The protective role of sex hormones in females and exercise prehabilitation in males on sternotomy-induced cranial hypoperfusion in aortic banded mini-swine

Abstract

During cardiac surgery, specifically sternotomy, cranial hypoperfusion is linked to cerebral ischemia, increased risk of perioperative watershed stroke, and other neurocognitive complications. The purpose of this study was to retrospectively examine the effect of sex hormones in females and exercise prehabilitation in males on median sternotomy-induced changes in cranial perfusion in a large animal model of heart failure. Cranial blood flow (CBF) before and 10 and 60 min poststernotomy was analyzed in eight groups of Yucatan mini-swine: female control, aortic banded, ovariectomized, and ovariectomized + aortic banded; male control, aortic banded, aortic banded + continuous exercise trained, and aortic banded + interval exercise trained. A median sternotomy decreased cranial perfusion during surgery in all pigs (~24 ± 2% relative to baseline; ≤ 0.05). CBF was 30 ± 7% lower across all time points in all females vs. all males ( ≤ 0.05) and sternotomy decreased cranial perfusion ( ≤ 0.05) independent of sex (females = 34 ± 3% and males = 14 ± 3%) and aortic banding (intact control = 31 ± 5% and intact aortic banded = 31 ± 4%). CBF recovery at 60 min tended to be better in females vs. males (relative to 10 min poststernotomy, females = 23 ± 13% vs. males = -1 ± 5%) and intact aortic banded vs. control pigs (relative to 10 min poststernotomy, aortic banded = 43 ± 20% vs. control = 6 ± 16%; ≤ 0.05) at 60 min poststernotomy. Ovariectomy impaired CBF recovery during cranial reperfusion 60 min following sternotomy (relative to baseline, all intact females = -1 ± 9% vs. all ovariectomized females = -15 ± 4%; ≤ 0.05). Chronic exercise training completely prevented significant sternotomy-induced cranial hypoperfusion independent of aortic banding (sternotomy-induced deficit, all sedentary males = -24 ± 6% vs. all exercise-trained males = -7 ± 3%; ≤ 0.05). Female sex hormones protected against impaired CBF recovery during reperfusion, while chronic exercise training prevented sternotomy-induced cranial hypoperfusion despite cardiac pressure overload. Our findings suggest a median sternotomy may predispose patients, possibly postmenopausal women and sedentary men, to perioperative cerebral ischemia, an increased risk of cardiac surgery-related stroke, and resulting neurocognitive impairments. Specifically, data from this common surgical procedure show: ) median sternotomy independently decreases cranial perfusion;) female sex hormones improve cranial blood flow recovery following sternotomy; and ) exercise prehabilitation prevents sternotomy-induced cranial hypoperfusion. Exercise prehabilitation before cardiac surgery may be advantageous for capable patients.

Western Diet-Fed, Aortic-Banded Ossabaw Swine

“…In the present study, we assessed cardiac reserve at only the cellular level. Our group has a history of using both exercise and dobutamine dose−response protocols in the catheter laboratory to assess cardiac reserve in vivo 22, 23, 24, 25, 27, 111, 112, 113. Although practical considerations (including an extensive focus on the transcriptome) limited our ability to perform these experiments, examination of cardiac reserve in future studies will be important to the continued verification of HF in this model.…”

“…The CON group ingested a standard chow diet (5L80, Lab Diet; 3.03 kcal/g −1 ; carbohydrate: 71%; protein: 18.5%, and fat: 10.5%; 500 g/day), whereas the WD-AB group was fed a WD (1,000 g/day) high in fat, high-fructose corn syrup, and cholesterol (5B4L, Laboratory Diet; 4.14 kcal/g −1 ; carbohydrate: 40.8% [17.8% of total calories from high-fructose corn syrup]; protein: 16.2%; fat: 43%, 2% cholesterol wt/wt) as previously reported 13, 14, 15, 16, 17. At 6 months of age, aortic banding was used to induce HF as previously described 19, 20, 21, 22, 23, 25, 26, 27. A trans-stenotic systolic gradient of approximately 70 mm Hg (72 ± 2 mm Hg) was achieved under anesthesia using phenylephrine (intravenously 1 to 3 μg/kg/min) to maintain a distal peripheral vascular mean aortic pressure of approximately 90 mm Hg (87 ± 2 mm Hg) at a heart rate of 85 beats/min (84 ± 3 beats/min).…”

“…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.…”

Cerebral vs. Cardiovascular Responses to Exercise in Type 2 Diabetic Patients

“…The size of cardiac output is important for regulation of CBF beyond arterial pressure both at rest and during exercise ( Hellstrøm et al, 1994 , 1996 ; Magnusson et al, 1997 ; Ide et al, 1998 , 1999a , b , 2000 ; Gruhn et al, 2001 ; Van Lieshout et al, 2001 ; Ogoh et al, 2005a ; Secher et al, 2008 ; Braz and Fisher, 2016 ). In consequence, an incompetence to increase cardiac output sufficiently during exercise may jeopardize cerebral perfusion and thereby the ability of the central nervous system to recruit and adequately drive the motoneurons.…”

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.…”