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A3748 - Biomarkers of Inflammation and Metabolic Stress in a Bovine Model of Pulmonary Hypertension with Left Ventricular Fibrosis and Pulmonary Venous Remodeling
Author Block: G. M. Krafsur1, R. Brown2, T. N. Holt3, D. H. Gould4, F. Garry3, S. Riddle5, J. Neary6, M. Enns7, M. Thomas7, K. R. Stenmark8; 1Cardiopulmonary Research and Lung Developmental Biology, UC Denver Anschutz School of Medicine, Aurora, CO, United States, 2Ped Crit Care Med, UC Denver Anschutz School of Medicine, Aurora, CO, United States, 3Livestock Medicine, CSU College of Veterinary Medicine and Biomedical Sciences, Fort Collins, CO, United States, 4Microbiology, Immunology and Pathology, CSU College of Veterinary Medicine and Biomedical Sciences, Fort Collins, CO, United States, 5UC Denver Anschutz School of Medicine, Aurora, CO, United States, 6Animal and Food Sciences, Texas Tech University, Lubbock, TX, United States, 7Animal Sciences, Colorado State University, Fort Collins, CO, United States, 8Univ of Colorado Denver, Aurora, CO, United States.
Introduction: Overweight and obese Americans bear the burden of chronic illness relating to metabolic syndrome, predisposing them to cardiovascular diseases, including pulmonary hypertension and left heart disease (WHO Group 2 PH). Similarly, genetic manipulation of modern beef cattle, combined with high intensity fattening programs intended to enhance production and carcass traits, have resulted in historic slaughter and carcass weights, often with inadvertent consequences on animal health and welfare. Our group has shown an unfavorable relationship between growth, adiposity and hemodynamic parameters during the fattening phase of the production cycle, suggesting that fattening beef cattle are at risk for development of PH secondary to LV dysfunction. We hypothesized that biomarkers of inflammation and metabolic stress in susceptible individuals would be elevated during fattening. Methods: Sequential right heart catheterizations and blood collections (3 total) to measure mean pulmonary arterial pressure (mPAP) and blood-based biomarkers were performed on Angus steers (N=50) at weaning (CSU-Beef Improvement Center, Rouse Angus Ranch; Encampment, WY, 2,150 m), and during fattening with a high energy corn-based ration at a low altitude feedlot (Eastern Colorado Research Center, Akron, CO, 1,400 m). We identified PH-susceptible versus PH-resistant animal phenotypes (N=10 each). The final mPAP was measured 3 weeks before slaughter together with arterial and venous (A-V) blood gas determinations. Target cardiopulmonary tissues were collected at slaughter (age 20 mos) for histomorphologic analysis. Results: Growth was unfavorably related to mPAP, as we confirmed the greatest increase in mPAP occurred late in the fattening phase, not during early life as typically occurs with cattle exposed to environmental hypoxia. Plasma IL-6 expression was significantly greater in steers exhibiting fattening-induced PH, in the absence of clinical illness. Serum uric acid was not statistically different between PH-susceptible versus resistant steers early in the production cycle, however uric acid concentration was significantly higher in hypertensive animals during the fattening phase. Hypertensive steers had notable LV fibrosis, pulmonary venous remodeling, predictable pulmonary arterial remodeling and adaptive RV hypertrophy. Conspicuous mononuclear infiltration of the epicardial and perivascular adipose tissues surrounding mural branches of the coronary and main pulmonary artery with consequential perivascular fibrosis was observed. Conclusions: Fattening beef cattle provide a natural large animal model for human obesity-related cardiovascular diseases and PH, leading to discovery of novel blood biomarkers facilitating early diagnosis and therapies for WHO Group 2 patients. Inflammatory activation may initiate metabolic stress, worsen cardiopulmonary remodeling and PH in fattening beef cattle.