Hypoglycosylated Follistatin-Like 1 Attenuates the Loss of Coronary and Cerebral Vascular Functional Capacity in Ossabaw Swine with Cardiometabolic Heart Failure with Reduced Ejection Fraction.

Ischemic heart disease is a leading cause of death, often resulting from heart failure caused by myocardial infarction. Diabetic cardiomyopathy is increasingly problematic clinically, with the combination of metabolic syndrome and chronic inflammation greatly increasing the risk for both coronary and cerebral vascular disease. Follistatin-like 1 (FSTL1) is a protein that, when non-glycosylated, displays regenerative properties including pro-angiogenic effects and prevention of abnormal vascular remodeling. Thus, the objective of the current study was to assess the therapeutic benefit of human recombinant non-glycosylated FSTL1 protein on both coronary and cerebral vascular function in a pre-clinical Ossabaw swine model of myocardial infarction (MI). We hypothesized FSTL1 would attenuate the development of coronary and cerebral vascular dysfunction in an experimental setting of cardiometabolic heart failure with reduced ejection fraction (HFrEF). Intact female Ossabaw swine (2 months old) were fed a Western Diet for 4 months to develop metabolic syndrome. At 6 months of age, animals were subjected to 90 minutes ischemia followed by reperfusion (I/R) to induce MI. One month post-MI, ALZET osmotic pumps were implanted and either vehicle (MI group) or FSTL1 (MI+FSTL1 group) was delivered over two weeks, with terminal vascular experiments performed 2 months post-MI. In vitroassessment of isolated coronary (n=5-6 for infarct, border, and remote regions of the left ventricle; 139.5 ± 4.9 μm diameter) and cerebral (n=2-6 for middle cerebral artery second order pial; 385.3 ± 18.7 μm diameter) arteriole function was examined using pressure myography. Dose response curves for: 1) U46619 (thromboxane A2 agonist); and 2) NS-1619 (large-conductance calcium-activated potassium channel activator; BK ) were conducted. A 2x2 ANOVA (Group X Dose) was used to determine significance at the p < 0.05 level. Cardiometabolic HFrEF was indicated by a combined ejection fraction of 38 ± 2% and a fasting HOMA-IR of 3.8 ± 0.4 (vs. 0.6 ± 0.1 historical control). In coronary arterioles, the NS-1619 induced vasodilatory capacity was increased ~18-fold in MI+FSTL1 animals relative to MI (100 ± 13% vs. 1832 ± 3% in MI and MI+FSTL1, respectively) in the remote region of the heart (interaction effect), but not the infarct nor border regions. In cerebral arterioles, the vasoconstrictor capacity in response to U46619 was increased ~2-fold in MI+FSTL1 relative to MI animals (100 ± 19% vs. 213 ± 25% in MI and MI+FSTL1, respectively; interaction effect). In conclusion, FSTL1 partially attenuates the loss of functional capacity in both coronary and cerebral arterioles, demonstrating its potential to improve vascular function in an experimental setting of cardiometabolic HFrEF.