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.
Highlights
Materials and methodsPulmonary vascular disease (PVD) is prevalent in a large proportion of patients with heart failure with preserved ejection fraction (HFpEF); about one out of four patients meet the criteria of overt pulmonary hypertension (PH) in this population (mean pulmonary arterial (PA) pressure > 25 mmHg at rest), which is associated with increased mortality and cardiac hospitalization [31, 32, 60]
Renal dysfunction was present in diabetes mellitus (DM) + HC + chronic kidney disease (CKD) swine reflected by increased creatinine plasma levels and a significantly lower glomerular filtration rate (GFR)
The exercise-induced increase in heart rate was blunted in DM + HC + CKD swine, the relation between heart rate and body oxygen consumption (BVO2) was unaltered compared to Healthy swine (Fig. 1)
Summary
Materials and methodsPulmonary vascular disease (PVD) is prevalent in a large proportion of patients with heart failure with preserved ejection fraction (HFpEF); about one out of four patients meet the criteria of overt pulmonary hypertension (PH) in this population (mean pulmonary arterial (PA) pressure > 25 mmHg at rest), which is associated with increased mortality and cardiac hospitalization [31, 32, 60]. Contrary to the current belief that PH progresses from early post-capillary PH due to elevated left atrial pressures, to combined pre- and postcapillary PH with pulmonary vascular changes, a direct detrimental effect of the systemic pro-inflammatory state on the pulmonary vasculature may be present, suggesting that PVD could develop prior to overt HFpEF-PH in a subgroup of patients. This pro-inflammatory state may induce pulmonary endothelial dysfunction reflected by an imbalance between the influences of the vasoconstrictor endothelin (ET) and the vasodilator nitric oxide (NO) on control of pulmonary vascular tone [41]
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