Cardiac Presynaptic Sympathetic Nervous Function Evaluated by Cardiac PET in Patients with Chronotropic Incompetence Without Heart Failure

Chronotropic incompetence (CTI), the inability of the heart to increase its rate with increased activity, leads to exercise intolerance and predicts overall mortality. We previously reported that cardiac β-adrenergic receptor downregulation occurs in patients with CTI without heart failure (HF), indicating postsynaptic sympathetic nervous dysfunction. However, cardiac presynaptic sympathetic nervous system function in CTI is not fully understood. Notably, ¹¹C-hydroxyephedrine PET assesses cardiac presynaptic sympathetic nervous system function. Therefore, we investigated cardiac presynaptic sympathetic nervous system function using cardiac ¹¹C-hydroxyephedrine PET in patients with CTI without HF. Methods: We performed cardiac PET in 13 patients with CTI without HF and 9 age-matched healthy controls using ¹¹C-hydroxyephedrine (mean age, 75.1 ± 6.3 y; 59.1% male). The global hydroxyephedrine retention index was determined as myocardial tracer (¹¹C-hydroxyephedrine) activity between 30 and 40 min divided by the activity input integral. CTI was defined as failing to achieve 80% of the heart rate reserve during bicycle ergometer exercise testing. Results: The clinical characteristics, including echocardiographic parameters, did not significantly differ between patients with CTI and controls. Peak heart rate was significantly lower in patients with CTI than in controls (107.0 ± 8.2 vs. 138.4 ± 13.6 beats/min, P < 0.001). The global hydroxyephedrine retention index was significantly higher in patients with CTI than in controls (0.14 ± 0.04 vs. 0.10 ± 0.05 min^-1, P = 0.046). Conclusion: Hydroxyephedrine retention index was significantly higher in patients with CTI without HF than in controls. Our data suggested that impaired norepinephrine release in presynaptic sympathetic nerves contributes to the mechanism of CTI without HF.