Cardiac sympathetic denervation mitigated ischemic cardiomyopathy progression in a rat model of sleep apnea.
Aims Ischemic cardiomyopathy with comorbid sleep apnea syndrome (SAS) is associated with worse long-term outcomes. Intermittent hypoxia (IH), a key feature of SAS, exacerbates sympathetic activity, hastening cardiac dysfunction and remodeling in ischemic cardiomyopathy rat models. This study explores whether targeted cardiac sympathetic denervation (CSD) can limit IH-induced progression of ischemic cardiomyopathy.  Methods and results Male Wistar rats underwent myocardial infarction (MI) via permanent left coronary artery ligation, and CSD was simultaneously achieved through ablation of the left middle cervical and stellate ganglions. Rats were exposed to IH (21–5% fraction of inspired O2, 60 s cycle, 8 h/day) or normoxia (N) for 14 weeks starting 3 days post-surgery. Throughout the intervention period, cardiac sympathetic activity was assessed using spectral analysis of heart rate variability (HRV) from vigil ECG collected with a specialized jacket. Cardiac function and remodeling were monitored via echocardiography. Additionally, isolated cardiomyocytes from rats exposed to IH or N for 6 weeks were assessed for calcium transient, sarcomere shortening and adrenergic reserve using isoproterenol stimulation (100 nM). CSD reduced cardiac sympathetic activity and prevented IH-induced blunting of cardiomyocyte response to isoproterenol challenge. In hypoxic animals, CSD reduced alterations in long-term ejection fraction and mitigated cardiomyocyte hypertrophy. Transcriptomic analysis unveiled that CSD triggered biological processes related to cardiac repair and regeneration. Immunohistochemistry further supported these findings, demonstrating increased cardiomyocyte proliferation in the hypoxic group, as indicated by elevated Ki67 expression colocalized with MF20 markers.  Conclusions Our data demonstrate that cardiac sympathetic denervation prevents IH-induced depletion of cardiac adrenergic reserve and deterioration of cardiac function in a rat model of ischemic cardiomyopathy. This study questions the role of sympathetic activity and hypoxia in cardiac regeneration and on the optimal management of sympathetic hyperactivity in ischemic cardiomyopathy in the specific context of associated SAS. Overall design: Male Wistar rats were submitted to myocardial infarction (MI) and cardiac sympathetic denervation (CSD) or sham surgery. After 3-day recovery, rats were randomly exposed to intermittent hypoxia (IH) or normoxia (N) for 14 weeks. Randomization was adjusted to form homogeneous groups based on baseline ejection fraction. Animals were exposed daily to 8 consecutive hours of IH or N during their daytime sleep period. The IH stimulus was performed using a specifically designed device (HypE platform Grenoble), with alternating 30 s of hypoxia (5% fraction of inspired O2 (FiO2)) and 30 s of normoxia (21% FiO2). Normoxic rats were exposed to similar air streams to reproduce equivalent levels of noise and turbulence related to gas circulation. Then, we performed a transcriptomic analysis by RNA-seq on left ventricle heart in the remote area of the infarct.  Groups: Two surgical groups (MI CSD and MI Sham CSD) underwent two exposure conditions (N or HI) : - MI_NOC_NO = Myocardial infarction + Sham CSD + Normoxia (n = 5) - MI_NOC_IH =  Myocardial infarction + Sham CSD + Intermittent Hypoxia (n = 5) - MI_CSD_NO = Myocardial infarction + CSD + Normoxia (n = 5) - MI_CSD_IH =  Myocardial infarction + CSD + Intermittent Hypoxia (n = 5)