Right ventricular function as assessed by cardiac magnetic resonance imaging-derived strain parameters compared to high-fidelity micromanometer catheter measurements.

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.

Serum uric acid as a marker of disease risk, severity, and survival in systemic sclerosis-related pulmonary arterial hypertension.

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 < 0.001). Each mg/dL higher UA was associated with a 14% increase in mortality (hazard ratio [HR] = 1.14, 95% CI = 1.02-1.28, P < 0.05). In multivariable models adjusting for potential confounders of the relationship between UA and survival, UA > 6.3 mg/dL remained significantly associated with increased mortality (HR = 1.84, 95% CI = 1.02-3.32, P < 0.05). Among SSc patients with suspected PAH, elevated serum UA is associated with increased risk of SSc-PAH. Among individuals diagnosed with SSc-PAH by RHC, UA is associated with disease severity and survival. These results indicate UA is a useful predictor of PAH risk and prognosis in SSc.

Validation of the REVEAL Prognostic Equation and Risk Score Calculator in Incident Systemic Sclerosis-Associated Pulmonary Arterial Hypertension.

OBJECTIVE: A prognostic equation and risk score calculator derived from the Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management (REVEAL) are being used to predict 1-year survival in patients with pulmonary arterial hypertension (PAH), but little is known about the performance of these REVEAL survival prediction tools in systemic sclerosis (SSc)-associated PAH (SSc-PAH). METHODS: Prospectively gathered data from the Johns Hopkins Pulmonary Hypertension Program and Pulmonary Hypertension Assessment and Recognition of Outcome in Scleroderma Registries were used to evaluate the predictive accuracy of the REVEAL models for predicting the probability of 1-year survival in patients with SSc-PAH. Model discrimination was assessed by comparison of the Harrell's C-index, model fit was assessed using multivariable regression techniques, and model calibration was assessed by comparing predicted to observed survival estimates. RESULTS: The validation cohort consisted of 292 SSc-PAH patients with a 1-year survival rate of 87.4%. The C-index for predictive accuracy of the REVEAL prognostic equation (0.734, 95% confidence interval [95% CI] 0.652-0.816) and for the risk score (0.743, 95% CI 0.663-0.823) demonstrated good discrimination, comparable to that in the model development cohort. The calibration slope was 0.707 (95% CI 0.400-1.014), indicating that the overall model fit was marginal (P = 0.06). The magnitude of risk assigned to low distance on the 6-minute walk test (6MWD) and elevated serum levels of brain natriuretic peptide (BNP) was lower in the validation cohort than was originally seen in the REVEAL derivation cohort. Model calibration was poor, particularly for the highest risk groups. CONCLUSION: In predicting 1-year survival in patients newly diagnosed as having SSc-PAH, the REVEAL prognostic equation and risk score provide very good discrimination but poor calibration. REVEAL prediction scores should be interpreted with caution in newly diagnosed SSc-PAH patients, particularly those with higher predicted risk of poor 1-year survival resulting from a low 6MWD or a high BNP serum level.

The impact of ambrisentan and tadalafil upfront combination therapy on cardiac function in scleroderma associated pulmonary arterial hypertension patients: cardiac magnetic resonance feature tracking study.

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.).

The Minimal Important Difference in Borg Dyspnea Score in Pulmonary Arterial Hypertension.

RATIONALE: 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. OBJECTIVES: 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. METHODS: 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. MEASUREMENTS AND MAIN RESULTS: 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. CONCLUSIONS: 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.

Health-related Quality of Life and Survival in Pulmonary Arterial Hypertension.

RATIONALE: 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. OBJECTIVE: To assess the relationship between HRQOL and outcomes in patients with pulmonary arterial hypertension. METHODS: 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. MEASUREMENTS AND MAIN RESULTS: 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. CONCLUSIONS: 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.

Ambrisentan and Tadalafil Up-front Combination Therapy in Scleroderma-associated Pulmonary Arterial Hypertension.

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).