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Background: Scleroderma-associated pulmonary arterial hypertension (SSc-PAH) is a rare disease characterized by a very dismal response to therapy and poor survival. We assessed the effects of up-front combination PAH therapy in patients with SSc-PAH., Methods: In this prospective, multicenter, open-label trial, 24 treatment-naive patients with SSc-PAH received ambrisentan 10 mg and tadalafil 40 mg daily for 36 weeks. Functional, hemodynamic, and imaging (cardiac magnetic resonance imaging and echocardiography) assessments at baseline and 36 weeks included changes in right ventricular (RV) mass and pulmonary vascular resistance as co-primary endpoints and stroke volume/pulmonary pulse pressure ratio, tricuspid annular plane systolic excursion, 6-minute walk distance, and N-terminal pro-brain natriuretic peptide as secondary endpoints., Results: At 36 weeks, we found that treatment had resulted in significant reductions in median (interquartile range [IQR]) RV mass (28.0 g [IQR, 20.6-32.9] vs. 32.5 g [IQR, 23.2-41.4]; P < 0.05) and median pulmonary vascular resistance (3.1 Wood units [IQR, 2.0-5.7] vs. 6.9 Wood units [IQR, 4.0-12.9]; P < 0.0001) and in improvements in median stroke volume/pulmonary pulse pressure ratio (2.6 ml/mm Hg [IQR, 1.8-3.5] vs. 1.4 ml/mm Hg [IQR 8.9-2.4]; P < 0.0001) and mean ( ± SD) tricuspid annular plane systolic excursion (2.2 ± 0.12 cm vs. 1.65 ± 0.11 cm; P < 0.0001), 6-minute walk distance (395 ± 99 m vs. 343 ± 131 m; P = 0.001), and serum N-terminal pro-brain natriuretic peptide (647 ± 1,127 pg/ml vs. 1,578 ± 2,647 pg/ml; P < 0.05)., Conclusions: Up-front combination therapy with ambrisentan and tadalafil significantly improved hemodynamics, RV structure and function, and functional status in treatment-naive patients with SSc-PAH and may represent a very effective therapy for this patient population. In addition, we identified novel hemodynamic and imaging biomarkers that could have potential value in future clinical trials. Clinical trial registered with www.clinicaltrials.gov (NCT01042158).

Purpose: To determine whether chronic pulmonary arterial pressure (PAP) elevation affects regional biventricular function and whether regional myocardial function may be reduced in pulmonary arterial hypertension (PAH) patients with preserved global right ventricular (RV) function., Materials and Methods: After informed consent, 35 PAH patients were evaluated with right heart catheterization and cardiac magnetic resonance (MR) imaging and compared with 13 healthy control subjects. Biventricular segmental, section, and mean ventricular peak systolic longitudinal strain (E(LL)), as well as left ventricular (LV) circumferential and RV tangential strains were compared between PAH patients and control subjects and correlated with global function and catheterization of the right heart indexes. Spearman ρ correlation with Bonferroni correction was used. Multiple linear regression analysis was performed to determine predictors for regional myocardial function., Results: In the RV of PAH patients, longitudinal contractility was reduced at the basal, mid, and apical levels, and tangential contractility was reduced at the midventricular level. Mean RV E(LL) positively correlated with mean PAP (r = 0.62, P < .0014) and pulmonary vascular resistance index (PVRI) (r = 0.77, P < .0014). Mean PAP was a predictor of mean RV E(LL) (β = .19, P = .005) in a multiple linear regression analysis. In the LV, reduced LV longitudinal and circumferential contractility were noted at the base. LV anteroseptal E(LL) positively correlated with increased mean PAP (r = 0.5, P = .03) and septal eccentricity index (r = 0.5, P = .01). In a subgroup of PAH patients with normal global RV function, significantly reduced RV longitudinal contractility was noted at basal and mid anterior septal insertions, as well as the mid anterior RV wall (P < .05 for all)., Conclusion: In PAH patients, reduced biventricular regional function is associated with increased RV afterload (mean PAP and PVRI). Cardiac MR imaging helps identify regional RV dysfunction in PAH patients with normal global RV function., Supplemental Material: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.12111599/-/DC1., (RSNA, 2012)

Purpose: To prospectively compare contrast material-enhanced (CE) magnetic resonance (MR) imaging-derived right-to-left ventricle pulmonary transit time (PTT), left ventricular (LV) full width at half maximum (FWHM), and LV time to peak (TTP) between patients with pulmonary arterial hypertension (PAH) and healthy volunteers and to correlate these measurements with survival markers in patients with PAH., Materials and Methods: This HIPAA-compliant study received institutional review board approval. Written informed consent was obtained from all participants. Forty-three patients (32 with PAH [29 women; median age, 55.4 years], 11 with scleroderma but not PAH [seven women; median age, 58.9 years]) underwent right-sided heart catheterization and 3-T CE cardiac MR imaging. Eighteen age- and sex-matched healthy control subjects (12 women; median age, 51.7 years) underwent only CE MR imaging. A short-axis saturation-recovery gradient-echo section was acquired in the basal third of both ventricles, and right-to-left-ventricle PTT, LV FWHM, and LV TTP were calculated. Statistical analysis included Kruskal-Wallis test, Wilcoxon rank sum test, Spearman correlation coefficient, multiple linear regression analysis, and Lin correlation coefficient analysis., Results: Patients had significantly longer PTT (median, 8.2 seconds; 25th-75th percentile, 6.9-9.9 seconds), FWHM (median, 8.2 seconds; 25th-75th percentile, 5.7-11.4 seconds), and TTP (median, 4.8 seconds; 25th-75th percentile, 3.9-6.5 seconds) than did control subjects (median, 6.4 seconds; 25th-75th percentile, 5.7-7.1 seconds; median, 5.2 seconds; 25th-75th percentile, 4.1-6.1 seconds; median, 3.2 seconds; 25th-75th percentile, 2.8-3.8 seconds, respectively; P < .01 for each) and subjects with scleroderma but not PAH (median, 6.5 seconds; 25th-75th percentile, 5.6-7.0 seconds; median, 5.0 seconds; 25th-75th percentile, 4.0-7.3 seconds; median, 3.6 seconds; 25th-75th percentile, 2.7-4.0 seconds, respectively; P < .02 for each). PTT, LV FWHM, and LV TTP correlated with pulmonary vascular resistance index (P < .01), right ventricular stroke volume index (P ≤ .01), and pulmonary artery capacitance (P ≤ .02). In multiple linear regression models, PTT, FWHM, and TTP were associated with mean pulmonary arterial pressure and cardiac index., Conclusion: CE MR-derived PTT, LV FWHM, and LV TTP are noninvasive compound markers of pulmonary hemodynamics and cardiac function in patients with PAH. Their predictive value for patient outcome warrants further investigation.

Objective: The tricuspid annular plane systolic excursion (TAPSE) strongly reflects right ventricular (RV) function and predicts survival in idiopathic pulmonary arterial hypertension (PAH). But its role in systemic sclerosis (SSc)-associated PAH has not been established. Our objective was to validate the TAPSE in the assessment of RV function and prediction of survival in SSc-PAH., Methods: Fifty consecutive patients with SSc-PAH who underwent echocardiography with TAPSE measurement within 1 h of clinically indicated right heart catheterization were followed prospectively. The relationship between TAPSE and measures of RV function and measures of survival was assessed., Results: The majority of the cohort were women in New York Heart Association class III/IV with severe PAH (mean cardiac index 2.4 ± 0.8 l/min/m(2)). RV function was significantly impaired (mean cardiac index 2.1 ± 0.7 vs 2.9 ± 0.8 l/min/m(2); p < 0.01) and RV afterload was significantly greater (mean pulmonary vascular resistance 11.1 ± 5.1 vs 5.8 ± 2.5 Wood units; p < 0.01) in subjects with a TAPSE ≤ 1.7 cm. The proportion surviving in the low TAPSE group was significantly lower [0.56 (95% CI 0.37-0.71) and 0.46 (95% CI 0.28-0.62) vs 0.87 (95% CI 0.55-0.96) and 0.79 (95% CI 0.49-0.93), 1- and 2-year survival, respectively]. TAPSE ≤ 1.7 cm conferred a nearly 4-fold increased risk of death (HR 3.81, 95% CI 1.31-11.1, p < 0.01)., Conclusion: TAPSE is a robust measure of RV function and strongly predicts survival in patients with PAH-SSc. Future studies are needed to identify the responsiveness of TAPSE to PAH-specific therapy and to assess its diagnostic utility in PAH-SSc.

Objective: : To prospectively evaluate the cardiac magnetic resonance (MR) imaging-derived measurement of right ventricular (RV) septomarginal trabeculation (SMT) mass as a noninvasive marker for pulmonary hypertension (PH), compared with the ventricular mass index (VMI = RV mass/left ventricular mass) and RV mass., Materials and Methods: : A total of 49 patients (60 ± 12 years; 35 female) with suspected PH underwent cardiac MR and right heart catheterization on the same day. Eighteen normal volunteers were also included. The performance of SMT mass, VMI and RV mass measurement, with regard to PH detection, was analyzed using receiver operating characteristic curves. Logistic regression analysis was used to assess the association between SMT mass, RV mass, VMI, and PH., Results: : The area under the receiver operating characteristic curve for SMT mass/body surface area (BSA), VMI, and RV mass/BSA in diagnosing the presence or absence of PH was 0.88, 0.87, and 0.73 respectively. In multivariable models, both SMT mass/BSA (P = 0.005, odds ratio: 8.6) and VMI (P = 0. 012, odds ratio: 1.1) were found to be significant, independent predictors of PH., Conclusion: : Compared with right heart catheterization measurement, SMT mass and VMI are reproducible and noninvasive MR imaging markers for the diagnosis of PH.

The aim of this study was to examine the causes and outcomes of hospitalisation in patients with pulmonary arterial hypertension (PAH). 205 consecutive hospitalisations occurring between 2000 and 2009 in 90 PAH patients were studied. The leading causes for hospitalisation were right heart failure (RHF; 56%), infection (16%) and bleeding disorders (8%). For patients with RHF, in-hospital mortality was 14% overall, 46% for patients receiving inotropes and 48% for those admitted to the intensive care unit. The predictors for in-hospital mortality were the presence of connective tissue disease (CTD) (OR 4.92), systolic blood pressure <100 mmHg (OR 4.32) and Na ≤ 136 mEq · L(-1) (OR 4.29). Mortality after discharge was 13, 26 and 35% at 3, 6 and 12 months, respectively. World Health Organization functional class prior to admission, renal dysfunction, Charlson comorbidity index, and the presence of CTD were all predictors of mortality after discharge. Hyponatraemia and low systolic blood pressure upon admission and underlying CTD are the main prognostic factors for in-hospital mortality in patients with PAH admitted for RHF. The short-term outcomes after discharge are poor and remarkably worse in patients with underlying CTD or renal impairment. Early recognition of these factors may guide decisions regarding more aggressive therapy, including consideration for lung transplantation.

Objective: Precapillary pulmonary hypertension (PH) is an important cause of death in patients with systemic sclerosis (SSc). It can occur in isolation (pulmonary arterial hypertension [PAH]) or in association with interstitial lung disease (ILD). Importantly, the outcomes and efficacy of PAH therapies in patients with SSc-related PH complicating ILD (PH-ILD) remain unknown. This study was undertaken to evaluate our experience with PH-ILD with regard to the efficacy and safety of PAH therapies in this patient cohort., Methods: We conducted a retrospective analysis of consecutive SSc patients from 2 large referral centers who had PH-ILD confirmed by right-sided heart catheterization and who received targeted PAH therapies. World Health Organization (WHO) functional class, 6-minute walk distance, and hemodynamic parameters were assessed at baseline and after a mean ± SD of 7.7 ± 6.2 months of treatment for PAH. Kaplan-Meier and Cox proportional hazards models were used to analyze survival and to identify prognostic factors., Results: Seventy patients were included in the study. No significant changes were observed in WHO functional class, 6-minute walk distance, or hemodynamic parameters after therapy. The 1-, 2-, and 3-year survival estimates were 71%, 39%, and 21%, respectively. In the multivariate model, worsening oxygenation during followup and reduced renal function were the only significant risk factors for death., Conclusion: This study represents the largest series to date in which the impact of PAH therapies in SSc-related PH-ILD was examined. In this cohort, PAH therapies were associated with no clear benefits. Deterioration in oxygenation was an important determinant of long-term survival. Prospective clinical trials focusing on this group of patients are warranted., (Copyright © 2011 by the American College of Rheumatology.)

Background: Pulmonary hypertension (PH) in COPD carries a poor prognosis. Statin therapy has been associated with numerous beneficial clinical effects in COPD, including a possible improvement in PH. We examined the association between statin use and pulmonary hemodynamics in a well-characterized cohort of patients undergoing evaluation for lung transplantation., Methods: We conducted a cross-sectional analysis of 112 subjects evaluated for lung transplant with a diagnosis of COPD. Clinical characteristics, pulmonary function, cardiac catheterization findings and medical comorbidities were compared between statins users and non-users., Results: Thirty-four (30%) subjects were receiving statin therapy. Statin users were older and had an increased prevalence of systemic hypertension and coronary artery disease (CAD). Mean pulmonary arterial pressure (mPAP) in the statin group was lower [26 ± 7 vs 29 ± 7 mmHg, p = 0.02], as was pulmonary artery wedge pressure (PAWP) [12 ± 5 vs. 15 ± 6 mmHg, p = 0.02]. Pulmonary vascular resistance did not differ between the groups. In multiple regression analysis, statin use was associated with a 4.2 mmHg (95% CI: 2 to 6.4, p = <0.001) lower PAWP and a 2.6 mmHg (95% CI: 0.3 to 4.9, p = 0.03) reduction in mPAP independent of PAWP., Conclusions: In patients with severe COPD, statin use is associated with significantly lower PAWP and mPAP. These finding should be evaluated prospectively.

Purpose: To evaluate the relationships of right ventricular (RV) and left ventricular (LV) myocardial perfusion reserves with ventricular function and pulmonary hemodynamics in patients with pulmonary arterial hypertension (PAH) by using adenosine stress perfusion cardiac magnetic resonance (MR) imaging., Materials and Methods: This HIPAA-compliant study was institutional review board approved. Twenty-five patients known or suspected to have PAH underwent right heart catheterization and adenosine stress MR imaging on the same day. Sixteen matched healthy control subjects underwent cardiac MR imaging only. RV and LV perfusion values at rest and at adenosine-induced stress were calculated by using the Fermi function model. The MR imaging-derived RV and LV functional data were calculated by using dedicated software. Statistical testing included Kruskal-Wallis tests for continuous data, Spearman rank correlation tests, and multiple linear regression analyses., Results: Seventeen of the 25 patients had PAH: 11 with scleroderma-associated PAH, and six with idiopathic PAH. The remaining eight patients had scleroderma without PAH. The myocardial perfusion reserve indexes (MPRIs) in the PAH group (median RV MPRI, 1.7 [25th-75th percentile range, 1.3-2.0]; median LV MPRI, 1.8 [25th-75th percentile range, 1.6-2.1]) were significantly lower than those in the scleroderma non-PAH (median RV MPRI, 2.5 [25th-75th percentile range, 1.8-3.9] [P = .03]; median LV MPRI, 4.1 [25th-75th percentile range, 2.6-4.8] [P = .0003]) and control (median RV MPRI, 2.9 [25th-75th percentile range, 2.6-3.6] [P < .01]; median LV MPRI, 3.6 [25th-75th percentile range, 2.7-4.1] [P < .01]) groups. There were significant correlations between biventricular MPRI and both mean pulmonary arterial pressure (mPAP) (RV MPRI: ρ = -0.59, Bonferroni P = .036; LV MPRI: ρ = -0.79, Bonferroni P < .002) and RV stroke work index (RV MPRI: ρ = -0.63, Bonferroni P = .01; LV MPRI: ρ = -0.75, Bonferroni P < .002). In linear regression analysis, mPAP and RV ejection fraction were independent predictors of RV MPRI. mPAP was an independent predictor of LV MPRI., Conclusion: Biventricular vasoreactivity is significantly reduced with PAH and inversely correlated with RV workload and ejection fraction, suggesting that reduced myocardial perfusion reserve may contribute to RV dysfunction in patients with PAH., (© RSNA, 2010)

Objective: The purpose of this study was to assess predictors of MRI-identified septal delayed enhancement mass at the right ventricular (RV) insertion sites in relation to RV remodeling, altered regional mechanics, and pulmonary hemodynamics in patients with suspected pulmonary hypertension (PH)., Subjects and Methods: Thirty-eight patients with suspected PH were evaluated with right heart catheterization and cardiac MRI. Ten age- and sex-matched healthy volunteers acted as controls for MRI comparison. Septal delayed enhancement mass was quantified at the RV insertions. Systolic septal eccentricity index, global RV function, and remodeling indexes were quantified with cine images. Peak systolic circumferential and longitudinal strain at the sites corresponding to delayed enhancement were measured with conventional tagging and fast strain-encoded MRI acquisition, respectively., Results: PH was diagnosed in 32 patients. Delayed enhancement was found in 31 of 32 patients with PH and in one of six patients in whom PH was suspected but proved absent (p = 0.001). No delayed enhancement was found in controls. Delayed enhancement mass correlated with pulmonary hemodynamics, reduced RV function, increased RV remodeling indexes, and reduced eccentricity index. Multiple linear regression analysis showed RV mass index was an independent predictor of total delayed enhancement mass (p = 0.017). Regional analysis showed delayed enhancement mass was associated with reduced longitudinal strain at the basal anterior septal insertion (r = 0.6, p < 0.01). Regression analysis showed that basal longitudinal strain remained an independent predictor of delayed enhancement mass at the basal anterior septal insertion (p = 0.02)., Conclusion: In PH, total delayed enhancement burden at the RV septal insertions is predicted by RV remodeling in response to increased afterload. Local fibrosis mass at the anterior septal insertion is associated with reduced regional longitudinal contractility at the base.

Rationale: Pulmonary arterial hypertension (PAH) related to systemic sclerosis (SSc) has a poorer prognosis compared with other forms of PAH for reasons that remain unexplained., Objectives: To identify risk factors of mortality in a well-characterized cohort of patients with PAH related to systemic sclerosis (SSc-PAH)., Methods: Seventy-six consecutive patients with SSc (64 women and 12 men; mean age 61 +/- 11 yr) were diagnosed with PAH by heart catheterization in a single center, starting in January 2000, and followed over time. Kaplan-Meier estimates were calculated and mortality risk factors were analyzed., Measurements and Main Results: Forty (53%) patients were in World Health Organization functional class III or IV. Mean pulmonary artery pressure was 41 +/- 11 mm Hg, pulmonary vascular resistance (PVR) was 8.6 +/- 5.6 Wood units, and cardiac index was 2.4 +/- 0.7 L/min/m(2). Median follow-up time was 36 months, with 42 deaths observed. Survival estimates were 85%, 72%, 67%, 50%, and 36% at 1, 2, 3, 4, and 5 years, respectively. Multivariate analysis identified PVR (hazard ratio [HR], 1.10; 95% confidence interval [CI], 1.03-1.18; P < 0.01), stroke volume index (HR, 0.94; 95% CI, 0.89-0.99; P = 0.02), and pulmonary arterial capacitance (HR, 0.43; 95% CI, 0.20-0.91; P = 0.03) as strong predictors of survival. An estimated glomerular filtration rate less than 60 ml/min/1.73 m(2) portended a threefold risk of mortality., Conclusions: Our results suggest that specific components of right ventricular dysfunction and renal impairment contribute to increased mortality in SSc-PAH. Understanding the mechanisms of right ventricular dysfunction in response to increased afterload should lead to improved targeted therapy in these patients.

N-terminal pro-brain natriuretic peptide (NT-proBNP) is a marker of neurohormonal activation that is useful in the diagnosis and prognosis of various forms of pulmonary arterial hypertension (PAH). We sought to characterise and compare NT-proBNP in a cohort of PAH related to systemic sclerosis (PAH-SSc) and idiopathic PAH (IPAH) patients. NT-proBNP levels, collected from PAH-SSc and IPAH patients followed prospectively, were compared and correlated with haemodynamic variables. Cox proportional hazard models were created to assess the predictive value of NT-proBNP. 98 patients (55 PAH-SSc, 43 IPAH) were included. Haemodynamics were similar, except for lower mean pulmonary arterial pressure in PAH-SSc. NT-proBNP levels were significantly higher in PAH-SSc (3,419+/-3,784 versus 1,393+/-1,633 pg x mL(-1); p<0.01) and were more closely related to haemodynamics in PAH-SSc than IPAH. 28 patients died. NT-proBNP predicted survival (hazard ratio (HR) 3.18; p<0.01) in the overall cohort; however, when stratified by group, predicted survival only in PAH-SSc (HR 3.07, p<0.01 versus 2.02, p = 0.29 in IPAH). This is the first description showing NT-proBNP levels are 1) significantly higher in PAH-SSc than IPAH despite less severe haemodynamic perturbations, and 2) stronger predictors of survival in PAH-SSc, suggesting that neurohormonal regulation may differ between PAH-SSc and IPAH. Future studies to define pertinent mechanisms are warranted.