Dynamic right ventricular-pulmonary arterial uncoupling during maximum incremental exercise in exercise pulmonary hypertension and pulmonary arterial hypertension

Despite recent advances, the prognosis of pulmonary hypertension (PH) remains poor. While the initial insult in PH implicates the pulmonary vasculature, the functional state, exercise capacity, and survival of such patients are closely linked to right ventricular (RV) function. In the current study, we sought to investigate the effects of maximum incremental exercise on the matching of RV contractility and afterload (i.e. right ventricular-pulmonary arterial [RV-PA] coupling) in patients with exercise PH (ePH) and pulmonary arterial hypertension (PAH). End-systolic elastance (Ees), pulmonary arterial elastance (Ea), and RV-PA coupling (Ees/Ea) were determined using single-beat pressure-volume loop analysis in 40 patients that underwent maximum invasive cardiopulmonary exercise testing. Eleven patients had ePH, nine had PAH, and 20 were age-matched controls. During exercise, the impaired exertional contractile reserve in PAH was associated with blunted stroke volume index (SVI) augmentation and reduced peak oxygen consumption (peak VO2 %predicted). Compared to PAH, ePH demonstrated increased RV contractility in response to increasing RV afterload during exercise; however, this was insufficient and resulted in reduced peak RV-PA coupling. The dynamic RV-PA uncoupling in ePH was associated with similarly blunted SVI augmentation and peak VO2 as PAH. In conclusion, dynamic rest-to-peak exercise RV-PA uncoupling during maximum exercise blunts SV increase and reduces exercise capacity in exercise PH and PAH. In ePH, the insufficient increase in RV contractility to compensate for increasing RV afterload during maximum exercise leads to deterioration of RV-PA coupling. These data provide evidence that even in the early stages of PH, RV function is compromised.Open access articleThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Pathogenic Role of mTORC1 and mTORC2 in Pulmonary Hypertension.

Concentric lung vascular wall thickening due to enhanced proliferation of pulmonary arterial smooth muscle cells is an important pathological cause for the elevated pulmonary vascular resistance reported in patients with pulmonary arterial hypertension. We identified a differential role of mammalian target of rapamycin (mTOR) complex 1 and complex 2, two functionally distinct mTOR complexes, in the development of pulmonary hypertension (PH). Inhibition of mTOR complex 1 attenuated the development of PH; however, inhibition of mTOR complex 2 caused spontaneous PH, potentially due to up-regulation of platelet-derived growth factor receptors in pulmonary arterial smooth muscle cells, and compromised the therapeutic effect of the mTOR inhibitors on PH. In addition, we describe a promising therapeutic strategy using combination treatment with the mTOR inhibitors and the platelet-derived growth factor receptor inhibitors on PH and right ventricular hypertrophy. The data from this study provide an important mechanism-based perspective for developing novel therapies for patients with pulmonary arterial hypertension and right heart failure

Treatment With Treprostinil and Metformin Normalizes Hyperglycemia and Improves Cardiac Function in Pulmonary Hypertension Associated With Heart Failure With Preserved Ejection Fraction

Objective: Pulmonary hypertension (PH) due to left heart disease (group 2), especially in the setting of heart failure with preserved ejection fraction (HFpEF), is the most common cause of PH worldwide; however, at present, there is no proven effective therapy available for its treatment. PH-HFpEF is associated with insulin resistance and features of metabolic syndrome. The stable prostacyclin analog, treprostinil, is an effective and widely used Food and Drug Administration-approved drug for the treatment of pulmonary arterial hypertension. While the effect of treprostinil on metabolic syndrome is unknown, a recent study suggests that the prostacyclin analog beraprost can improve glucose intolerance and insulin sensitivity. We sought to evaluate the effectiveness of treprostinil in the treatment of metabolic syndrome-associated PH-HFpEF. Approach and Results: Treprostinil treatment was given to mice with mild metabolic syndrome-associated PH-HFpEF induced by high-fat diet and to SU5416/obese ZSF1 rats, a model created by the treatment of rats with a more profound metabolic syndrome due to double leptin receptor defect (obese ZSF1) with a vascular endothelial growth factor receptor blocker SU5416. In high-fat diet-exposed mice, chronic treatment with treprostinil reduced hyperglycemia and pulmonary hypertension. In SU5416/Obese ZSF1 rats, treprostinil improved hyperglycemia with similar efficacy to that of metformin (a first-line drug for type 2 diabetes mellitus); the glucose-lowering effect of treprostinil was further potentiated by the combined treatment with metformin. Early treatment with treprostinil in SU5416/Obese ZSF1 rats lowered pulmonary pressures, and a late treatment with treprostinil together with metformin improved pulmonary artery acceleration time to ejection time ratio and tricuspid annular plane systolic excursion with AMPK (AMP-activated protein kinase) activation in skeletal muscle and the right ventricle. Conclusions: Our data suggest a potential use of treprostinil as an early treatment for mild metabolic syndrome-associated PH-HFpEF and that combined treatment with treprostinil and metformin may improve hyperglycemia and cardiac function in a more severe disease

Progress in pulmonary hypertension with left heart failure: Beyond new definitions and acronyms

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Hematocrit-corrected pulmonary vascular resistance

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Pulmonary hypertension and chronic mountain sickness.

Chronic mountain sickness is a syndrome of severe symptomatic polycythemia and hypoxemia occurring in natives or long-term high altitude sojourners. The condition may be complicated by pulmonary hypertension in proportion to decreased oxygenation, indicating hypoxic vasoconstriction and remodeling. Exercise in these patients is associated with a steep slope of pulmonary artery pressure-flow relationships and decreased vascular distensibility. Correction of pulmonary vascular resistance for increased hematocrit decreases the severity of pulmonary hypertension. Exercise-induced pulmonary hypertension in chronic mountain sickness does not affect exercise capacity, in relation to high oxygen content of the blood and increased lung diffusing capacity. Right ventricular failure seems to be an uncommon complication of chronic mountain sickness, but the exact prevalence of the condition is not known. Acetazolamide given for 6 months to patients with chronic mountain sickness improves oxygenation, polycythemia, and pulmonary artery pressure.Journal ArticleSCOPUS: ar.jinfo:eu-repo/semantics/publishe

Impedance in isolated mouse lungs for the determination of site of action of vasoactive agents and disease.

Hypoxic pulmonary hypertension is a disease of the lung vasculature that is usually quantified by pulmonary vascular resistance (PVR). However, a more complete description of lung vascular function and right ventricular afterload is provided by pulmonary vascular impedance (PVZ) from spectral analysis of pulsatile pressure-flow relationships. We studied pulsatile pressure-flow relationships in isolated, perfused lungs of mice in normoxia, after induction of hypoxic pulmonary hypertension by 10 days of hypoxic exposure, and after the administration of the vasoactive agents sodium nitroprusside and serotonin in order to gain insight into the effects of disease and vasoactive agents on afterload. Chronic hypoxia exposure increased 0 Hz impedance (Z(0)) from 2.0 +/- 0.2 to 3.3 +/- 0.2 mmHg min/mL but decreased characteristic impedance (Z(C)) from 0.21 +/- 0.02 to 0.18 +/- 0.01 mmHg min/mL (both p < 0.05). Sodium nitroprusside only slightly decreased Z(0) but increased Z(C) in normal lungs (p < 0.05) and did not affect Z(C) and decreased Z(0) in hypertensive lungs (p < 0.05). Serotonin increased Z(C) in normal and hypertensive lungs but decreased Z(0) in hypertensive lungs (p < 0.05). There was an inverse correlation between mean pulmonary artery pressure and Z(C) in all circumstances. These findings demonstrate that vasoactive interventions can have different sites of action (i.e. proximal vs. distal segments) in the normal and chronically hypoxic pulmonary vasculature, and the pressure-dependency of Z(C) and R(W). The measurement of PVZ in isolated lungs allows for an improved understanding of the modes of action of drugs and hypoxia on the pulmonary circulation.Journal ArticleResearch Support, N.I.H. ExtramuralResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe