Introduction
Autonomic dysfunction—driven by excessive afferent signaling including peripheral chemoreceptors and diminished inhibitory efferent tone—substantially contributes to cardiovascular morbidity. Current therapies do not address afferent hyperactivity, leaving a large subset of heart failure (HF) patients inadequately treated despite optimized medical and device management. Up to 40–50% of chronic HF patients (HFrEF and HFpEF) display increased chemosensitivity, which independently predicts adverse outcomes and associates with autonomic imbalance and central sleep apnea. We tested the hypothesis that pharmacologic inhibition of peripheral chemoreceptors using a T‑type calcium channel blocker (T‑type CCB) would normalize chemoreflex sensitivity and improve cardiac dysfunction in an ischemic HF rat model.
Methods
Chemoreflex function was measured in anesthetized adult Sprague Dawley rats by recording ventilatory responses to hypoxia (8% oxygen) using an esophageal catheter to capture breathing rate. To quantify the increase in breathing rate following hypoxia, the Area under the breathing rate curve (AUC) was calculated over 2 min hypoxia. A selective T‑type CCB was administered orally three hours prior to measurement to determine dose‑dependent effects on the hypoxic ventilatory response. To assess therapeutic relevance, efficacy of the T‑type CCB was evaluated in a myocardial infarction (MI) rat model of chronic left-anterior-descending artery (LAD) ligation with assessment of cardiac structure and function with echocardiography and invasive left ventricular catheterization.
Results
Application of 8% hypoxia to rats resulted in immediate increase in breathing rate that was quantified as Area under the breathing rate curve. Ventilatory response to hypoxia was significantly attenuated in a dose-dependent manner by oral pre-treatment with T‑type CCB, consistent with suppression of peripheral chemoreflex sensitivity: Placebo 7660 ± 1322, 0.3 mg/kg 7117 ± 1711, 1mg/kg 5574 ± 1656 (p<0.05), 3 mg/kg 5417 ± 769 (p<0.05).
In the MI‑induced rat HF model, chronic T‑type CCB treatment showed hemodynamically beneficial effects: Systolic and diastolic arterial pressure remained unchanged at all applied doses while heart rate decreased in a dose‑dependent manner (Placebo 353.2 ± 30.2 bpm; 1 mg/kg 361.3 ± 21.4 bpm; 6 mg/kg 326.3 ± 25.2 bpm, p<0.01; 12 mg/kg 307.0 ± 22.8 bpm, p<0.001)
Left ventricular cardiac function improved or trended favorably: left ventricular ejection fraction significantly increased (Placebo 45.4 ± 8.9 %; 1 mg/kg 50.3 ± 7.2 %; 6 mg/kg 51.9 ± 7.6%, p<0.01; 12 mg/kg 54.5 ± 6.9%, p<0.001), left atrial (LA) enlargement was reduced (Placebo 32.5 ± 10.8 mm2; 1 mg/kg 24.3± 6.5 3 mm2, p<0.05; 6 mg/kg 23.8± 4.3 mm2, p<0.01; 12 mg/kg 23.0 ± 3.9 mm2, p<0.001), indicative of less backward failure, and left ventricular end‑diastolic pressure showed a non-significant downward trend with increasing doses of T-Type CCB.
Conclusion
These preclinical data demonstrate that T‑type calcium channel blockade inhibits peripheral chemoreflex activity and is associated with improved cardiac function in a post‑MI rat heart failure model without adverse effects on systemic arterial pressure. The findings support further translational evaluation of T‑type calcium channel blockade as a novel strategy to target chemoreflex hypersensitivity in HF.
