Al‐Naamani, Nadine

Abstract Introduction Insulin resistance is prevalent in pulmonary arterial hypertension (PAH) and is associated with worse health outcomes. The triglyceride-glucose (TyG) index as a measure of insulin resistance is superior to HOMA-IR in predicting metabolic syndrome. This study utilizes the Redefining Pulmonary Hypertension through Pulmonary Vascular Disease Phenomics (PVDOMICS) data registry to further examine the relationship between TyG index and reported quality of life (QOL) in patients with PAH. Methods 327 patients with a diagnosis of PAH in PVDOMICS were stratified into insulin resistant (IR) (TyG index >8.55) and insulin sensitive (IS) (TyG < 8.55) groups where TyG = (ln[triglyceride*glucose/2]. QOL measures assessed were the Minnesota Living With Heart Failure (MLHF) Physical and Emotional domain surveys, Short Form (36) (SF-36) Physical and Mental Component Health Surveys (PCS and MCS, respectively), and emPHasis-10 (E10). Reported measures between groups were compared using least squares means adjusted for age, sex, fat mass index (FMI), PAH etiology, 6-minute walk distance (6MWD) and NT-pro-brain natriuretic peptide (NTproBNP). Kaplan-Meier curves and Cox proportional hazards models adjusted for these same variables were performed to assess difference in survival between groups. Results 155 patients with PAH (47%) were classified as IR. Patients with IR were more likely to be female (79% vs 69%, p = 0.04), more likely to be non-Hispanic white, and less likely to be non-Hispanic Black (p = 0.045). There were no differences in age or etiology of PAH between groups. Patients with IR had higher body mass index (30.9 vs 27.3 kg/m2, p < 0.001) with higher FMI (16.2 vs 13.2 kg/m2, p < 0.001). Patients with IR were more likely to have diabetes mellitus (24% vs 11%, p = 0.004). Compared to their IS counterparts and after adjusting for possible confounders, patients with IR had higher (worse QOL) MLHF physical domain (p = 0.04), higher (worse QOL) emPhasis-10 scores (p = 0.03), and lower (worse QOL) SF36 physical component scores (p = 0.03) (Figure). IR and IS groups had no significant differences in the MLHF emotional domain and SF36 mental component scores. After multivariable adjustment, there was no difference in survival between groups (HR 0.91, 95% CI 0.56-1.46). Conclusion Patients with PAH and IR had worse QOL compared to their IS counterparts but no difference in survival in this large prospective cohort. This abstract is funded by: This work was supported by the National Institutes of Health grants K23HL 141584, R01 HL173533

Abstract Rationale Non-selective beta-blockers (BB) are the standard of care for variceal prophylaxis in patients with cirrhosis. It is unclear whether BB negatively affect exercise capacity in patients with portopulmonary hypertension (POPH) or hepatopulmonary syndrome (HPS). We hypothesize that BB use is associated with shorter six-minute walk distance (6MWD) in HPS and POPH than in patients without pulmonary vascular complications of liver disease. Methods The Pulmonary Vascular Complications of Liver Disease 2 (PVCLD2) Study enrolled patients evaluated for liver transplantation or pulmonary hypertension at eight U.S. centers (2013-2017). We conducted a retrospective analysis of 333 patients with HPS, POPH, and portal hypertension without lung complications to evaluate whether disease state modified the association of BB on 6MWD. Multivariable linear regression adjusted for a priori covariates including age, sex, body mass index (BMI), MELD-Na, and WHO functional class. An interaction term between disease category and BB use was included. Results We included 85 patients with HPS, 48 with POPH, and 200 patients with liver disease. Compared to liver disease controls, those with HPS were younger, had higher MELD-Na scores, and more often had worse WHO functional class. POPH patients were similar to controls in age and liver disease severity but had higher WHO functional class. Sex, BMI, and left ventricular ejection fraction did not differ significantly between groups. Higher age, BMI, MELD-Na, and WHO functional class were all significantly associated with lower 6MWD while male sex was associated with higher 6MWD. Adjusting for age, sex, BMI, MELD-Na score, and WHO functional class, there was a significant interaction between BB use and disease category (p = 0.024). Patients with HPS had a 53.4 m longer 6MWD with BB use (95% CI 4.21- 102.5, p = 0.03 for interaction) compared to liver disease controls, whereas patients with POPH had a 72.4 m longer 6MWD (95% CI 7.60- 137.2, p = 0.03 for interaction) compared to liver disease controls. Conclusion The association of BB with 6MWD in advanced liver disease appears to be modified by whether a person has a pulmonary vascular complication including HPS or POPH. The mechanisms for these differences and their clinical implications require further study. This abstract is funded by: NIH T32 Grant

Abstract Rationale: Since the initial descriptions of pulmonary arterial hypertension (PAH), there has been a significant increase in PAH diagnoses among the geriatric population. Studies suggest that older PAH patients exhibit unique hemodynamic profiles and treatment responses. We hypothesized that patients ≥80 years old would have a unique clinical profile and worse outcomes. Methods: The Pulmonary Hypertension Association Registry (PHAR) is a prospective cohort of PAH and chronic thromboembolic pulmonary hypertension (CTEPH) patients new to care at a Pulmonary Hypertension Care Center in the US. Individuals <18 years of age and those with CTEPH were excluded. Clinical data, quality of life measures, and functional capacity were recorded at time of enrollment and at follow up visits. Octogenarians were defined as those ≥80 years old and non-octogenarians as <80 years old. Associations between age subgroups with the change in six-minute walk distance (6MWD), and worsened WHO functional class (WHO FC) at the next visit, and time to all-cause mortality were assessed using linear, binomial, and Cox regression, respectively. Results: The study sample included 87 PAH octogenarian patients and 2,583 non-octogenarian patients at enrollment. The Table shows that octogenarian PAH patients were of similar sex and race distribution as others, but had lower body mass index. Octogenarians were more likely to have idiopathic or CTD-related PAH, and differed from younger patients in terms of several sociodemographic variables. PAH treatment, WHO FC, quality of life, and hemodynamic also differed between the groups. Octogenarians had a lower change in 6MWD (-26m, 95%CI -52 – -2, p = 0.066) and worse WHO FC (2.0, 95%CI 1.1 – 3.8, p = 0.038) over time compared to other adults after adjustment for sex, BMI, PAH etiology, annual income, marital status, right atrial pressure, mean pulmonary artery pressure, and PAH treatment. Octogenarians had an increased risk of death compared to younger adults (hazard ratio 1.7, 95%CI 1.1 – 2.6, p = 0.022) after adjustment for covariates. Conclusions: While the eldest PAH patients may have some comparable features to younger patients, they are different in a variety of socioeconomic variables, disease type, hemodynamics, and number of PAH therapies. The eldest PAH patients demonstrate worse exercise and functional capacity with time and a 70% increased risk of death compared to younger patients. Further studies are needed to better characterize PAH in the elderly, as this may lead to more effective treatments and enhanced quality of life.

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.

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 and Aims: Hepatopulmonary syndrome (HPS) and a hyperdynamic circulation are common complications of advanced liver disease, but the relationship between HPS and cardiac index (CI) is poorly understood. We sought to compare CI in patients with and without HPS and to assess the relationship between CI and symptoms, quality of life, gas exchange, and exercise capacity among liver transplantation (LT) candidates. We performed a cross-sectional analysis within the Pulmonary Vascular Complications of Liver Disease 2 study, a multicenter prospective cohort study of patients being evaluated for LT. We excluded patients with obstructive or restrictive lung disease, intracardiac shunting, and portopulmonary hypertension. We included 214 patients (81 with HPS and 133 controls without HPS). Compared with controls, patients with HPS had a higher CI (least square mean 3.2 L/min/m2, 95% CI 3.1–3.4 vs. 2.8 L/min/m2, 95% CI 2.7–3.0, p < 0.001) after adjustment for age, sex, Model for End-stage Liver Disease-Sodium (MELD-Na) score and beta-blocker use, and a lower systemic vascular resistance. Among all LT candidates, CI was correlated with oxygenation (Alveolar-arterial oxygen gradient r=0.27, p< 0.001), intrapulmonary vasodilatation severity (p < 0.001), and biomarkers of angiogenesis. Higher CI was independently associated with dyspnea and worse functional class and physical quality of life after adjusting for age, sex, MELD-Na, beta-blocker use, and HPS status. HPS was associated with a higher CI among LT candidates. Independent of HPS, higher CI was associated with increased dyspnea and worse functional class, quality of life, and arterial oxygenation.

A 6-minute walk test is a simple tool for assessing submaximal exercise capacity. We sought to determine whether a 6-minute walk distance (6MWD) predicts outcomes in patients with cirrhosis. The Pulmonary Vascular Complications of Liver Disease 2 study is a multicenter, prospective cohort study that enrolled adults with portal hypertension during liver transplantation evaluation. We excluded subjects with an incident or prevalent portopulmonary hypertension. The 6-minute walk test was performed using standardized methods. Cox proportional hazards modeling and multivariable linear regression analysis were performed to determine the relationship between baseline 6MWD and outcomes. The study sample included 352 subjects. The mean 6MWD was 391±101 m. For each 50-meter decrease in 6MWD, there was a 25% increase in the risk of death (HR 1.25, 95% CI [1.11, 1.41], p < 0.001) after adjustment for age, gender, body mass index, MELD-Na, and liver transplant as a time-varying covariate. In a multistate model, each 50-meter decrease in 6MWD was associated with an increased risk of death before the liver transplant ( p < 0.001) but not after the transplant. 6MWD was similar to MELD-Na in discriminating mortality. Each 50-meter decrease in 6MWD was associated with an increase in all-cause ( p < 0.001) and transplant-free hospitalizations ( p < 0.001) in multivariable models for time-to-recurrent events. Shorter 6MWD was associated with worse Short Form-36 physical ( p < 0.001) and mental component scores ( p = 0.05). In conclusion, shorter 6MWD is associated with an increased risk of death, hospitalizations, and worse quality of life in patients evaluated for liver transplantation. The 6-minute walk distance may be a useful adjunct for risk assessment in patients undergoing liver transplant evaluation.