Abstract
Purpose: Previous reports have suggested that active exercise aside, intrinsic aerobic running capacity (Low = LCR, high = HCR) in otherwise sedentary animals may influence several cardiovascular health-related indicators. Relative to the HCR phenotype, the LCR phenotype is characterized by decreased endothelial reactivity, increased susceptibility to reperfusion-induced arrhythmias following short, non-infarction ischemia, and increased diet-induced insulin resistance. More broadly, the LCR phenotype has come to be characterized as a “disease prone” model, with the HCRs as “disease resistant.” Whether these effects extend to injury outcomes in an overt infarction or whether the effects are gender specific is not known. This study was designed to determine whether HCR/LCR phenotypic differences would be evident in injury responses to acute myocardial ischemia-reperfusion injury (AIR), measured as infarct size and to determine whether sex differences in infarction size were preserved with phenotypic selection.Methods: Regional myocardial AIR was induced in vivo by either 15 or 30 min ligation of the left anterior descending coronary artery, followed by 2 h of reperfusion. Global ischemia was induced in isolated hearts ex vivo using a Langendorff perfusion system and cessation of perfusion for either 15 or 30 min followed by 2 h of reperfusion. Infarct size was determined using 2, 3, 5–triphenyltetrazolium chloride (TTC) staining, and normalized to area at risk in the regional model, or whole heart in the global model. Portions of the tissue were paraffin embedded for H&E staining and histology analysis.Results: Phenotype dependent differences in infarct size were seen with 15 min occlusion/2 h reperfusion (LCR > HCR, p < 0.05) in both regional and global models. In both models, longer occlusion times (30 min/2 h) produced significantly larger infarctions in both phenotypes, but phenotypic differences were no longer present (LCR vs. HCR, p = n.s.). Sex differences in infarct size were present in each phenotype (LCR male > LCR female, p < 0.05; HCR male > HCR female, p < 0.05 regardless of length of occlusion, or ischemia model.Conclusions: There is cardioprotection afforded by high intrinsic aerobic capacity, but it is not infinite/continuous, and may be overcome with sufficient injury burden. Phenotypic selection based on endurance running capacity preserved sex differences in response to both short and longer term coronary occlusive challenges. Outcomes could not be associated with differences in system characteristics such as circulating inflammatory mediators or autonomic nervous system influences, as similar phenotypic injury patterns were seen in vivo, and in isolated crystalloid perfused heart ex vivo.
Highlights
Enhanced aerobic capacity has been associated with diminished morbidity, improved quality of life, and decrease risk for cardiovascular diseases [1,2,3]
As understanding of the mechanisms involved with tissue injury following arterial occlusion, and subsequent appreciation of additional injury associated with relieving the occlusion advanced [4,5,6], it became clear that periods of intermittent ischemia that either immediately preceded the ischemic event, or immediately preceded the reperfusion event could induce multiple pathways that could limit the extent of injury and improve recovery [4,5,6,7]
Similar results were seen in the global ischemia model (HCR males = 45.7% ± 4.4, low-capacity runners (LCR) males = 49.9% ± 4.7, high-capacity runners (HCR) females = 37.5% ± 3.6, LCR females = 36.6% ± 3.9) (Figure 3)
Summary
Enhanced aerobic capacity has been associated with diminished morbidity, improved quality of life, and decrease risk for cardiovascular diseases [1,2,3]. The most common fatal consequence of coronary artery disease is an acute myocardial infarction, and death due to coronary artery disease appears to decrease with treatments that include an aerobic exercise component [2, 3] It remains unclear whether the benefits of exercise derive primarily from altered risk profiles (lipid, obesity, etc.) or directly from intrinsic myocardial resistance to injury. Pre-and post-conditioning effects were associated with erythropoietin, the heme-oxygenase system, and atrial natriuretic peptide among many others [8,9,10], and those effects could I turn depend on underlying conditions such as diabetes, hyperlipidemia, and estrogen status [8,9,10] Though, both pre-conditioning and post-conditioning have had limited success, due to the inherent challenges of creating controlled, intentional ischemia. Active exercise increasingly has become the option of choice both for reducing the impact of underlying conditions/comorbidities, as well as upregulating processes that could be recruited by pharmacologically and mechanically induced protective strategies [4, 5]
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