Relationship of TAPSE Normalized by Right Ventricular Area With Pulmonary Compliance, Exercise Capacity, and Clinical Outcomes.

BACKGROUND: While tricuspid annular plane systolic excursion (TAPSE) captures the predominant longitudinal motion of the right ventricle (RV), it does not account for ventricular morphology and radial motion changes in various forms of pulmonary hypertension. This study aims to account for both longitudinal and radial motions by dividing TAPSE by RV area and to assess its clinical significance. METHODS: We performed a retrospective analysis of 71 subjects with New York Heart Association class II to III dyspnea who underwent echocardiogram and invasive cardiopulmonary exercise testing (which defined 4 hemodynamic groups: control, isolated postcapillary pulmonary hypertension, combined postcapillary pulmonary hypertension, and pulmonary arterial hypertension). On the echocardiogram, TAPSE was divided by RV area in diastole (TAPSE/RVA-D) and systole (TAPSE/RVA-S). Analyses included correlations (Pearson and linear regression), receiver operating characteristic, and survival curves. RESULTS: On linear regression analysis, TAPSE/RVA metrics (versus TAPSE) had a stronger correlation with pulmonary artery compliance (r=0.48-0.54 versus 0.38) and peak VO2 percentage predicted (0.23-0.30 versus 0.18). Based on the receiver operating characteristic analysis, pulmonary artery compliance ≥3 mL/mm Hg was identified by TAPSE/RVA-D with an under the curve (AUC) of 0.79 (optimal cutoff ≥1.1) and by TAPSE/RVA-S with an AUC of 0.83 (optimal cutoff ≥1.5), but by TAPSE with only an AUC of 0.67. Similarly, to identify peak VO2 <50% predicted, AUC of 0.66 for TAPSE/RVA-D and AUC of 0.65 for TAPSE/RVA-S. Death or cardiovascular hospitalization at 12 months was associated with TAPSE/RVA-D ≥1.1 (HR, 0.38 [95% CI, 0.11-0.56]) and TAPSE/RVA-S ≥1.5 (HR, 0.44 [95% CI, 0.16-0.78]), while TAPSE was not associated with adverse outcomes (HR, 0.99 [95% CI, 0.53-1.94]). Among 31 subjects with available cardiac magnetic resonance imaging, RV ejection fraction was better correlated with novel metrics (TAPSE/RVA-D r=0.378 and TAPSE/RVA-S r=0.328) than TAPSE (r=0.082). CONCLUSIONS: In a broad cohort with suspected pulmonary hypertension, TAPSE divided by RV area was superior to TAPSE alone in correlations with pulmonary compliance and exercise capacity. As a prognostic marker of right heart function, TAPSE/RVA-D <1.1 and TAPSE/RVA-S <1.5 predicted adverse cardiovascular outcomes.

Complexities and outcomes of pulmonary hypertension in kidney transplant patients: a comprehensive review.

Pulmonary hypertension (PH) is often present in patients presenting for kidney transplant listing. While PH can complicate kidney transplant (KTx), with multidisciplinary management that includes both the transplant center and pulmonary hypertension center or experts both pre- and post-transplant. This review summaries the approach and management of PH in KTx candidates and recipients, along with expected outcomes and controversies surrounding arteriovenous fistula and graft management.

Impact of the COVID-19 pandemic on chronic disease management and patient reported outcomes in patients with pulmonary hypertension: The Pulmonary Hypertension Association Registry.

To better understand the impact of the COVID-19 pandemic on the care of patients with pulmonary hypertension, we conducted a retrospective cohort study evaluating health insurance status, healthcare access, disease severity, and patient reported outcomes in this population. Using the Pulmonary Hypertension Association Registry (PHAR), we defined and extracted a longitudinal cohort of pulmonary arterial hypertension (PAH) patients from the PHAR's inception in 2015 until March 2022. We used generalized estimating equations to model the impact of the COVID-19 pandemic on patient outcomes, adjusting for demographic confounders. We assessed whether insurance status modified these effects via covariate interactions. PAH patients were more likely to be on publicly-sponsored insurance during the COVID-19 pandemic compared with prior, and did not experience statistically significant delays in access to medications, increased emergency room visits or nights in the hospital, or worsening of mental health metrics. Patients on publicly-sponsored insurance had higher healthcare utilization and worse objective measures of disease severity compared with privately insured individuals irrespective of the COVID-19 pandemic. The relatively small impact of the COVID-19 pandemic on pulmonary hypertension-related outcomes was unexpected but may be due to pre-established access to high quality care at pulmonary hypertension comprehensive care centers. Irrespective of the COVID-19 pandemic, patients who were on publicly-sponsored insurance seemed to do worse, consistent with prior studies highlighting outcomes in this population. We speculate that previously established care relationships may lessen the impact of an acute event, such as a pandemic, on patients with chronic illness.

Recumbent Ergometer vs Treadmill Cardiopulmonary Exercise Test in HFpEF: Implications for Chronotropic Response and Exercise Capacity.

BACKGROUND: Cardiopulmonary exercise testing (CPET) can identify mechanisms of exercise intolerance in heart failure with preserved ejection fraction (HFpEF), but exercise modalities with differing body positions (eg, recumbent ergometer, treadmill) are broadly used. In this study, we aimed to determine whether body position affects CPET parameters in patients with HFpEF. METHODS: Subjects with stable HFpEF (n = 23) underwent noninvasive treadmill CPET, followed by an invasive recumbent-cycle ergometer CPET within 3 months. A comparison group undergoing similar studies included healthy subjects (n = 5) and subjects with pulmonary arterial hypertension (n = 6). RESULTS: The peak oxygen consumption (VO2peak) and peak heart rate were significantly lower in the recumbent vs the upright position (10.1 vs 13.1 mL/kg/min [Δ-3 mL/kg/min]; P < 0.001; and 95 vs 113 bpm [Δ-18 bpm]; P < 0.001, respectively). No significant differences were found in the minute ventilation to carbon dioxide production ratio, end-tidal pressure of carbon dioxide or respiratory exchange ratio. A similar pattern was observed in the comparison groups. CONCLUSIONS: Compared to recumbent ergometer, treadmill CPET revealed higher VO2peak and peak heart rate response. When determining chronotropic incompetence to adjust beta-blocker administration in HFpEF, body position should be taken into account.

Erratum: Health disparities and treatment approaches in portopulmonary hypertension and idiopathic pulmonary arterial hypertension: An analysis of the Pulmonary Hypertension Association Registry.

[This corrects the article DOI: 10.1177/20458940211020913.].

Prevalence of aortic stenosis and TAVR outcomes in patients with systemic sclerosis-associated pulmonary hypertension.

There is little known about performing transcatheter aortic valve replacement (TAVR) in patients with group 1 pulmonary arterial hypertension (PAH) on advanced pulmonary vasodilator therapy. Retrospective cohort study among 90 patients with systemic sclerosis-associated pulmonary arterial hypertension and systemic sclerosis-associated pulmonary hypertension (SSc-PAH/PH) evaluated at a tertiary PH center. The SSc-PAH/PH cohort was stratified by the presence or absence of aortic stenosis (AS) to identify differences in baseline characteristics, hemodynamics, and long-term outcomes. Of the 90 SSc-PAH/PH patients, 13 patients were diagnosed with AS at PH diagnosis and another 6 patients developed AS during the study period. The period prevalence of AS was 21.1% (19/90, 95% confidence interval: 13.2%-30.1%) of which 94.7% was mild (18/19) at diagnosis with mean age at AS diagnosis of 66.3 + 2.2 years. Among AS patients, 31.6% (6/19) progressed to severe AS, five of which underwent TAVR (median age: 70 years) while on advanced PAH therapy. One of the five TAVR patients developed worsening pulmonary hypertension post-TAVR. The 5-year survival rate for all AS patients from diagnosis date was 37.2%. There was a high prevalence of AS in this cohort of SSc-PAH/PH patients, with mean age of onset younger than patients with nonbicuspid aortic valve stenosis. This is the largest series of SSc-PAH/PH patients on advanced pulmonary vasodilator therapy who underwent TAVR with acceptable early outcomes.

Increased RV:LV ratio on chest CT-angiogram in COVID-19 is a marker of adverse outcomes.

BACKGROUND: Right ventricular (RV) dilation has been used to predict adverse outcomes in acute pulmonary conditions. It has been used to categorize the severity of novel coronavirus infection (COVID-19) infection. Our study aimed to use chest CT-angiogram (CTA) to assess if increased RV dilation, quantified as an increased RV:LV (left ventricle) ratio, is associated with adverse outcomes in the COVID-19 infection, and if it occurs out of proportion to lung parenchymal disease. RESULTS: We reviewed clinical, laboratory, and chest CTA findings in COVID-19 patients (n = 100), and two control groups: normal subjects (n = 10) and subjects with organizing pneumonia (n = 10). On a chest CTA, we measured basal dimensions of the RV and LV in a focused 4-chamber view, and dimensions of pulmonary artery (PA) and aorta (AO) at the PA bifurcation level. Among the COVID-19 cohort, a higher RV:LV ratio was correlated with adverse outcomes, defined as ICU admission, intubation, or death. In patients with adverse outcomes, the RV:LV ratio was 1.06 ± 0.10, versus 0.95 ± 0.15 in patients without adverse outcomes. Among the adverse outcomes group, compared to the control subjects with organizing pneumonia, the lung parenchymal damage was lower (22.6 ± 9.0 vs. 32.7 ± 6.6), yet the RV:LV ratio was higher (1.06 ± 0.14 vs. 0.89 ± 0.07). In ROC analysis, RV:LV ratio had an AUC = 0.707 with an optimal cutoff of RV:LV ≥ 1.1 as a predictor of adverse outcomes. In a validation cohort (n = 25), an RV:LV ≥ 1.1 as a cutoff predicted adverse outcomes with an odds ratio of 76:1. CONCLUSIONS: In COVID-19 patients, RV:LV ratio ≥ 1.1 on CTA chest is correlated with adverse outcomes. RV dilation in COVID-19 is out of proportion to parenchymal lung damage, pointing toward a vascular and/or thrombotic injury in the lungs.

Distinguishing exercise intolerance in early-stage pulmonary hypertension with invasive exercise hemodynamics: Rest VE /VCO2 and ETCO2 identify pulmonary vascular disease.

BACKGROUND: Among subjects with exercise intolerance and suspected early-stage pulmonary hypertension (PH), early identification of pulmonary vascular disease (PVD) with noninvasive methods is essential for prompt PH management. HYPOTHESIS: Rest gas exchange parameters (minute ventilation to carbon dioxide production ratio: VE /VCO2 and end-tidal carbon dioxide: ETCO2 ) can identify PVD in early-stage PH. METHODS: We conducted a retrospective review of 55 subjects with early-stage PH (per echocardiogram), undergoing invasive exercise hemodynamics with cardiopulmonary exercise test to distinguish exercise intolerance mechanisms. Based on the rest and exercise hemodynamics, three distinct phenotypes were defined: (1) PVD, (2) pulmonary venous hypertension, and (3) noncardiac dyspnea (no rest or exercise PH). For all tests, *p < .05 was considered statistically significant. RESULTS: The mean age was 63.3 ± 13.4 years (53% female). In the overall cohort, higher rest VE /VCO2 and lower rest ETCO2 (mm Hg) correlated with high rest and exercise pulmonary vascular resistance (PVR) (r ~ 0.5-0.6*). On receiver-operating characteristic analysis to predict PVD (vs. non-PVD) subjects with noninvasive metrics, area under the curve for pulmonary artery systolic pressure (echocardiogram) = 0.53, rest VE /VCO2 = 0.70* and ETCO2 = 0.73*. Based on this, optimal thresholds of rest VE /VCO2 > 40 mm Hg and rest ETCO2 < 30 mm Hg were applied to the overall cohort. Subjects with both abnormal gas exchange parameters (n = 12, vs. both normal parameters, n = 19) had an exercise PVR 5.2 ± 2.6* (vs. 1.9 ± 1.2), mPAP/CO slope with exercise 10.2 ± 6.0* (vs. 2.9 ± 2.0), and none included subjects from the noncardiac dyspnea group. CONCLUSIONS: In a broad cohort of subjects with suspected early-stage PH, referred for invasive exercise testing to distinguish mechanisms of exercise intolerance, rest gas exchange parameters (VE /VCO2 > 40 mm Hg and ETCO2 < 30 mm Hg) identify PVD.

Incidence, Clinical Correlates, and Outcomes of Pulmonary Hypertension After Kidney Transplantation: Analysis of Linked US Registry and Medicare Billing Claims.

BACKGROUND: The incidence, risks, and outcomes associated with pulmonary hypertension (P-HTN) in the kidney transplant (KTx) population are not well described. METHODS: We linked US transplant registry data with Medicare claims (2006-2016) to investigate P-HTN diagnoses among Medicare-insured KTx recipients (N = 35 512) using billing claims. Cox regression was applied to identify independent correlates and outcomes of P-HTN (adjusted hazard ratio [aHR] 95%LCLaHR95%UCL) and to examine P-HTN diagnoses as time-dependent mortality predictors. RESULTS: Overall, 8.2% of recipients had a diagnostic code for P-HTN within 2 y preceding transplant. By 3 y posttransplant, P-HTN was diagnosed in 10.310.6%11.0 of the study cohort. After adjustment, posttransplant P-HTN was more likely in KTx recipients who were older (age ≥60 versus 18-30 y a HR, 1.912.403.01) or female (aHR, 1.151.241.34), who had pretransplant P-HTN (aHR, 4.384.795.24), coronary artery disease (aHR, 1.051.151.27), valvular heart disease (aHR, 1.221.321.43), peripheral vascular disease (aHR, 1.051.181.33), chronic pulmonary disease (aHR, 1.201.311.43), obstructive sleep apnea (aHR, 1.151.281.43), longer dialysis duration, pretransplant hemodialysis (aHR, 1.171.371.59), or who underwent transplant in the more recent era (2012-2016 versus 2006-2011: aHR, 1.291.391.51). Posttransplant P-HTN was associated with >2.5-fold increased risk of mortality (aHR, 2.572.843.14) and all-cause graft failure (aHR, 2.422.642.88) within 3 y posttransplant. Outcome associations of newly diagnosed posttransplant P-HTN were similar. CONCLUSIONS: Posttransplant P-HTN is diagnosed in 1 in 10 KTx recipients and is associated with an increased risk of death and graft failure. Future research is needed to refine diagnostic, classification, and management strategies to improve outcomes in KTx recipients who develop P-HTN.

A 48-Year-Old Amateur Bodybuilder With History of Provoked DVT With Subacute Progressive Shortness of Breath.

CASE PRESENTATION: A 48-year-old man presented with 6 months of progressive shortness of breath, intermittent exertional left-sided chest pain, and bilateral lower extremity edema. During the 2 days before admission, he experienced new onset confusion, fatigue, and malaise that prompted evaluation. He denied fever, chills, cough, or sputum production. He used anabolic steroids for 20 years as part of his bodybuilding hobby. Recently, he also began injecting mineral oil into his pectoral, bicep, and shoulder muscles for an improved muscular appearance. Additionally, he had a history of provoked DVT after traumatic fracture, schizophrenia, hypertension, and epilepsy. He was a former cigarette smoker with 2.5 pack-year history, having quit 10 years earlier. The patient's occupation was construction, installing aluminum gutters. He specifically denied exposures to sand-blasting, coal, beryllium, hard metals, silicone, and fine particles. He had no recent travel, sick contacts, or animal exposures.

Interferon-ß-Induced Pulmonary Arterial Hypertension: Approach to Diagnosis and Clinical Monitoring.

A 48-year-old woman who had been receiving long-term interferon-ß for 8 years for multiple sclerosis developed drug-induced World Health Organization group I pulmonary arterial hypertension. Triple therapy for pulmonary arterial hypertension and suspension of interferon-ß led to improvement from a high-risk to low-risk state and improvement in exercise hemodynamics, including vascular distensibility, and right ventricle-pulmonary artery coupling. (Level of Difficulty: Advanced.).

Health disparities and treatment approaches in portopulmonary hypertension and idiopathic pulmonary arterial hypertension: an analysis of the Pulmonary Hypertension Association Registry.

Compared to idiopathic pulmonary arterial hypertension (IPAH), patients with portopulmonary hypertension (POPH) have worse survival. Health disparities may contribute to these differences but have not been studied. We sought to compare socioeconomic factors in patients with POPH and IPAH and to determine whether socioeconomic status and/or POPH diagnosis were associated with treatment and health-care utilization. We performed a cross-sectional study of adults enrolled in the Pulmonary Hypertension Association Registry. Patients with IPAH (n = 344) and POPH (n = 57) were compared. Compared with IPAH, patients with POPH were less likely to be college graduates (19.6% vs. 34.9%, p = 0.02) and more likely to be unemployed (54.7% vs. 30.5%, p < 0.001) and have an annual household income below poverty level (45.7% vs. 19.0%, p < 0.001). Patients with POPH had similar functional class, quality of life, 6-min walk distance, and mean pulmonary arterial pressure with a higher cardiac index. Compared with IPAH, patients with POPH were less likely to receive combination therapy (46.4% vs. 62.2%, p = 0.03) and endothelin receptor antagonists (28.6% vs. 55.1%, p < 0.001) at enrollment with similar treatment at follow-up. Patients with POPH had more emergency department visits (1.7 ± 2.1 vs. 0.9 ± 1.2, p = 0.009) and hospitalizations in the six months preceding enrollment (1.5 ± 2.1 vs. 0.8 ± 1.1, p = 0.02). Both POPH diagnosis and lower education level were independently associated with a higher number of emergency department visits. Compared to IPAH, patients with POPH have lower socioeconomic status, are less likely to receive initial combination therapy and endothelin receptor antagonists but have similar treatment at follow-up, and have increased health-care utilization.

Long-term Outcomes and Survival in Moderate-severe Portopulmonary Hypertension After Liver Transplant.

BACKGROUND: Portopulmonary hypertension is present in an estimated 5.3% to 8.5% of liver transplant candidates. Untreated, 5-year survival is estimated between 14% and 28%. Moderate-severe disease is a contraindication to liver transplant due to the high perioperative mortality, but patients optimized with pulmonary vasodilator therapy can become eligible for transplant. There is minimal data regarding posttransplant outcomes and ability to discontinue pulmonary vasodilator therapy posttransplant. METHODS: We performed a single-center retrospective analysis to evaluate long-term outcomes of patients with moderate-severe portopulmonary hypertension who were optimized with pulmonary vasodilator therapy, became eligible for liver transplant, and subsequently underwent transplant. We identified 24 patients optimized with pulmonary vasodilator therapy who underwent subsequent liver transplantation and 25 patients who were treated with pulmonary vasodilator therapy alone. RESULTS: In the transplanted cohort, 1-year survival from portopulmonary hypertension diagnosis date: 95.8%, 3-year survival: 90.9%, and 5-year survival: 90.9%. Posttransplant; 1-, 3-, and 5-year survival was 86.9%. Among transplanted patients, 41.6% (10/24) were optimized with nonparenteral therapy. Following transplantation, 100% (14/14) of the surviving patients were able to discontinue parenteral therapy; median time: 7.2 months (interquartile range: 5.1-8.9 mo), while 61.9% (13/21) were able to discontinue pulmonary vasodilator therapy altogether; median time: 13.9 months (interquartile range: 5.1-17.6 mo). CONCLUSIONS: Patients who are optimized with pulmonary vasodilator therapy before liver transplant can have excellent long-term outcomes posttransplant. Oral pulmonary vasodilator therapy can be effective treatment to qualify a patient for transplant, and the majority are able to wean from pulmonary vasodilator therapy entirely posttransplant.

Outcomes of Liver Transplantation in Treated Portopulmonary Hypertension Patients With a Mean Pulmonary Arterial Pressure ≥35 mm Hg.

Portopulmonary hypertension (POPH), pulmonary arterial hypertension (PAH) that develops in the setting of portal hypertension, affects 5%-6% of patients with liver disease and is associated with significant morbidity and mortality. A mean pulmonary arterial pressure (mPAP) threshold of 35 mm Hg is used to stratify perioperative risk and liver transplant eligibility in treated POPH patients but does not take into account the specific factors that contribute to the pressure elevation. METHODS: In this case series, we describe the characteristics and posttransplant outcomes of patients with treated POPH and an mPAP ≥35 mm Hg and pulmonary vascular resistance (PVR) <250 dynes-s-cm-5 at or just before liver transplantation (LT). We also describe the effect of PAH therapy on pulmonary hemodynamics in patients with POPH. RESULTS: Sixteen patients were included. All patients were on PAH therapy at the time of LT. PAH therapy resulted in a decrease of mPAP (median 18.4%; interquartile range [IQR] 8.9%-27.0%) with a reduction in PVR (median 50.5%; IQR, 45.4%-70.7%), and an increase in both cardiac output (CO) (median 28.1%; IQR 5.7%-63.8%) and PAWP (median 50.0%; IQR 16.7%-108.3%) before LT. One year posttransplant survival was 69% (11/16); however, only 1 death was attributed to POPH. At 1-year posttransplant, 63.6% (7/11) of patients were weaned off all PAH therapy with clinical and echocardiographic resolution of POPH. CONCLUSIONS: In treated POPH patients with an mPAP ≥35 mm Hg and PVR < 250 dynes-s-cm-5 before LT, 1-year posttransplant survival was 69% and the majority of patients were able to discontinue PAH therapy.

Exercise-Induced Changes in Pulmonary Artery Stiffness in Pulmonary Hypertension.

Background: Pulmonary hypertension causes pulmonary artery (PA) stiffening, which overloads the right ventricle (RV). Since symptoms of pulmonary hypertension (PH) are exacerbated by exercise, exercise-induced PA stiffening is relevant to cardiopulmonary status. Here, we sought to demonstrate the feasibility of using magnetic resonance imaging (MRI) for non-invasive assessment of exercise-induced changes in PA stiffness in patients with PH. Methods: MRI was performed on 7 PH patients and 8 age-matched control subjects at rest and during exercise stress. Main pulmonary artery (MPA) relative area change (RAC) and pulse wave velocity (PWV) were measured from 2D-PC images. Invasive right heart catheterization (RHC) was performed on 5 of the PH patients in conjunction with exercise stress to measure MPA pressures and stiffness index (ß). Results: Heart rate and cardiac index (CI) were significantly increased with exercise in both groups. In controls, RAC decreased from 0.27 ± 0.05 at rest to 0.22 ± 0.06 with exercise (P < 0.05); a modest increase in PWV was not significant (P = 0.06). In PH patients, RAC decreased from 0.15 ± 0.02 to 0.11 ± 0.01 (P < 0.05) and PWV and ß increased from 3.9 ± 0.54 m/s and 1.86 ± 0.12 at rest to 5.75 ± 0.70 m/s and 3.25 ± 0.26 with exercise (P < 0.05 for both), respectively. These results confirm increased MPA stiffness with exercise stress in both groups and the non-invasive metrics of MPA stiffness correlated well with ß. Finally, as assessed by PWV but not RAC, PA stiffness of PH patients increased more than that of controls for comparable levels of moderate exercise. Conclusion: These results demonstrate the feasibility of using MRI for non-invasive assessment of exercise-induced changes in MPA stiffness in a small, heterogeneous group of PH patients in a research context. Similar measurements in a larger cohort are required to investigate differences between PWV and RAC for estimation of MPA stiffness.

Multidisciplinary approach to cardiac and pulmonary vascular disease risk assessment in liver transplantation: An evaluation of the evidence and consensus recommendations.

Liver transplant (LT) candidates today are older, have greater medical severity of illness, and have more cardiovascular comorbidities than ever before. In addition, there are specific cardiovascular responses in cirrhosis that can be detrimental to the LT candidate. Cirrhotic cardiomyopathy, a condition characterized by increased cardiac output and a reduced ventricular response to stress, is present in up to 30% of patients with cirrhosis, thus challenging perioperative management. Current noninvasive tests that assess for subclinical coronary and myocardial disease have low sensitivity, and altered hemodynamics during the LT surgery can unmask latent cardiovascular disease either intraoperatively or in the immediate postoperative period. Therefore, this review, assembled by a group of multidisciplinary experts in the field and endorsed by the American Society of Transplantation Liver and Intestine and Thoracic and Critical Care Communities of Practice, provides a critical assessment of the diagnosis of cardiac and pulmonary vascular disease and interventions aimed at managing these conditions in LT candidates. Key points and practice-based recommendations for the diagnosis and management of cardiac and pulmonary vascular disease in this population are provided to offer guidance for clinicians and identify gaps in knowledge for future investigations.

Reduced haemodynamic coupling and exercise are associated with vascular stiffening in pulmonary arterial hypertension.

OBJECTIVE: Inadequate right ventricular (RV) and pulmonary arterial (PA) functional responses to exercise are important yet poorly understood features of pulmonary arterial hypertension (PAH). This study combined invasive catheterisation with echocardiography to assess RV afterload, RV function and ventricular-vascular coupling in subjects with PAH. METHODS: Twenty-six subjects with PAH were prospectively recruited to undergo right heart catheterisation and Doppler echocardiography at rest and during incremental exercise, and cardiac MRI at rest. Measurements at rest included basic haemodynamics, RV function and coupling efficiency (η). Measurements during incremental exercise included pulmonary vascular resistance (Z0), characteristic impedance (ZC, a measure of proximal PA stiffness) and proximal and distal PA compliance (CPA). RESULTS: In patients with PAH, the proximal PAs were significantly stiffer at maximum exercise (ZC =2.31±0.38 vs 1.33±0.15 WU×m2 at rest; p=0.003) and PA compliance was decreased (CPA=0.88±0.10 vs 1.32±0.17 mL/mm Hg/m2 at rest; p=0.0002). Z0 did not change with exercise. As a result, the resistance-compliance (RC) time decreased with exercise (0.67±0.05 vs 1.00±0.07 s at rest; p<10-6). When patients were grouped according to resting coupling efficiency, those with poorer η exhibited stiffer proximal PAs at rest, a lower maximum exercise level, and more limited CPA reduction at maximum exercise. CONCLUSIONS: In PAH, exercise causes proximal and distal PA stiffening, which combined with preserved Z0 results in decreased RC time with exercise. Stiff PAs at rest may also contribute to poor haemodynamic coupling, reflecting reduced pulmonary vascular reserve that contributes to limit the maximum exercise level tolerated.

BMP9 mutations cause a vascular-anomaly syndrome with phenotypic overlap with hereditary hemorrhagic telangiectasia.

Hereditary hemorrhagic telangiectasia (HHT), the most common inherited vascular disorder, is caused by mutations in genes involved in the transforming growth factor beta (TGF-ß) signaling pathway (ENG, ACVRL1, and SMAD4). Yet, approximately 15% of individuals with clinical features of HHT do not have mutations in these genes, suggesting that there are undiscovered mutations in other genes for HHT and possibly vascular disorders with overlapping phenotypes. The genetic etiology for 191 unrelated individuals clinically suspected to have HHT was investigated with the use of exome and Sanger sequencing; these individuals had no mutations in ENG, ACVRL1, and SMAD4. Mutations in BMP9 (also known as GDF2) were identified in three unrelated probands. These three individuals had epistaxis and dermal lesions that were described as telangiectases but whose location and appearance resembled lesions described in some individuals with RASA1-related disorders (capillary malformation-arteriovenous malformation syndrome). Analyses of the variant proteins suggested that mutations negatively affect protein processing and/or function, and a bmp9-deficient zebrafish model demonstrated that BMP9 is involved in angiogenesis. These data confirm a genetic cause of a vascular-anomaly syndrome that has phenotypic overlap with HHT.