Tonelli, Adriano R.

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 Patients with chronic thromboembolic pulmonary disease (CTEPD) without resting pulmonary hypertension (PH) frequently experience dyspnea which is not explained by stationary assessment and therefore requires cardiopulmonary exercise testing for further diagnostic insight. Ventilatory inefficiency in CTEPD is commonly identified; however, consensus definitions are lacking. Upright iCPET and careful definition of ventilatory inefficiency (i.e., lack of reduction in VD/VT with exercise) may allow optimal characterization of patients with chronic thromboembolic disease and specifically helps correctly identify patients with preload insufficiency who may otherwise be misclassified or undiagnosed.

Abstract Background Patients with pulmonary hypertension due to interstitial lung disease (PH-ILD) have worse exercise capacity and survival than ILD patients without PH. Vasoreactivity with inhaled nitric oxide (NO) provides prognostic and therapeutic implications in pulmonary arterial hypertension, but little is known about its value in PH-ILD. We evaluated the pulmonary hemodynamic changes following inhaled NO and their association with outcomes in PH-ILD. Methods We measured pulmonary hemodynamics in patients with PH-ILD who underwent inhaled NO administration during right heart catheterization. We recorded baseline clinical, echocardiographic, and pulmonary function testing measures, and investigated the use of inhaled treprostinil as well as the rate of hospitalization, death, and lung transplantation. Results In 120 patients (age 67 ± 11 years, 62% women), the administration of inhaled NO resulted in a median (IQR) decrease in mean pulmonary artery pressure (mPAP) of −3 (−5, −1) mmHg, P < 0.001, and pulmonary vascular resistance (PVR) of −0.8 (−1.8, −0.2) wood units (WU), P < 0.001. The % change in mPAP and PVR were −6.3 (−10.9, −1.8) % and −16.8 (−27.3, −3.3) %, respectively. Factors associated with the % drop in PVR included baseline PVR (r = 0.30, P < 0.001), cardiac output (r = −0.19, P = 0.04), and WHO functional class (r = 0.25, P = 0.01). The median (IQR) follow-up was 14.5 (7, 25) months. During this time, 40 (33%) patients died, 8 (7%) underwent lung transplantation, and 76 (63%) experienced either hospitalization due to respiratory failure, transplantation, or death. The % drop in mPAP and PVR during inhalation of NO had no significant impact on these outcomes and was not associated with clinical response to inhaled treprostinil measured by changes in six-minute walk distance (6MWD) and forced vital capacity (FVC). Conclusion Inhaled NO caused a modest reduction in mPAP and PVR in patients with PH-ILD, but the acute hemodynamic response to inhaled NO was not associated with outcomes or response to inhaled treprostinil therapy.

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.

Purpose: New 2022 European Society of Cardiology/European Respiratory Society PAH guidelines recommend treatment guided by a multi-parameter risk assessment. 1 Patients with low/intermediate risk without cardiopulmonary comorbidities should start dual PAH combination therapy; those with cardiopulmonary comorbidities should be reassessed early for rapid escalation to dual therapy. Initial triple therapy is recommended for high-risk patients. We examined use of dual and triple PAH therapy in the US (before guideline update). Methods: We used the Pulmonary Hypertension Association Registry (PHAR), a prospective US registry of pulmonary hypertension (PH) patients, enrolled within 6 months of their first outpatient visit at one of 54 participating PH care centers in the US, between Sep 2015-Jun 2022. We included adults (≥18 years at enrollment) with incident PAH (newly diagnosed and treated within 6 months of enrollment) and ≥1 follow-up clinic visit post baseline visit. Chronic thromboembolic PH patients were excluded. Results: We analyzed (descriptive statistics) 794 incident patients (baseline characteristics in Table 1). Treatment patterns at baseline (n=794)/last follow-up visit (n=610) were 289 (36.4%)/102 (16.7%) on monotherapy, 419 (52.8%)/314 (51.5%) on dual combination, 83 (10.5%)/179 (29.3%) on triple combination therapy, respectively. Mean time from enrollment to dual and triple combination therapy was 86.1 (standard deviation [SD]: 209.0) and 346.1 days (SD: 430.8), respectively. Conclusions: Among incident PHAR patients, half received initial dual and 10% triple upfront combination therapy. At last follow-up, most (>80%) patients had escalated to dual/triple combination therapies. Clinical Implications: At PH care centers, most incident PHAR patients are escalated to dual and triple therapy (at last follow-up) per current guidelines. Reference 1. Humbert M, et al. Eur Heart J. 2022;43:3618-731.

Background. Postcapillary pulmonary hypertension (PH) can be seen in cirrhosis. Research and treatment goals exist for patients with portopulmonary hypertension but not for postcapillary PH. The aim of this study was to investigate outcomes after liver transplant (LT) for patients with postcapillary PH. Methods. This was a retrospective cohort study of 1173 patients who underwent LT at our center between 2010 and 2020. Using a propensity score matched analysis followed by multivariable Cox modeling on matched patients, we compared post-LT survival between patients with and without postcapillary PH. We also compared several post-LT outcomes between patient with different types of PH. Results. Sixty-eight patients had PH, and 50 had postcapillary PH. The median age was 59 y and the sample was 54% male. There was no significant difference in mortality between patients with postcapillary PH and patients without PH (hazard ratio, 1.72; 95% confidence interval, 0.90-3.31; P = 0.10). There was no significant difference in survival between patients with any type of PH and those without PH. There was no significance difference in post-LT survival, acute kidney injury, or pulmonary edema between patients with different types of PH. Patients with postcapillary PH who survived had a higher cardiac output than those who died (11 L/min in patients who lived, as compared with 8 L/min in patients who died; P = 0.03). Conclusions. Postcapillary PH does not appear to convey a negative impact on post-LT survival. A higher cardiac output may be protective against mortality in patients with postcapillary PH.

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.