Original ArticleNeural mechanism of angiotensin-converting enzyme inhibitors in improving heart rate variability and sleep disturbance after myocardial infarction
Introduction
Cardiovascular disease is the most common cause of death worldwide, contributing to an estimated 17.3 million (31.5%) out of 54 million total deaths [1]. Heart rate variability (HRV) evaluates an autonomic nervous system by analyzes variations of RR intervals. It is an easy, non-invasive, and cost-effective method [2], [3]. The HRV spectrum is comprised of low frequency (LF) and high frequency (HF) components. The LF component represents cardiac sympathetic and parasympathetic activity, the HF component represents parasympathetic activity; and the LF/HF ratio represents cardiac sympathetic activity. In a previous study, an increase in the LF/HF ratio was observed using HRV spectrum analysis in post-myocardial infarction (MI) patients [4], [5].
Furthermore, a previous study showed that 20% of MI and 15% of all sudden cardiac deaths occur at night which might be related to changes in the autonomic nervous system [6]. In a previous report, 50–66% of patients with MI also experienced sleep apnea [7]. Sleep apnea can be classified as either obstructive sleep apnea (OSA) or central sleep apnea (CSA). OSA is caused by obstructions of the upper airway. In CSA, breathing is either diminished or stopped during sleep. However, the underlying mechanism for CSA is still unclear. Currently, the CSA event and its relationship with cardiac autonomic activity has never been evaluated in post MI subjects.
Angiotensin-converting enzyme (ACE) inhibitors are recommended for post-MI patients to reduce infarct size, morbidity, and mortality [8]. Walsh et al., found that captopril may improve breathing abnormalities during sleep and sleep quality in patients with heart failure [9], however the mechanisms underlying the action of captopril are unclear. Captopril is a drug commonly used for treating MI, and the study by Stead et al. found that it could significantly decrease sympathetic response in rabbits with hypotension [10]. In previous studies, ACE inhibitors were shown to reduce sympathetic and enhance parasympathetic activities in patients with heart failure [11], [12]. In our previous study, we found significant sleep fragmentations with sympathetic hyperactivity during QS stages after MI [5]. Therefore, we hypothesized that ACE inhibitors could improve sleep quality by reducing sympathetic activity in MI rats.
Section snippets
Animal preparation
The experiments were carried out on adult male Wistar-Kyoto (WKY) rats (8–10 weeks old). The rats were obtained from BioLASCO (Taiwan Co., Ltd). The present study protocol was reviewed and approved by the Institutional Animal Care and Committee of Taipei Veterans General Hospital (IACUC number: 2015-007), and the investigation was conducted in accordance with the US National Institute of Health's Guide for the Care and Use of Laboratory Animals. In regards to investigator blinding, the
Baseline characteristics
A total of 31 rats were studied in this experiment, including 14 sham rats and 17 MI rats. Six sham and eight MI rats died during surgery. Therefore, eight sham rats were used in group 1, before and after treatment with captopril. Nine MI rats were used in group 2, before and after treatment with captopril.
HRV analysis
In the HRV analysis, we found that the LF/HF ratio significantly increased in MI rats before treatment with captopril during sleep compared to that in sham rats. The LF/HF ratio was
Main findings
In this experiment, we found that: (1) captopril treatment can ameliorate sympathetic hyperactivity after MI, especially at the QS stage; (2) attenuation of sympathetic hyperactivity and increased parasympathetic activity improved the sleep quality in MI rats; and (3) CSA events developed after MI, and captopril treatment can restore this phenomenon possibly through amelioration of sympathetic hyperactivity. These findings suggest that MI impairs sleep quality and increases both CSA and
Study limitation
Our study had some limitations. First, polysomnography is needed in human clinical sleep studies. In our study, we recorded EEG, dorsal neck EMG, ECG, and diaphragm EMG (respiratory effort) via implanted electrodes in rats. Unfortunately, electrooculogram, air flow, and blood oxygen saturation cannot be recorded in freely moving animals because of technological limitations.
Second, we used the sham group as the control group to evaluate autonomic activity. We did not record in normal rats with
Conclusion
In this study, we found that captopril treatment can ameliorate sympathetic hyperactivity after MI, especially at the QS stage. Attenuation of sympathetic hyperactivity and increased parasympathetic activity improved the sleep quality in MI rats. CSA events developed after MI, and captopril treatment can restore this phenomenon, possibly by the amelioration of sympathetic hyperactivity. These findings suggest that MI impairs sleep quality and increases both CSA and arrhythmia episodes, which
Funding sources
The present work was supported by the Taipei Veterans General Hospital (V102B-002, V102E7-003, V103C-042, V103C-126, V103E7-002, VGHUST103-G1-3-1, V104C-131, V104E7-003, V105C-60, V106C-114, V107C-099, VGHUST107-G1-8-1), Ministry of Science and Technology (NSC 101-2911-I-008-001, NSC 102-2325-B-010-005, MOST 103-2314-B-075-062-MY3, MOST 104-2314-B-075-065-MY2, MOST 106-2314-B-010-054), and Research Foundation of Cardiovascular Medicine (RFCM 100-02-011, 101-01-001, 104-01-009-01).
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