Deborah Paul

Background: Accurate cardiac output (CO) measurements during exercise are essential for the diagnosis of exercise pulmonary hypertension (PH), exercise precapillary PH, and exercise postcapillary PH. The purpose of this study is to compare performance of thermodilution CO to gold‐standard direct Fick CO (dfCO) at rest and exercise. Methods: A single‐center prospective cohort study of patients undergoing invasive cardiopulmonary exercise test over a 3‐year period. For the primary outcome, we predicted CO at each stage of exercise and recovery using generalized additive modeling. In secondary analysis, we assessed mean differences in CO across exercise stages and Bland–Altman analysis at rest and peak exercise. Finally, we assessed the impact in classification of exercise PH, exercise precapillary PH, and exercise postcapillary PH between the 2 CO methods. Results: A total of 302 patients were included. In the primary analysis, the generalized additive model smooth term was significantly different between thermodilution and dfCO ( P P <0.001). Conclusions: There are differences and wide limits of agreement between thermodilution and dfCO both at rest and during exercise. Sequential measurement of thermodilution during exercise with computing of mPAP/CO and PAWP/CO slopes, reduced the clinical impact of the differences in the diagnosis of exercise PH or exercise postcapillary PH.

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by elevated pulmonary arterial pressures that can lead to right heart failure and death. No cure exists for this disease, but therapeutic advancements have extended its median survival from 2 to 7 years. Mechanistic research in PAH has been limited by factors including that a) animal models do not fully recapitulate the disease or provide insights into its pathogenesis, and b) cellular material from PAH patients is primarily obtained from donor lungs during autopsy or transplantation, which reflect end-stage disease. Therefore, there is a need to identify tools that can elucidate the specific mechanisms of human disease in individual patients, a critical step to guide treatment decisions based on specific pathway abnormalities. Here we demonstrate a simple method to isolate and culture circulating endothelial cells (CECs) obtained at the time of right heart catheterization in PAH patients. We tested these CECs using transcriptomics and found that they have typical traits of PAH, including those involving key treatment pathways, i.e. nitric oxide, endothelin, prostacyclin and BMP/activin pathways. CECs show important gene expression changes in other central PAH disease pathways. In summary, we present a new cellular model for the ex-vivo mechanistic evaluation of critical PAH pathways that participate in the pathogenesis of the disease and may help personalized therapeutic decisions.