Impaired pulmonary vasomotor control in exercising swine with multiple comorbidities

Abstract

Pulmonary hypertension is common in heart failure with preserved ejection fraction (HFpEF). Here, we tested the hypothesis that comorbidities [diabetes mellitus (DM, streptozotocin), hypercholesterolemia (HC, high-fat diet) and chronic kidney disease (CKD, renal microembolization)] directly impair pulmonary vasomotor control in a DM + HC + CKD swine model. 6 months after induction of DM + HC + CKD, pulmonary arterial pressure was similar in chronically instrumented female DM + HC + CKD (n = 19) and Healthy swine (n = 18). However, cardiac output was lower both at rest and during exercise, implying an elevated pulmonary vascular resistance (PVR) in DM + HC + CKD swine (153 ± 10 vs. 122 ± 9 mmHg∙L−1∙min∙kg). Phosphodiesterase 5 inhibition and endothelin receptor antagonism decreased PVR in DM + HC + CKD (− 12 ± 12 and − 22 ± 7 mmHg∙L−1∙min∙kg) but not in Healthy swine (− 1 ± 12 and 2 ± 14 mmHg∙L−1∙min∙kg), indicating increased vasoconstrictor influences of phosphodiesterase 5 and endothelin. Inhibition of nitric oxide synthase produced pulmonary vasoconstriction that was similar in Healthy and DM + HC + CKD swine, but unmasked a pulmonary vasodilator effect of endothelin receptor antagonism in Healthy (− 56 ± 26 mmHg∙L−1∙min∙kg), whereas it failed to significantly decrease PVR in DM + HC + CKD, indicating loss of nitric oxide mediated inhibition of endothelin in DM + HC + CKD. Scavenging of reactive oxygen species (ROS) had no effect on PVR in either Healthy or DM + HC + CKD swine. Cardiovascular magnetic resonance imaging, under anesthesia, showed no right ventricular changes. Finally, despite an increased contribution of endogenous nitric oxide to vasomotor tone regulation in the systemic vasculature, systemic vascular resistance at rest was higher in DM + HC + CKD compared to Healthy swine (824 ± 41 vs. 698 ± 35 mmHg∙L−1∙min∙kg). ROS scavenging induced systemic vasodilation in DM + HC + CKD, but not Healthy swine. In conclusion, common comorbidities directly alter pulmonary vascular control, by enhanced PDE5 and endothelin-mediated vasoconstrictor influences, well before overt left ventricular backward failure or pulmonary hypertension develop.

Preclinical models of congestive heart failure, advantages, and limitations for application in clinical practice

“…It is increasingly common to identify HF with preserved LVEF, although its etiology, progression and therapeutic targets are largely unknown. In this regard, systemic PO models have been developed in combination with streptozotocin-treated diabetic pigs undergoing renal artery embolization and fed a hypercholesterolemic diet to create a clear model of HF with preserved LVEF and microvascular dysfunction ( van de Wouw et al, 2021 ). More recently, a new model of HF with preserved LVEF has been developed, integrating most of the comorbidities of this pathology, exhibiting sensitivity to obesity, metabolic syndrome, and vascular disease, through a combination of hypercholesterolemic diet and treatment with deoxycorticosterone as a hypertensive agent.…”

Ultra-high field cardiac MRI in large animals and humans for translational cardiovascular research

“…Pig models are an important part of both translational and imaging research., e.g., to assess post-infarction inflammation using fluorine-19 MRI ( 91 ), to understand functional and microstructural changes ( 92 ) or myocardial strain ( 93 ) following acute myocardial infarction, to understand pulmonary vasomotor control and ROS in exercising swine with multiple comorbidities ( 94 ), in resuscitation research ( 12 , 95 ), to better understand imaging contrast such as the influence of myocardial blood flow on T2 ( 96 ), to develop medical devices, and as basis for computational modelling of the heart ( 7 , 97 – 100 ).…”

Identification of Potential Biomarkers for Group I Pulmonary Hypertension Based on Machine Learning and Bioinformatics Analysis

“…Pulmonary vascular remodeling represents an important pathological characteristic of PAH, and it is characterized by endothelial dysfunction, extracellular matrix accumulation, and the proliferation of medium smooth muscle cells (SMCs), resulting in thickened vascular wall as well as enhanced pulmonary vascular resistance. In pulmonary vascular endothelium, oxidative stress is suggested to suppress the activity of endothelial nitric oxide synthase, reduce nitric oxide content in blood vessels, and induce abnormal EC and SMC proliferation, thus accelerating pulmonary vascular remodeling as well as PAH [53]. Iron in the cytoplasm can be transported to mitochondria and catalyzed by the Fenton reaction and the Harber-Weiss pathway leading to ROS generation.…”