Myocardial infarction and mechanisms of impaired sleep and breathing

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SUMMARY Impaired sleep and breathing has multiple systemic and organ-specific effects including inflammation, sympathetic activation and heightened metabolic and cardiovascular risk. Recently, attention has focused on the relationship between cardiac events and disrupted sleep and breathing; sleep disordered breathing is associated with poor cardiac outcomes, and cardiac disease has, in turn, been identified as a possible cause of sleep disordered breathing and fragmentation of sleep. We propose that poor sleep quality may affect primary outcomes after myocardial infarction (MI), and contribute to a feedforward mechanism leading to subsequent cardiac events and worse outcomes. We have developed murine models to examine the relationship between experimentally-induced MI and impaired sleep and breathing in both the presence and absence of obesity, a major co-morbidity in cardiovascular disease. Our preliminary studies demonstrate that two days of sleep fragmentation in healthy lean mice induces a pro-inflammatory state in the heart and significantly increases cardiac dysfunction and mortality to subsequent MI. Conversely, in mice with MI there are marked sleep disturbances, primarily characterized by (1) a striking increase in total NREM sleep time in the dark/active period, simulating `daytime sleepiness' in humans and (2) a marked increase in arousal frequency, predominantly in the light period of consolidated sleep, simulating fractured, poor sleep quality in humans. Associated with these changes in sleep after MI, we observed an increase in cytokine expression in the hypothalamus that was dependent on intact cardiac sympathetic pathways. We, will use state-of-the-art physiologic techniques to investigate the relationship between sleep disruption and MI and mechanistically examine the role of cardiac neural and pro-inflammatory pathways in lean and obese mice. Aim 1 will examine the effect of prior sleep disruption on worsening MI outcomes and Aims 2-4 will examine the effect of MI on subsequent sleep and breathing disruption and the development of a feedforward mechanism further worsening MI outcomes. Our aims are: Aim 1: To determine the impact of prior sleep fragmentation and the role of cardiac sympathetic pathways and obesity on cardiac function and mortality after MI. Aim 2: To determine the role of MI-mediated breathing instability on the development of sleep fragmentation and `daytime sleepiness.' Aim 3: To determine the role of cardiac afferent sympathetic pathways in fragmenting sleep and increasing `daytime sleepiness' after MI. Aim 4: To determine the role of activation of CNS cytokines in increasing `daytime sleepiness' after MI. This study will provide insights into the relationship between dysfunctional sleep and breathing and cardiac pathology using discrete interventions to define mechanistic pathways that are not possible in clinical studies. Moreover, our long-term goal is to translate our findings back to the clinical arena and improve outcomes and therapeutic options in this vulnerable population.