Chronic Sleep Fragmentation Mimicking Sleep Apnea Does Not Worsen Left-Ventricular Function in Healthy and Heart Failure Mice

Abstract

Aims: Obstructive sleep apnea (OSA) has been associated with heart failure (HF). Sleep fragmentation (SF), one of the main hallmarks of OSA, induces systemic inflammation, oxidative stress and sympathetic activation, hence potentially participating in OSA-induced cardiovascular consequences. However, whether SF per se is deleterious to heart function is unknown. The aim of this study was to non-invasively evaluate the effect of SF mimicking OSA on heart function in healthy mice and in mice with HF. Methods and Results: Forty C57BL/6J male mice were randomized into 4 groups: control sleep (C), sleep fragmentation (SF), isoproterenol-induced heart failure (HF), and mice subjected to both SF+HF. Echocardiography was performed at baseline and after 30 days to evaluate left ventricular end-diastolic (LVEDD) and end-systolic (LVESD) diameters, left ventricular ejection fraction (LVEF) and fraction shortening (FS). The effects of SF and HF on these parameters were assessed by two-way ANOVA. Mice with isoproterenol-induced HF had significant increases in LVEDD and LVESD, as well as a decreases in LVEF and FS (p = 0.013, p = 0.006, p = 0.027, and p = 0.047, respectively). However, no significant effects emerged with SF (p = 0.480, p = 0.542, p = 0.188, and p = 0.289, respectively). Conclusion: Chronic SF mimicking OSA did not induce echocardiographic changes in cardiac structure and function in both healthy and HF mice. Thus, the deleterious cardiac consequences of OSA are likely induced by other perturbations associated with this prevalent condition, or result from interactions with underlying comorbidities in OSA patients.

A Mouse Model Suggests That Heart Failure and Its Common Comorbidity Sleep Fragmentation Have No Synergistic Impacts on the Gut Microbiome

“…To test whether HF and SF showed synergistic effects we designed an experiment (see Materials and Methods) in which four groups ( n = 10) of male mice (the gender where this condition is most common) were subjected for four weeks to each of the following conditions (see Materials and Methods): Heart failure (HF): This condition was induced by continuous infusion of isoproterenol, as previously described [ 18 ]. Sleep fragmentation (SF): SF was induced daily by means of a previously validated device for mice (Lafayette Instruments, Lafayette, IN), based on automated intermittent tactile stimulation.…”

“…In two groups (SF, HF + SF), SF was imposed, and in two groups (HF, HF + SF) heart failure was induced. The animal experiment including the setting of the HF and SF models were approved by the institution ethical committee and has been recently described in detail [ 18 ].…”

“…HF was induced by continuous infusion of isoproterenol [ 18 ]. Briefly, mice were anesthetized by isoflurane inhalation and an osmotic minipump (model 1004, Alzet, Cupertino, CA, USA) was implanted subcutaneously in the flank.…”

“…Sleep arousals were induced by a mechanical near-silent motor with a horizontal bar sweeping just above the cage floor from one side to the other side in the standard mouse laboratory cage. Each sweep was applied in 2-min intervals during the murine sleep period (8 a.m.–8 p.m.) for 28 d (until day 30 from surgery) [ 18 ].…”

The conventional isoproterenol-induced heart failure model does not consistently mimic the diaphragmatic dysfunction observed in patients

“…Second, as we mainly focused on documenting the existence of isoproterenol-induced diaphragm increase in contractile force, we did not focus on involved mechanisms, such as whether force production correlated to Ca+2 handling, or on ultrastructural analysis of the diaphragm fibers. the HF model was evaluated at 30 days of continuous isoproterenol infusion, which is a previously validated method [ 64 ]. Whether further beta-adrenergic stimulation during longer periods of time could lead to greater vulnerability to diaphragm fatigue and secondary dysfunctional contractility (reproducing the effects of chronic beta-stimulation at the heart) is unknown.…”