Hassoun, Paul M.

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.

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.

Pulmonary hypertension (PH) is highly heterogeneous and despite treatment advances it remains a life‐shortening condition. There have been significant advances in imaging technologies, but despite evidence of their potential clinical utility, practice remains variable, dependent in part on imaging availability and expertise. This statement summarizes current and emerging imaging modalities and their potential role in the diagnosis and assessment of suspected PH. It also includes a review of commonly encountered clinical and radiological scenarios, and imaging and modeling‐based biomarkers. An expert panel was formed including clinicians, radiologists, imaging scientists, and computational modelers. Section editors generated a series of summary statements based on a review of the literature and professional experience and, following consensus review, a diagnostic algorithm and 55 statements were agreed. The diagnostic algorithm and summary statements emphasize the key role and added value of imaging in the diagnosis and assessment of PH and highlight areas requiring further research.

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.

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by severe remodeling of the pulmonary artery resulting in increased pulmonary artery pressure and right ventricular hypertrophy and, ultimately, failure. Bone marrow–derived progenitor cells play a critical role in vascular homeostasis and have been shown to be involved in the pathogenesis of PAH. A proliferation of c‐Kit+ hematopoietic progenitors and mast cells has been noted in the remodeled vessels in PAH. Imatinib, a tyrosine kinase inhibitor that targets c‐Kit, has been shown to be beneficial for patients with PAH. Here we hypothesize that the clinical benefit of imatinib in PAH could be related to c‐Kit inhibition of progenitor cell mobilization and maturation into mast cells. As a corollary to the phase 3 study using imatinib in PAH, blood samples were collected from 12 patients prior to starting study drug (baseline) and while on treatment at weeks 4 and 24. Eight were randomized to imatinib and 4 to placebo. Circulating c‐Kit+ and CD34+ CD133+ hematopoietic progenitors as well as biomarkers of mast cell numbers and activation were measured. Circulating CD34+ CD133+ and c‐Kit+ progenitor cells as well as c‐Kit+/CD34+ CD133+ decreased with imatinib therapy (all P < 0.05). In addition, total tryptase, a marker of mast cell load, dropped with imatinib therapy (P = 0.02) and was related to pulmonary vascular resistance (R = 0.7, P = 0.02). The findings support c‐Kit inhibition as a potential mechanism of action of imatinib in PAH and suggest that tryptase is a potential biomarker of response to therapy.

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.