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Background: Right ventricular (RV) function is a major determinant of exercise intolerance and outcome in idiopathic pulmonary arterial hypertension. The aim of the study was to evaluate the incremental prognostic value of echocardiography of the right ventricle and cardiopulmonary exercise testing (CPET) on long-term prognosis in these patients.Methods: One hundred and thirty treatment-naïve patients with idiopathic pulmonary arterial hypertension were enrolled and prospectively followed. Clinical worsening (CW) was defined by a reduction in 6-min walk distance plus an increase in functional class, or nonelective hospitalization for PAH, or death. Baseline evaluation included clinical, hemodynamic, echocardiographic, and CPET variables. Cox regression modeling with c-statistic and bootstrapping validation methods were done.Results: During a mean period of 528 ± 304 days, 54 patients experienced CW (53%). Among demographic, clinical, and hemodynamic variables at catheterization, functional class and cardiac index were independent predictors of CW (model 1). With addition of echocardiographic and CPET variables (model 2), peak O2 pulse (peak V˙o2/heart rate) and RV fractional area change (RVFAC) independently improved the power of the prognostic model (area under the curve, 0.81 vs 0.66, respectively; P = .005). Patients with low RVFAC and low O2 pulse (low RVFAC + low O2 pulse) and high RVFAC + low O2 pulse showed a 99.8 and 29.4 increase in the hazard ratio, respectively (relative risk, 41.1 and 25.3, respectively), compared with high RVFAC + high O2 pulse (P = .0001).Conclusions: Echocardiography combined with CPET provides relevant clinical and prognostic information. A combination of low RVFAC and low O2 pulse identifies patients at a particularly high risk of clinical deterioration. [ABSTRACT FROM AUTHOR]

Abstract: Pulmonary hypertension (PH) is a clinical condition characterised by elevated pulmonary artery pressure (PAP) and vascular resistances. At the onset of the disease, symptoms are frequently atypical so that PH diagnosis is usually made when the disease is advanced, which often is too late for efficacious treatment. As a consequence the prognosis is poor. Echo–Doppler evaluation allows: (a) an early identification of patients with PH, (b) to establish a patient''s prognosis and (c) to evaluate a proper patient''s follow-up. In patients with PH echocardiography provides information about right heart dimensions, pulmonary artery pressures, right ventricle systolic and diastolic function and left and right ventricle interdependence. Most importantly Echo–Doppler evaluation has became a major diagnostic tool for PH allowing evaluation of changes with time and with different treatments which are aimed at reducing pulmonary artery pressure and right heart dimensions and at improving right heart function. [Copyright &y& Elsevier]

Background: Prostanoids are a well-established therapy for pulmonary arterial hypertension (PAH), and observational studies suggest their efficacy even in chronic thromboembolic pulmonary hypertension (CTEPH) patients. Objective: To compare the effects of 6 months of treatment with beraprost, an orally-active prostacyclin analog, in patients with distal CTEPH and PAH. Design: Case-control study. Population: Sixteen patients with severe pulmonary hypertension (NYHA II–IV), eight with distal CTEPH matched with eight patients with idiopathic PAH for similar effort tolerance. Methods: All patients were in stable clinical and hemodynamic condition for 3 months with maximal standard therapy. During the titration phase (4 weeks) beraprost was increased to maximal tolerated dose (mean daily dosage: CTEPH 275 ± 47 μg, PAH 277 ± 47 μg) in adjunction of standard therapy, patients were followed-up for 6 months. Main Outcome Measures: World Heart Organization (WHO) functional class, exercise capacity measured by distance walked in 6 min, and systolic pulmonary pressure (echocardiography), were evaluated at baseline, and at 1-, 3- and 6-month interval. Results: At 6 months WHO class decreased significantly in both groups (CTEPH from 2.7 ± 0.6 to 2.0 ± 0.24, p < 0.05; PAH from 3.0 ± 0.26 to 2.1 ± 0.25, p < 0.05), similarly the 6-min walk distance increased significantly from baseline (CTEPH from 312 ± 31 to 373 ± 29 m, p < 0.003; PAH from 303 ± 31 to 347 ± 29, p < 0.0003). Systolic pulmonary artery pressure showed a trend toward lower value (CTEPH from 85 ± 7 m to 81 ± 6 mm Hg, p = NS; PAH from 89 ± 7 to 82 ± 5, p = NS). During the observation period we did not have any death. The drug was well-tolerated with minor side-effects. Conclusion: In patients with CTEPH beraprost had similar mid-term clinical and hemodynamic improvements than in patients with PAH. Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Chronic thromboembolic pulmonary hypertension (CTEPH) is a severe and under-recognized complication of acute pulmonary embolism (PE). Forty consecutive patients with acute PE (Group 1), predominantly female (22, 55%) with a mean age of 69 ± 15 years, were matched for demographic data with 40 healthy subjects (Group 2), 40 systemic hypertension patients (Group 3) and 45 prevalent idiopathic pulmonary arterial hypertension (IPAH) patients (Group 4). The baseline evaluation included physical examination, NYHA/WHO functional class, right heart catheterization (RHC) limited to IPAH patients, echocardiographic assessment and systemic arterial stiffness measurement by cardio-ankle vascular index (CAVI). Patients with PE underwent an echocardiographic evaluation within 1 month from hospital discharge (median 27 days; IQR 21–30) to assess the echo-derived probability of PH. The CAVI values were significantly higher in the PE and IPAH groups compared with the others (Group 1 vs. Group 2, p < 0.001; Group 1 vs. Group 3, p < 0.001; Group 1 vs. Group 4, p = ns; Group 4 vs. Group 2, p < 0.001; Group 4 vs. Group 3, p < 0.001; Group 2 vs. Group 3, p = ns). The predicted probability of echocardiography-derived high-risk criteria of PH increases for any unit increase of CAVI (OR 9.0; C.I.3.9–20.5; p = 0.0001). The PE patients with CAVI ≥ 9.0 at the time of hospital discharge presented an increased probability of PH. This study highlights a possible positive predictive role of CAVI as an early marker for the development of CTEPH. [ABSTRACT FROM AUTHOR]

Pulmonary arterial hypertension (PAH) is a rare, progressive disease with a poor prognosis. The pathophysiologic model is mainly characterized by an afterload mismatch in which an increased right ventricle afterload, driven by increased pulmonary vascular resistance (PVR), leads to right heart failure. International guidelines recommend optimization of treatment based on regular risk assessments to achieve or maintain a low-risk status. Current risk scores are based on a multi-modality approach, including demographic, clinical, functional, exercise, laboratory, and hemodynamic parameters, which lack significant echocardiographic parameters. The originality of echocardiography relies on the opportunity to assess in a non-invasive way a physiologically meaningful combination of easy to measure variables tightly related to right ventricle adaptation/maladaptation to increased afterload, the main determinant of a patient's prognosis. Echo-derived morphological and functional parameters have been investigated in PAH, proving to have prognostic relevance. Different therapeutic strategies proved to have different effects in reducing PVR. An upfront combination of drugs, including a parenteral prostacyclin, has shown to be associated with right heart reverse remodeling in a greater proportion of patients than other treatment strategies as a function of PVR reduction. Adding echocardiographic data to current risk scores would allow better identification of right ventricle (RV) adaptation in PAH patients' follow-up. This additional information would allow better stratification of the patient, leading to optimized and personalized therapeutic management. [ABSTRACT FROM AUTHOR]

>Despite advances in drug development, life expectancy in idiopathic pulmonary arterial hypertension (IPAH) remains unacceptable. Contemporary IPAH characterization is based on criteria that may not adequately capture disease heterogeneity and may be proposed as a possible explanation for why patient outcome is still unfavorable. The aim of this study was to apply cluster analysis to improve phenotyping of patients with IPAH and analyze long-term clinical outcome of derived clusters. Patients with IPAH from 2 referral centers (n = 252) were evaluated with clinical, hemodynamic, and echocardiographic assessment and cardiopulmonary exercise test. Patients were classified according to cluster analysis and followed for clinical worsening occurrence. The cluster analysis identified 4 IPAH phenotypes. Cluster 1 was characterized by young patients, mild pulmonary hypertension (PH), mild right ventricular (RV) dilation and high oxygen (O 2) pulse; Cluster 2 by severe PH and RV dilation and high O 2 pulse; and Cluster 3 by male patients, severe PH and RV dilation, and low O 2 pulse. Cluster 4 patients were older and overweight, with mild PH and RV dilation and low O 2 pulse. After a mean follow-up of 995 ± 623 days, 123 (48.8%) patients had clinical worsening. Cluster 1 patients presented the best prognosis, whereas Cluster 3 had the highest rates of clinical worsening. Compared with Cluster 1, risk of clinical worsening ranged from 4.12 (confidence interval [CI] 1.43–11.92; p = 0.009) for Cluster 4 to 7.38 (CI 2.80–19.40) for Cluster 2 and 13.8 (CI 5.60–34.0; p = 0.0001) for Cluster 3. Cluster analysis of clinical variables identified 4 distinct phenotypes of IPAH. Our findings underscore the high degree of disease heterogeneity that exists within patients with IPAH and the need for advanced clinical testing to define phenotypes to improve treatment strategy decision-making. CONDENSED ABSTRACT Idiopathic pulmonary arterial hypertension (IPAH) characterization is based on criteria that may not adequately capture disease heterogeneity. The aim of this study was to apply cluster analysis to improve phenotyping of IPAH. Patients with IPAH (n = 252) were evaluated with clinical, hemodynamic, and echocardiographic assessment and cardiopulmonary exercise test. Within the umbrella category of IPAH, it was the combination of mean pulmonary arterial pressure, right ventricular size, and oxygen pulse that further stratified patients into novel IPAH phenotypes that significantly associate with clinical worsening. These findings underscore the need for novel multidimensional IPAH phenotyping for improved patient care and trial quality. [ABSTRACT FROM AUTHOR]

BACKGROUND The added value of cardiopulmonary exercise testing (CPET) in the follow-up of patients with stable pulmonary arterial hypertension (PAH) remains undefined. METHODS Idiopathic, heritable, and drug-induced PAH patients free from clinical worsening (CW) after 1 year of treatment were enrolled in derivation (n = 80) and validation (n = 80) cohorts at an interval of 6 years and followed for 3 years. Prognostic models were constructed and validated in low-risk patients in World Health Organization (WHO) Functional Class I or II with cardiac index (CI) ≥2.5 liters/min/m2 and right atrial pressure (RAP) <8 mm Hg. Discrimination and calibration were assessed. RESULTS Forty-one derivation cohort patients had CW (51.2%) during 722 ± 349 days. Changes (∆) in WHO classification and CI and absolute value of RAP were independent predictors of CW. With addition of CPET variables, peak oxygen uptake (VO 2 peak) and ∆CI independently improved the power of the prognostic model. Receiver operating characteristic (ROC)-derived cut-off values for ∆CI and VO 2 peak were 0.40 liter/min/m2 and 15.7 ml/kg/min (≥60% predicted value), respectively. Twenty-nine validation cohort patients had CW (36.2%) during 710 ± 282 days. Different combinations of cut-off values of VO 2 peak and ∆CI defined 4 groups. The event-free survival rates at 1, 2, and 3 years were 100%, 100%, and 100%, respectively, for the high ∆CI with high VO 2 peak combination; 100%, 88%, and 71% for low ∆CI/high VO 2 peak; 80%, 54%, and 40% for high ∆CI/low VO 2 peak; and 72%, 54%, and 33% for low ∆CI/low VO 2 peak. CONCLUSIONS The combinations of baseline VO 2 peak and change in CI during follow-up is important in prognostication of low-risk patients with idiopathic, heritable, and drug-induced PAH. [ABSTRACT FROM AUTHOR]

Background Right ventricular (RV) failure is a major determinant of symptoms and shortened survival in pulmonary arterial hypertension (PAH). This study assessed the prognostic relevance of increased right heart (RH) dimensions determined by echocardiography and RH reverse remodeling (RHRR) with targeted therapies in idiopathic PAH (IPAH). Methods The study prospectively monitored 102 therapy-naïve IPAH patients for the presence of clinical worsening. Baseline evaluation included RH catheterization and echocardiography. RHRR at the 1-year follow-up was defined by a decrease in RV end-diastolic area, right atrial area, and the left ventricular systolic eccentricity index. Results At the 1-year follow-up, 18 of 102 patients (17.6%) presented with RHRR. A decrease in pulmonary vascular resistance was the only independent determinant of RHRR. The 94 surviving patients were monitored for 995 ± 529 days. RHRR was an independent prognostic factor and significantly improved the power of the prognostic model based on traditional clinical and hemodynamic parameters. The respective event-free survival rates at 1, 3, and 5 years were 94%, 94%, and 94% in patients with RHRR and 75%, 55%, and 24% in those without RHRR ( p = 0.0001). Interestingly, RHRR was able to further stratify patients’ risk assessment through the Registry to Evaluate Early And Long-term PAH Disease Management risk score. Conclusions RHRR after 1 year of treatment is an independent predictor of prognosis in IPAH. The likelihood of RHRR is proportional to decreased pulmonary vascular resistance. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background Heart failure (HF) and chronic obstructive pulmonary disease (COPD) coexistence increases morbidity and mortality. The intercept of ventilation (VEint) on the VE vs. carbon dioxide production (VCO2) relationship during exercise has been found to vary in proportion with dead space (VD) in HF. Considering that increased VD is the key pathophysiological abnormality in COPD but a secondary finding in HF we hypothesized that a high VEint would be useful in suggesting COPD as HF co-morbidity. Our aim was to assess whether an elevated VEint suggests the presence of COPD in HF. Methods In a multicenter retrospective study, the VE-VCO2 relationship was analyzed both as slope and intercept in HF (n = 108), HF-COPD (n = 106) and COPD (n = 95). Patients with pulmonary arterial hypertension (PAH) (n = 85) and healthy subjects (HF) (n = 56) served as positive and negative controls relative to VE-VCO2 abnormalities, respectively. Results Slope and VEint varied in opposite directions in all groups (p < 0.05) being VE-VCO2 slope highest and lowest in PAH and healthy subjects, respectively. No slope differences were observed among HF, HF-COPD and COPD (32 ± 7, 31 ± 7, and 31 ± 6, respectively). VEint was higher in HF-COPD and COPD compared to HF, PAH and controls (4.8 ± 2.4 L/min, 5.9 ± 3.0 L/min, 3.0 ± 2.6 L/min, 2.3 ± 3.3 L/min and 3.9 ± 2.5 L/min, respectively; p < 0.01). A VEint ≥ 4.07 L/min identified patients with high probability of having COPD or HF-COPD (sensitivity of 71.6% and specificity of 72.0%). Conclusion These data provide novel evidence that a high VEint (≥ 4.07 L/min) should be valued to suggest coexistent COPD in HF patients. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract: Aim: To study the role of endothelin (ET-1) and adrenomedullin (AM) on pulmonary vascular pressure/flow characteristic (pulmonary arterial pressure/cardiac output (Pap/CO)) during low-dose dobutamine infusion. Methods: Case control study of 14 patients (12 men, 2 women) with severe lung disease (chronic obstructive pulmonary disease, COPD n =5; cystic fibrosis, CF n =9) and 5 control subjects (CTRL, 4 men, 1 woman). ET-1 and AM plasma levels in pulmonary artery (mixed venous blood, ven) and aorta or femoral artery (arterial, art), were measured at baseline and during dobutamine infusion (5–10–15 mcg kg−1 min−1). The Ppa/CO coordinates obtained at baseline and during dobutamina infusion for each patients were used to calculate the Slope and Intercept by linear regression analysis. Results: Baseline hemodynamics measurements were similar in the three groups with a trend towards a mild elevation in Ppa in CF group (Ppa mm Hg: CTRL 19±3.5, COPD 19.4±5.5, CF 22.7±7.5). Baseline plasma ET-1(ET-1ven pg ml−1: CTRL 13.9±6.7, COPD 20.1±14, CF 20.4±7.1; ET-1art pg ml−1: CTRL 16.7±6.4, COPD 20.1±11.7, CF 18.1±3.9) and AM (AMven pg ml−1: CTRL 15.8±5, COPD 31.8±17.6, CF 27.7±7.6; AMart pg ml−1: CTRL 15.9±1.4, COPD 21.4±3.8, CF 27±7.6) showed a trend towards higher value among patients'' groups compared to the controls. Baseline ET-1 pulmonary gradient did not show significant difference among the three groups as well AM pulmonary gradient. Dobutamine infusion caused a comparable increase of heart rate and CO in the three groups. Mean pulmonary pressure had a trend towards a greater increase in COPD and CF than in controls, consequently, pulmonary Pap/CO relationship showed a steeper slope in patients'' groups (Slope mm Hg L−1 min−1: CTRL 0.9±0.3, COPD 2.1±0.8 p <0.02 vs. CTRL, CF 1.9±0.9 p <0.03 vs CTRL). During dobutamine plasma ET-1 and AM showed a great individual variability resulting in no significant difference among groups. ET-1 pulmonary gradient showed a trend towards pulmonary uptake in patients'' groups (ET-1art-ven pg min−1: CTRL 2.7±2.9, COPD-6.1±7.8, CF −4±4.8) while AM pulmonary gradient did not show any particular pattern. During dobutamine ET-1 was significantly correlated to Pap/CO characteristics (Slope and ET-1ven, r =−0.59, p <0.05; Slope and ET-1art-ven, r =−0.60, p <0.05; Intercept and ET-1art-ven, r =0.63, p <0.004), and ET-1art-ven was the only independent variable related to Slope and Intercept. Conclusions: In patients with moderate pulmonary vascular impairment, ET-1 pulmonary gradient, but not AM pulmonary gradient, is inversely correlated with pulmonary incremental resistance, suggesting a role of ET-1 in the regulation of pulmonary vascular resistance. [Copyright &y& Elsevier]