Silvia Papa

Therapy for pulmonary arterial hypertension due to congenital heart disease and Down's syndrome

BACKGROUND Oral bosentan is effective in pulmonary arterial hypertension (PAH) related to congenital heart disease (CHD). In patients with Downs syndrome, the effect of bosentan is largely unknown. Aim of the study was to evaluate the long-term effects of bosentan in adult patients with CHD-related PAH with and without Downs syndrome. METHODS WHO functional class, resting oxygen saturation, 6-minute walk test (6 MWT) and hemodynamics were assessed at baseline and after 12 months of bosentan therapy in patients with CHD-related PAH with and without Downs syndrome. RESULTS Seventy-four consecutive patients were enrolled: 18 with and 56 without Downs syndrome. After 12 months of bosentan therapy, both with and without Downs syndrome patients showed an improvement in WHO functional class (Down: 2.5 ± 0.5 vs 2.9 ± 0.6, p=0.005; controls: 2.5 ± 0.5 vs 2.9 ± 0.5, p=0.000002), 6-minute walk distance (Down: 288 ± 71 vs 239 ± 74 m, p=0.0007; controls: 389 ± 80 vs 343 ± 86 m, p=0.00003), and hemodynamics (pulmonary flow, Down: 4.0 ± 1.6 vs 3.5 ± 1.4 l/m/m(2), p=0.006; controls: 3.5 ± 1.4 vs 2.8 ± 1.0 l/m/m(2), p=0.0005; pulmonary to systemic flow ratio, Down: 1.4 ± 0.7 vs 1.0 ± 0.4, p=0.003; controls: 1.1 ± 0.7 vs 0.9 ± 0.3, p=0.012; pulmonary vascular resistance index, Down: 15 ± 9 vs 20 ± 13 WUm(2), p=0.007; controls: 2 0 ± 10 vs 26 ± 15 WUm(2), p=0.002). No differences in the efficacy of therapy were observed between the two groups. CONCLUSIONS Bosentan was safe and well tolerated in adult patients with CHD-related PAH with and without Downs syndrome during 12 months of treatment. Clinical status, exercise tolerance, and pulmonary hemodynamics improved, regardless of the presence of Downs syndrome.

Prognostic factors in severe pulmonary hypertension patients who need parenteral prostanoid therapy: The impact of late referral

BACKGROUND Oral drugs have made the treatment of pulmonary hypertension (PH) feasible in non-expert centers, which could delay patient access to prostanoid therapy. METHODS Fifty-seven consecutive patients with precapillary PH received a prostanoid in our center. Data at prostanoid initiation included modality of center referral, medical history, New York Heart Association [NYHA] class, exercise capacity, echocardiographic parameters, and hemodynamics. RESULTS Overall survival at 1, 2, and 3 years was 85%, 69%, 55%, respectively. Non-survivors had worse NYHA class III/IV (17/12) than survivors (27/1; p < 0.01) and exercise capacity on 6-minute-walk distance (254 ± 114 vs 354 ± 91 meters; p < 0.01). Non-survivors were more frequently referred on oral therapy (83% vs 36%; p < 0.01) and had a higher rate of urgent prostanoid treatment (69% vs 17%; p < 0.0001). Multivariate analysis (hazard ratio [95% confidence interval]) found the independent prognostic factors were urgent prostanoid therapy (2.0 [1.1-3.9]) and NYHA class (3.5 [1.5-8.2]). Survivors had a significant response to prostanoid, improving NYHA class from 2.8 ± 0.4 to 2.3 ± 0.5 (p = 0.002), 6-minute walk distance from 354 ± 91 to 426 ± 82 meters (p = 0.0001), and pulmonary hemodynamics (pulmonary artery pressure from 56 ± 13 to 44 ± 18 mm Hg [p < 0.05]; cardiac index from 2.0 ± 1.2 to 3.1 ± 1.2 liters/min/m(2) [p = 0.002], and pulmonary vascular resistance from 17 ± 10 to 8 ± 6 WU [p = 0.001]). CONCLUSIONS Referral of patients on oral treatment to a tertiary PH center is delayed and significantly affects prognosis.

Right intraventricular dyssynchrony in idiopathic, heritable, and anorexigen-induced pulmonary arterial hypertension: Clinical impact and reversibility

OBJECTIVES The aim of this study was to determine the prevalence of right intraventricular dyssynchrony, its determinants and prognostic impact in idiopathic, heritable, and anorexigen-induced pulmonary arterial hypertension. BACKGROUND Right ventricular dyssynchrony has been described in pulmonary arterial hypertension, but no evidence is available on its prognostic impact and evolution after therapy. METHODS In 83 consecutive therapy-naïve patients, right ventricular dyssynchrony was evaluated by 2-dimensional speckle-tracking echocardiography calculating the standard deviation of the times to peak-systolic strain for the 4 mid-basal right ventricular segments (RV-SD4). After baseline (World Health Organization [WHO] class, pulmonary hemodynamics, 6-min walk test [6 MWT]), a second assessment was performed after 12 months or when clinical worsening occurred. RESULTS Patients with right ventricular dyssynchrony (RV-SD4 >18 ms) had advanced WHO class, worse 6 MWT, right ventricular remodeling, and hemodynamic profile compared with patients ≤ 18 ms. Determinants of dyssynchrony included pulmonary vascular resistance, QRS duration, and right ventricular end-diastolic area (r(2) = 0.38; p < 0.000001). At 12 months, 32.5% of patients presented clinical worsening (actuarial rates: 19% at 6 months, 31% at 1 year). Multivariable models for clinical worsening prediction showed that the addition of RV-SD4 to clinical and hemodynamic variables (WHO IV, 6 MWT, and cardiac index) significantly increased the prognostic power of the model (0.74 vs. 0.81; p = 0.005, 95% confidence interval [CI]: 0.02 to 0.11). Receiver operating characteristic analysis identified RV-SD4 ≥ 23 ms as the best cutoff value for clinical worsening prediction (95% negative predictive value). At 12 months, normalization of dyssynchrony was achieved in patients with a large reduction of pulmonary vascular resistance (-42 ± 4%). CONCLUSIONS Right ventricular dyssynchrony is frequent in pulmonary arterial hypertension, is an independent predictor of clinical worsening, and might regress during effective treatments.

Systemic sclerosis patients with and without pulmonary arterial hypertension: a nailfold capillaroscopy study

OBJECTIVE Pulmonary arterial hypertension (PAH) is a complication of SSc due to increased vascular resistance, and abnormal vascularity is a well-known feature of the disease as shown by nailfold videocapillaroscopy (NVC). This study investigated for specific NVC changes in SSc patients with and without PAH to assess any useful difference. METHODS Twenty-four SSc patients, 12 with PAH and 12 without, entered the study. Evidence of PAH was defined as increased systolic pulmonary artery pressure (PAP) (≥35 mmHg), indirectly assessed by echocardiography and confirmed by right heart catheterization (mPAP > 25 mmHg). NVC was performed, and a semi-quantitative rating scale, a rating system for avascular areas and a specific NVC pattern evaluation, namely early, active and late, were used. RESULTS An NVC score >1 was more frequently found in patients with PAH than those without, 11 cases (92%) vs 5 cases (42%) (P = 0.03); an avascular areas grade >1 was present in 10 (83%) and 2 (17%) cases, respectively (P = 0.003); and a more severe NC pattern (active/late) was described in 11 (92%) and 5 (42%) patients, respectively (P = 0.03). When we compared the mPAP with NVC parameters, we found significant correlations between mPAP values and the NVC score (P < 0.005) and with the avascular areas score (P < 0.001). CONCLUSION Our results underline the relevance of early microvascular assessment in patients at risk of developing a severe complication such as PAH that can amplify the systemic microvascular impairment in SSc. More severe NVC abnormalities should lead to strict cardiopulmonary surveillance and a complete NVC study is indicated.

Right ventricular dyssynchrony in idiopathic pulmonary arterial hypertension: Determinants and impact on pump function

BACKGROUND Right ventricular (RV) dyssynchrony has been described in pulmonary arterial hypertension (PAH), but no evidence is available on its morphologic determinants and its effect on systolic function. The aim of this study was to evaluate the morphologic determinants of RV dyssynchrony by echocardiographic and cardiac magnetic resonance imaging and its effect on systolic function. METHODS In 60 consecutive idiopathic PAH (IPAH) patients with narrow QRS, RV dyssynchrony was evaluated by 2D speckle-tracking echocardiography, calculating the standard deviation of the times to peak systolic strain for the four mid-basal RV segments (RV-SD4). Patients were grouped by the median value of RV-SD4 (19 milliseconds) and compared for RV remodeling and systolic function parameters, WHO class, pulmonary hemodynamics and 6-minute walk test (6MWT). RESULTS Despite similar pulmonary vascular resistance and mean pulmonary arterial pressure, patients with RV-SD4 at >19 milliseconds had advanced WHO class and worse 6MWT, RV hemodynamics, RV remodeling and systolic function parameters compared with patients at ≤19 milliseconds. The morphologic determinants of RV dyssynchrony resulted RV end-diastolic area, LV diastolic eccentricity index and RV mass volume ratio (r = 0.69, r(2) = 0.47, p < 0.0001). Finally, we found a significant inverse correlation between RV mid-basal segments post-systolic shortening time and cardiac index (r = -0.64, r(2) = 0.41, p = 0.001), accounting for the significant correlation between RV-SD4 and cardiac index (r = 0.57, r(2) = 0.32, p = 0.003). CONCLUSIONS In IPAH with narrow QRS, RV dyssynchrony is associated with RV dilation and eccentric hypertrophy pattern, suggesting a role of segmental wall stress heterogeneity as the major determinant of mechanical delay. Post-systolic shortening, as inefficient contraction, contributes to pump dysfunction.

Right ventricular remodeling in idiopathic pulmonary arterial hypertension: adaptive versus maladaptive morphology

BACKGROUND Although increased pulmonary pressure is caused by changes in the pulmonary vasculature, prognosis in idiopathic pulmonary arterial hypertension (IPAH) is strongly associated with right ventricular (RV) function. The aim of this study was to describe the best RV adaptive remodeling pattern to increased afterload in IPAH. METHODS In 60 consecutive patients with IPAH, RV morphologic and functional features were evaluated by echocardiography and cardiac magnetic resonance imaging. To address the question of the best RV adaptation pattern, we divided the study population into two groups by the median value of RV mass/volume ratio (0.46) because this parameter allows the distinction between RV eccentric (≤0.46) and concentric hypertrophy (>0.46). The two groups were compared for RV remodeling and systolic function parameters, World Health Organization class, pulmonary hemodynamics, and 6-minute walk test. RESULTS Despite similar pulmonary vascular resistance, mean pulmonary pressure, and compliance, patients with eccentric hypertrophy had advanced World Health Organization class and worse 6-minute walk test, hemodynamics, RV remodeling, and systolic function parameters compared with patients with concentric hypertrophy. The group with concentric hypertrophy had higher RV to pulmonary arterial coupling compared with the group with eccentric hypertrophy (1.24 ± 0.26 vs 0.83 ± 0.33, p = 0.0001), indicating higher RV efficiency. A significant correlation was found between pulmonary vascular resistance and RV to pulmonary arterial coupling (r = -0.55, r(2) = 0.31, p = 0.0001), with patients with RV mass/volume ratio > 0.46 at the higher part of the scatterplot, confirming more adequate RV function. CONCLUSIONS Concentric hypertrophy might represent a more favorable RV adaptive remodeling pattern to increased afterload in IPAH because it is associated with more suitable systolic function and mechanical efficiency.

Pulmonary arterial dilatation in pulmonary hypertension: prevalence and prognostic relevance.

Objectives: Pulmonary arterial dilatation is considered a consequence of chronic pulmonary hypertension (PH), but despite its relatively common detection, its prevalence and prognostic impact have not yet been systematically investigated. The aim of the study was to investigate these factors in a relatively large cohort of severe PH patients. Methods: One hundred and forty-one consecutive patients diagnosed with PH were monitored for a mean of 957 days. Data including functional class, exercise capacity, invasive hemodynamics and pulmonary artery (PA) echo/CT scan measurement were performed and outcomes prospectively collected. Results: PA dilatation is a common feature, present in the 76.6% of cases in this cohort of severe PH patients. Survival at 1, 2 and 3 years was 83, 71 and 58%, respectively. On univariate analysis, the baseline variables associated with a poor outcome were related to pulmonary arterial hypertension associated with connective tissue disease (CDT-PAH), New York Heart Association (NYHA) functional class, 6-min walk test and right atrial pressure. On multivariate analysis only CDT-PAH and NYHA functional class remained independently associated with poor survival. Conclusions: PA dilatation is commonly detected in severe PH patients and is not associated with an increased risk of death.

Right ventricular concentric hypertrophy and clinical worsening in idiopathic pulmonary arterial hypertension

BACKGROUND Because the pathophysiology of idiopathic pulmonary arterial hypertension (IPAH) is an afterload mismatch, wall stress represents the most important feature affecting the overloaded right ventricle (RV). Thus, the RV mass/volume (M/V) ratio may reflect more adequately the suitability of the remodeling pattern in minimizing RV wall stress compared with the lone RV volume. This study investigated the prognostic effect of the RV M/V ratio in IPAH. METHODS Enrolled in our center were 74 therapy-naïve IPAH patients who were prospectively monitored for the presence of clinical worsening (CW). Baseline evaluation included clinical, hemodynamic, and echocardiographic parameters. Cardiac magnetic resonance was used for RV M/V ratio determination. RESULTS During 541 ± 283 days of follow-up, 31 of 74 patients (42%) presented with CW. Actuarial rates of CW were 14%, 28%, and 46%, at 6, 12, and 24 months, respectively. The RV M/V ratio significantly improved the power of the prognostic model based on traditional clinical, hemodynamic, and imaging parameters (area under the curve: 0.74 vs 0.66, respectively; p = 0.01). When the cutoff values of the RV M/V ratio and cardiac index (CI) derived from receiver operating characteristic curve analysis were combined, patients with a low RV M/V ratio/low CI, low RV M/V ratio/high CI, and high RV M/V ratio/low CI showed a 28.8, 8.8, and 6.1 increase in the hazard ratio, respectively, compared with high RV M/V ratio/high CI patients (p = 0.0001). CONCLUSIONS The RV M/V ratio is an independent predictor of prognosis in IPAH and may allow clinicians to better stratify patients with normal CI, identifying at an early stage those patients at higher risk of right heart failure development before hemodynamic instability appears.

Relationship between baseline ET-1 plasma levels and outcome in patients with idiopathic pulmonary hypertension treated with bosentan

OBJECTIVES To address if baseline endothelin-1 (ET-1) plasma levels might predict clinical worsening (CW) in patients with idiopathic pulmonary hypertension (IPAH) treated with bosentan. METHODS Forty-four consecutive patients with IPAH (WHO classes II-III) were included in this study. After an initial assessment (clinical status, pulmonary hemodynamics, samples for adrenomedullin (ADM), ET-1 and brain natriuretic peptide (BNP) plasma levels), patients were treated with bosentan and followed-up for CW. RESULTS We observed CW in 24 patients. Actuarial rates of freedom from CW were 74% at 1 year, 56% at 2 years, and 43% at 3 years. Patients with CW had a worse WHO functional class (II/III; no-CW 14/6 vs CW 5/19, p=0.002), six-minute walk-test distance (no-CW 439+94 m vs CW 385+82 m, p=0.04), mean pulmonary artery pressure (no-CW 47.4+10.6mm Hg vs CW 56+12.6mm Hg, p=0.02) and pulmonary vascular resistance (PVR no-CW 12.5+4.8 WU vs CW 16.4+6.3 WU, p=0.03) than the no-CW group. Moreover ET-1 (no-CW 14.1+4.2 pg/ml vs CW 21.3+6.3 pg/ml, p=0.0001), ADM (no-CW 14.9+7 pg/ml vs CW 21.5+10.4 pg/ml p=0.002) and BNP (no-CW 82.8+35.3 pg/ml vs CW 115.4+39.6 pg/ml, p=0.007) plasma levels were significantly higher in the CW group than in the no-CW group. The multivariate Cox proportional hazards model identified WHO class III (RR 4.6, 95%CI 14.6-1.45), ET-1 plasma levels (RR 1.1, 95%CI 2.05-1.01) and PVR (RR 1.2, 95%CI 1.3-1.03) as independent risk factors for CW. CONCLUSIONS These data confirm the high rate of CW in patients with IPAH treated with bosentan and document the impact of the endothelin system on CW of these patients.

Right ventricular dyssynchrony and exercise capacity in idiopathic pulmonary arterial hypertension

Survival in patients with pulmonary arterial hypertension (PAH) is determined by right ventricular (RV) function adaptation to afterload. How altered RV function impacts on exercise capacity in PAH is not exactly known. 104 idiopathic PAH (IPAH) patients aged 52±14 years underwent a diagnostic right heart catheterisation, a comprehensive echocardiography including two-dimensional speckle tracking for RV dyssynchrony evaluation and a cardiopulmonary exercise test. Multivariate analyses were performed to identify independent predictors of peak oxygen uptake (peak V′O2). A first multivariate analysis of only resting haemodynamic variables identified cardiac index, right atrial (RA) pressure and pulmonary arterial compliance as independent predictors, with low predictive capacity (r2=0.31; p<0.001). A second multivariate analysis model which considered only echocardiographic parameters but without RV dyssynchrony, identified RV fractional area change (FAC) and RA area as independent predictors with still low predictivity (r2=0.35; p<0.001). Adding RV dyssynchrony to the second model increased its predictivity (r2=0.48; p<0.001). Repetition of the three multivariate analyses in patients with preserved RVFAC confirmed that inclusion of RV dyssynchrony results in the highest predictive capability of peak V′O2 (r2=0.53; p=0.001). A comprehensive echocardiography with speckle tracking-derived assessment of the heterogeneity of RV contraction improves the prediction of aerobic exercise capacity in IPAH. Speckle tracking assessment of RV dyssynchrony improves the prediction of aerobic exercise capacity in IPAH http://ow.ly/yHyh30bedtD