0.05) lower in HCM mice compared to WT. Contrary to our hypothesis, bolus infusion of APETx2 resulted in a similar attenuation of MSLVP (HCM Δ-11.3±1.4 vs. WT Δ-12.0±2.7 mmHg; p=0.40), and dP/dt max (HCM Δ-1092±98 vs. WT Δ-1367±189 mmHg/s; p=0.10) in both HCM and WT mice. In contrast, consistent with our hypothesis, the fall in HR in response to APETx2 was significantly (p<0.05) greater in HCM (Δ-55.2±7.6 beats/min) compared to WT (Δ-33.9±7.6 beats/min) mice. Next, we utilized western blot to measure ASIC3 protein expression in LV tissue from HCM and littermate wild-type (WT) mice (n=4 male mice in each group). LV ASIC3 protein expression was standardized to neuronal content with PGP9.5. ASIC3 protein expression tended to be higher in HCM (HCM 130±13% vs. WT 100±12%; p=0.06) yet did not reach statistical significance. In conclusion, blocking ASIC3 channel function with APETx2 resulted in a greater fall in HR in HCM mice compared to WT suggesting that expression of ASIC3 may contribute to the selective increase in sympathetic drive to the heart in HCM. We speculate that differential chronotropic responses to APETx2 could be due to regional differences in ASIC3 expression in HCM mice. Funding: Michigan Technological University Health Research Institute This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.