Chronic intermittent hypoxia exposure improves left ventricular contractility in transgenic mice with heart failure

Abstract

We previously reported the unexpected finding that 4 wk of exposure to intermittent hypoxia (IH), which simulates the hypoxic stress of obstructive sleep apnea, improved LV cardiac function in healthy, lean C57BL/6J mice. The purpose of the present study was to assess the impact of 4 wk of IH on cardiac function in a transgenic murine model that exhibits a natural history of heart failure. We hypothesized that IH exposure would exacerbate cardiac decompensation in heart failure. Adult male FVB (wild type) and transgenic mice with cardiac overexpression of tumor necrosis factor α (TNF-αTG) at 10-12 wk of age were exposed to 4 wk of IH (nadir inspired oxygen 5-6% at 60 cycles/h for 12 h during light period) or intermittent air (IA) as control. Cardiac function was assessed by echocardiography and pressure-volume loop analyses, and mRNA and protein expression were performed on ventricular homogenates. TNF-αTG mice exposed to IA exhibited impaired LV contractility and increased LV dilation associated with markedly elevated cardiac expression of atrial natriuretic peptide and brain natriuretic peptide compared with wild-type mice. When wild-type FVB mice were exposed to IH, they exhibited increases in arterial pressure and dP/dt(max), consistent with our previous report in C57BL/6J mice. Surprisingly, we found that TNF-αTG mice exposed to IH showed a reduction in end-diastolic volume (38.7 ± 3.8 to 22.2 ± 2.1 ul; P < 0.01) and an increase in ejection fraction (29.4 ± 2.5 to 41.9 ± 3.1%; P < 0.05). In contrast to our previous study in C56Bl/6J mice, neither FVB nor TNF-αTG mice exhibited an upregulation in β-adrenergic expression or cAMP in response to IH exposure. We conclude that 4 wk of exposure to IH in mice induces adaptive responses that improve cardiac function in not only healthy animals but also in animals with underlying heart failure.

Impact of the Phosphatidylinositide 3-Kinase Signaling Pathway on the Cardioprotection Induced by Intermittent Hypoxia

“…Collectively, these effects led to two important hallmarks in cardiovascular protection. First, cardiac function was improved, in qualitative agreement with data obtained in healthy and transgenic (over-expression of tumor necrosis factor α, which induces heart failure) rodent models [23]. Second, cardioprotection was ameliorated as from reduced infarct size after LAD ligature and reduced formation of protein carbonyl groups in response to LAD.…”

Rodent models of sleep apnea

“…The duration of IH was shown to be important in that mice treated with 4 weeks of IH had reduced cardiac damage compared to mice treated for shorter durations. Similarly, a protective effect on left ventricular function has been described in a genetically modified murine model of heart failure when the animals were exposed to four weeks of IH (Naghshin et al, 2012). In summary, there has been heterogeneity in IH studies, with outcomes, in general, affected more by the duration of exposure rather than the hypoxic nadir or the rate of hypoxic cycling.…”

Humans In Hypoxia: A Conspiracy Of Maladaptation?!

“…Apparently, these forms of short-term, low-frequency moderate IH alter the expression of hypoxic-sensitive growth and trophic factors within respiratory motoneurons (3,24,37). These forms of IH treatment have also been shown to improve cardiac function in both healthy and transgenic mice in heart failure (81,82), to protect against myocardial infarction (13), to enhance innate immunity, and to lower blood pressure in hypertensive patients (107), although these latter studies in humans were not placebo controlled. A potential role for reactive oxygen species (ROS) in the response to different forms and severities of IH has been suggested, with low levels of ROS emerging as protective of specific cells, tissues, and organs but higher levels being detrimental (see below) (3,100).…”