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]

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