Differences in intrinsic aerobic capacity alters sensitivity to ischemia-reperfusion injury but not cardioprotective capacity by ischemic preconditioning in rats

Abstract

Introduction Aerobic capacity is a strong predictor of cardiovascular mortality. Whether aerobic capacity influences myocardial ischemia and reperfusion (IR) injury is unknown. Purpose To investigate the impact of intrinsic differences in aerobic capacity and the cardioprotective potential on IR injury. Methods We studied hearts from rats developed by selective breeding for high (HCR) or low (LCR) capacity for treadmill running. The rats were randomized to: (1) control, (2) local ischemic preconditioning (IPC) or (3) remote ischemic preconditioning (RIC) followed by 30 minutes of ischemia and 120 minutes of reperfusion in an isolated perfused heart model. The primary endpoint was infarct size. Secondary endpoints included uptake of labelled glucose, content of selected mitochondrial proteins in skeletal and cardiac muscle, and activation of AMP-activated kinase (AMPK). Results At baseline, running distance was 203±7 m in LCR vs 1905±51 m in HCR rats (p<0.01). Infarct size was significantly lower in LCR than in HCR controls (49±5% vs 68±5%, p = 0.04). IPC reduced infarct size by 47% in LCR (p<0.01) and by 31% in HCR rats (p = 0.01). RIC did not modulate infarct size (LCR: 52±5, p>0.99; HCR: 69±6%, p>0.99, respectively). Phosphorylaion of AMPK did not differ between LCR and HCR controls. IPC did not modulate cardiac phosphorylation of AMPK. Glucose uptake during reperfusion was similar in LCR and HCR rats. IPC increased glucose uptake during reperfusion in LCR animals (p = 0.02). Mitochondrial protein content in skeletal muscle was lower in LCR than in HCR (0.77±0.10 arbitrary units (AU) vs 1.09±0.07 AU, p = 0.02), but not in cardiac muscle. Conclusion Aerobic capacity is associated with altered myocardial sensitivity to IR injury, but the cardioprotective effect of IPC is not. Glucose uptake, AMPK activation immediately prior to ischemia and basal mitochondrial protein content in the heart seem to be of minor importance as underlying mechanisms for the cardioprotective effects.

Augmented Cardiac Mitochondrial Capacity in High Capacity Aerobic Running “Disease-Resistant” Phenotype at Rest Is Lost Following Ischemia Reperfusion

“…We did not have sufficient animals available to complete a preliminary dose response study to determine the optimal cold storage time, and it is possible that despite the cardioplegia, the ischemic time was simply too long and overwhelmed and benefit the HCR phenotype might have conferred. However, the results are consistent with those reported by others working with the model ( 55 , 56 ). Still, there are important differences worth noting.…”

“…Interestingly, the HCR/LCR strains demonstrate many of the same traits related to CVD that had been previously associated with active exercise ( 48 – 52 ) including some mitochondrial/metabolic effects ( 53 , 54 ). Still, cardioprotection in the HCRs is not always observed ( 55 – 57 ), and while LCR did associate with a higher incidence of pump failure, it did not associate with multiorgan system failure in hemorrhagic shock ( 58 ). We have previously reported that cardioprotection in HCRs was present but limited, was likely intrinsic to the tissue, and could be overwhelmed by IR severity ( 57 ).…”

Exercise training and experimental myocardial ischemia and reperfusion: A systematic review and meta-analysis

“…Table 2 presents sample characteristics (size, number of groups and animals per group) and exercise protocol (exercise type and intensity, session duration and frequency, and training and detraining duration). The exercise protocols included forced swimming [15] , [16] , [17] , [18] , resistance exercise [19] , and running training [20] , [21] , [22] , [23] , [24] , [25] , [26] , [27] , [28] , [29] , [30] , [31] , [32] , [33] , [34] , [35] , [36] , [37] , [38] , being some few exercise protocols were voluntary [17] , [39] , [32] . Table 2 also reports the I/R procedures (ischemia and reperfusion duration until sacrifice, and dependent variables evaluated.…”

“…Regarding the infarct size, although it has been measured in 22 studies by various techniques (i.e. echocardiogram, tetrazolium, or risk area by Evans Blue), 20 have shown that exercise led to smaller infarct sizes [15] , [20] , [21] , [22] , [23] , [24] , [25] , [26] , [27] , [29] , [28] , [34] , [35] , [36] , [37] , [38] , [32] , [31] and only two studies did not report differences between exercised versus non-exercised animals [16] , [19] . Heart-to-body weight index was accessed by 13 studies, of which 12 articles reported increased in this indication of cardiac hypertrophy [17] , [18] , [20] , [23] , [27] , [36] , [38] , [29] , [30] , [31] .…”

“…Cardiac function parameters also were significantly improved in exercised groups reported by the selected studies. Left ventricular systolic and diastolic pressures as well as positive and negative pressure derivatives were increased by exercise in 8 of the 9 studies that evaluated ventricular hemodynamics [16] , [19] , [21] , [24] , [25] , [30] , [36] ; and ejection fraction was improved in 5 of the 6 studies that performed transthoracic echocardiography [17] , [21] , [26] , [27] , [32] indicating functional benefits of physical exercise in I/R. When arrhythmias were evaluated as an outcome (6 studies), all authors reported reduction on the post-I/R arrhythmias [22] , [31] , [32] , [33] , [34] , [38] .…”