Nadine Al-Naamani

Pulmonary arterial hypertension (PAH) was historically viewed as a disease of young adults; however, emerging evidence suggests rising prevalence in the elderly, which is an insufficiently characterized population. We evaluated clinical and sociodemographic features of PAH patients over 80 years and compared their outcomes with younger patients. We performed a prospective cohort study utilizing the Pulmonary Hypertension Association Registry to compare clinical characteristics, functional capacity, and quality of life measures between octogenarians (≥ 80 years) and non‐octogenarians (< 80 years) at enrollment and follow‐up visits. Associations between age subgroups and outcomes were assessed using linear, binomial, and Cox regression. The cohort comprised 113 octogenarians and 3,094 non‐octogenarians with PAH. Smoking history was more common in octogenarians, who also more frequently had idiopathic or connective tissue disease–related PAH. Octogenarians had lower right atrial pressure and mean pulmonary artery pressure ( p < 0.001) than younger patients. At baseline, octogenarians had a lower absolute 6‐min walk distance and higher World Health Organization functional class ( p < 0.001). Octogenarians were more often initially treated with monotherapy and less likely to receive a prostacyclin analog. Octogenarians had a 57% higher risk of all‐cause hospitalization and twice the mortality of younger adults after covariate adjustment (IRR 1.57, 95%CI 1.06–2.33, p < 0.05 and HR 2.38, 95%CI 1.62–3.52, p = 0.001, respectively). The oldest PAH patients exhibit distinct clinical profiles, therapies, and outcomes compared to younger adults, though it remains uncertain whether these differences reflect a unique phenotype, reduced therapy response, or the cumulative effects of aging and comorbid conditions.

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.

Patients with chronic liver disease commonly have abnormal lung function; however, the impact of smoking on outcomes in these patients is unknown. We hypothesized current or past smoking would be associated with worse survival in patients with advanced liver disease. The Pulmonary Vascular Complications in Liver Disease Study 2 (PVCLD2) was a prospective cohort of patients with advanced liver disease undergoing evaluation for liver transplantation (LT). Patients were classified by self-report as a “non-smoker,” “past smoker,” or “current smoker.” We used Cox proportional hazards models and Fine-Gray models with LT as a competing risk. Models were adjusted for age, sex, body mass index, race, family income, liver disease etiology, and Model for End-Stage Liver Disease-Sodium score. Of the 410 patients included, most (65%) were male and the mean age at enrollment was 56.5 years. One hundred sixty (39%) patients were nonsmokers, 183 (45%) were past smokers, and 67 (16%) were current smokers. In total, 151 (37%) patients received an LT, and 88 (20%) patients died. When compared to nonsmokers, current smokers had a 2.17-fold increase in risk of death overall (95% CI: 1.12–4.18, p = 0.02). There was a 7% increase in overall risk of death for every 5 pack-years increase (95% CI: 1.01–1.13, p = 0.02). With LT as a competing risk, the subdistributional HR of current smokers versus nonsmokers for death was 2.45 (95% CI: 1.31–4.60, p = 0.005). In this model, past smokers displayed a nonsignificant increase in the risk of death compared to nonsmokers (subdistributional HR: 1.58, 95% CI: 0.91–2.72, p = 0.10). Patients with advanced liver disease undergoing evaluation for LT who smoke have an increased risk of death. Smoking cessation could lead to improved overall survival with or without LT.

Background: Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are disorders of the pulmonary vasculature that cause right ventricular dysfunction. Systemic consequences of right ventricular dysfunction include damage to other solid organs, such as the liver. However, the profiles and consequences of hepatic injury due to PAH and CTEPH have not been well-studied. Methods: We aimed to identify underlying patterns of liver injury in a cohort of PAH and CTEPH patients enrolled in 15 randomized clinical trials conducted between 1998 and 2012. We used unsupervised machine learning to identify liver injury clusters in 13 trials and validated the findings in two additional trials. We then determined whether these liver injury clusters were associated with clinical outcomes or treatment effect heterogeneity. Results: Our training dataset included 4,219 patients and our validation dataset included 1,756 patients with complete liver laboratory panels (serum total bilirubin, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, and albumin). Using k-means clustering paired with factor analysis, we identified four unique liver phenotypes (no liver injury, hepatocellular injury, cholestatic injury, and combined injury patterns). Patients in the cholestatic injury liver cluster had the shortest time to clinical worsening and highest chance of worsening World Health Organization functional class. Randomization to the experimental arm was associated with a transition to healthier liver clusters compared to randomization to the control arm. The cholestatic injury group experienced the greatest placebo-corrected treatment benefit in terms of six-minute walk distance. Conclusions: Liver injury patterns were associated with adverse outcomes in patients with PAH and CTEPH. Randomization to active treatment of pulmonary hypertension in these clinical trials had beneficial effects on liver health compared to placebo. The independent role of liver disease (often subclinical) in determining outcomes warrants prospective studies of the clinical utility of liver phenotyping for PAH prognosis and contribution to clinical disease.

Background: It is currently unknown if disease severity modifies response to therapy in pulmonary arterial hypertension (PAH). We aimed to explore if disease severity, as defined by established risk-prediction algorithms, modified response to therapy in randomised clinical trials in PAH.Methods: We performed a meta-analysis using individual participant data from 18 randomised clinical trials of therapy for PAH submitted to the United States Food and Drug Administration to determine if predicted risk of 1-year mortality at randomisation modified the treatment effect on three outcomes: change in 6-min walk distance (6MWD), clinical worsening at 12 weeks and time to clinical worsening.Results: Of 6561 patients with a baseline US Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL 2.0) score, we found that individuals with higher baseline risk had higher probabilities of clinical worsening but no difference in change in 6MWD. We detected a significant interaction of REVEAL 2.0 risk and treatment assignment on change in 6MWD. For every 3-point increase in REVEAL 2.0 score, there was a 12.49 m (95% CI 5.86–19.12 m; p=0.001) greater treatment effect in change in 6MWD. We did not detect a significant risk by treatment interaction on clinical worsening with most of the risk-prediction algorithms.Conclusions: We found that predicted risk of 1-year mortality in PAH modified treatment effect as measured by 6MWD, but not clinical worsening. Our findings highlight the importance of identifying sources of treatment heterogeneity by predicted risk to tailor studies to patients most likely to have the greatest treatment response.