Cajigas, Héctor

ABSTRACT In 567 PH‐COPD patients from the PVRI GoDeep Meta‐Registry, ACE inhibitor use was associated with improved survival only in severe PH (PVR > 5 WU), supporting prospective trials targeting this high‐risk subgroup.

Abstract Rationale Sotatercept is a novel activin signaling inhibitor approved for the treatment of pulmonary arterial hypertension (PAH). Sotatercept has been studied in randomized clinical trials, but little is known regarding the real-world use of sotatercept. We sought to describe the safety, tolerability and efficacy of sotatercept in our clinical practice. Methods We performed a combined prospective and retrospective cohort study of all patients treated with sotatercept at Mayo Clinic Rochester since its approval in March 2024. Patients enrolled in a separate clinical trial of sotatercept were excluded from this analysis as their data will be reported separately. Clinical data was abstracted from the electronic health record. Follow-up data was collected at 6 ± 3 months after initiation of sotatercept. Data is summarized as n (%) and mean ± SD. We used paired t-tests to compare baseline and follow-up characteristics within individuals. Results Fifty-eight PAH patients treated with sotatercept were included. Patients were 48.4 ± 37.6 years old at treatment initiation and were predominantly female with a mean duration of PAH of 6.7 years and a range of PAH etiologies including portopulmonary hypertension, congenital heart disease, and pulmonary veno-occlusive disease (Table 1). Twenty-one (36%) of patients had mixed etiologies of PH. Six months after initiation of sotatercept, patients had a significant improvement in NTproBNP (1922 ± 4464 to 363 ± 596 pg/ml, p = 0.04), 6 minute walk distance (378.8 ±144.6 to 395.7±129.5 meters, p = 0.02) and right ventricular systolic pressure (74.6 ± 20.5 to 60.6 ± 20.3 mm Hg, p < 0.001). No patients permanently discontinued due to abnormal laboratory values. Mean highest hemoglobin achieved over the initial 6 months of treatment was 15.5 ± 2.1 g/dL and mean lowest platelet count was 181 ± 74K. Seven patients discontinued sotatercept at a range of 170-275 days after starting. Four patients discontinued due to possible treatment-related adverse effects: 1 each of gastrointestinal hemorrhage, retinal hemorrhage, hypoxia/intrapulmonary vasodilatation and spontaneous bilateral subdural hematomas. Three patients discontinued due to other reasons: newly diagnosed metastatic cancer leading to transition to hospice and two due to lack of improvement. Conclusions In this real-world registry of sotatercept in PAH, sotatercept was well-tolerated among patients with PAH and associated with improvements in exercise capacity, echocardiographic parameters, and NTproBNP. Overall discontinuation due to possible treatment-related adverse effects was low and reasons for discontinuation included bleeding and hypoxia attributed to intrapulmonary vasodilatation. This abstract is funded by: None

Background: Lung cancer is classified into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC – including adenocarcinoma, squamous cell, and large cell carcinoma). The incidence of major adverse cardiovascular events (MACE)—defined as acute myocardial infarction, acute coronary syndrome/ischemic heart disease requiring revascularization, stroke, and cardiovascular death—have not been well defined in lung cancer patients following treatment. Coronary artery calcifications (CAC) and aortic calcifications (CA) are known cardiovascular risk markers in non-cancer populations. Purpose: To determine whether the presence of CAC or CA, as identified on baseline PET-CT (Positron Emission Tomography–Computed Tomography) or chest CT imaging, is predictive of MACE and all-cause mortality (ACM) in patients with lung cancer. Methods: We conducted a retrospective cohort study of patients diagnosed with SCLC or NSCLC who received chemotherapy, between January 1, 2010, and December 31, 2024. The baseline PET-CT or chest CT scans were reviewed for the presence of CAC and/or CA. Patients were excluded if they lacked baseline imaging or had experienced a MACE before treatment. Univariate and multivariate adjusted Cox regression models were employed to assess associations between CAC/CA and MACE or ACM. The Kaplan-Meier survival analyses was performed to evaluate event-free survival. Results: A total of 385 patients were included (mean age: 74 years, IQR: 67–79), predominantly female (158 [55%]) and white (279 [96.2%]). NSCLC was found in 255 (88%) and SCLC in 35 (12%). CAC was identified in 172 (60%) and CA in 87 (30%). Among patients with NSCLC, the presence of CAC was significantly associated with MACE (HR: 2.84 [95% CI: 1.6–4.8], p=0.0001) (Fig. a), particularly in those with adenocarcinoma (Fig. b). In SCLC, (HR: 1.56 [95% CI: 0.1–14.0], p=ns). On multivariable analysis, CAC remained the strongest predictor of MACE after adjusting for age, hypertension, diabetes, dyslipidemia, and smoking status (HR: 2.6 [95% CI: 1.5–4.4], p=0.0008) (Fig. d). No significant association was found between CA and MACE in either group (p>0.05). ACM was similar for SCLC, squamous cell, and NSCLC (Fig. c). Conclusion: In patients with NSCLC especially lung adenocarcinoma, the presence of CAC in the baseline PET/CT was an independent predictor of MACE. This finding supports the value of CAC as a non-invasive cardiovascular risk marker.

Abstract Rationale Pulmonary hypertension (PH) in interstitial lung disease (ILD) lacks approved therapies. Objectives The Pulmonary Vascular Research Institute GoDeep metaregistry collects real-world data of patients with PH from international PH referral centers. Methods Patients with ILD-PH and relevant subgroups (idiopathic interstitial pneumonia [IIP], idiopathic pulmonary fibrosis [IPF]) were stratified by pulmonary vascular resistance (PVR). Kaplan-Meier survival analyses and adjusted Cox proportional hazards models were employed, additionally accounting for immortal time bias, sensitivity analyses, Heller explained relative risk statistics, and target trial emulation framework analysis. Measurements and Main Results Among 34,482 patients, 940 with hemodynamically fully characterized incident ILD-PH (median age, 67 [IQR, 59–74] yr) were identified. A total of 62% had severe ILD-PH with PVR >5 Wood units (WU) and poor survival rates (29% and 18% at 3 and 5 yr), significantly worse than patients with ILD-PH with PVR ≤5 WU and patients with pulmonary arterial hypertension. Survival was poorest in severe IPF-PH. A total of 59% of all patients ILD-PH received PH-targeted therapy, predominantly phosphodiesterase-5 inhibitors (PDE5is). PDE5i treatment was consistently associated with significantly improved survival in patients with severe PH (hazard ratios of 0.537 [0.370–0.781], 0.461 [0.233–0.913], and 0.435 [0.215–0.8] for IIP-PH, IPF-PH, and IIP-PH with nintedanib/pirfenidone background therapy), but not in patients with less severe hemodynamic impairment, supported by sensitivity analyses, Heller statistics, and target trial emulation framework analysis. The survival statistics of patients with PDE5i-treated IIP-PH or IPF-PH were validated in the independent COMPERA registry. Combination therapy with PDE5is and inhaled prostacyclin analogues was superior to monotherapy using PDE5is (hazard ratio, 0.341; 0.205–0.566). Conclusions Prognosis in ILD-PH was generally very poor and was related to PH severity. PDE5i treatment in severe IIP-PH and IPF-PH was associated with improved survival, which is to be further verified in controlled trials.

ABSTRACTPortopulmonary hypertension (PoPH), a type of pulmonary arterial hypertension (PAH) in patients with liver disease, is associated with high morbidity and mortality. The relationship between cardiopulmonary hemodynamics, PAH therapy, and survival in PoPH remains unclear. We performed a retrospective cohort study of PoPH patients from the international pulmonary hypertension (PH) meta‐registry, PVRI GoDeep. PAH was defined by a mean pulmonary arterial pressure > 20 mmHg, pulmonary arterial wedge pressure ≤ 15 mmHg, and a pulmonary vascular resistance (PVR) > 2 Wood Units. PoPH diagnoses were assigned by each center's PH specialist based on international guidelines at the time of enrollment. 246 incident PoPH patients met eligibility criteria and were included in the analysis, equally split between males (51%) and females (49%), with a median age of 54 years. When compared to both patients with IPAH and those with other subtypes of PAH (not classified as PoPH or IPAH), those with PoPH had significantly lower 5‐year survival rates (46% vs. 68% vs. 65%, log‐rank p < 0.001). Amongst the PoPH patients, however, there was no significant difference in 5‐year survival when dichotomized by disease severity, either by a PVR of 5 Wood Units or a CI of 2.5 L/min/m2. Treatment of the PoPH patients with PAH‐targeted therapies was associated with significantly higher 5‐year survival rates compared to those not receiving such treatments, as shown by Kaplan–Meier analysis. This survival benefit was observed for PDE5i (50% vs. 34%, log‐rank p = 0.029), ERA (58% vs. 34%, log‐rank p < 0.001), and the combination of PDE5i and/or ERA (51% vs. 22%, log‐rank p < 0.001), as well as any PAH‐targeting treatment (50% vs. 26%, log‐rank p = 0.007). Corresponding survival advantage was noted when including only PoPH patients with MELD Score ≥ 13. PoPH is a disease with significantly worse long‐term survival than other PAH subtypes, but targeted PAH therapy is associated with a robust survival benefit. Survival did not differ across high‐risk PVR and cardiac index thresholds, suggesting the factors that influence prognosis and survival in PoPH may be unique as compared to other PAH subtypes, and warrant further investigation.

Abstract Introduction Sex-based differences in morbidity and mortality for pulmonary hypertension (PH) are insufficiently addressed in current research. However, recognizing these differences is crucial for optimal clinical management and improving outcomes. This study assesses the effect of sex on survival among PH patients, while accounting for disease severity, comorbidities, treatment, and race. Methods We analyzed data from the PVRI GoDeep meta-registry, including all incident patients with complete hemodynamic profiles. Survival was evaluated using Kaplan-Meier and Cox proportional hazards models, adjusted for various confounders. Analyses included both PAH and non-PAH groups and risk assessment by the ESC/ERS 2022, REVEAL lite 2, and COMPERA 4-strata scores. All analyses were performed using R (The R Foundation). Results A total of 19,663 incident PH patients were included in the analysis, with 5,581 patients (28%) diagnosed with Group 1 PH and a median age of 64 years [IQR: 52-73]. Among these, male patients (8,704, 44%) had a significantly higher mortality risk than female patients across the entire cohort and within all PH subtypes. The adjusted hazard ratio for mortality in male versus female patients was 1.391 [95% CI: 1.260-1.536] in the overall population and 1.404 [95% CI: 1.264-1.561] for those with PAH. This survival difference was consistent across various severity levels, age groups, and in the presence of comorbidities such as obesity and cardiovascular diseases, as well as among those receiving PAH-specific therapies as well as patients who remained without treatment during the observation period. Notably, male disadvantage in survival was observed in low, intermediate, and high-risk categories for ESC/ERS 2022, REVEAL lite 2, and COMPERA scores but not within REVEAL 2.0, which includes male sex as a non-modifiable risk factor. Racial analysis revealed a greater mortality risk for males among White patients, with no significant differences noted in Black or Asian populations. Conclusion Our PVRI GoDeep meta-registry analysis demonstrates that male PH patients face higher mortality risk across both PAH and non-PAH groups, independent of disease etiology, age, severity, comorbidities, and treatment factors, with this risk amplified in White patients. These findings suggest that male sex should be further considered as a risk factor to refine predictive models for survival in PH.

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.

Background. The current model for end-stage liver disease (MELD) exception policies for portopulmonary hypertension (POPH) require serial right heart catheterizations (RHCs) every 3 mo to maintain exception points. RHC is necessary for the initial diagnosis of POPH, but the utility of serial catheterizations has not been studied. In patients with POPH MELD exceptions, we sought to compare noninvasive and invasive hemodynamics and determine the sensitivity of echocardiography for the detection of hemodynamically severe POPH that would preclude liver transplant. Methods. We performed a single-center retrospective cohort study of patients with POPH MELD exceptions who underwent liver transplant from December 2008 to January 2024. Results were validated at an external center. Echocardiograms and RHCs performed within 1 mo were compared. Pearson correlation coefficient and Bland-Altman plots assessed the association between echocardiogram and RHC variables. We examined varied echocardiographic parameters to optimize sensitivity for the detection of hemodynamically severe POPH. Results. Twenty-two individuals underwent 60 follow-up RHCs with paired echocardiograms. Right ventricular systolic pressure (RVSP) and cardiac index estimated with echocardiogram were not strongly correlated with RHC measurements at follow-up (RVSP and RHC pulmonary artery systolic pressure: R = 0.30, P = 0.02; cardiac index: R = 0.17, P = 0.21). However, echocardiograms with RVSP ≥48 mm Hg had 100% sensitivity for detecting hemodynamically severe POPH, with 100% negative predictive value. In external validation of 13 paired echocardiograms and RHCs, our algorithm had 64% specificity and 100% negative predictive value. Conclusions. Although echocardiogram and RHC hemodynamic estimates were not strongly correlated, these results could potentially negate the current requirement for repeat RHC every 3 mo to maintain POPH MELD exception.

Introduction: Portopulmonary hypertension (POPH) and associated pulmonary vascular resistance (PVR) elevation is seen in the context of underlying portal hypertension and liver disease. In the systemic circulation, liver cirrhosis can cause inappropriate splanchnic and systemic vasodilation with decreased systemic vascular resistance (SVR). Midodrine is used to maintain blood pressure in the setting of low SVR. Pulmonary vasodilators have systemic vasodilatory effects; the implications of combined midodrine and pulmonary vasodilator use in POPH are unanswered questions. Hypothesis: We hypothesized that SVR would decrease over time in patients with POPH started on pulmonary vasodilators, and that use of midodrine (as a surrogate for depressed SVR), may be associated with increased risk of mortality in patients with POPH starting pulmonary vasodilator therapy. Methods: Patients from the 3 Mayo Clinic sites (Rochester, MN; Jacksonville, FL; Scottsdale, AZ) diagnosed with POPH from 1988-2020 were included in the database. Patients met hemodynamic criteria for POPH via right heart catheterization (RHC). Hemodynamics were obtained from echocardiography and RHC at initial and subsequent visits. The hazard ratio for risk of death was estimated using Cox proportional hazards method. SVR was calculated using mean arterial pressure and cardiac output. Results: Analysis included 147 POPH patients, 34 (23%) on midodrine and 113 (77%) not requiring midodrine. There were 116 patients with longitudinal SVR data. The mean initial SVR was 1224 Dyne sec cm-5 and decreased 251 Dyne sec cm-5 [95% CI -337 to -165 251 Dyne sec cm-5, p<0.0001] with no difference between midodrine groups (p=0.57). Patients in the midodrine POPH group had an increased risk of mortality compared to those without midodrine use (HR 1.51, 95% CI: 1.02-2.21, p=0.0371). Conclusions: Patients with POPH starting pulmonary vasodilator have a reduction in SVR related to vasodilator therapy. Midodrine use with pulmonary vasodilator therapy is associated with increased mortality in the POPH population. Further study of the safety of combined midodrine and pulmonary vasodilator use in POPH is needed along with exploration of more selective pulmonary vasodilators.