Impact of IH-induced sympathetic hyperactivity and metabolic dysfunctions on ischemic cardiomyopathy progression

Abstract

Patients with obstructive sleep apnea (OSA) exhibit poor prognosis after myocardial infarction (MI). Intermittent hypoxia (IH), the hallmark feature of OSA, promotes sympathetic hyperactivity and systemic insulin resistance, and has been identified as a major contributor to post-MI cardiac remodeling and contractile dysfunction. We hypothesize that sympathetic hyperactivity and metabolic alterations induced by IH promote desensitization of cardiac adrenergic and insulin pathways via activation of G protein-coupled receptors (GRK2), and subsequently participate in the aggravation of ischemic cardiomyopathy. MI is induced in C57bl6 mice by permanent ligation of the left coronary artery (MI). Mice are then randomized to IH (21–5% FiO2, 60 s cycle, 8 h/day) or normoxia for up to 6 weeks. After two weeks, mice are treated with a GRK2 inhibitor, Paroxetine (5 mg/kg/d), or 25% DMSO (Alzet® pumps). Longitudinal follow-up of mice includes evaluation of sympathetic activity (spectral analysis of heart rate variability (HRV), systemic insulin sensitivity (dynamic insulin tolerance test) and determination of cardiac function/remodeling (echocardiography). At the end of the protocol, cardiac interstitial fibrosis and hypertrophy are evaluated by RT-qPCR and histology (Sirius Red and WGA staining, respectively). Assessment of insulin signaling pathway is performed by Western blot. IH induces sympathetic hyperactivity in MI mice, demonstrated by a modification of the sympathovagal balance (LF increase). Paroxetine treatment abolishes the increase in LF in MI-IH condition and restores mRNA expression of β1 and β2 adrenergic receptors. MI-IH induces systemic insulin resistance compared to MI-N condition, which is prevented by Paroxetine treatment. In addition, Paroxetine treatment improves insulin signaling in the liver of MI-IH mice (pIRβ and pAKT). IH exacerbates cardiac interstitial fibrosis and worsens contractile dysfunction in MI mice, resulting in a significant decrease in ejection fraction (19.4 ± 2.1% vs. 29.9 ± 3.6% in IH vs. N respectively, P < 0.05). The effect of paroxetine on cardiac remodeling and function is currently being analyzed. These findings demonstrate that IH induces cardiac sympathetic hyperactivity and insulin resistance, which could contribute to the worsening of ischemic heart disease via GRK2.