Pulmonary vascular disease in swine with multiple comorbidities

Abstract

IntroductionDiabetes mellitus (DM), chronic kidney disease (CKD) and hypercholesterolemia are common co‐morbidities associated with low‐grade inflammation and endothelial dysfunction leading to increased systemic vascular resistance, diastolic dysfunction and exercise intolerance. Diastolic dysfunction is a risk factor for development of post‐capillary pulmonary hypertension (PH), which, in a subgroup of patients, deteriorates into combined pre‐and post‐capillary PH. This process is characterized by an increase in pulmonary vascular resistance (PVR) due to pulmonary vascular dysfunction and remodeling. It is incompletely understood which factors predispose to the development of combined pre‐and post‐capillary PH. We hypothesize that comorbidities cause pulmonary endothelial dysfunction, which in turn initiates pulmonary vascular remodeling, increases PVR and further reduces exercise tolerance.ObjectiveTo investigate the contribution of endothelial dysfunction, characterized by perturbances in the nitric oxide (NO)‐cGMP‐phosphodiesterase 5 (PDE5) pathway, to changes in PVR at rest and during exercise in a swine model with multiple co‐morbidities.MethodsDM (streptozotocin 3×50mg/kg iv) and CKD (renal embolization) were induced in 6 female swine fed a high fat diet (DM+HFD+CKD), while 8 female healthy swine on normal diet served as controls (CON). Six months later, swine were chronically instrumented and hemodynamics were studied at rest and during exercise, in the absence and presence of eNOS‐inhibition (LNNA, 20 mg/kg iv) and PDE5‐inhibition (sildenafil, 100 mg iv).ResultsDM+HFD+CKD swine exhibited hyperglycemia (18.7±1.9 vs 7.5±0.6mmol/L), hypercholesterolemia (7.3±0.7 vs 1.7±0.1mmol/l), renal dysfunction (glomerular filtration rate: 123±12 vs 202±8 ml/min), and inflammation (TNF‐α 51.6±5.1 vs 24.6±5.5pg/ml, all P<0.05).DM+HFD+CKD swine had similar pulmonary arterial pressures at rest and during exercise compared to CON swine, while cardiac index was significantly reduced, reflecting the higher PVR in DM+HFD+CKD. DM+HFD+CKD swine showed a similar increase in PVR in response to eNOS‐inhibition compared to CON swine at rest and during exercise. However, PDE5 inhibition resulted in a significant reduction in PVR, reflecting pulmonary vasodilation in CON, but not in DM+HFD+CKD swine. Altogether, these data suggest that impaired PDE5‐activity acts to preserve the vasodilator effect of endogenous NO in DM+HFD+CKD.ConclusionsExposure to multiple co‐morbidities in a swine model causes an increase in inflammatory factors, which is accompanied by a reduced activity in the NO‐pathway, that is counterbalanced by reduction in PDE5‐activity in swine with DM+HFD+CKD. Hence, exposure to co‐morbidities causes pulmonary endothelial dysfunction and an increase in PVR, even in the absence of overt PH. Thus, pulmonary vascular disease might be an underestimated contributing factor in the disease progress in patients with multiple co‐morbidities and diastolic dysfunction.Support or Funding InformationFunding: CVON‐RECONNECTThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.