Mathai, Stephen C.

Abstract Aims There is a wide spectrum of diseases associated with pulmonary hypertension, pulmonary vascular remodelling, and right ventricular dysfunction. The NIH-sponsored PVDOMICS network seeks to perform comprehensive clinical phenotyping and endophenotyping across these disorders to further evaluate and define pulmonary vascular disease. Methods and results Echocardiography represents the primary non-invasive method to phenotype cardiac anatomy, function, and haemodynamics in these complex patients. However, comprehensive right heart evaluation requires the use of multiple echocardiographic parameters and optimized techniques to ensure optimal image acquisition. The PVDOMICS echo protocol outlines the best practice approach to echo phenotypic assessment of the right heart/pulmonary artery unit. Conclusion Novel workflow processes, methods for quality control, data for feasibility of measurements, and reproducibility of right heart parameters derived from this study provide a benchmark frame of reference. Lessons learned from this protocol will serve as a best practice guide for echocardiographic image acquisition and analysis across the spectrum of right heart/pulmonary vascular disease.

Pulmonary hypertension resulting from chronic lung disease such as chronic obstructive pulmonary disease and interstitial lung disease is categorized by the World Health Organization as Group 3 pulmonary hypertension. To identify the symptoms and impacts of World Health Organization Group 3 pulmonary hypertension and to capture data related to the patient experience of this disease, qualitative research interviews were undertaken with 3 clinical experts and 14 individuals with pulmonary hypertension secondary to chronic obstructive pulmonary disease or interstitial lung disease. Shortness of breath, fatigue, cough, and swelling were the most frequently reported symptoms of pulmonary hypertension due to chronic obstructive pulmonary disease or interstitial lung disease, and shortness of breath was further identified as the single most bothersome symptom for most patients (71.4%). Interview participants also described experiencing a number of impacts related to pulmonary hypertension and pulmonary hypertension symptoms, including limitations in the ability to perform activities of daily living and impacts on physical functioning, family life, and social life as well as emotional impacts, which included frustration, depression, anxiety, isolation, and sadness. Results of these qualitative interviews offer an understanding of the patient experience of pulmonary hypertension due to chronic obstructive pulmonary disease or interstitial lung disease, including insight into the symptoms and impacts that are most important to patients in this population. As such, these results may help guide priorities in clinical treatment and assist researchers in their selection of patient‐reported outcome measures for clinical trials in patients with pulmonary hypertension due to chronic obstructive pulmonary disease or interstitial lung disease.

Abstract Rationale Obesity is associated with pulmonary arterial hypertension (PAH), but its impact on outcomes such as health-related quality of life (HRQoL), hospitalizations, and survival is not well understood. Objectives To assess the effect of obesity on HRQoL, hospitalizations, and survival in patients with PAH. Methods We performed a cohort study of adults with PAH from the Pulmonary Hypertension Association Registry, a prospective multicenter registry. Multivariate linear mixed-effects regression was used to examine the relationship between weight categories and HRQoL using the Short Form-12 and emPHasis-10. We used multivariable negative binomial regression to estimate hospitalization incidence rate ratios (IRRs) and Cox regression to estimate hazard ratios (HRs) for transplant-free survival by weight status. Results A total of 767 subjects were included (mean age of 57 years, 74% female, 33% overweight, and 40% with obesity), with median follow-up duration of 527 days. Overweight patients and patients with obesity had higher baseline emPHasis-10 scores (worse HRQoL), which persisted over time (P < 0.001). Patients who are overweight and obese have a trend toward increased incidence of hospitalizations compared with normal-weight patients (IRR, 1.34; 95% confidence interval [95% CI], 0.94–1.92 and IRR, 1.33; 95% CI 0.93–1.89, respectively). Overweight patients and patients with obesity had lower risk of transplant or death compared with normal-weight patients (HR, 0.45; 95% CI, 0.25–0.80 and HR, 0.39; 95% CI, 0.22–0.70, respectively). Conclusions In a large multicenter, prospective cohort of PAH, patients who were overweight or obese had worse disease-specific HRQoL despite better transplant-free survival compared with normal-weight patients. Future interventions should address the specific needs of these patients.

Abstract Rationale Single-center studies demonstrated that methamphetamine use is associated with pulmonary arterial hypertension (Meth-APAH). We used the Pulmonary Hypertension Association Registry to evaluate the national distribution of Meth-APAH and to compare its impact on patient-reported and clinical outcomes relative to idiopathic PAH. Objectives To determine if patients with Meth-APAH differ from those with idiopathic PAH in demographics, regional distribution in the United States, hemodynamics, health-related quality of life, PAH-specific treatment, and health care use. Methods The Pulmonary Hypertension Association Registry is a U.S.-based prospective cohort of patients new to care at a Pulmonary Hypertension Care Center. The registry collects baseline demographics, clinical parameters, and repeated measures of health-related quality of life, World Health Organization functional class, 6-minute walk distance, therapy, and health care use. Repeated measures of functional class, health-related quality of life, type of therapy, emergency department visits, and hospitalizations were compared using generalized estimating equations. Results Of 541 participants included, 118 had Meth-APAH; 83% of Meth-APAH arose in the western United States. The Meth-APAH group was younger and had a poorer socioeconomic status and lower cardiac index than the idiopathic PAH group, despite no difference in mean pulmonary artery pressure or pulmonary vascular resistance. The Meth-APAH group had a more advanced functional class in longitudinal models (0.22 points greater; 95% confidence interval [CI], 0.07 to 0.37) and worse PAH-specific (emPHasis-10) health-related quality of life (−5.4; 95% CI, −8.1 to −2.8). There was no difference in dual combination therapy; however, participants with Meth-APAH were less likely to be initiated on triple therapy (odds ratio [OR], 0.43; 95% CI, 0.24 to 0.77) or parenteral therapy (OR, 0.10; 95% CI, 0.04 to 0.24). Participants with Meth-APAH were more likely to seek care in the emergency department (incidence rate ratio, 2.30; 95% CI, 1.71 to 3.11) and more likely to be hospitalized (incidence rate ratio, 1.42; 95% CI, 1.10 to 1.83). Conclusions Meth-APAH represents a unique clinical phenotype of PAH, most common in the western United States. It accounts for a notable proportion of PAH in expert centers. Assessment for methamphetamine use is necessary in patients with PAH.

Background: Patients with combined post- and precapillary pulmonary hypertension due to left heart disease have a worse prognosis compared with isolated postcapillary. However, it remains unclear whether increased mortality in combined post- and precapillary pulmonary hypertension is simply a result of higher total right ventricular load. Pulmonary effective arterial elastance (Ea) is a measure of total right ventricular afterload, reflecting both resistive and pulsatile components. We aimed to test whether pulmonary Ea discriminates survivors from nonsurvivors in patients with pulmonary hypertension due to left heart disease and if it does so better than other hemodynamic parameters associated with combined post- and precapillary pulmonary hypertension. Methods and Results: We combined 3 large heart failure patient cohorts (n=1036) from academic hospitals, including patients with pulmonary hypertension due to heart failure with preserved ejection fraction (n=232), reduced ejection fraction (n=335), and a mixed population (n=469). In unadjusted and 2 adjusted models, pulmonary Ea more robustly predicted mortality than pulmonary vascular resistance and the transpulmonary gradient. Along with pulmonary arterial compliance, pulmonary Ea remained predictive of survival in patients with normal pulmonary vascular resistance. The diastolic pulmonary gradient did not predict mortality. In addition, in a subset of patients with echocardiographic data, Ea and pulmonary arterial compliance were better discriminators of right ventricular dysfunction than the other parameters. Conclusions: Pulmonary Ea and pulmonary arterial compliance more consistently predicted mortality than pulmonary vascular resistance or transpulmonary gradient across a spectrum of left heart disease with pulmonary hypertension, including patients with heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, and pulmonary hypertension with a normal pulmonary vascular resistance.

Abstract The Division of Lung Diseases of the NHLBI and the Cardiovascular Medical Education and Research Fund held a workshop to discuss how to leverage the anticipated scientific output from the recently launched “Redefining Pulmonary Hypertension through Pulmonary Vascular Disease Phenomics” (PVDOMICS) program to develop newer approaches to pulmonary vascular disease. PVDOMICS is a collaborative, protocol-driven network to analyze all patient populations with pulmonary hypertension to define novel pulmonary vascular disease (PVD) phenotypes. Stakeholders, including basic, translational, and clinical investigators; clinicians; patient advocacy organizations; regulatory agencies; and pharmaceutical industry experts, joined to discuss the application of precision medicine to PVD clinical trials. Recommendations were generated for discussion of research priorities in line with NHLBI Strategic Vision Goals that include: (1) A national effort, involving all the stakeholders, should seek to coordinate biosamples and biodata from all funded programs to a web-based repository so that information can be shared and correlated with other research projects. Example programs sponsored by NHLBI include PVDOMICS, Pulmonary Hypertension Breakthrough Initiative, the National Biological Sample and Data Repository for PAH, and the National Precision Medicine Initiative. (2) A task force to develop a master clinical trials protocol for PVD to apply precision medicine principles to future clinical trials. Specific features include: (a) adoption of smaller clinical trials that incorporate biomarker-guided enrichment strategies, using adaptive and innovative statistical designs; and (b) development of newer endpoints that reflect well-defined and clinically meaningful changes. (3) Development of updated and systematic variables in imaging, hemodynamic, cellular, genomic, and metabolic tests that will help precisely identify individual and shared features of PVD and serve as the basis of novel phenotypes for therapeutic interventions.

Inhaled treprostinil (Tyvaso) has been shown to be a safe and effective addition to pulmonary arterial hypertension (PAH) oral therapies; however, the respiratory‐related safety profile of inhaled treprostinil required further elucidation in the setting of routine clinical care. The objectives of this study were to characterize respiratory‐related adverse events (AEs) associated with current or recent treatment with inhaled treprostinil and to compare the incidence of respiratory‐related AEs in PAH patients treated with inhaled treprostinil with that in patients treated with other Food and Drug Administration (FDA)–approved PAH therapies. This was a long‐term, prospective, observational study. All respiratory‐related AEs were recorded during the study. The number of PAH patients enrolled was 1,333, 666 treated with inhaled treprostinil and 667 controls (treated with an FDA‐approved PAH therapy other than inhaled treprostinil), for a total of 958 and 1,094 patient‐years of exposure, respectively. In the inhaled‐treprostinil group, 1,281 respiratory‐related AEs were reported in 403 patients (61%), and in the control group, 1,295 respiratory‐related AEs were reported in 388 patients (58%). Cough, throat irritation, nasal discomfort, and hemoptysis were the most common respiratory‐related AEs (occurring in ≥2% of patients in either treatment group) that demonstrated a higher number of events per patient‐year of exposure in the inhaled‐treprostinil group than in the control group (risk ratio [95% confidence interval]: 1.487 [1.172–1.887], 3.777 [2.050–6.956], 2.039 [1.072–3.879], and 1.957 [1.024–3.741], respectively). Overall, inhaled treprostinil was well tolerated by PAH patients in routine clinical care, with respiratory‐related AEs consistent with the known safety profile (trial registration: clinicaltrials.gov identifier: NCT01266265).

Background— Right ventricular failure from increased pulmonary vascular loading is a major cause of morbidity and mortality, yet its modulation by disease remains poorly understood. We tested the hypotheses that, unlike the systemic circulation, pulmonary vascular resistance (R PA ) and compliance (C PA ) are consistently and inversely related regardless of age, pulmonary hypertension, or interstitial fibrosis and that this relation may be changed by elevated pulmonary capillary wedge pressure, augmenting right ventricular pulsatile load. Methods and Results— Several large clinical databases with right heart/pulmonary catheterization data were analyzed to determine the R PA -C PA relationship with pulmonary hypertension, pulmonary fibrosis, patient age, and varying pulmonary capillary wedge pressure. Patients with suspected or documented pulmonary hypertension (n=1009) and normal pulmonary capillary wedge pressure displayed a consistent R PA -C PA hyperbolic (inverse) dependence, C PA =0.564/(0.047+R PA ), with a near-constant resistance-compliance product (0.48±0.17 seconds). In the same patients, the systemic resistance-compliance product was highly variable. Severe pulmonary fibrosis (n=89) did not change the R PA -C PA relation. Increasing patient age led to a very small but statistically significant change in the relation. However, elevation of the pulmonary capillary wedge pressure (n=8142) had a larger impact, significantly lowering C PA for any R PA and negatively correlating with the resistance-compliance product ( P <0.0001). Conclusions— Pulmonary hypertension and pulmonary fibrosis do not significantly change the hyperbolic dependence between R PA and C PA , and patient age has only minimal effects. This fixed relationship helps explain the difficulty of reducing total right ventricular afterload by therapies that have a modest impact on mean R PA . Higher pulmonary capillary wedge pressure appears to enhance net right ventricular afterload by elevating pulsatile, relative to resistive, load and may contribute to right ventricular dysfunction.