Relative Change in Donor-Derived Cell-free DNA is Superior to Absolute Values for Diagnosis of Acute Lung Allograft Dysfunction.

Donor-derived cell-free DNA (dd-cfDNA%) is a biomarker of early acute lung allograft dysfunction (ALAD), with a value of ≥1.0% indicating injury. Whether dd-cfDNA% is a useful biomarker in patients >2 y posttransplant is unknown. Our group previously demonstrated that median dd-cfDNA% in lung recipients ≥2 y posttransplant without ALAD was 0.45%. In that cohort, biologic variability of dd-cfDNA% was estimated by a reference change value (RCV) of 73%, suggesting that change exceeding 73% may be pathologic. In this study, we aimed to determine whether dd-cfDNA% variability or absolute thresholds are optimal for detecting ALAD. Methods: We prospectively measured plasma dd-cfDNA% every 3 to 4 mo in patients ≥2 y post-lung transplant. ALAD was defined as infection, acute cellular rejection, possible antibody-mediated rejection, or change in forced expiratory volume in 1 s >10%, and was adjudicated retrospectively. We analyzed area under the curve for RCV and absolute dd-cfDNA% and reported performance of RCV ≥73% versus absolute value >1% for discriminating ALAD. Results: Seventy-one patients had ≥2 baseline measurements of dd-cfDNA%; 30 developed ALAD. RCV of dd-cfDNA% at ALAD had a greater area under the receiver operator characteristic curve than absolute dd-cfDNA% values (0.87 versus 0.69, P = 0.018). Test characteristics of RCV >73% for ALAD diagnosis were sensitivity 87%, specificity 78%, positive predictive value 74%, and negative predictive value 89%. In contrast, dd-cfDNA% ≥1% had sensitivity 50%, specificity 78%, positive predictive value 63%, and negative predictive value 68%. Conclusions: Relative change in dd-cfDNA% has improved test characteristics for diagnosing ALAD compared with absolute values.

Assessment of dd-cfDNA Levels in Clinically Stable Lung Allograft Recipients Beyond the Initial 2 y Posttransplant.

Donor-derived cell-free DNA (dd-cfDNA) is a useful biomarker for the diagnosis of acute allograft injury within the first 1 to 2 y after lung transplant, but its utility for diagnosing chronic lung allograft dysfunction (CLAD) has not yet been studied. Understanding baseline dd-cfDNA kinetics beyond the initial 2 y posttransplant is a necessary first step in determining the utility of dd-cfDNA as a CLAD biomarker. We seek to establish baseline dd-cfDNA% levels in clinically stable lung allograft recipients who are >2 y posttransplant. Methods: We performed a prospective, single-center, observational study to identify plasma dd-cfDNA levels in clinically stable lung allograft recipients >2 y posttransplant. Results: Fifty-one subjects were enrolled and ≥3 baseline dd-cfDNA measurements were acquired during a median of 252 d. The median baseline percent dd-cfDNA level in our cohort was 0.45% (interquartile range [IQR], 0.26-0.69). There were statistically significant differences in dd-cfDNA based on posttransplant duration (≤5 y posttransplant median 0.41% [IQR, 0.21-0.64] versus >5 y posttransplant median 0.50% [IQR, 0.33-0.76]; P < 0.02). However, the clinical significance of this small change in dd-cfDNA is uncertain because this magnitude of change is within the biologic test variation of 73%. Conclusions: This study is the first to define levels of dd-cfDNA in clinically stable patients who are >2 y post-lung transplant. These findings lay the groundwork for the study of dd-cfDNA as a possible biomarker for CLAD.

Clinical course of SARS-CoV-2 infection and recovery in lung transplant recipients.

BACKGROUND: Reports on outcomes following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in lung transplant recipients remain limited. METHODS: We performed a single-center, observational study of outcomes in lung transplant recipients diagnosed with SARS-CoV-2 between 5/1/2020 and 3/15/2022 that were followed for a median of 123 days. We analyzed changes in spirometry, acute lung allograft dysfunction (ALAD) incidence, hospitalization, mechanical ventilation needs, secondary infection, and survival. RESULTS: In our cohort of 336 patients, 103 developed coronavirus disease (COVID) (27 pre-Delta, 20 Delta, and 56 Omicron-era). Twenty-five patients (24%) required hospitalization and 10 patients ultimately died (10%). Among 85 survivors who completed ambulatory spirometry, COVID-19 did not alter change in forced expiratory volume in 1 s (FEV1 ) or forced vital capacity (FVC) over time compared to the preceding 6 months. The pre-COVID FEV1 change was -0.05 ml/day (IQR -0.50 to 0.60) compared to -0.20 ml/day (IQR -1.40 to 0.70) post-COVID (p = .16). The pre-COVID change in FVC was 0.20 ml/day (IQR -0.60 to 0.70) compared to 0.05 ml/day (IQR -1.00 to 1.10) post-COVID (p = .76). Although the cohort overall had stable lung function, 33 patients (39%) developed ALAD or accelerated chronic lung allograft dysfunction (FEV1 decline >10% from pre-COVID baseline). Nine patients (35%) with ALAD recovered lung function. Within 3 months of acute COVID infection, 18 patients (17%) developed secondary infections, the majority being bacterial pneumonia. Finally, vaccination with at least two doses of mRNA vaccine was not associated with improved outcomes. CONCLUSIONS: This study describes the natural history of SARS-CoV-2 infection in a large cohort of lung transplant recipients. Although one third of patients develop ALAD requiring augmented immunosuppression, infection with SARS-CoV-2 is not associated with worsening lung function.

Evaluation and management of patients with chronic thromboembolic pulmonary hypertension - consensus statement from the ISHLT.

ISHLT members have recognized the importance of a consensus statement on the evaluation and management of patients with chronic thromboembolic pulmonary hypertension. The creation of this document required multiple steps, including the engagement of the ISHLT councils, approval by the Standards and Guidelines Committee, identification and selection of experts in the field, and the development of 6 working groups. Each working group provided a separate section based on an extensive literature search. These sections were then coalesced into a single document that was circulated to all members of the working groups. Key points were summarized at the end of each section. Due to the limited number of comparative trials in this field, the document was written as a literature review with expert opinion rather than based on level of evidence.

Results From the United States Chronic Thromboembolic Pulmonary Hypertension Registry: Enrollment Characteristics and 1-Year Follow-up.

BACKGROUND: The United States Chronic Thromboembolic Pulmonary Hypertension Registry (US-CTEPH-R) was designed to characterize the demographic characteristics, evaluation, clinical course, and outcomes of surgical and nonsurgical therapies for patients with chronic thromboembolic pulmonary hypertension. RESEARCH QUESTION: What are the differences in baseline characteristics and 1-year outcomes between operated and nonoperated subjects? STUDY DESIGN AND METHODS: This study describes a multicenter, prospective, longitudinal, observational registry of patients newly diagnosed (< 6 months) with CTEPH. Inclusion criteria required a mean pulmonary artery pressure ≥ 25 mm Hg documented by right heart catheterization and radiologic confirmation of CTEPH. Between 2015 and 2018, a total of 750 patients were enrolled and followed up biannually until 2019. RESULTS: Most patients with CTEPH (87.9%) reported a history of acute pulmonary embolism. CTEPH diagnosis delays were frequent (median, 10 months), and most patients reported World Health Organization functional class 3 status at enrollment with a median mean pulmonary artery pressure of 44 mm Hg. The registry cohort was subdivided into Operable patients undergoing pulmonary thromboendarterectomy (PTE) surgery (n = 566), Operable patients who did not undergo surgery (n = 88), and those who were Inoperable (n = 96). Inoperable patients were older than Operated patients; less likely to be obese; have a DVT history, non-type O blood group, or thrombophilia; and more likely to have COPD or a history of cancer. PTE resulted in a median pulmonary vascular resistance decline from 6.9 to 2.6 Wood units (P < .001) with a 3.9% in-hospital mortality. At 1-year follow-up, Operated patients were less likely treated with oxygen, diuretics, or pulmonary hypertension-targeted therapy compared with Inoperable patients. A larger percentage of Operated patients were World Health Organization functional class 1 or 2 at 1 year (82.9%) compared with the Inoperable (48.2%) and Operable/No Surgery (56%) groups (P < .001). INTERPRETATION: Differences exist in the clinical characteristics between patients who exhibited operable CTEPH and those who were inoperable, with the most favorable 1-year outcomes in those who underwent PTE surgery. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT02429284; URL: www.clinicaltrials.gov.

Mechanistic Phase II Clinical Trial of Metformin in Pulmonary Arterial Hypertension.

Background Metabolic dysfunction is highly prevalent in pulmonary arterial hypertension (PAH) and likely contributes to both pulmonary vascular disease and right ventricular (RV) failure in part because of increased oxidant stress. Currently, there is no cure for PAH and human studies of metabolic interventions, generally well tolerated in other diseases, are limited in PAH. Metformin is a commonly used oral antidiabetic that decreases gluconeogenesis, increases fatty acid oxidation, and reduces oxidant stress and thus may be relevant to PAH. Methods and Results We performed a single-center, open-label 8-week phase II trial of up to 2 g/day of metformin in patients with idiopathic or heritable PAH with the co-primary end points of safety, including development of lactic acidosis and study withdrawal, and plasma oxidant stress markers. Exploratory end points included RV function via echocardiography, plasma metabolomic analysis performed before and after metformin therapy, and RV triglyceride content by magnetic resonance spectroscopy in a subset of 9 patients. We enrolled 20 patients; 19/20 reached the target dose and all completed the study protocol. There was no clinically significant lactic acidosis or change in oxidant stress markers. Metformin did not change 6-minute walk distance but did significantly improve RV fractional area change (23±8% to 26±6%, P=0.02), though other echocardiographic parameters were unchanged. RV triglyceride content decreased in 8/9 patients (3.2±1.8% to 1.6±1.4%, P=0.015). In an exploratory metabolomic analysis, plasma metabolomic correlates of ≥50% reduction in RV lipid included dihydroxybutyrate, acetylputrescine, hydroxystearate, and glucuronate (P<0.05 for all). In the entire cohort, lipid metabolites were among the most changed by metformin. Conclusions Metformin therapy was safe and well tolerated in patients with PAH in this single-arm, open-label phase II study. Exploratory analyses suggest that metformin may be associated with improved RV fractional area change and, in a subset of patients, reduced RV triglyceride content that correlated with altered lipid and glucose metabolism markers. Registration URL: http://www.clinicaltrials.gov; Unique identifier: NCT01884051.

Pulmonary Hypertension and Right Ventricular Failure: Lung Transplant Versus Heart-Lung Transplant.

Pulmonary arterial hypertension is a highly morbid disease with limited treatment options that improve survival and currently the only curative treatment is transplantation. There is a small body of literature comparing the efficacy of lung and heart-lung transplantation in this population. The bulk of evidence suggests that most patients with severe right ventricular failure undergoing transplant will have recovery of right ventricular function after lung transplantation. Existing data suggest that, in the absence of complex congenital heart disease or significant left ventricular dysfunction, double-lung transplant is the surgical procedure of choice.

Echocardiographic Detection of Occult Diastolic Dysfunction in Pulmonary Hypertension After Fluid Challenge.

Background Identification of occult diastolic dysfunction often requires invasive right heart catheterization with provocative maneuvers such as fluid challenge. Non-invasive predictors of occult diastolic dysfunction have not been identified. We hypothesized that echocardiographic measures of diastolic function are associated with occult diastolic dysfunction identified at catheterization. Methods and Results We retrospectively examined hemodynamic and echocardiographic data from consecutive patients referred for right heart catheterization with fluid challenge from 2009 to 2017. A replication cohort of 52 patients who prospectively underwent simultaneous echocardiography and right heart catheterization before and after fluid challenge at Monaldi Hospital, Naples, Italy. In the retrospective cohort of 126 patients (83% female, 56+14 years), 27/126 (21%) had occult diastolic dysfunction. After adjusting for tricuspid regurgitant velocity and left atrial volume index, E velocity (odds ratio 1.8, 95% CI 1.1-2.9, P=0.01) and E/e' (odds ratio 1.9, 95% CI 1.1-3, P=0.005) were associated with occult diastolic dysfunction with an optimal threshold of E/e' >8.6 for occult diastolic dysfunction (sensitivity 70%, specificity 64%). In the prospective cohort, 5/52 (10%) patients had diastolic dysfunction after fluid challenge. Resting E/e' (odds ratio 8.75, 95% CI 2.3-33, P=0.001) and E velocity (odds ratio 7.7, 95% CI 2-29, P=0.003) remained associated with occult diastolic dysfunction with optimal threshold of E/e' >8 (sensitivity 73%, specificity 90%). Conclusions Among patients referred for right heart catheterization with fluid challenge, E velocity and E/e' are associated with occult diastolic dysfunction after fluid challenge. These findings suggest that routine echocardiographic measurements may help identify patients like to have occult diastolic dysfunction non-invasively.

Human PAH is characterized by a pattern of lipid-related insulin resistance.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a deadly disease of the small pulmonary vasculature with an increased prevalence of insulin resistance (IR). Insulin regulates both glucose and lipid homeostasis. We sought to quantify glucose- and lipid-related IR in human PAH, testing the hypothesis that lipoprotein indices are more sensitive indices of IR in PAH. METHODS: Oral glucose tolerance testing in PAH patients and triglyceride-matched (TG-matched) controls and proteomic, metabolomics, and lipoprotein analyses were performed in PAH and controls. Results were validated in an external cohort and in explanted human PAH lungs. RESULTS: PAH patients were similarly glucose intolerant or IR by glucose homeostasis metrics compared with control patients when matched for the metabolic syndrome. Using the insulin-sensitive lipoprotein index, TG/HDL ratio, PAH patients were more commonly IR than controls. Proteomic and metabolomic analysis demonstrated separation between PAH and controls, driven by differences in lipid species. We observed a significant increase in long-chain acylcarnitines, phosphatidylcholines, insulin metabolism-related proteins, and in oxidized LDL receptor 1 (OLR1) in PAH plasma in both a discovery and validation cohort. PAH patients had higher lipoprotein axis-related IR and lipoprotein-based inflammation scores compared with controls. PAH patient lung tissue showed enhanced OLR1 immunostaining within plexiform lesions and oxidized LDL accumulation within macrophages. CONCLUSIONS: IR in PAH is characterized by alterations in lipid and lipoprotein homeostasis axes, manifest by elevated TG/HDL ratio, and elevated circulating medium- and long-chain acylcarnitines and lipoproteins. Oxidized LDL and its receptor OLR1 may play a role in a proinflammatory phenotype in PAH. FUNDING: NIH DK096994, HL060906, UL1 RR024975-01, UL1 TR000445-06, DK020593, P01 HL108800-01A1, and UL1 TR002243; American Heart Association 13FTF16070002.

A potential therapeutic role for angiotensin-converting enzyme 2 in human pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a deadly disease with no cure. Alternate conversion of angiotensin II (AngII) to angiotensin-(1-7) (Ang-(1-7)) by angiotensin-converting enzyme 2 (ACE2) resulting in Mas receptor (Mas1) activation improves rodent models of PAH. Effects of recombinant human (rh) ACE2 in human PAH are unknown. Our objective was to determine the effects of rhACE2 in PAH.We defined the molecular effects of Mas1 activation using porcine pulmonary arteries, measured AngII/Ang-(1-7) levels in human PAH and conducted a phase IIa, open-label pilot study of a single infusion of rhACE2 (GSK2586881, 0.2 or 0.4 mg·kg-1 intravenously).Superoxide dismutase 2 (SOD2) and inflammatory gene expression were identified as markers of Mas1 activation. After confirming reduced plasma ACE2 activity in human PAH, five patients were enrolled in the trial. GSK2586881 was well tolerated with significant improvement in cardiac output and pulmonary vascular resistance. GSK2586881 infusion was associated with reduced plasma markers of inflammation within 2-4 h and increased SOD2 plasma protein at 2 weeks.PAH is characterised by reduced ACE2 activity. Augmentation of ACE2 in a pilot study was well tolerated, associated with improved pulmonary haemodynamics and reduced markers of oxidant and inflammatory mediators. Targeting this pathway may be beneficial in human PAH.

The transpulmonary ratio of endothelin 1 is elevated in patients with preserved left ventricular ejection fraction and combined pre- and post-capillary pulmonary hypertension.

Pulmonary hypertension complicating left heart disease (PH-LHD) is associated with increased morbidity and mortality, especially in patients who develop combined pre- and post-capillary PH (Cpc-PH). Mechanisms underlying PH-LHD are incompletely understood, particularly for individuals with preserved left ventricular ejection fraction (LVEF). We hypothesized that transpulmonary concentrations of biomarkers representing signaling pathways with known effects on the pulmonary circulation could provide insight into the molecular etiology of PH-LHD in patients with preserved LVEF. Blood samples were collected from the pulmonary artery (PA) and wedge positions of outpatients with normal LVEF referred for right heart catheterization. Hemodynamic tracings were reviewed to classify patients as "no PH" (n = 23) or "PH-LHD" (n = 22). A biomarker's transpulmonary ratio (TPR) was calculated as the quotient of wedge and PA concentrations. The TPR of endothelin 1 (ET-1) was elevated in Cpc-PH (n = 10) compared to no PH or isolated post-capillary PH (Ipc-PH, n = 12); cAMP and cGMP TPRs were not different among groups. Higher ET-1 TPR in Cpc-PH was due to increased wedge ET-1 concentration. Pulmonary vascular resistance (PVR) strongly correlated with wedge ET-1 exclusively in Cpc-PH patients. In patients with normal LVEF and Cpc-PH, ET-1 TPR is higher, due to elevated wedge ET-1, compared to those without PH or with Ipc-PH. Strong correlation between PVR and wedge ET-1, observed only in the Cpc-PH group, may suggest increased pulmonary vascular responsiveness to ET-1 in these patients. These findings implicate elevated pulmonary ET-1 as a marker of, and a potential contributor to, development of Cpc-PH in this population.

Prognostic Effect and Longitudinal Hemodynamic Assessment of Borderline Pulmonary Hypertension.

Importance: Pulmonary hypertension (PH) is diagnosed by a mean pulmonary arterial pressure (mPAP) value of at least 25 mm Hg during right heart catheterization (RHC). While several studies have demonstrated increased mortality in patients with mPAP less than that threshold, little is known about the natural history of borderline PH. Objective: To test the hypothesis that patients with borderline PH have decreased survival compared with patients with lower mPAP and frequently develop overt PH and to identify clinical correlates of borderline PH. Design, Setting, and Participants: Retrospective cohort study from 1998 to 2014 at Vanderbilt University Medical Center, comprising all patients undergoing routine RHC for clinical indication. We extracted demographics, clinical data, invasive hemodynamics, echocardiography, and vital status for all patients. Patients with mPAP values of 18 mm Hg or less, 19 to 24 mm Hg, and at least 25 mm Hg were classified as reference, borderline PH, and PH, respectively. Exposures: Mean pulmonary arterial pressure. Main Outcome and Measures: Our primary outcome was all-cause mortality after adjusting for clinically relevant covariates in a Cox proportional hazards model. Our secondary outcome was the diagnosis of overt PH in patients initially diagnosed with borderline PH. Both outcomes were determined prior to data analysis. Results: We identified 4343 patients (mean [SD] age, 59 [15] years, 51% women, and 86% white) among whom the prevalence of PH and borderline PH was 62% and 18%, respectively. Advanced age, features of the metabolic syndrome, and chronic heart and lung disease were independently associated with a higher likelihood of borderline PH compared with reference patients in a logistic regression model. After adjusting for 34 covariates in a Cox proportional hazards model, borderline PH was associated with increased mortality compared with reference patients (hazard ratio, 1.31; 95% CI, 1.04-1.65; P = .001). The hazard of death increased incrementally with higher mPAP, without an observed threshold. In the 70 patients with borderline PH who underwent a repeated RHC, 43 (61%) had developed overt PH, with a median increase in mPAP of 5 mm Hg (interquartile range, -1 to 11 mm Hg; P < .001). Conclusions and Relevance: Borderline PH is common in patients undergoing RHC and is associated with significant comorbidities, progression to overt PH, and decreased survival. Small increases in mPAP, even at values currently considered normal, are independently associated with increased mortality. Prospective studies are warranted to determine whether early intervention or closer monitoring improves clinical outcomes in these patients.

End-Tidal Carbon Dioxide as a Prognostic Feature in Pulmonary Arterial Hypertension.

RATIONALE: Pulmonary arterial hypertension (PAH) is characterized in part by increased dead space ventilation, which can be estimated noninvasively at the bedside by measurement of end-tidal CO2 (ETco2). OBJECTIVES: Prior work has demonstrated that ETco2 is lower in patients with PAH than in control patients, but whether ETco2 has prognostic value is unknown. We hypothesized that lower measurements of ETco2 in patients with PAH correlate with worse long-term outcomes. METHODS: Patients with PAH seen in our referral clinic were prospectively recruited for ETco2 measurement between September 2009 and February 2010. Vital status as of July 2015 was documented using medical records and the Social Security Death Index. RESULTS: Eighty-two patients were followed for a median of 60 months. Twenty-six patients died, and two were lost to follow-up. Patients who died were more likely to be older (58.5 ± 14.9 vs. 47.6 ± 12.2 yr; P < 0.05) and to have shorter 6-minute walk distance (296 ± 127 vs. 401 ± 92 m; P < 0.05). Mean ETco2 in survivors was 30.5 ± 4.8 mm Hg, whereas mean ETco2 in patients who died was 27.1 ± 4.2 mm Hg (P = 0.004). After stratification by median baseline ETco2 of 29 mm Hg, survival in each group was analyzed. Patients with lower ETco2 had shorter survival (P = 0.006). Cox regression analysis with ETco2 as a continuous variable revealed the hazard ratio to be 0.88 (95% confidence interval, 0.80-0.97; P = 0.006). In 52 patients with more than one measurement a median of 17 months apart, ETco2 was unchanged. CONCLUSIONS: Our single-center data suggest that lower ETco2 is associated with shorter survival and that ETco2 is stable over time in patients with PAH.

Update on chronic thromboembolic pulmonary hypertension.

Chronic, unresolved thromboemboli are an important cause of pulmonary hypertension (PH) with specific treatment strategies differing from other types of PH. Chronic thromboembolic pulmonary hypertension (CTEPH) is classified as group 4 PH by the World Health Organization. It is a rare, but underdiagnosed, complication of acute pulmonary embolism that does not resolve and results in occlusion of large pulmonary arteries with a fibro-thrombotic material. The etiology of CTEPH remains uncertain, and it is unknown why certain patients with acute pulmonary embolism develop this disorder. The evaluation for CTEPH is an important part of the evaluation for PH in general, and it is crucial not to overlook this diagnosis, as it is the only form of PH that is potentially curable. Patients diagnosed with CTEPH should be referred to an expert center for consideration of pulmonary endarterectomy, and surgical removal of the chronic thromboembolic material. Not all patients with CTEPH are surgical candidates, however, and there are emerging treatments-medical therapy and balloon pulmonary angioplasty-that have shown benefit in this patient population. Without treatment, CTEPH can lead to progressive pulmonary vascular obstruction, right heart failure, and death. Thus, it is important for clinicians to recognize this subtype of PH. In this review, we provide an overview of current understanding of the pathogenesis of CTEPH and highlight recommendations and recent advances in the evaluation and treatment of CTEPH.

Hemodynamic evidence of vascular remodeling in combined post- and precapillary pulmonary hypertension.

Although commonly encountered, patients with combined postcapillary and precapillary pulmonary hypertension (Cpc-PH) have poorly understood pulmonary vascular properties. The product of pulmonary vascular resistance and compliance, resistance-compliance (RC) time, is a measure of pulmonary vascular physiology. While RC time is lower in postcapillary PH than in precapillary PH, the RC time in Cpc-PH and the effect of pulmonary wedge pressure (PWP) on RC time are unknown. We tested the hypothesis that Cpc-PH has an RC time that resembles that in pulmonary arterial hypertension (PAH) more than that in isolated postcapillary PH (Ipc-PH). We analyzed the hemodynamics of 282 consecutive patients with PH referred for right heart catheterization (RHC) with a fluid challenge from 2004 to 2013 (cohort A) and 4,382 patients who underwent RHC between 1998 and 2014 for validation (cohort B). Baseline RC time in Cpc-PH was higher than that in Ipc-PH and lower than that in PAH in both cohorts (P < 0.001). In cohort A, RC time decreased after fluid challenge in patients with Ipc-PH but not in those with PAH or Cpc-PH (P < 0.001). In cohort B, the inverse relationship of pulmonary vascular compliance and resistance, as well as that of RC time and PWP, in Cpc-PH was similar to that in PAH and distinct from that in Ipc-PH. Our findings demonstrate that patients with Cpc-PH have pulmonary vascular physiology that resembles that of patients with PAH more than that of Ipc-PH patients. Further study is warranted to identify determinants of vascular remodeling and assess therapeutic response in this subset of PH.

Severity of pulmonary hypertension and obesity are not associated with worse functional outcomes after pulmonary thromboendarterectomy.

Predictors of functional outcomes in patients with chronic thromboembolic pulmonary hypertension (CTEPH) undergoing pulmonary thromboendarterectomy (PTE) are important to identify preoperatively. We hypothesized that baseline severity of pulmonary hypertension and obesity would not be associated with 6-month functional outcomes after PTE. Clinical and hemodynamic data were collected on consecutive patients undergoing PTE from 2008 to 2014. Patients were stratified according to baseline pulmonary vascular resistance (PVR) and body mass index (BMI). Six-minute walk distance (6MWD), New York Heart Association functional class (FC), and echocardiography were assessed in each group at baseline and 6 months after PTE. Regression analyses were performed to evaluate for associations between functional outcomes and baseline PVR and BMI. Forty-two patients underwent PTE and had 6-month follow up data. In comparisons of patients with high and low baseline PVR, the baseline characteristics, distribution of disease, 6MWD, and FC were similar. Postoperative hemodynamics for both groups were similar. At 6 months, both groups achieved improvements in FC, and there were no between-group differences in the change in 6MWD or FC. In comparisons of obese and nonobese patients, perioperative and FC improvement were similar; however, obese patients achieved a greater improvement in 6MWD than nonobese patients (P = 0.04). In conclusion, our data suggest that baseline severity of CTEPH and obesity were not associated with worse functional outcome. Further studies are needed to confirm these results, as these findings could have implications for patient selection for PTE.

Critical Genomic Networks and Vasoreactive Variants in Idiopathic Pulmonary Arterial Hypertension.

RATIONALE: Idiopathic pulmonary arterial hypertension (IPAH) is usually without an identified genetic cause, despite clinical and molecular similarity to bone morphogenetic protein receptor type 2 mutation-associated heritable pulmonary arterial hypertension (PAH). There is phenotypic heterogeneity in IPAH, with a minority of patients showing long-term improvement with calcium channel-blocker therapy. OBJECTIVES: We sought to identify gene variants (GVs) underlying IPAH and determine whether GVs differ in vasodilator-responsive IPAH (VR-PAH) versus vasodilator-nonresponsive IPAH (VN-PAH). METHODS: We performed whole-exome sequencing (WES) on 36 patients with IPAH: 17 with VR-PAH and 19 with VN-PAH. Wnt pathway differences were explored in human lung fibroblasts. MEASUREMENTS AND MAIN RESULTS: We identified 1,369 genes with 1,580 variants unique to IPAH. We used a gene ontology approach to analyze variants and identified overrepresentation of several pathways, including cytoskeletal function and ion binding. By mapping WES data to prior genome-wide association study data, Wnt pathway genes were highlighted. Using the connectivity map to define genetic differences between VR-PAH and VN-PAH, we found enrichment in vascular smooth muscle cell contraction pathways and greater genetic variation in VR-PAH versus VN-PAH. Using human lung fibroblasts, we found increased stimulated Wnt activity in IPAH versus controls. CONCLUSIONS: A pathway-based analysis of WES data in IPAH demonstrated multiple rare GVs that converge on key biological pathways, such as cytoskeletal function and Wnt signaling pathway. Vascular smooth muscle contraction-related genes were enriched in VR-PAH, suggesting a potentially different genetic predisposition for VR-PAH. This pathway-based approach may be applied to next-generation sequencing data in other diseases to uncover the contribution of unexpected or multiple GVs to a phenotype.

Valsalva Maneuver in Pulmonary Arterial Hypertension: Susceptibility to Syncope and Autonomic Dysfunction.

BACKGROUND: Patients with pulmonary arterial hypertension (PAH) are routinely instructed to avoid performing the Valsalva maneuver for fear of syncope or sudden cardiac death. The mechanism of this action has not been elucidated. We conducted a case-control trial of nine patients with PAH and 15 healthy control subjects to determine if systemic hemodynamic changes during the Valsalva maneuver in these patients invoke greater susceptibility to syncope than healthy control subjects. Metrics commonly employed in autonomic testing were used to assess the degree of autonomic failure. METHODS: Common Valsalva parameters, including adrenergic baroreflex sensitivity, pressure recovery time, systolic BP (SBP) recovery, diastolic BP (DBP) recovery, mean arterial pressure recovery, and the Valsalva ratio, were calculated. Mann-Whitney U tests were used to compare continuous variables. The primary end point was adrenergic baroreflex sensitivity. RESULTS: Patients with PAH had lower adrenergic baroreflex sensitivity (9.7 ± 4.6 mm Hg/s vs 18.8 ± 9.2 mm Hg/s; P = .005), longer pressure recovery time (3.6 ± 2.5 s vs 1.7 ± 0.8 s; P = .008), similar SBP recovery (-13 ± 11 mm Hg vs -12 ± 23 mm Hg; P = .640), less DBP recovery (-1 ± 12 mm Hg vs 13 ± 14 mmHg; P = .025), less mean arterial pressure recovery (-5 ± 11 mm Hg vs 5 ± 17 mm Hg; P = .048), and a decreased Valsalva ratio (1.25 ± 0.11 vs 1.60 ± 0.22; P < .001) compared with healthy control subjects. CONCLUSIONS: Compared with healthy control subjects, patients with PAH are more susceptible to syncope during the Valsalva maneuver because of autonomic dysfunction causing cerebral hypoperfusion. These study patients with PAH exhibited a degree of susceptibility to syncope similar to a spectrum of patients with intermediate autonomic failure who typically experience a SBP drop of 10 to 30 mm Hg with standing.