Rosenzweig, Erika B.

Abstract The diagnosis and management of pulmonary arterial hypertension (PAH) includes several advances, such as a broader recognition of extrapulmonary vascular organ system involvement, validated point-of-care clinical assessment tools, and focus on the early initiation of multiple pharmacotherapeutics in appropriate patients. Indeed, a principal goal in PAH today is an early diagnosis for prompt initiation of treatment to achieve a minimal symptom burden; optimize the patient’s biochemical, hemodynamic, and functional profile; and limit adverse events. To accomplish this end, clinicians must be familiar with novel risk factors and the revised hemodynamic definition for PAH. Fresh insights into the role of developmental biology (i.e., perinatal health) may also be useful for predicting incident PAH in early adulthood. Emergent or underused approaches to PAH management include a novel TGF-β ligand trap pharmacotherapy, remote pulmonary arterial pressure monitoring, next-generation imaging using inert gas–based magnetic resonance and other technologies, right atrial pacing, and pulmonary arterial denervation. These and other PAH state of the art advances are summarized here for the wider pulmonary medicine community.

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.

Introduction: The prevalence of acute vasodilator response (AVR) to inhaled NO (defined as a reduction in mPAP ≥ 10 mmHg with an absolute value of mPAP ≤ 40 mmHg with increased/unchanged CO) is reported to be around 12% in incident patients with idiopathic PAH (IPAH). The prevalence of AVR, however, is reportedly lower in other disease-associated PAH in Group 1, such as connective tissue disease (CTD). Furthermore, the prevalence of AVR for combined inhaled NO and oxygen, and in patients on PAH therapy (prevalent cohort), is less known. Hypothesis: We hypothesized there would be differences in the prevalence of AVR in PAH subgroups in the large PVDOMICS cohort of incident and prevalent patients. Methods: Group 1 PAH patients enrolled in PVDOMICS underwent right heart catheterization for baseline measurements. AVR was then measured in response to 100% inhaled oxygen (O 2 ) and 100% O 2 plus NO at 40 ppm (O 2 +NO) for 5 min each before hemodynamic measurements. Details of the PVDOMICS methodology and core adjudication of hemodynamic measurements were reported previously. Rates of AVR to 100% O 2 and 100% O 2 +NO were compared between incident and prevalent patients in each PAH subgroup. Results: 351 patients, mostly female (73%), average age of 52.9 years, with mostly prevalent disease (87%) and an average of 4 years from PAH diagnosis, underwent AVR assessment. A positive AVR was found in 0.6% of patients in response to 100% oxygen and 6% of patients in response to 100%+NO for the overall cohort. AVR was similar in incident and prevalent IPAH patients (6 and 6.9%, respectively). It was, however, 0% and 6.9%, in incident vs. prevalent CTD-PAH patients, respectively. There were no responders to either challenge in any other PAH subgroup. Conclusions: The prevalence of AVR is relatively rare in IPAH and CTD-PAH (~ 6%) and absent in other subgroups. There was no response to 100% O2 alone, suggesting specificity of AVR to NO in PAH. AVR is more common than previously reported in CTD-PAH, but only in prevalent disease. Whether the latter is related to long-term PAH therapy affecting pulmonary vasomotor response and/or vascular remodeling in these patients would warrant further studies.

Intro: Recent World Symposium of Pulmonary Hypertension (WSPH) Group 1 data indicate significant racial and ethnic disparities in disease severity and mortality. It is unclear if these differences extend to other forms of PH and if they are a reflection of comorbidities. The PVDOMICS program incorporates deep phenotyping across all WSPH groups allowing for a first-time side-by-side comparison. The aims of this study are to evaluate inter-racial/ethnic factors of disease severity and comorbidities among patients with PH. Methods/Results: Participants in PVDOMICS prospectively underwent comprehensive testing for echocardiography, PFT, chest imaging, 6-minute walk, cardiac MRI, and hemodynamics with provocation. WSPH group assignment was assessed according to guideline recommendations. Race and ethnicity were self-reported. Statistical testing and sample sizes are described in the Table . In 692 PH participants, Non-Hispanic whites (NHW) were older and more often male than non-Hispanic African American (AA) and Hispanic patients. WSPH Group 1 was less but Groups 4 and 5 more common in AA than NHW. There were no inter-race/ethnicity differences in the percent of PH patients on PH therapy (range 53-63%, p=0.23). Comorbidities such as diabetes and lung disease were more common in AA vs. NHW. Hispanics showed lower left atrial (LA) volume on echo, LA filling pressures with exercise, as well as increased cardiac index relative to NHW. Right ventricular function on cardiac MRI was similar between groups ( Table ). When WSPH Group 1 was analyzed separately, inter-racial/ethnic comparisons were generally similar. Conclusions: Significant inter-racial/ethnic differences are evident across all WSPH groups. Comorbidities appear to drive part of the differences among AA patients while Hispanic patients exhibit factors that may prove beneficial. How these differences contribute to varying disease risk and outcomes across race and ethnicity remain to be seen.

Left atrial (LA) size and function is recognized as a cumulative index of pulmonary capillary wedge pressure (PCWP) and an index of left heart disease (LHD). While anticipated that LA features contribute to LHD-associated pulmonary hypertension (PH), we hypothesized that LA abnormalities (LAA) may exist in other WSPH groups. Therefore, we examined LA structure and function in the PVDOMICS cohorts. PVDOMICS enrolled 1097 total subjects with PH (mPA > 25 mmHg) and at-risk disease comparators (mPA<25 mmHg) for each of the WSPH groups. Patients with WSPH Groups 1, 3, 4, and 5 [non-Group 2] (n=618) were younger (56.2 ± 14.5 vs 60.1 ± 12.7 yrs, p<.02) and had less hypertension (38.6% vs 51.5 %, p<.02) than their non-Group 2 comparators (n=204). They also had less hypertension, diabetes, and a lower BMI than WSPH Group 2 (n=145), whereas WSPH Group 2 and its comparator Group 2 (n=130) were similar. LA area by echo was greater in WSPH Group 2 compared to non-Group 2 (22.8 ± 6.6 vs 16.9 ± 5.0 cm 2 , p<.02), in the comparator Group 2 vs. non-Group 2 comparators (22.7 ± 7.9 vs 16.4 ± 4.7 cm 2 , p<.02) but similar between WSPH group 2 and its comparator. MRI LA ejection fraction was lowest in Group 2 (33.2 ± 17.7%) and comparator Group 2 (38.9 ±16.7%, p=ns), significantly lower than WSPH non-Group 2 (45.9 ±14.7%, p<.02) which was lower than comparator non-Group 2 (50.9 14.6%, p<.02) which was lower than normal controls (n=96) (58.4 ±1.7%, p<.02). At right heart catheterization, whereas mPA pressures were similar between WSPH non-Group 2 and Group 2, resting PCW (11.1± 5.3 vs 20.3 5.6 mm Hg, p<0.02) was lower in WSPH non-Group 2 , PVR was higher (5.5[3.3, 8.7] vs. 3.7[7.2, 5.7] WU, p<0.02), and cardiac output was higher (5.4 ± 1.9 vs. 4.9 ± 1.6 L/min, p<0.02). Following a fluid challenge, PCW remained lower (14.9 ± 5.8 vs 20.7 ± 4.5 mm Hg, p<0.02) and PVR higher (5.2[3.1, 7.8] vs. 3.2[2.3, 5.5] WU, p<0.02). PCW and PVR at rest were lower in the comparator non-Group 2 vs WSPH non-Group 2 (8.9 ± 4.1 vs 11.1± 5.3 mm Hg, p<.02) and 1.7[1.2, 2.3] vs 5.5[3.3, 8.7] WU, p<.02. Thus, while LAA are most notable in WSPH and comparator Group 2’s, LAA differ between WSPH non-Group 2 and its non-Group 2 comparators. The role of LAA as predictors of PH outcomes remains to be determined.

Introduction: Previous reports have shown that atrial and ventricular arrhythmias (VA) are common in all forms of pulmonary hypertension (PH) with prevalence of supraventricular arrhythmias ranging from 13-25% and VA 27%. Arrhythmias are also associated with clinical worsening events. Reports have limited numbers of patients with a variety of forms of PH and limited data comparing the prevalence of atrial arrhythmias across WSPH groups and whether advancing age, WHO FC, echocardiographic, exercise capacity and hemodynamic patterns are associated with a higher prevalence of atrial arrhythmias. Methods: As part of the PVDOMICS program, we enrolled 1195 PH participants, controls and PH comparators and prospectively collected electrocardiograms (ECGs) at enrollment for 1147 of them. Comparisons across participants with and without atrial fibrillation/atrial flutter (afib/flutter) used analysis of variance (ANOVA) or Kruskal-Wallis test in continuous variables based on distribution with statistics presented as mean + SD or median [P25, P75] respectively. Pearson’s chi-square test was used for categorical variables. Results: Of 732 PH participants (467F) who had ECGs available at baseline, 527 (72.0%) were in normal sinus rhythm and 62 had afib/flutter (8.5%). Afib/flutter participants were older (75 + 8 vs 57 + 14 years; p<0.001), most commonly in WSPH group 2 (28.1%) vs. WSPH 1 (3.3%), WSPH 3(6.5%) and WSPH group 4 (3.7%), had predominantly WHO FC II/III symptoms (89.5%), higher RAP (12.6 + 5 vs.7.8 + 5mmHg; p<0.001) and PCWPm (17.8 + 5.8 vs. 12.3 + 6.2mmHg; p<0.001) and lower CO (4.3+ 1.5 vs. 5.2 +1.8L/min;p<0.001). Participants with afib/flutter had lower 6MWD 277 + 117 vs.356 + 134meters (p<0.001) than PH participants without. Echocardiography demonstrated increase in LA volume index (mL/m2), RA volume (mL) and tricuspid regurgitation severity with reduced TAPSE and LVEF (54 + 10 vs. 61 + 10%;p<0.001). ProBNP was higher in afib/flutter participants 2029 [1073, 2964] vs.268 [100, 1074]pg/ml; P<0.001) Conclusions: In this analysis of atrial arrhythmias in a large cohort of PH participants across all WSPH groups, afib/flutter was present most often in older WSPH group 2 patients who demonstrated clinical and hemodynamic features of worse heart failure.

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 &lt; 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.

Background: Invasive hemodynamic evaluation through right heart catheterization plays an essential role in the diagnosis, categorization, and risk stratification of patients with pulmonary hypertension. Methods: Subjects enrolled in the PVDOMICS (Redefining Pulmonary Hypertension through Pulmonary Vascular Disease Phenomics) program undergo an extensive invasive hemodynamic evaluation that includes repeated measurements at rest and during several provocative physiological challenges. It is a National Institutes of Health/National Heart, Lung, and Blood Institute initiative to reclassify pulmonary hypertension groups based on clustered phenotypic and phenomic characteristics. At a subset of centers, participants also undergo an invasive cardiopulmonary exercise test to assess changes in hemodynamics and gas exchange during exercise. Conclusions: When coupled with other physiological testing and blood -omic analyses involved in the PVDOMICS study, the comprehensive right heart catheterization protocol described here holds promise to clarify the diagnosis and clustering of pulmonary hypertension patients into cohorts beyond the traditional 5 World Symposium on Pulmonary Hypertension groups. This article will describe the methods applied for invasive hemodynamic characterization in the PVDOMICS program. Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02980887.