Tonelli, Adriano

Background The current classification of pulmonary hypertension (PH), based largely on expert opinion, has limitations in prognostication and guiding therapies. We hypothesize that novel PH clusters that predict survival will reveal mechanistic phenotypes associated with biomarkers of vascular health across all PH groups. Methods We first identify novel PH clinical clusters by performing unsupervised clustering analysis on the CC‐PH (Cleveland Clinic PH) registry (N=1529). We develop classification models to predict the new PH clusters and then apply them to the multicenter PVDOMICS (Pulmonary Vascular Diseases Phenomics) cohort (N=853) for validation. We compare transplantation‐free survival across the new PH clusters. We quantify metabolites of the arginine‐nitric oxide pathway and D‐dimer levels and calculate global arginine bioavailability (arginine/[ornithine+citrulline]) to assess endothelial function and activation in the new clusters and link these biomarkers to clinical outcomes. Results Clustering analysis identify 3 clear clusters in CC ‐ PH that are validated in PVDOMICS and outperform conventional classifications in predicting transplantation‐free survival. The phenotype associated with the worst survival is characterized by reduced lung diffusion capacity, decreased arginine bioavailability and nitrate levels, and elevated D‐dimer levels, consistent with loss of pulmonary microcirculation and endothelial dysfunction. Conclusions We identify new informative PH phenotypes associated with mortality and defined by biomarkers of endothelial function and activation. Loss of endothelial health and pronounced pulmonary vascular rarefication contribute more substantially to mortality across the spectrum of PH than right heart function. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02980887.

Abstract Pulmonary hypertension is a complex and irreversible pulmonary vascular disease with a significant impact on patients’ lives. Pulmonary hypertension is categorized into five groups according to its etiology. Frailty is a multifaceted disorder that leads to physical, social, cognitive, and psychological decline. Several studies have linked a high occurrence of frailty to heart failure and chronic lung diseases, but the prevalence and impact of frailty in pulmonary arterial hypertension (PAH) remain largely unexplored. At the molecular level, inflammation, oxidative stress, cellular senescence, and mitochondrial dysfunction play pivotal roles in the pathophysiology of frailty in pulmonary hypertension. Dysfunction of cardiac, respiratory, and skeletal muscles results in exercise intolerance, which promotes deconditioning and frailty. Exercise training in PAH, heart failure, and chronic lung disease has shown promise in improving quality of life, exertion tolerance, and frailty scores. Properly designed studies are needed to elucidate the predictive value of frailty and to identify assessment and treatment tools in pulmonary hypertension, particularly PAH, to aid clinicians in individualizing care plans and improving patient outcomes. In this narrative review, we describe the pathobiology of frailty in pulmonary hypertension, assessment tools, the impact of frailty on different pulmonary hypertension groups, and suggestions for potential interventions.

Abstract Rationale Current guidelines recognize the utility of provocative maneuvers during right heart catheterization to aid the diagnosis of pulmonary hypertension. Few studies have compared the performance of different provocation maneuvers. Objectives To assess the hemodynamic correlation among three provocative maneuvers, including their effect on pulmonary hypertension classification. Methods This prospective trial was conducted between October 2016 and May 2018. Adult patients underwent three provocative maneuvers during right heart catheterization: passive leg raise (PLR), load-targeted supine bicycle exercise, and rapid crystalloid fluid infusion. Patients were classified as follows: no pulmonary hypertension, precapillary pulmonary hypertension, isolated postcapillary pulmonary hypertension, combined pre- and postcapillary pulmonary hypertension, and uncategorized pulmonary hypertension. We assessed the hemodynamic changes associated with each maneuver. We also assessed whether provocative maneuvers led to hemodynamic reclassification of the patient to either postcapillary pulmonary hypertension with provocation or exercise pulmonary hypertension. Results Eighty-five patients (mean age 62 ± 12 years, 53% women) were included. Correlation between exercise and fluid challenge was moderate to strong (0.49–0.82; P < 0.001) for changes in right atrial pressure, mean pulmonary arterial pressure, pulmonary arterial wedge pressure, and cardiac index from baseline. Correlation between PLR and exercise (0.4–0.65; P < 0.001) and between PLR and fluid challenge (0.45–0.6; P < 0.001) was moderate for changes in right atrial pressure, mean pulmonary arterial pressure, pulmonary arterial wedge pressure, pulmonary vascular resistance, and cardiac index. Hemodynamic correlation between other provocative maneuvers was poor. Depending on provocative maneuver and classification criteria, there was significant variation in the number of patients reclassified as having exercise pulmonary hypertension (3–50%) or postcapillary pulmonary hypertension with provocation (11–48%). Conclusions Hemodynamic determinations during exercise and fluid challenge showed moderate to strong hemodynamic correlation. Moderate hemodynamic correlation was seen between PLR and exercise or fluid challenge. Although some provocative maneuvers demonstrate good hemodynamic correlation, there is inconsistency when using these maneuvers to identify patients with postcapillary or exercise pulmonary hypertension.

Portopulmonary hypertension (PoPH) is a form of pulmonary arterial hypertension (PAH) that can develop as a complication of portal hypertension. Treatment of PoPH includes PAH‐specific therapies, and in certain cases, such therapies are necessary to facilitate a successful liver transplantation. A significant number of barriers may limit the adequate treatment of patients with PoPH and explain the poorer survival of these patients when compared to patients with other types of PAH. Until recently, only one randomized controlled trial has included PoPH patients, and the majority of treatment data have been derived from relatively small observational studies. In the present article, we review some of the barriers in the treatment of patients with PoPH and implications for liver transplantation.