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Right ventricular function has prognostic significance in patients with pulmonary hypertension. We evaluated whether cardiac magnetic resonance-derived strain and strain rate parameters could reliably reflect right ventricular systolic and diastolic function in precapillary pulmonary hypertension. End-systolic elastance and the time constant of right ventricular relaxation tau, both derived from invasive high-fidelity micromanometer catheter measurements, were used as gold standards for assessing systolic and diastolic right ventricular function, respectively. Nineteen consecutive precapillary pulmonary hypertension patients underwent cardiac magnetic resonance and right heart catheterization prospectively. Cardiac magnetic resonance data were compared with those of 19 control subjects. In pulmonary hypertension patients, associations between strain- and strain rate-related parameters and invasive hemodynamic parameters were evaluated. Longitudinal peak systolic strain, strain rate, and early diastolic strain rate were lower in PAH patients than in controls; peak atrial-diastolic strain rate was higher in pulmonary hypertension patients. Similarly, circumferential peak systolic strain rate was lower and peak atrial-diastolic strain rate was higher in pulmonary hypertension. In pulmonary hypertension, no correlations existed between cardiac magnetic resonance-derived and hemodynamically derived measures of systolic right ventricular function. Regarding diastolic parameters, tau was significantly correlated with peak longitudinal atrial-diastolic strain rate ( r = −0.61), deceleration time ( r = 0.75), longitudinal systolic to diastolic time ratio ( r = 0.59), early diastolic strain rate ( r = −0.5), circumferential peak atrial-diastolic strain rate ( r = −0.52), and deceleration time ( r = 0.62). Strain analysis of the right ventricular diastolic phase is a reliable non-invasive method for detecting right ventricular diastolic dysfunction in PAH.

The object of this paper is to assess associations between serum uric acid (UA) and pulmonary arterial hypertension (PAH) risk, disease severity, and mortality in a well-characterized cohort of systemic sclerosis (SSc) patients referred for evaluation of possible PAH. Consecutive SSc patients aged >18 years with serum UA drawn within two weeks of a diagnostic right heart catheterization (RHC) were included. Associations between baseline serum UA and PAH at RHC were examined using logistic regression and receiver operating characteristic curves. Relationships between UA levels and metrics of disease severity were assessed using Pearson and Spearman correlation. Associations between UA and survival were assessed using Kaplan–Meier analysis and Cox proportional hazard modeling. A total of 162 SSc patients were included; 82 received a diagnosis of PAH at RHC. Patients found to have PAH had significantly higher UA than those without PAH. Elevated baseline UA was associated with significantly increased odds of PAH diagnosis at RHC (odds ratio [OR] = 4.07, 95% confidence interval [CI] = 2.11–7.87, P 6.3 mg/dL remained significantly associated with increased mortality (HR = 1.84, 95% CI = 1.02–3.32, P

The aim of this study was to evaluate the effect of upfront combination therapy with ambrisentan and tadalafil on left ventricular (LV) and right ventricular (RV) function in patients with systemic sclerosis-associated pulmonary arterial hypertension (SSc-PAH). LV and RV peak longitudinal and circumferential strain and strain rate (SR), which consisted of peak systolic SR (SRs), peak early diastolic SR (SRe), and peak atrial-diastolic SR (SRa) were analyzed using cardiac magnetic resonance imaging (CMRI) data from the recently published ATPAHSS-O trial (ambrisentan and tadalafil upfront combination therapy in SSc-PAH). Twenty-one patients completed the study protocol. Measures of RV systolic function (RV free wall [RVFW] peak longitudinal strain [pLS], RVFW peak longitudinal SRs [pLSRs]) and RV diastolic function (RVFW peak longitudinal SRa [pLSRa], RVFW peak circumferential SRe) were improved after treatment. LV systolic function (LV peak global longitudinal strain [pGLS]) and diastolic function (LV peak global longitudinal SRe [pGLSRe]) were also significantly improved at follow-up. Increased 6-min walk distance was significantly correlated with RVFW pLS and pLSRs, while the decrease in N-terminal pro-brain natriuretic peptide was correlated with LV pGLS. Increased cardiac index was associated with improved LV pGLSRe, and reduction in mean right atrial pressure was correlated with improved RVFW pLS and pLSRa. Combination therapy was associated with a significant improvement in both RV and LV function as assessed by CMR-derived strain and SR. Importantly, the improvement in RV and LV strain and SR correlated with improvements in known prognostic markers of PAH. (Approved by clinicaltrials.gov [NCT01042158] before patient recruitment.).

Background: Right ventricular (RV) dysfunction is the leading cause of mortality in pulmonary arterial hypertension (PAH), and cardiac magnetic resonance (CMR) measures of RV volumes and mass are known to predict mortality in PAH. Ventricular mass index (VMI), a ratio of RV mass to left ventricular (LV) mass, predicts the presence of PAH in scleroderma. We hypothesized that VMI would predict mortality in incident PAH. Methods: 65 subjects with incident PAH underwent CMR, and VMI was calculated (RV end-diastolic mass/LV end-diastolic mass). Subjects were followed prospectively until death or censor. Associations between VMI and mortality were assessed with Kaplan-Meier (KM) analysis and Cox proportional hazard (CPH) modeling. Results: Subjects were 57±11 years of age; most were women (91%) with connective tissue disease (CTD) (72%) and NYHA functional class I/II symptoms (64%). There was 52% mortality over a median follow up of 8.3 years. KM analysis showed that VMI>0.43, the median for the cohort, was associated with increased risk of death (HR 2.2, 95% CI 1.07-4.46, p Conclusion: VMI, a CMR metric that reflects the effect of PAH on both RV and LV remodeling, most robustly predicts mortality in PAH. Supported by NIH R01HL114910 and U01HL125175

Increased right ventricular mass and VMI, the ratio of RV mass to LV mass, are predictors of mortality in incident, treatment-naive PAH. These findings challenge the notion that RV hypertrophy is adaptive in pulmonary hypertension.http://ow.ly/qzvt30ntJze

Despite therapeutic advances, pulmonary arterial hypertension remains a disease without a cure. Focusing on symptoms, such as dyspnea, is an important part of assessing response to therapy.To determine the minimal important differences for the Borg dyspnea score and the Borg fatigue score in adult patients undergoing initial therapy for pulmonary arterial hypertension.We studied 129 patients enrolled between 2003 and 2013 in the Pulmonary Arterial Hypertension Program registry at Johns Hopkins University Hospital in Baltimore, Maryland. We analyzed baseline demographics, clinical characteristics, 6-minute-walk test distance, and Borg dyspnea and fatigue scores at baseline and at follow up 3 months after initiation of pulmonary arterial hypertension therapy. The minimal important differences for the Borg dyspnea and fatigue scores were determined using distributional and anchor-based methods, using 6-minute-walk test distance as the anchor.Most subjects were in New York Heart Association functional class II or III and had moderate to severe pulmonary arterial hypertension. The baseline Borg dyspnea score was 3.4 ± 1.9 units; the baseline Borg fatigue score was 2.8 ± 2.2 units. After therapy, the average change in the dyspnea score was -0.16 ± 1.9 units and the average change in the fatigue score was -0.21 ± 2.4 units. Using distributional methods, the minimum important difference for Borg dyspnea score ranged from 0.7 to 1.24 units and for Borg fatigue score ranged from 0.73 to 1.39 units. Using anchor-based methods, the minimum important difference for the Borg dyspnea scales was 0.36; this could not be calculated for the Borg fatigue score.Using distributional and anchor-based methods, we estimate the minimum important difference for Borg dyspnea scale in pulmonary arterial hypertension is approximately 0.9 units. Using distributional methods only, we estimate the minimum important difference for the Borg fatigue scale is around 1 unit. Further studies are needed to determine the clinical utility of these scores in patients with pulmonary arterial hypertension.

Pulmonary arterial hypertension is a progressive disease with high morbidity and mortality despite advances in medical therapy. The relationship between patient-related outcomes, such as health-related quality of life (HRQOL), and survival is not well described.To assess the relationship between HRQOL and outcomes in patients with pulmonary arterial hypertension.Consecutive patients with right heart catheterization-proven pulmonary arterial hypertension who completed the Medical Outcomes Survey Short Form-36 survey (SF-36) were included. Demographic, clinical, physiological, and hemodynamic data were collected at baseline. Survival was assessed from the time of diagnosis of pulmonary arterial hypertension. Cox proportional hazard models were constructed to assess the relationship between HRQOL and transplant-free survival.Eighty-seven patients with pulmonary arterial hypertension were enrolled and followed prospectively for a median of 3.8 years. At baseline, HRQOL was significantly worse than U.S. normal values for six of eight domains of the SF-36. Several domains demonstrated moderate correlation (r value ≥ 0.40) with 6-minute-walk distance and World Health Organization functional class; there were no significant associations with hemodynamics. In univariable Cox proportional hazard models, six of eight domains and both summary scores were significantly associated with survival. In multivariable models, adjusted for age, disease type, and cardiac function, these relationships largely persisted.In this cohort of patients with pulmonary arterial hypertension, HRQOL, as assessed by the SF-36, was strongly associated with transplant-free survival. These relationships persisted when controlling for potential confounders such as disease type and disease severity. These findings suggest that HRQOL may be an important predictor of outcomes in pulmonary arterial hypertension and therefore a target for future therapeutic interventions.

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.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.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]; P0.05) and median pulmonary vascular resistance (3.1 Wood units [IQR, 2.0-5.7] vs. 6.9 Wood units [IQR, 4.0-12.9]; P0.0001) 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]; P0.0001) and mean ( ± SD) tricuspid annular plane systolic excursion (2.2 ± 0.12 cm vs. 1.65 ± 0.11 cm; P0.0001), 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; P0.05).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).

Introduction: Scleroderma-associated pulmonary arterial hypertension (SSc-PAH) responds poorly to current PAH therapy. Aims: To assess the effects of upfront, combination therapy with tadalafil and ambrisentan in a multicenter, prospective open label trial for treatment of SSc-PAH. Methods: 25 treatment naive SSc-PAH patients received tadalafil (40 mg daily) and ambrisentan (10 mg daily) for 36 weeks. Right heart catheterization, cMRI, and echocardiography were performed at baseline and 36 weeks. Primary endpoints were changes in RV mass and PVR. Secondary endpoints were changes in pulmonary compliance (Pca=stroke volume over pulmonary pulse pressure), ventricular mass index (VMI=RV/LV mass index), tricuspid annular plane systolic excursion (TAPSE), six-minute walk distance (6 MWD) and N-terminal pro-brain natriuretic peptide (NTproBNP). Results: Treatment resulted in significant reductions in RV mass index (21.7±10.6 g/m² vs 18.0±6.7 g/m²; P=0.04), PVR (8.1±5.8 Wood Units (WU) vs. 3.9±3.5 WU; P Conclusions: Upfront combination therapy resulted in significant changes in hemodynamics, RV structure and function, and RV-pulmonary vascular coupling as well as functional status at 36 weeks of therapy. When compared to previous clinical trials, these data suggest initial combination therapy is very effective for SSc-PAH.