Chronic interval exercise training prevents BK_Ca channel-mediated coronary vascular dysfunction in aortic-banded miniswine

Abstract

Conventional treatments have failed to improve the prognosis of heart failure with preserved ejection fraction (HFpEF) patients. Thus, the purpose of this study was to determine the therapeutic efficacy of chronic interval exercise training (IT) on large-conductance Ca-activated K (BK) channel-mediated coronary vascular function in heart failure. We hypothesized that chronic interval exercise training would attenuate pressure overload-induced impairments to coronary BK channel-mediated function. A translational large-animal model with cardiac features of HFpEF was used to test this hypothesis. Specifically, male Yucatan miniswine were divided into three groups ( n = 7/group): control (CON), aortic banded (AB)-heart failure (HF), and AB-interval trained (HF-IT). Coronary blood flow, vascular conductance, and vasodilatory capacity were measured after administration of the BK channel agonist NS-1619 both in vivo and in vitro in the left anterior descending coronary artery and isolated coronary arterioles, respectively. Skeletal muscle citrate synthase activity was decreased and left ventricular brain natriuretic peptide levels increased in HF vs. CON and HF-IT animals. A parallel decrease in NS-1619-dependent coronary vasodilatory reserve in vivo and isolated coronary arteriole vasodilatory responsiveness in vitro were observed in HF animals compared with CON, which was prevented in the HF-IT group. Although exercise training prevented BK channel-mediated coronary vascular dysfunction, it did not change BK channel α-subunit mRNA, protein, or cellular location (i.e., membrane vs. cytoplasm). In conclusion, these results demonstrate the viability of chronic interval exercise training as a therapy for central and peripheral adaptations of experimental heart failure, including BK channel-mediated coronary vascular dysfunction. NEW & NOTEWORTHY Conventional treatments have failed to improve the prognosis of heart failure with preserved ejection fraction (HFpEF) patients. Our findings show that chronic interval exercise training can prevent BK channel-mediated coronary vascular dysfunction in a translational swine model of chronic pressure overload-induced heart failure with relevance to human HFpEF.

Western Diet-Fed, Aortic-Banded Ossabaw Swine

“…Stroke volume (Table 1) and torsion (Supplemental Figure 1D) relative to cardiac remodeling were similar between groups. There was a trend toward increased LV contractility (measured as preload recruitable stroke work, shown by our laboratory and others in AB swine) 20, 23, 24, 40 in the WD-AB group, which was observed in parallel with a decreased stroke volume index (Table 1). Figure 2 outlines the potential contributions of individual cardiomyocyte function to whole heart cardiac dysfunction (representative traces of calcium transients and sarcomere length are presented in Supplemental Figures 2A and 2B).…”

“…A number of previous reports from our laboratory (and others) showed that Ossabaw swine, a unique translational large animal model genetically predisposed to obesity and metabolic derangement, do not develop HF from dietary intervention alone 10, 11, 12, 13, 14, 15, 16, 17. Furthermore, our laboratory previously published numerous studies that examined the impact of aortic banding alone (in the absence of comorbidities) on developing disease in a separate preclinical swine model of HF 18, 19, 20, 21, 22, 23, 24, 25, 26, 27. Thus, the primary goal of this study was to develop a swine model of experimental cardio-metabolic HF.…”

Exercise and Ion-Channel Remodeling in Vascular Smooth Muscle During Hypertension: Therapeutic Implications

“…In exercise-trained rats, the Po of the BK Ca channel is significantly increased without any changes in the unitary conductance [1]. Other studies have suggested that chronic interval exercise training ameliorates the dysfunction of BK Ca channels in the coronary vasculature [56]. Our study [65] showed that the BK Ca β1 subunit and Ca 2+ release from RyRs (ryanodine receptors) increased in cerebral arteries of SHR, with an upregulation of RyRs-BK Ca coupling compared with normotensive rats, while endurance exercise markedly inhibited this increased coupling (Fig.…”

Large Animal Models of Heart Failure

“…Aortic banding was also used to induce chronic pressure overload−induced HF in both 3- and 8-month-old Yucatan miniature swine using a 50- or 70-mm Hg systolic pressure gradient, respectively, placed on the ascending aorta over 6 months (see Figure 1 for surgical visualization) ( 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 ). In this model, classic signs of experimental HF included increased LV brain natriuretic peptide mRNA levels and lung weight.…”