natriuretic-peptide--brain and Familial-Primary-Pulmonary-Hypertension

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Topics: Familial Primary Pulmonary Hypertension; Hemodynamics; Humans; Hypertension, Pulmonary; Iron Deficiencies; Natriuretic Peptide, Brain; Peptide Fragments; Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a frequent complication in connective tissue diseases (CTD), especially in systemic sclerosis (SSc), and is associated with a high degree of morbidity and mortality. We undertook a systematic review for the screening tests for CTD-PAH.. A systematic literature search of PAH in CTD was performed in available databases through June 2012. Our evaluation of diagnostic tests was focused on patients with PAH confirmed by right heart catheterization (RHC).. The search resulted in 2805 titles and 838 abstracts. Our final inclusion encompassed 22 articles-six of which were case-control studies and 16 were cohort studies. Twelve studies assessed the tricuspid regurgitation velocity (VTR) or equivalent right ventricular systolic pressure (RVSP) using transthoracic echocardiogram (TTE) as a threshold for RHC in patients suspected as having PAH. The screening threshold for RHC was VTR from >2.73 to >3.16 m/s without symptoms or 2.5-3.0m/s with symptoms and resulted in 20-67% of patients having RHC-proven PAH. Three studies looked at pulmonary function tests and found that a low lung diffusing capacity for carbon monoxide (DLCO) (45-70% of predicted) is associated with a 5.6-7.4% development of PAH, and a decline in DLCO% is associated with an increase in the specificity (for DLCO ≤ 60%, spec = 45%; and for DLCO ≤ 50%, spec = 90%) for PAH. Five studies assessed N-terminal prohormone of brain natriuretic peptide (NT-ProBNP), where a cutoff >239 pg/ml had a sensitivity of 90-100%.. Our systematic review revealed that most evidence exists for TTE, pulmonary function tests, and NT-ProBNP for screening and diagnosis of SSc-PAH; however, more robust studies are needed.

Topics: Connective Tissue Diseases; Echocardiography; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Natriuretic Peptide, Brain; Peptide Fragments; Respiratory Function Tests; Sensitivity and Specificity

Pulmonary hypertension (PH) is a hemodynamic condition that has a poor prognosis and can lead to right-sided heart failure. It may result from common diseases such as left-sided heart or lung disease or may present as the rare entity of idiopathic pulmonary arterial hypertension. Biomarkers that specifically indicate the pathologic mechanism, the severity of the disease, and the treatment response would be ideal tools for the management of PH. In this review, markers related to heart failure, inflammation, hemostasis, remodeling, and endothelial cell-smooth muscle cell interaction are discussed, and their limitations are emphasized. Anemia, hypocarbia, elevated uric acid, and C-reactive protein levels are unspecific markers of disease severity. Brain natriuretic peptide and N-terminal fragment of pro-brain natriuretic peptide have been recommended in current guidelines, whereas other prognostic markers, such as growth differentiation factor-15, osteopontin, and red cell distribution width, are emerging. Chemokines of the CC family and matrix metalloproteases have been linked to the vascular pathologic mechanisms, and new markers such as apelin have been described. Circulating endothelial and progenitor cells have received much attention as markers of disease activity, but with controversial findings. A lack of standards for cell isolation and characterization methods and differences in the pathologic mechanisms of the investigated patients may have contributed to the discrepancies. In conclusion, although several promising markers have been identified over the past few years, the development of more specific markers, standardization, and prospective validation are warranted.

Topics: Biomarkers; Endothelial Cells; Familial Primary Pulmonary Hypertension; Growth Differentiation Factor 15; Humans; Hypertension, Pulmonary; Natriuretic Peptide, Brain; Osteopontin; Peptide Fragments; Prognosis

Pulmonary arterial hypertension (PAH) is a progressive vasculopathy that is advanced by the time symptoms develop. As symptoms are nonspecific and the condition uncommon, continued progression toward end-stage disease occurs for an average of 2 years between symptom onset and diagnosis. There is need for earlier diagnosis and treatment, as most patients are severely symptomatic when diagnosed and their mortality is high despite therapy. Screening can help; however, it is not straightforward due to the diversity of patient profiles and lack of sufficiently accurate tools. Echocardiography, currently the best available screening tool, lacks both sensitivity and specificity. The low prevalence of PAH renders many screening tools unfit for purpose. However, this may be overcome, in some instances, by using enrichment tools to preselect screening populations. The majority of data are available for systemic sclerosis. A recent study has demonstrated how lung function can be used to enrich PAH prevalence in a systemic sclerosis population. A screening bundle then selects patients for right heart catheterisation with improved rates of sensitivity compared to current guidelines.

Topics: Algorithms; Biomarkers; Diagnostic Techniques and Procedures; Disease Progression; Early Diagnosis; Echocardiography; Exercise Test; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Lung; Natriuretic Peptide, Brain; Peptide Fragments; Practice Guidelines as Topic; Predictive Value of Tests; Prognosis; Respiratory Function Tests; Risk Factors; Scleroderma, Systemic; Time Factors

Brain natriuretic peptide (BNP) and N-terminal brain natriuretic peptide (NT-proBNP) are important biomarkers for pediatric cardiovascular diseases. Peptide levels are associated with age and gender. Current studies have shown that BNP and NT-proBNP are valuable in the diagnosis of heart failure, with a high specificity and sensitivity. They also contribute to differentiating heart failure from acute respiratory distress induced by simple pulmonary factors. In addition, BNP and NT-proBNP are useful in the evaluation of disease severity and treatment guidance in children with pulmonary hypertension, cardiomyopathy and Kawasaki disease. Current limitations include the relatively small sample size of the study, the detection method and a range of normal values that are not completely uniform.

Topics: Cardiomyopathies; Cardiovascular Diseases; Child; Dyspnea; Familial Primary Pulmonary Hypertension; Heart Failure; Humans; Hypertension, Pulmonary; Mucocutaneous Lymph Node Syndrome; Natriuretic Peptide, Brain; Peptide Fragments

Effective management of patients with pulmonary arterial hypertension (PAH) requires comprehensive prognostic evaluation in order to determine optimal management strategies. Although a number of clinical and hemodynamic parameters linked to PAH prognosis have been identified, some are associated with significant limitations (eg, invasive techniques, subjective measures). There is a need for noninvasive and objective measures to be established that function as biomarkers for the diagnosis and assessment of disease prognosis, and that determine response to therapy in patients with PAH. Reflecting the highly complex etiology of the disease, a large number of potential biomarkers have been, and continue to be, investigated in PAH, including those reflecting right heart function, endothelial dysfunction, and markers of inflammation and second organ failure. However, it has become clear that scientifically interesting biomarkers may not necessarily be clinically useful. Of the range of biomarkers investigated in PAH to date, only brain natriuretic peptide and its N-terminal cleavage product have been included as prognostic parameters in treatment guidelines. It is unlikely that any single biomarker will provide all the relevant information required for an individual patient, and the potential for combining markers is currently of considerable interest. Future studies are required to determine the optimal combination of existing and emerging biomarkers in the clinical setting.

Topics: Biomarkers; Creatinine; Endothelium, Vascular; Familial Primary Pulmonary Hypertension; Heart Failure; Humans; Hypertension, Pulmonary; Inflammation; Natriuretic Peptide, Brain; Oxidative Stress; Peptide Fragments; Prognosis; Sodium; Troponin T

Citrulline is an amino acid which is produced by the urea cycle and also a precursor for NO, that is, a vasodilator for normal function of pulmonary vasculature. Thereby, enhancing l-citrulline malate in patients with idiopathic pulmonary arterial hypertension and those with congenital heart disease identified as Eisenmenger Syndrome results in reduction of pulmonary hypertension.. In this clinical trial before and after study, we assigned 25 patients with arterial pulmonary hypertension (idiopathic or Eisenmenger Syndrome) to receive l-citrulline malate 1g three times daily for two weeks. The primary measurement was the change in exercise capacity, as considered as a result of the total distance walked in six minutes, from baseline to week 2. We also assessed mean pulmonary artery pressure, the change in the quality of life, and the change in pro-brain natriuretic peptide (BNP) level. The study was not powered to evaluate mortality.. The mean walking distance in six minutes was significantly increased by about 44m (p=0.005) after receiving l-citrulline malate. Mean pulmonary artery pressure significantly reduced from 83.34mmHg before receiving l-citrulline malate to 79.1mmHg after that (p=0.01). All dimensions of the quality of life had statistical differences after receiving l-citrulline malate except limit due to physical health, limit due to emotional health and social functioning (p>0.05). Finally, pro-BNP difference was not statistically significant (p=0.9).. l-Citrulline malate improves the distance walk in six minutes and also the quality of life of patients with idiopathic arterial pulmonary hypertension and Eisenmenger Syndrome and also reduced mean arterial pulmonary hypertension.

Topics: Administration, Oral; Adult; Arterial Pressure; Citrulline; Eisenmenger Complex; Familial Primary Pulmonary Hypertension; Female; Humans; Malates; Male; Natriuretic Peptide, Brain; Pulmonary Artery; Quality of Life; Treatment Outcome; Walking; Young Adult

In translational models of pulmonary arterial hypertension (PAH), spironolactone improves cardiopulmonary hemodynamics by attenuating the adverse effects of hyperaldosteronism on endothelin type-B receptor function in pulmonary endothelial cells. This observation suggests that coupling spironolactone with inhibition of endothelin type-A receptor-mediated pulmonary vasoconstriction may be a useful treatment strategy for patients with PAH. We examined clinical data from patients randomized to placebo or the selective endothelin type-A receptor antagonist ambrisentan (10 mg/day) and in whom spironolactone use was reported during ARIES-1 and -2, which were randomized, double-blind, placebo-controlled trials assessing the effect of ambrisentan for 12 weeks on clinical outcome in PAH. From patients randomized to placebo (n = 132) or ambrisentan (n = 67), we identified concurrent spironolactone use in 21 (15.9%) and 10 (14.9%) patients, respectively. Compared with patients treated with ambrisentan alone (n = 57), therapy with ambrisentan + spironolactone improved change in 6-minute walk distance by 94% at week 12 (mean ± SE, +38.2 ± 8.1 vs +74.2 ± 27.4 m, p = 0.11), improved plasma B-type natriuretic peptide concentration by 1.7-fold (p = 0.08), and resulted in a 90% relative increase in the number of patients improving ≥1 World Health Organization functional class (p = 0.08). Progressive illness, PAH-associated hospitalizations, or death occurred as an end point for 5.3% of ambrisentan-treated patients; however, no patient treated with ambrisentan + spironolactone reached any of these end points. In conclusion, these pilot data suggest that coupling spironolactone and endothelin type-A receptor antagonism may be clinically beneficial in PAH. Prospective clinical trials are required to further characterize our findings.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antihypertensive Agents; Diuretics; Double-Blind Method; Drug Therapy, Combination; Exercise Test; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Natriuretic Peptide, Brain; Phenylpropionates; Pilot Projects; Pyridazines; Severity of Illness Index; Spironolactone; Treatment Outcome; Young Adult

To evaluate the clinical utility of tissue Doppler imaging (TDI) in assessment of disease severity and prognostic value in children with idiopathic pulmonary arterial hypertension (PAH).. A prospective study was performed to evaluate TDI velocities (systolic myocardial velocity, early diastolic myocardial relaxation velocity [Em], late diastolic myocardial velocity associated with atrial contraction), brain natriuretic peptide, New York Heart Association (NYHA) functional class, and hemodynamics in 51 children (mean age; 11.6 years) with idiopathic PAH. Fifty-one healthy children with comparable demographics served as controls.. Em, Em/late diastolic myocardial velocity associated with atrial contraction ratio, and systolic myocardial velocity at mitral annulus, septum, and tricuspid annulus in PAH were significantly reduced compared with controls. Tricuspid Em had significant inverse correlations with plasma brain natriuretic peptide levels (r = -0.60, P < .001), right ventricular end-diastolic pressure (r = -0.79, P < .001), and mean pulmonary arterial pressure (r = -0.67, P < .001). Statistically significant differences were observed in tricuspid Em between NYHA functional class II vs combined III and IV (mean and SD; 11.9 ± 4.2 cm/s vs 8.2 ± 3.6 cm/s, respectively, P = .002). Cumulative event-free survival rate was significantly lower when tricuspid Em was ≤8 cm/s (log-rank test, P < .001). Tricuspid Em velocity correlated with NYHA functional class as disease severity and may serve as a useful prognostic marker in children with idiopathic PAH. The present study is the initial report to evaluate TDI velocities against midterm outcome variables in a relatively large pediatric PAH population.

Topics: Adolescent; Biomarkers; Blood Flow Velocity; Blood Pressure; Case-Control Studies; Child; Disease-Free Survival; Echocardiography, Doppler, Color; Echocardiography, Doppler, Pulsed; Exercise Test; Familial Primary Pulmonary Hypertension; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Kaplan-Meier Estimate; Logistic Models; Male; Natriuretic Peptide, Brain; Prognosis; Prospective Studies; ROC Curve; Severity of Illness Index

Edema is a common side effect of endothelin receptor antagonists. Ambrisentan is an endothelin type A-selective endothelin receptor antagonist approved for the treatment of pulmonary arterial hypertension. We examined the clinical outcomes of patients who developed edema with and without ambrisentan treatment in 2 phase III, randomized placebo-controlled trials, ambrisentan for the treatment of pulmonary arterial hypertension: results of the ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebo-controlled, multicenter, efficacy (ARIES) study 1 and 2 (ARIES-1 and ARIES-2) (n = 393). Edema-related adverse events were extracted using broad adverse event search terms. The present post hoc analysis included 132 placebo patients and 261 ambrisentan patients. Of these patients, 14% of the placebo patients and 23% of the ambrisentan patients experienced edema-related adverse events. Overall, the patients who experienced edema tended to have a worse baseline World Health Organization (WHO) functional class (edema 76%, WHO functional class III-IV; no edema 56%, WHO functional class III-IV). In the ambrisentan patients, those with edema were older (mean age 58 ± 13 years) and heavier (mean weight 75 ± 19 kg) than those without edema (mean age 49 ± 15 years; mean weight 70 ± 17 kg). At week 12 of treatment, the ambrisentan patients had significantly increased their 6-minute walk distance (6MWD) by 34.4 m compared to the placebo patients in whom the 6MWD had deteriorated by -9.0 m (p <0.001). Among the ambrisentan patients, those without edema had a 6MWD increase of 38.9 m and those with edema had a 6MWD increase of 19.4 m. Ambrisentan significantly improved the brain natriuretic peptide levels by -34% compared to the brain natriuretic peptide levels in the placebo group that had worsened by +11% (p <0.001). Ambrisentan reduced the brain natriuretic peptide concentrations similarly in patients with and without edema. In conclusion, the present subanalysis of patients with pulmonary arterial hypertension has revealed that ambrisentan therapy provides clinical benefit compared to placebo, even in the presence of edema.

Topics: Adult; Age Factors; Aged; Analysis of Variance; Confidence Intervals; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Edema; Familial Primary Pulmonary Hypertension; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Incidence; Male; Middle Aged; Natriuretic Peptide, Brain; Phenylpropionates; Pyridazines; Reference Values; Risk Assessment; Safety Management; Severity of Illness Index; Sex Factors; Treatment Outcome

A diagnosis of idiopathic pulmonary arterial hypertension (IPAH) is frequently made in elderly patients who present with comorbidities, especially hypertension, coronary heart disease, diabetes mellitus, and obesity. It is unknown to what extent the presence of these comorbidities affects the response to PAH therapies and whether risk stratification predicts outcome in patients with comorbidities.. We assessed the database of COMPERA, a European pulmonary hypertension registry, to determine changes after initiation of PAH therapy in WHO functional class (FC), 6-minute walking distance (6MWD), brain natriuretic peptide (BNP) or N-terminal fragment of probrain natriuretic peptide (NT-pro-BNP), and mortality risk assessed by a 4-strata model in patients with IPAH and no comorbidities, 1-2 comorbidities and 3-4 comorbidities.. The analysis was based on 1,120 IPAH patients (n = 208 [19%] without comorbidities, n = 641 [57%] with 1-2 comorbidities, and n = 271 [24%] with 3-4 comorbidities). Improvements in FC, 6MWD, BNP/NT-pro-BNP, and mortality risk from baseline to first follow-up were significantly larger in patients with no comorbidities than in patients with comorbidities, while they were not significantly different in patients with 1-2 and 3-4 comorbidities. The 4-strata risk tool predicted survival in patients without comorbidities as well as in patients with 1-2 or 3-4 comorbidities.. Our data suggest that patients with IPAH and comorbidities benefit from PAH medication with improvements in FC, 6MWD, BNP/NT-pro-BNP, and mortality risk, albeit to a lesser extent than patients without comorbidities. The 4-strata risk tool predicted outcome in patients with IPAH irrespective of the presence of comorbidities.

Topics: Aged; Familial Primary Pulmonary Hypertension; Follow-Up Studies; Humans; Hypertension, Pulmonary; Natriuretic Peptide, Brain; Peptide Fragments; Pulmonary Arterial Hypertension; Risk Assessment

Risk stratification and assessment of disease progression in patients with pulmonary arterial hypertension (PAH) are challenged by the lack of accurate disease-specific and prognostic biomarkers. To date, brain natriuretic peptide (BNP) and/or its N-terminal fragment (NT-proBNP) are the only markers for right ventricular dysfunction used in clinical practice, in association with echocardiographic and invasive haemodynamic variables to predict outcome in patients with PAH.. This study was designed to identify an easily measurable biomarker panel in the serum of 80 well-phenotyped PAH patients with idiopathic, heritable or drug-induced PAH at baseline and at first follow-up. The prognostic value of identified cytokines of interest was secondly analysed in an external validation cohort of 125 PAH patients.. Among the 20 biomarkers studied with the multiplex Ella platform, we identified a three-biomarker panel composed of β-NGF, CXCL9 and TRAIL that were independently associated with prognosis both at the time of PAH diagnosis and at the first follow-up after initiation of PAH therapy. β-NGF and CXCL9 were predictors of death or transplantation, whereas high levels of TRAIL were associated with a better prognosis. Furthermore, the prognostic value of the three cytokines was more powerful for predicting survival than usual non-invasive variables (New York Heart Association Functional Class, 6-min walk distance and BNP/NT-proBNP). The results were validated in a fully independent external validation cohort.. The monitoring of β-NGF, CXCL9 and TRAIL levels in serum should be considered in the management and treatment of patients with PAH to objectively guide therapeutic options.

Topics: Biomarkers; Cytokines; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Natriuretic Peptide, Brain; Peptide Fragments; Prognosis; Pulmonary Arterial Hypertension

Connective tissue growth factor (CTGF) has diagnostic value for pulmonary arterial hypertension (PAH) associated with congenital heart disease (CHD) in children; however, its value in adult patients remains unclear. This study evaluated CTGF as a biomarker in adult PAH-CHD patients.Methods and Results: Based on mean pulmonary artery pressure (mPAP), 56 CHD patients were divided into 3 groups: without PAH (W; mPAP <25 mmHg; n=28); mild PAH (M; mPAP 25-35 mmHg; n=18); and moderate and severe PAH (H; mPAP ≥35 mmHg; n=10). The control group consisted of 28 healthy adults. Plasma CTGF and B-type natriuretic peptide (BNP) concentrations were determined. Plasma CTGF concentrations were higher in the H and M groups than in the W and control groups, and were higher in the H than M group. Plasma CTGF concentrations were positively correlated with pulmonary artery systolic pressure (PASP), mPAP, and pulmonary vascular resistance, and negatively correlated with mixed venous oxygen saturation. CTGF, BNP, red blood cell distribution width, and World Health Organization Class III/IV were risk factors for PAH in CHD patients, and CTGF was an independent risk factor for PAH-CHD. The efficacy of CTGF in the diagnosis of PAH was not inferior to that of BNP.. CTGF is a biomarker of PAH associated with CHD. It can be used for early diagnosis and severity assessment in adult patients with CHD-PAH.

Topics: Adult; Biomarkers; Child; Connective Tissue Growth Factor; Familial Primary Pulmonary Hypertension; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Natriuretic Peptide, Brain; Pulmonary Arterial Hypertension

Pulmonary arterial hypertension is a common complication in patients with congenital heart disease. In the absence of early diagnosis and treatment, pediatric patients with PAH has a poor survival rate. Here, we explore serum biomarkers for distinguishing children with pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD) from CHD.. Samples were analyzed by nuclear magnetic resonance spectroscopy-based metabolomics and 22 metabolites were further quantified by ultra-high-performance liquid chromatography-tandem mass spectroscopy.. Serum levels of betaine, choline, S-Adenosyl methionine (SAM), acetylcholine, xanthosine, guanosine, inosine and guanine were significantly altered between CHD and PAH-CHD. Logistic regression analysis showed that combination of serum SAM, guanine and N-terminal pro-brain natriuretic peptide (NT-proBNP), yielded the predictive accuracy of 157 cases was 92.70% with area under the curve of the receiver operating characteristic curve value of 0.9455.. We demonstrated that a panel of serum SAM, guanine and NT-proBNP is potential serum biomarkers for screening PAH-CHD from CHD.

Topics: Biomarkers; Child; Familial Primary Pulmonary Hypertension; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Metabolomics; Natriuretic Peptide, Brain; Peptide Fragments; Pulmonary Arterial Hypertension

Right ventricular (RV) adaptation is the principal determinant of outcomes in pulmonary arterial hypertension (PAH), however, RV function is challenging to assess. RV responses to hemodynamic stressors are particularly difficult to interrogate without invasive testing. This study sought to identify metabolomic markers of in vivo right ventricular function and exercise performance in PAH. Consecutive subjects with PAH (

Topics: Arginine; Biomarkers; Familial Primary Pulmonary Hypertension; Humans; Kynurenine; Natriuretic Peptide, Brain; Pulmonary Arterial Hypertension; Ventricular Dysfunction, Right; Ventricular Function, Right

Risk stratification plays an essential role in the management of patients with pulmonary arterial hypertension (PAH). The current European guidelines propose a three-stratum model to categorise risk as low, intermediate or high, based on the expected 1-year mortality. However, with this model, most patients are categorised as intermediate risk. We investigated a modified approach based on four risk categories, with intermediate risk subdivided into intermediate-low and intermediate-high risk.. We analysed data from the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA), a European pulmonary hypertension registry, and calculated risk at diagnosis and first follow-up based on World Health Organization functional class, 6-min walk distance (6MWD) and serum levels of brain natriuretic peptide (BNP) or N-terminal pro-BNP (NT-proBNP), using refined cut-off values. Survival was assessed using Kaplan-Meier analyses, log-rank testing and Cox proportional hazards models.. Data from 1655 patients with PAH were analysed. Using the three-stratum model, most patients were classified as intermediate risk (76.0% at baseline and 63.9% at first follow-up). The refined four-stratum risk model yielded a more nuanced separation and predicted long-term survival, especially at follow-up assessment. Changes in risk from baseline to follow-up were observed in 31.1% of the patients with the three-stratum model and in 49.2% with the four-stratum model. These changes, including those between the intermediate-low and intermediate-high strata, were associated with changes in long-term mortality risk.. Modified risk stratification using a four-stratum model based on refined cut-off levels for functional class, 6MWD and BNP/NT-proBNP was more sensitive to prognostically relevant changes in risk than the original three-stratum model.

Topics: Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Natriuretic Peptide, Brain; Peptide Fragments; Pulmonary Arterial Hypertension; Registries; Risk Assessment

Prognosis in pulmonary arterial hypertension (PAH) is closely related to indexes of right ventricular function. A better understanding of their relationship may provide important implications for risk stratification in PAH.. Can clinical network graphs inform risk stratification in PAH?. The study cohort consisted of 231 patients with PAH followed up for a median of 7.1 years. An undirected, correlation network was used to visualize the relationship between clinical features in PAH. This network was enriched for right heart parameters and included N-terminal pro-hormone B-type natriuretic peptide (NT-proBNP), comprehensive echocardiographic parameters, and hemodynamics, as well as 6-min walk distance (6MWD), vital signs, laboratory data, and diffusing capacity for carbon monoxide (Dlco). Connectivity was assessed by using eigenvector and betweenness centrality to reflect global and regional connectivity, respectively. Cox proportional hazards regression was used to model event-free survival for the combined end point of death or lung transplantation.. A network of closely intertwined features centered around NT-proBNP with 6MWD emerging as a secondary hub were identified. Less connected nodes included Dlco, systolic BP, albumin, and sodium. Over the follow-up period, death or transplantation occurred in 92 patients (39.8%). A strong prognostic model was achieved with a Harrell's C-index of 0.81 (0.77-0.85) when combining central right heart features (NT-proBNP and right ventricular end-systolic remodeling index) with 6MWD and less connected nodes (Dlco, systolic BP, albumin, sodium, sex, connective tissue disease etiology, and prostanoid therapy). When added to the baseline risk model, serial change in NT-proBNP significantly improved outcome prediction at 5 years (increase in C-statistic of 0.071 ± 0.024; P = .003).. NT-proBNP emerged as a central hub in the intertwined PAH network. Connectivity analysis provides explainability for feature selection and combination in outcome models.

Topics: Albumins; Biomarkers; Familial Primary Pulmonary Hypertension; Humans; Natriuretic Peptide, Brain; Peptide Fragments; Prognosis; Pulmonary Arterial Hypertension; Risk Assessment; Sodium; Ventricular Remodeling

Topics: Area Under Curve; Biomarkers; Familial Primary Pulmonary Hypertension; Humans; Natriuretic Peptide, Brain; Peptide Fragments; Prognosis; Proteome; Pulmonary Arterial Hypertension

The coronavirus disease 2019 (COVID-19) outbreak has led to significant restrictions on routine medical care. We conducted a multicentre nationwide survey of patients with pulmonary arterial hypertension (PAH) to determine the consequences of governance measures on PAH management and risk of poor outcome in patients with COVID-19.. The present study, which included 25 Italian centres, considered demographic data, the number of in-person visits, 6-min walk and echocardiographic test results, brain natriuretic peptide/N-terminal pro-brain natriuretic peptide test results, World Health Organization functional class assessment, presence of elective and non-elective hospitalisation, need for treatment escalation/initiation, newly diagnosed PAH, incidence of COVID-19 and mortality rates. Data were collected, double-checked and tracked by institutional records between March 1 and May 1, 2020, to coincide with the first peak of COVID-19 and compared with the same time period in 2019.. Among 1922 PAH patients, the incidences of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and COVID-19 were 1.0% and 0.46%, respectively, with the latter comparable to that in the overall Italian population (0.34%) but associated with 100% mortality. Less systematic activities were converted into more effective remote interfacing between clinicians and PAH patients, resulting in lower rates of hospitalisation (1.2%. A cohesive partnership between healthcare providers and regional public health officials is needed to prioritise PAH patients for remote monitoring by dedicated tools.

Topics: COVID-19; Disease Progression; Familial Primary Pulmonary Hypertension; Humans; Natriuretic Peptide, Brain; Pulmonary Arterial Hypertension; SARS-CoV-2

The prognostic value of improvement endpoints that have been used in clinical trials of treatments for pulmonary arterial hypertension (PAH) needs to be further investigated.. Using the COMPERA database, we evaluated the prognostic value of improvements in functional class (FC) and absolute or relative improvements in 6-min walking distance (6MWD) and N-terminal fragment of pro-brain natriuretic peptide (NT-proBNP). In addition, we investigated multicomponent endpoints based on prespecified improvements in FC, 6MWD and NT-proBNP that have been used in recent PAH trials. Finally, we assessed the predictive value of improvements determined by risk stratification tools. The effects of changes from baseline to first follow-up (3-12 months after initiation of PAH therapy) on consecutive survival were determined by Kaplan-Meier analysis with Log-Rank testing and Cox proportional hazard analyses.. All analyses were based on 596 patients with newly diagnosed PAH for whom complete data were available at baseline and first follow-up. Improvements in FC were associated with improved survival, whereas absolute or relative improvements in 6MWD had no predictive value. For NT-proBNP, absolute declines conferred no prognostic information while relative declines by ≥35% were associated with better survival. Improvements in multicomponent endpoints were associated with improved survival and the same was found for risk stratification tools.. While sole improvements in 6MWD and NT-proBNP had minor prognostic relevance, improvements in multicomponent endpoints and risk stratification tools based on FC, 6MWD, and NT-proBNP were associated with improved survival. These tools should be further explored as outcome measures in PAH trials.

Topics: Biomarkers; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Natriuretic Peptide, Brain; Peptide Fragments; Prognosis; Pulmonary Arterial Hypertension; Treatment Outcome

While the performance of the emPHasis-10 (e10) score has been evaluated against limited patient characteristics within the United Kingdom, there is an unmet need for exploring the performance of the e10 score among pulmonary arterial hypertension (PAH) patients in the United States.. Using the Pulmonary Hypertension Association Registry, we evaluated relationships between the e10 score and demographic, functional, haemodynamic and additional clinical characteristics at baseline and over time. Furthermore, we derived a minimally important difference (MID) estimate for the e10 score.. We analysed data from 565 PAH (75% female) adults aged mean±sd 55.6±16.0 years. At baseline, the e10 score had notable correlation with factors expected to impact quality of life in the general population, including age, education level, income, smoking status and body mass index. Clinically important parameters including 6-min walk distance and B-type natriuretic peptide (BNP)/N-terminal proBNP were also significantly associated with e10 score at baseline and over time. We generated a MID estimate for the e10 score of -6.0 points (range -5.0--7.6 points).. The e10 score was associated with demographic and clinical patient characteristics, suggesting that health-related quality of life in PAH is influenced by both social factors and indicators of disease severity. Future studies are needed to demonstrate the impact of the e10 score on clinical decision-making and its potential utility for assessing clinically important interventions.

Topics: Adult; Aged; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Pulmonary Arterial Hypertension; Quality of Life; United Kingdom

No prior proteomic screening study has centred on the right ventricle (RV) in pulmonary arterial hypertension (PAH). This study investigates the circulating proteomic profile associated with right heart maladaptive phenotype (RHMP) in PAH.Plasma proteomic profiling was performed using multiplex immunoassay in 121 (discovery cohort) and 76 (validation cohort) PAH patients. The association between proteomic markers and RHMP, defined by the Mayo right heart score (combining RV strain, New York Heart Association (NYHA) class and N-terminal pro-brain natriuretic peptide (NT-proBNP)) and Stanford score (RV end-systolic remodelling index, NYHA class and NT-proBNP), was assessed by partial least squares regression. Biomarker expression was measured in RV samples from PAH patients and controls, and pulmonary artery banding (PAB) mice.High levels of hepatocyte growth factor (HGF), stem cell growth factor-β, nerve growth factor and stromal derived factor-1 were associated with worse Mayo and Stanford scores independently from pulmonary resistance or pressure in both cohorts (the validation cohort had more severe disease features: lower cardiac index and higher NT-proBNP). In both cohorts, HGF added value to the REVEAL score in the prediction of death, transplant or hospitalisation at 3 years. RV expression levels of HGF and its receptor c-Met were higher in end-stage PAH patients than controls, and in PAB mice than shams.High plasma HGF levels are associated with RHMP and predictive of 3-year clinical worsening. Both HGF and c-Met RV expression levels are increased in PAH. Assessing plasma HGF levels might identify patients at risk of heart failure who warrant closer follow-up and intensified therapy.

Topics: Animals; Cohort Studies; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Mice; Natriuretic Peptide, Brain; Proteomics; Pulmonary Arterial Hypertension

Topics: Familial Primary Pulmonary Hypertension; Humans; Natriuretic Peptide, Brain; Registries

The potential prognostic value of cardiovascular magnetic resonance (CMR)-derived right ventricular (RV) ejection/filling parameters in the assessment of RV function remains to be fully established. The goal of this study was to explore the prognostic value of these parameters in idiopathic pulmonary arterial hypertension (IPAH) patients.. In this prospective investigation, newly diagnosed IPAH patients without targeted therapy were recruited. Patients underwent right heart catheterization (RHC), 6-min walk test and CMR imaging within 1 week. Cardiopulmonary haemodynamics derived from RHC, and RV ejection/filling parameters derived from CMR were collected.. A total of 41 IPAH patients were recruited with the median follow-up time of 824 days. During this period, 13 patients significantly deteriorated and among them, 7 patients died. CMR-derived RV peak ejection rate (PER) correlated significantly with CMR-derived RV stroke volume index (r = 0.574, P < 0.001) and RV cardiac index (r = 0.611, P < 0.001), but had no significant correlation with RV end diastolic volume index (EDVI, r = 0.201, P = 0.208) and pulmonary vascular resistance (r = -0.134, P = 0.403). Multivariate Cox regression analysis showed that RV time to PER (TPER, hazard ratio (HR) = 1.010, 95% CI: 1.003-1.017, P = 0.005) and RV TPER/time of a cardiac cycle (TPER/TCC, HR = 1.085, 95% CI: 1.031-1.141, P = 0.002) were predictors of clinical deterioration after adjusting for N-terminal pro-brain natriuretic peptide (NT-proBNP) and RV EDVI. Kaplan-Meier survival analyses showed that patients with RV TPER ≥ 199.01 ms (log rank: P = 0.036) or RV TPER/TCC ≥ 20.02% (log rank: P = 0.007) had worse prognosis.. CMR-derived RV TPER and TPER/TCC can reflect RV early systolic function, and may be promising predictors for long-term prognosis in IPAH patients.

Topics: Adult; Cardiac Catheterization; China; Familial Primary Pulmonary Hypertension; Female; Humans; Magnetic Resonance Imaging, Cine; Male; Natriuretic Peptide, Brain; Peptide Fragments; Pilot Projects; Predictive Value of Tests; Prognosis; Prospective Studies; Stroke Volume; Vascular Resistance; Ventricular Function, Right; Walk Test

Topics: Blood Gas Analysis; Carbon Dioxide; Cardiac Catheterization; China; Chronic Disease; Exercise Test; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Lung; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Pulmonary Embolism; Respiratory Function Tests; Severity of Illness Index; Thromboembolism

Topics: Adolescent; Adult; Antihypertensive Agents; Endothelin Receptor Antagonists; Epoprostenol; Exercise Tolerance; Familial Primary Pulmonary Hypertension; Female; Hemodynamics; Humans; Japan; Male; Middle Aged; Natriuretic Peptide, Brain; Prognosis; Retrospective Studies; Survival Rate; Vascular Resistance; Walk Test; Young Adult

Childhood-onset pulmonary arterial hypertension (PAH) is considered complex and multifactorial, with relatively poor estimates of the natural history of the disease. Strategies allowing earlier detection, establishment of disease aetiology together with more accurate and sensitive biomarkers could enable better estimates of prognosis and individualise therapeutic strategies. Evidence is accumulating that genetic defects play an important role in the pathogenesis of idiopathic and hereditary forms of PAH. Altogether nine genes have been reported so far to be associated with childhood onset PAH suggesting that comprehensive multigene diagnostics can be useful in the assessment. Identification of disease-causing mutations allows estimates of prognosis and forms the most effective way for risk stratification in the family. In addition to genetic determinants the analysis of blood biomarkers are increasingly used in clinical practice to evaluate disease severity and treatment responses. As in genetic diagnostics, a multiplex approach can be helpful, as a single biomarker for PAH is unlikely to meet all requirements. This consensus statement reviews the current evidence for the use of genetic diagnostics and use of blood biomarkers in the assessment of paediatric patients with PAH.

Topics: Activin Receptors, Type II; Adolescent; Antigens, CD; Atrial Natriuretic Factor; Biomarkers; Bone Morphogenetic Protein Receptors; C-Reactive Protein; Caveolin 1; Child; Consensus; Disease Management; Endoglin; Endothelial Cells; Endothelins; Familial Primary Pulmonary Hypertension; Galectin 3; Genetic Testing; Growth Differentiation Factor 15; Humans; Hypertension, Pulmonary; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Peptide Fragments; Potassium Channels, Tandem Pore Domain; Prognosis; Protein Serine-Threonine Kinases; Receptor, Notch3; Receptors, Cell Surface; Receptors, Notch; Smad8 Protein; Troponin T; Uric Acid

The value of echocardiography in assessing disease severity and predicting outcome in pediatric pulmonary arterial hypertension (PAH) is insufficiently defined. The aim of this study was to describe correlations between echocardiography and disease severity and outcome in pediatric PAH.. Forty-three consecutive children (median age, 8.0 years; range, 0.4-21.5) with idiopathic/hereditary PAH (n=25) or PAH associated with congenital heart disease (n=18) were enrolled in a prospective single-center observational study. Anatomic and right ventricular-functional variables were obtained by two-dimensional echocardiography and Doppler-echocardiography at presentation and at standardized follow-up and were correlated with measures of disease severity (World Health Organization functional class [WHO-FC], N-terminal-pro-B-type natriuretic peptide, hemodynamics) and lung-transplantation-free survival. Right atrial and right ventricular dimensions correlated with WHO-FC and hemodynamics (P<0.05), whereas left ventricular dimensions correlated with hemodynamics and survival (P<0.05). Right-to-left ventricular dimension ratiocorrelated with WHO-FC, hemodynamics and survival (P<0.05). Right ventricular ejection time correlated with hemodynamics and survival (P<0.05) and tended to correlate with WHO-FC (P=0.071). Tricuspid annular plane systolic excursion correlated with WHO-FC, mean right atrial pressure and survival (P<0.05).. This early descriptive study shows that echocardiographic chararacteristics of both the right and the left heart correlate with disease severity and outcome in pediatric PAH, both at presentation and during the course of the disease. The preliminary data from this study support the potential value of echocardiography as a tool in guiding management in children with PAH.

Topics: Adolescent; Age Factors; Atrial Function, Right; Atrial Pressure; Biomarkers; Child; Child, Preschool; Disease Progression; Echocardiography, Doppler; Familial Primary Pulmonary Hypertension; Female; Heart Defects, Congenital; Heart Ventricles; Humans; Hypertension, Pulmonary; Infant; Kaplan-Meier Estimate; Lung Transplantation; Male; Natriuretic Peptide, Brain; Netherlands; Peptide Fragments; Predictive Value of Tests; Prognosis; Proportional Hazards Models; Prospective Studies; Risk Factors; Severity of Illness Index; Stroke Volume; Time Factors; Tricuspid Valve; Ventricular Function, Left; Ventricular Function, Right; Young Adult

While idiopathic pulmonary arterial hypertension (PAH) is a rare disease, it is seen more frequently in patients with HIV infection. The aim of this study was to evaluate the prevalence of pulmonary hypertension (PH) in patients with HIV infection by echocardiographic screening.. Echocardiography and N-terminal of the prohormone brain natriuretic peptide measurement were used to examine the prevalence of PH prospectively in HIV-positive patients (n = 374) during routine follow-up visits for HIV disease.. In echocardiographic screening, PH was detected in a total of 23 of 374 HIV-infected patients (6.1%). Of these, three patients (13%) presented with symptoms of dyspnoea and fatigue, and diagnosis of PAH was confirmed by right heart catheterization. Patients with systolic pulmonary artery pressure (sPAP) > 30 mmHg were more likely to be female, to have a history of injecting drug use and to originate from high-prevalence countries (HPCs).. Echocardiographic screening detected PH in a substantial proportion of HIV-positive patients. Female gender, a history of injecting drug use and HPC origin were associated with a higher prevalence of HIV-associated PH. The relevance and long-term outcome of these findings need to be validated in follow-up studies, which are ongoing.

Topics: Adult; Echocardiography; Familial Primary Pulmonary Hypertension; Female; HIV Infections; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Prevalence; Prospective Studies; Risk Factors

Pulmonary hypertension (PH) due to lung disease (World Health Organization (WHO) group 3) is common, but severe PH, arbitrarily defined as mean pulmonary artery pressure ≥35 mmHg is reported in only a small proportion. Whether these should be treated as patients in WHO group 1 (i.e. pulmonary arterial hypertension) with PH-targeted therapies is unknown. We compared the phenotypic characteristics and outcomes of 118 incident patients with severe PH and lung disease with 74 idiopathic pulmonary arterial hypertension (IPAH) patients, all treated with pulmonary vasodilators. Lung disease patients were older, more hypoxaemic, and had lower gas transfer, worse New York Heart Association functional class and lower 6-min walking distance (6MWD) than IPAH patients. Poorer survival in those with lung disease was driven by the interstitial lung disease (ILD) cohort. In contrast to IPAH, where significant improvements in 6MWD and N-terminal pro-brain natruiretic peptide (NT-proBNP) occurred, PH therapy in severe PH lung disease did not lead to improvement in 6MWD or functional class, but neither was deterioration seen. NT-proBNP decreased from 2200 to 1596 pg·mL(-1) (p=0.015). Response varied by lung disease phenotype, with poorer outcomes in patients with ILD and emphysema with preserved forced expiratory volume in 1 s. Further study is required to investigate whether vasodilator therapy may delay disease progression in severe PH with lung disease.

Topics: Adult; Aged; Exercise Test; Familial Primary Pulmonary Hypertension; Female; Forced Expiratory Volume; Humans; Kaplan-Meier Estimate; Lung Diseases; Magnetic Resonance Imaging; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Phenotype; Proportional Hazards Models; Retrospective Studies; Survival Rate; Treatment Outcome; Vasodilator Agents

To assess the exercise capacity of three kinds of pulmonary artery hypertension using cardiopulmonary exercise testing (CPET).. In the Center for Pulmonary Vascular Disease Diagnosis and Treatment of Fuwai Hospital, idiopathic pulmonary artery hypertension (IPAH), congenital heart disease associated pulmonary artery hypertension (CHD-PAH), connective tissue disease associated pulmonary artery hypertension (CTD-PAH) were enrolled into this study from December 2012 to May 2013. CPET was performed in all patients, and clinical features, routine tests results, N-terminal B-type natriuretic peptide (NT-proBNP), Six-minutes-walk distance (6MWD) were all collected.. Thirty-two patients with IPAH, 38 patients with CHD-PAH, 25 patients with CTD-PAH were enrolled. For IPAH, CHD-PAH, and CTD-PAH patients, the peak oxygen uptake via body weight (VO₂max/kg) was (12.3 ± 2.3), (14.9 ± 4.0), and (11.1 ± 2.5) ml·min⁻¹·kg⁻¹, respectively. The peak VO₂/kg was significantly different within these three groups (P<0.001), and was significantly higher in CHD-PAH patients compared with the other two groups (P=0.003, P<0.001). The peak VO2/heart rate (HR) was (5.8±1.4), (6.4 ± 1.8), (5.3 ± 1.7) ml·beat(-1)·min⁻¹ in the above three groups and was significantly different within these three groups (P=0.034). The peak VO₂/HR was significantly increased in CHD-PAH patients than CTD-PAD patients (P=0.012). The peak HR was (136.1 ± 21.4), (140.8 ± 19.9), (124.5 ± 21.6) beat/min respectively and was significantly lower in CTD-PAD patients than CHD-PAH patients (P=0.009). The 6MWD was significantly decreased in CTD-PAD patients compared with CHD-PAH and IPAH patients (P=0.006, 0.010). Nt-proBNP was significantly decreased in CTD-PAD patients compared with CHD-PAH patients (P=0.012). In Pearson and partial correlation analysis, the peak VO₂/kg was significantly correlated with peak VO₂/HR, peak HR, 6MWD, Nt-proBNP, left ventricular end-diastolic diameter, right ventricular end-diastolic diameter (r=0.477, 0.518, 0.387, 0.465, -0.350, 0.349, -0.259).. CPET parameters can objectively evaluate exercise capacity and cardiopulmonary function of the patients with pulmonary hypertension.

Topics: Connective Tissue Diseases; Exercise Test; Familial Primary Pulmonary Hypertension; Heart Defects, Congenital; Heart Rate; Humans; Hypertension, Pulmonary; Natriuretic Peptide, Brain; Peptide Fragments; Pulmonary Artery

We sought to evaluate the potential utility of echocardiography-derived morphological and functional right ventricular (RV) variables for assessing disease severity of pulmonary arterial hypertension (PAH) and determining the changes in the patient's hemodynamics in the clinical course.. This study consisted of 24 normal controls (the control group) and 24 patients with PAH at rest or with exercise (the PAH group) who underwent echocardiography, right heart catheterization, plasma brain natriuretic peptide (BNP) measurement, and six-minute walk distance (6MWD) test. The PAH group had poorer RV echocardiographic variables than the control group. RV Tei-index was more strongly correlated with 6MWD, BNP, cardiac index, mean pulmonary arterial pressure, and pulmonary vascular resistance (PVR) than other RV echocardiography-derived variables including RV end-diastolic areas, RV fractional area change, and tricuspid annular plane systolic excursion. In 16 of the 24 patients who successfully underwent repeated examination during follow up (13.3 ± 4.9 months; range, 5-24 months), PVR decreased from 486 ± 380 dynes cm(-5) to 346 ± 252 dynes cm(-5), and RV Tei-index decreased from 0.55 ± 0.30 to 0.42 ± 0.17, and the changes in RV Tei-index were correlated with the concomitant changes in PVR during the clinical course of PAH (r=0.706, p=0.002). Tricuspid annular plane systolic excursion and RV fractional area change did not change during the follow up.. Quantitative echocardiography revealed that the measurement of RV Tei-index is of great clinical utility for predicting disease severity of PAH and determining the changes in the patient's hemodynamics in the clinical course.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Blood Pressure; Cardiac Catheterization; Echocardiography; Exercise Test; Familial Primary Pulmonary Hypertension; Female; Follow-Up Studies; Heart Ventricles; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Middle Aged; Natriuretic Peptide, Brain; Pulmonary Artery; Severity of Illness Index; Vascular Resistance; Walking; Young Adult

Despite recent and major progresses in the field of pulmonary vascular diseases pulmonary arterial hypertension (PAH) outcome still needs improvement. In parallel, several changes are observed in a disease that is no longer described as typically affecting young women. This is outlined in the most recent reports from PAH registries, where increasing age at the time of diagnosis is constantly described. Regardless the cause of this changing face, the quest for the perfect prognostic factor in PAH is ongoing. Among the numerous variables of interest, biomarkers are particularly attractive, as they do not require expertise or invasive procedure. This is the case for brain natriuretic peptide (BNP) and the inactive N-terminal cleavage product of its pro-hormone (NT-proBNP), which have proven to be reliable. This might also be the case for endothelin-1 (ET-1), a potent vasoactive peptide involved in the endothelin pathway and its biologically stable surrogate, carboxy-terminal pro-endothelin-1 (CT-proET1) that could independently predict 1-year event-free survival in PAH. Of course, further research is warranted to confirm these results. Yet, even if there are probably few chances, if any, to discover the "Holy Grail", researcher's efforts must continue. The combination of pertinent parameters in composite scores is indeed promising and emphasized in the most recent PAH guidelines. Clinicians would probably need to use a subtle combination of several biomarkers and clinical, functional, hemodynamic and right ventricular parameter criteria to drive the most ambitious treatment goals in a complex and life threatening disease.

Topics: Adult; Biomarkers; Disease-Free Survival; Endothelin-1; Familial Primary Pulmonary Hypertension; Female; Guideline Adherence; Humans; Natriuretic Peptide, Brain; Peptide Fragments; Prognosis; Treatment Outcome; Young Adult

Pulmonary vascular remodelling and inflammation have been implicated in pulmonary arterial hypertension (PAH). YKL-40, a marker of tissue remodelling and inflammation, has recently been recognized as a risk predictor of cardiovascular and inflammatory diseases. The study aimed to investigate a potential role of YKL-40 in predicting prognosis in idiopathic PAH (IPAH).. Plasma YKL-40 levels were measured in 82 IPAH patients without current or previous PAH-specific treatment during right heart catheterization and in 54 healthy volunteers. Concurrent data included clinical, haemodynamic and biochemical variables.. Plasma YKL-40 levels were increased in IPAH patients compared with control subjects (median, interquartile range: IPAH: 24.90, 17.68-39.78 ng/mL; controls: 16.58, 14.20-19.64 ng/mL; P < 0.001). YKL-40 levels correlated with cardiac index (r = -0.244, P = 0.027) and N-terminal pro-brain natriuretic peptide (NT-proBNP, r = 0.263, P = 0.017). After a median follow-up of 578 days, YKL-40 outperformed NT-proBNP, uric acid, and 6-min walk distance in receiver operating characteristic (ROC) analyses in predicting both clinical worsening (area under the curve (AUC) 0.681) and death (AUC 0.717). Compared with patients with YKL-40 below the ROC-derived cut-off point (24.5 ng/mL), the high YKL-40 group showed higher pulmonary vascular resistance and serum uric acid levels, and showed more clinical worsening events and deaths in Kaplan-Meier analyses. Plasma YKL-40 was independently associated with clinical worsening in univariate and multivariate Cox analyses (all P < 0.05).. Plasma YKL-40 might serve as a promising indicator of disease severity and prognosis in patients with IPAH.

Topics: Adipokines; Adult; Biomarkers; Cardiac Catheterization; China; Chitinase-3-Like Protein 1; Disease Management; Disease Progression; Familial Primary Pulmonary Hypertension; Female; Humans; Inflammation; Kaplan-Meier Estimate; Lectins; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Predictive Value of Tests; Prognosis; Proportional Hazards Models; Pulmonary Circulation; Reproducibility of Results; ROC Curve

African Americans (AA) with systemic sclerosis (SSc) have a worse prognosis compared to Americans of European descent (EA). We conducted the current study to test the hypothesis that AA patients with SSc have more severe disease and poorer outcomes compared to EA patients when afflicted with pulmonary arterial hypertension (PAH). We studied 160 consecutive SSc patients with PAH diagnosed by right heart catheterization, comparing demographics, hemodynamics, and outcomes between AA and EA patients. The cohort included 29 AA and 131 EA patients with similar baseline characteristics except for increased prevalence of diffuse SSc in AA. AA patients had worse functional class (FC) (80% FC III-IV vs 53%; p = 0.02), higher brain natriuretic peptide (NT-pro-BNP) (5729 ± 9730 pg/mL vs 1892 ± 2417 pg/mL; p = 0.02), more depressed right ventricular function, a trend toward lower 6-minute walk distance (263 ± 111  m vs 333 ± 110  m; p = 0.07), and worse hemodynamics (cardiac index 1.95 ± 0.58 L/min/m vs 2.62 ± 0.80 L/min/m; pulmonary vascular resistance 10.3 ± 6.2 WU vs 7.6 ± 5.0 WU; p  < 0.05) compared with EA patients. Kaplan-Meier survival estimates for AA and EA patients, respectively, were 62% vs 73% at 2 years and 26% vs 44% at 5 years (p  > 0.05). In conclusion, AA patients with SSc-PAH are more likely to have diffuse SSc and to present with significantly more severe PAH compared with EA patients. AA patients also appear to have poorer survival, though larger studies are needed to investigate this association definitively.

Topics: Adult; Autoantibodies; Black or African American; Cardiac Catheterization; Echocardiography; Exercise Test; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Kaplan-Meier Estimate; Male; Middle Aged; Natriuretic Peptide, Brain; Outcome Assessment, Health Care; Peptide Fragments; Prevalence; Prognosis; Scleroderma, Systemic; Severity of Illness Index; United States; Ventricular Dysfunction, Right; White People

An obesity paradox, a "paradoxical" decrease in morbidity and mortality with increasing body mass index (BMI), has been shown in patients with heart failure. However, the impact of BMI in patients with idiopathic pulmonary arterial hypertension (IPAH) has not been studied. This study aims to find out whether BMI is a prognostic factor in IPAH.. We analysed 173 patients with IPAH. The patients were subclassified into categories of BMI defined as: under-weight (< 18.5 kg/m2), normal weight (18.5 to 24.9 kg/m2), overweight and obese (25 to 34.9 kg/m2). The three BMI groups had similar profiles in terms of haemodynamic parameters assessed by right heart catheterization and level of NT-proBNP. The overweight and obese group had higher age, and lower WHO functional class, larger left ventricular end-diastolic dimensions (LVEDDs) than the other two groups.The Kaplan-Meier survival curves for the three BMI categories demonstrated that the overweight and obese group had a significantly higher survival rate than the normal weight and underweight groups (log-rank test, P = 0.027, P = 0.000, respectively). In a stepwise forward regression, lower BMI, higher WHO functional class, lower cardiac index, smaller LVEDDs and absence of targeted medication remained independent predictors of mortality.. Excess body mass is a protective factor for death in patients with IPAH.

Topics: Adult; Biomarkers; Body Mass Index; Cardiac Catheterization; Familial Primary Pulmonary Hypertension; Female; Humans; Male; Natriuretic Peptide, Brain; Obesity; Peptide Fragments; Prognosis; Risk Factors; Survival Rate

Pulmonary arterial hypertension (PAH) still cannot be cured effectively, hence the search for novel treatments continues. The effects of sildenafil (25 mg/kg body weight) and fasudil (30 mg/kg body weight) given alone or in combination, on normalization of right ventricular pressure (RVP), right ventricle mass, as well as the levels of several biomarkers (HDL-C, BNP, VEGF-A), were assessed in a rat model of monocrotaline (MCT)-induced PAH. MCT (60 mg/kg body weight) induced clear PAH in male Wistar rats. After 21 days, a significant decrease in RVP accompanied by a reduction of right ventricular hypertrophy - a significant decrease in the right ventricle/left ventricle plus septum ratio - as a result of sildenafil or fasudil administration was assessed. The administration of fasudil and sildenafil alone or in combination caused a significant decrease in plasma BNP level as compared to MCT-treated rats. Fasudil alone or with sildenafil, but not sildenafil alone, significantly increased HDL-C level as compared to MCT-treated rats. Fasudil and sildenafil given alone or in combination caused a significant increase in plasma VEGF-A level as compared to rats exposed to MCT.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Animals; Cholesterol, HDL; Drug Therapy, Combination; Familial Primary Pulmonary Hypertension; Hemodynamics; Hypertension, Pulmonary; Male; Monocrotaline; Natriuretic Peptide, Brain; Phosphodiesterase 5 Inhibitors; Piperazines; Protein Kinase Inhibitors; Purines; Rats; Rats, Wistar; rho-Associated Kinases; Sildenafil Citrate; Sulfones; Vascular Endothelial Growth Factor A

To investigate ghrelin levels in patients with idiopathic pulmonary arterial hypertension (IPAH) and the association of ghrelin with N-terminal brain natriuretic peptide (N-BNP), endothelin-1 (ET-1) and nitric oxide (NO).. Plasma ghrelin, N-BNP, ET-1 and NO were measured, and echocardiography was performed in 20 IPAH patients and in 20 control subjects matched for age, sex and body mass index.. Plasma ghrelin and NT-proBNP levels were significantly higher in IPAH patients compared with values in control subjects (p < 0.05). In IPAH patients, ghrelin levels correlated positively with N-BNP (r = 0.616, p = 0.004), NO (r = 0.464, p = 0.039), right ventricle diameter (RVD; r = 0.485, p = 0.030) and pulmonary arterial systolic pressure (PASP; r = 0.591, p = 0.006). N-BNP levels correlated positively with RVD (r = 0.551, p = 0.012) and ET-1 (r = 0.451, p = 0.046).. Plasma ghrelin levels were elevated in IPAH. Increased ghrelin levels correlated positively with N-BNP, PASP, RVD and NO, and N-BNP levels correlated positively with RVD and ET-1. Pulmonary vascular pathology is a complex imbalance of opposing forces. Ghrelin may not only provide a novel prognostic biomarker for IPAH but also be a potential new therapeutic strategy.

Topics: Adult; Biomarkers; Case-Control Studies; Cross-Sectional Studies; Endothelin-1; Familial Primary Pulmonary Hypertension; Female; Ghrelin; Humans; Hypertension, Pulmonary; Male; Natriuretic Peptide, Brain; Nitric Oxide; Peptide Fragments; Prognosis

The current study aimed to investigate the release of myocardial high-sensitive Troponin T (hsTnT) in patients with pulmonary arterial hypertension (PAH) in response to maximal physical exercise.. In 24 patients with PAH, symptom-limited cardiopulmonary exercise testing was performed. hsTnT was measured by the novel hsTnT assay with a lower limit of detection of 2 ng/L and a total imprecision of less than 10% at the 99th percentile value. hsTnT was related to NT-proBNP, WHO functional class and right ventricular (RV) function. Serial measurement was performed before and 30 min, 180 min, and 300 min after exercise. Healthy volunteers served as a control group.. In 21 PAH patients, hsTnT levels were detectable before exercise with a close correlation between hsTnT and NT-proBNP. hsTnT was detectable in all PAH patients after exercise and significantly increased from 7.5 ng/L at baseline to 14.62 ng/L after 300 min, whereas levels of NT-proBNP remained constant with time.. Using the novel hsTnT assay, the current study provides first evidence that hsTnT levels increase in PAH patients after maximal physical exercise, while levels of other biomarkers remain constant after exercise testing. This might provide new insights into pathophysiology and individual risk assessment in patients with PAH.

Topics: Adult; Aged; Biomarkers; Cohort Studies; Exercise; Exercise Test; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Thromboembolism; Troponin T; Ventricular Function, Right; Walking

Increasing evidence implicates lymphocytes in pulmonary arterial hypertension (PAH) pathogenesis. Rats deficient in T-lymphocytes show increased propensity to develop PAH but when injected with endothelial progenitor cells are protected from PAH (a mechanism dependent on natural killer (NK) cells). A decreased quantity of circulating cytotoxic CD8+ T-lymphocytes and NK cells are now reported in PAH patients; however, the effect of lymphocyte depletion on disease outcome is unknown.. This prospective study analysed the lymphocyte profile and plasma brain natriuretic peptide (BNP) levels of patients with idiopathic PAH (IPAH), connective tissue disease-associated PAH (CTD-APAH) and matched healthy controls. Lymphocyte surface markers studied include: CD4+ (helper T-cell marker), CD8+ (cytotoxic T-cell marker), CD56/CD16 (NK cell marker) and CD19+ (mature B-cell marker). Lymphocyte deficiencies and plasma BNP levels were then correlated with clinical outcome.. Fourteen patients with PAH (9 IPAH, 5CTD) were recruited. Three patients were deceased at 1-year follow-up; all had elevated CD4 : CD8 ratios and deficiencies of NK cells and cytotoxic CD8+ T-lymphocytes at recruitment. Patients with normal lymphocyte profiles at recruitment were all alive a year later, and none were on the active transplant list. As univariate markers, cytotoxic CD8+ T-cell and NK cell counts were linked to short-term survival.. Deficiencies in NK cells and cytotoxic CD8+ T-cells may be associated with an increased risk of death in PAH patients. Further research is required in larger numbers of patients and to elucidate the mechanism of these findings.

Topics: Adult; Aged; Biomarkers; Case-Control Studies; CD8-Positive T-Lymphocytes; Cell Count; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Killer Cells, Natural; Male; Middle Aged; Natriuretic Peptide, Brain; Prognosis; Prospective Studies; Survival Rate

Tadalafil, a once-daily phosphodiesterase type 5 inhibitor (PDE-5I), offers clinicians an alternative to sildenafil, a 3-times-daily (t.i.d.) PDE-5I for treatment of pulmonary arterial hypertension (PAH). However, there are limited data describing the risks and benefits or recommended methodology of switching patients from sildenafil to tadalafil.. Chart reviews were conducted on all World Health Organization group 1 patients on sildenafil for ≥ 3 months who transitioned to tadalafil with documented clinic visits and 6-min walk tests on both drugs. Most patients were transitioned by discontinuing sildenafil after the evening dose and initiating tadalafil 40 mg/day the next day. Data collected included demographics, PAH etiology, diagnostic hemodynamics, 6-min walk distance (6MWD), PDE-5I side effects, and concomitant medications. Data on B-type natriuretic peptide (BNP) levels were available for most patients also receiving endothelin receptor antagonists (ERAs).. Medical records from 98 patients were evaluated. Most patients (92%) were on sildenafil for > 1 year, and 78% were receiving sildenafil 80-100 mg t.i.d. Ninety-seven percent of patients (95/98) were successfully transitioned and maintained on 40 mg/day. With a mean duration on tadalafil therapy of 243 ± 127 days at the time of analysis, 6MWD was unchanged. Patient-reported adverse events included headache (4%) and heartburn (2%). There was minimal change in BNP levels in the subset of patients receiving an ERA concomitantly.. Transition from sildenafil to tadalafil 40 mg/day appears feasible without clinical deterioration or intolerable side effects. This study provides guidance to physicians considering transition from sildenafil to tadalafil for selecting patients.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Carbolines; Endothelin Receptor Antagonists; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Natriuretic Peptide, Brain; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Retrospective Studies; Sildenafil Citrate; Sulfones; Tadalafil

Pulmonary arterial hypertension (PAH) is a rare, deadly condition. Although risk stratification is extremely important for assessment of prognosis and to guide therapy, there is lack of evidence concerning the role of novel biomarkers. In a pivotal study, we sought to comparatively investigate the predictive power of several new biomarkers in PAH.. Patients with prevalent PAH were enrolled in the study protocol, which included clinical, functional and echocardiographic assessment. Blood samples were collected at baseline for determination of NT-proBNP, CT-proET-1, MR-proANP, MR-proADM, copeptin and troponin I. Patients were clinically followed-up up to 12 months for first occurrence of hospital admission due to PAH-related clinical worsening, heart/lung transplantation or all-cause mortality.. Among the 28 included patients the pre-specified end-point occurred in 8 (29% event rate). There were higher baseline levels of CT-proET-1, copeptin, MR-proANP, NT-proBNP and troponin I in patients who reached the composite end-point. They also had larger right atria. In multivariate Cox regression, CT-proET-1 was the only biomarker associated with increased hazard of reaching the primary composite end-point (hazard ratio per tertile increase = 10.1; 95% CI 2.0 to 50.6).. CT-proET-1 provided prognostic information independent of other biomarkers. Importantly, we have provided the first evidence that CT-proET-1 may be superior to commonly used biomarkers.

Topics: Adult; Aged; Atrial Natriuretic Factor; Biomarkers; Cohort Studies; Echocardiography; Endothelin-1; Familial Primary Pulmonary Hypertension; Female; Follow-Up Studies; Glycopeptides; Humans; Hypertension, Pulmonary; Kaplan-Meier Estimate; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Predictive Value of Tests; Prognosis; Prospective Studies; Regression Analysis; Risk Factors; Troponin I

To explore the exercise characteristics of patients with idiopathic pulmonary arterial hypertension (IPAH).. From November 2010 to September 2012 , 76 consecutive IPAH patients and 24 healthy controls from Fuwai Cardiovascular Hospital were enrolled to undergo cardiopulmonary exercise testing. The exercise parameters were compared. Correlations among peak oxygen consumption, anaerobic threshold, peak oxygen pulse, New York Heart Association (NYHA) class, N-terminal pro-brain natriuretic peptide (NT-proBNP), 6-minute walking distance (6 MWD) and cardiac index are analyzed in IPAH.. There were 21 males and 55 females in IPAH and 8 males and 16 females in controls. Their mean ages were (31.5 ± 10.6) and (35.5 ± 6.4) years respectively. Significant differences (P = 0.000) existed between two groups in peak oxygen consumption ((12.7 ± 3.3) vs (25.6 ± 5.8) ml·min(-1)·kg(-1)), anaerobic threshold ((9.8 ± 2.5) vs (16.7 ± 3.9) ml·min(-1)·kg(-1)), peak oxygen pulse ((5.3 ± 1.6) vs (9.9 ± 2.5) ml/bpm) and ventilator efficiency (slope of minute ventilation in relation to CO2 produced) ((42.6 ± 2.0) vs (25.5 ± 3.5)). In IPAH, peak oxygen consumption was significantly correlated with NYHA class (r = -0.509, P = 0.000), 6 MWD (r = 0.443, P = 0.002) and NT-proBNP levels (r = -0.423, P = 0.011). And anaerobic threshold was significantly correlated with NYHA class (r = -0.362, P = 0.002), 6MWD (r = 0.343, P = 0.004) and NT-proBNP levels (r = -0.275, P = 0.017). Peak oxygen pulse and ventilator efficiency were both correlated well with total pulmonary vascular resistance. Partial correlation analysis demonstrated that there were significant correlations among peak oxygen consumption, anaerobic threshold, NYHA class, NT-proBNP levels and 6MWD after adjusting for age, gender and weight.. Peak oxygen consumption and anaerobic threshold decrease ventilator efficiency in IPAH patients. Cardiopulmonary exercise testing is an invasive tool of assessing safely the function of IPAH patients.

Topics: Adult; Case-Control Studies; Exercise Test; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Male; Natriuretic Peptide, Brain; Oxygen Consumption; Young Adult

Pulmonary arterial hypertension (PAH) is a major cause of mortality in systemic sclerosis (SSc). Screening guidelines for PAH recommend multiple investigations, including annual echocardiography, which together have low specificity and may not be cost-effective. We sought to evaluate the predictive accuracy of serum N-terminal pro-brain natriuretic peptide (NT-proBNP) in combination with pulmonary function tests (PFT) (‘proposed’ algorithm) in a screening algorithm for SSc-PAH.. We evaluated our proposed algorithm (PFT with NT-proBNP) on 49 consecutive SSc patients with suspected pulmonary hypertension undergoing right heart catherisation (RHC). The predictive accuracy of the proposed algorithm was compared with existing screening recommendations, and is presented as sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV).. Overall, 27 patients were found to have pulmonary hypertension (PH) at RHC, while 22 had no PH. The sensitivity, specificity, PPV and NPV of the proposed algorithm for PAH was 94.1%, 54.5%, 61.5% and 92.3%, respectively; current European Society of Cardiology (ESC)/European Respiratory Society (ERS) guidelines achieved a sensitivity, specificity, PPV and NPV of 94.1%, 31.8%, 51.6% and 87.5%, respectively. In an alternate case scenario analysis, estimating a PAH prevalence of 10%, the proposed algorithm achieved a sensitivity, specificity, PPV and NPV for PAH of 94.1%, 54.5%, 18.7% and 98.8%, respectively.. The combination of NT-proBNP with PFT is a sensitive, yet simple and non-invasive, screening strategy for SSc-PAH. Patients with a positive screening result can be referred for echocardiography, and further confirmatory testing for PAH. In this way, it may be possible to shift the burden of routine screening away from echocardiography. The findings of this study should be confirmed in larger studies.

Topics: Aged; Algorithms; Cohort Studies; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Respiratory Function Tests; Scleroderma, Systemic; Sensitivity and Specificity

To determine the levels of circulating copeptin in patients with pulmonary arterial hypertension (PAH), and to evaluate its relation with disease severity, outcome and response to treatment.. Vasopressin is a key regulator of body fluid homeostasis. The co-secreted protein copeptin serves as surrogate for plasma vasopressin levels and increases in acute and chronic left ventricular dysfunction. Copeptin has not been studied in PAH.. Serum copeptin levels were evaluated in a retrospective cohort of 92 treatment-naïve patients with PAH, 39 patients with normal right ventricular hemodynamics (diseased controls) and 14 apparently healthy individuals (healthy controls). In a second prospective cohort of 15 patients with PAH, serial changes of copeptin levels after initiation of PAH treatment were measured. Copeptin levels were compared with clinical, biochemical and hemodynamic parameters as well as response to treatment and clinical outcome.. Circulating copeptin levels were elevated in PAH patients compared to diseased controls (20.1 pmol/l vs. 5.1 pmol/l; p = 0.001). Baseline levels of copeptin correlated with NYHA functional class (r = 0.46; p = 0.01), 6 minute walking distance (r = -0.26; p = 0.04), NT-proBNP (r = 0.49, p = 0.01), creatinine (r = 0.39, p = 0.01) and estimated glomerular filtration rate (r = -0.32, p = 0.01). Copeptin levels did not correlate with hemodynamics but decreased after initiation of PAH therapy (p = 0.001). Elevated copeptin levels were associated with shorter survival (p < 0.001) and independent predictors of mortality in a multiple Cox regression analysis (HR1.4; 95% confidence interval 1.1-2.0; p = 0.02).. Patients with PAH had elevated copeptin levels. High circulating levels of copeptin were independent predictors of poor outcome, which makes copeptin a potentially useful biomarker in PAH.

Topics: Aged; Biomarkers; Case-Control Studies; Cohort Studies; Familial Primary Pulmonary Hypertension; Female; Glycopeptides; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Predictive Value of Tests; Prognosis; Regression Analysis; Retrospective Studies; Severity of Illness Index

Six-minute walk distance (6MWD) and brain natriuretic peptide (BNP) levels at baseline and after initiation of treatment have been associated with survival in patients with pulmonary arterial hypertension. Our objective was to determine the individual and additive ability of pretreatment and posttreatment 6MWD and BNP to discriminate 2-year survival in patients with pulmonary arterial hypertension.. We included patients enrolled in two randomized clinical trials of ambrisentan who had 2-year follow-up (N 5 370). 6MWD and BNP were assessed before and after 12 weeks of treatment. Receiver operating characteristic curve analyses were performed to identify optimal cutoffs that defi ned subgroups with a high 2-year mortality. Classifi cation and regression tree analysis was used to determine the incremental prognostic value of combined assessments.. 6MWD at baseline and after 12 weeks of therapy were similarly discriminatory of 2-year survival (c-statistics 5 0.77 [95% CI 0.70-0.84] and 0.82 [95% CI 0.75-0.88], respectively), whereas change in 6MWD from baseline to week 12 was not discriminating. The same observation was true of BNP at baseline and after 12 weeks of therapy (c-statistics 5 0.68 [95% CI 0.60-0.76] and 0.74 [95% CI 0.66-0.82], respectively). After consideration of baseline 6MWD, there was no prognostic information added by the week 12 6MWD or BNP at either time point.. 6MWD and BNP values at baseline or week 12 identifi ed a population with an elevated risk of death at 2 years. A repeat assessment of 6MWD or BNP after 12 weeks of ambrisentan therapy did not provide additional prognostic information beyond that obtained from baseline values.

Topics: Adult; Aged; Antihypertensive Agents; Exercise Test; Familial Primary Pulmonary Hypertension; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Kaplan-Meier Estimate; Longitudinal Studies; Male; Middle Aged; Natriuretic Peptide, Brain; Phenylpropionates; Predictive Value of Tests; Prognosis; Pyridazines; Survival Rate; Treatment Outcome; Walking

Patients with pulmonary hypertension (PH) typically have exercise intolerance and limitation in climbing steps.. To explore the exercise physiology of step climbing in PH patients, on a laboratory-based step test.. We built a step oximetry system from an 'aerobics' step equipped with pressure sensors and pulse oximeter linked to a computer. Subjects mounted and dismounted from the step until their maximal exercise capacity or 200 steps was achieved. Step-count, SpO(2) and heart rate were monitored throughout exercise and recovery. We derived indices of exercise performance, desaturation and heart rate. A 6-min walk test and serum NT-proBrain Natriuretic Peptide (BNP) level were measured. Lung function tests and hemodynamic parameters were extracted from the medical record.. Eighty-six subjects [52 pulmonary arterial hypertension (PAH), 14 chronic thromboembolic PH (CTEPH), 20 controls] were recruited. Exercise performance (climbing time, height gained, velocity, energy expenditure, work-rate and climbing index) on the step test was significantly worse with PH and/or worsening WHO functional class (ANOVA, p < 0.001). There was a good correlation between exercise performance on the step and 6-min walking distance-climb index (r = -0.77, p < 0.0001). The saturation deviation (mean of SpO(2) values <95 %) on the step test correlated with diffusion capacity of the lung (ρ = -0.49, p = 0.001). No correlations were found between the step test indices and other lung function tests, hemodynamic parameters or NT-proBNP levels.. Patients with PAH/CTEPH have significant limitation in step climbing ability that correlates with functional class and 6-min walking distance. This is a significant impediment to their daily activities.

Topics: Activities of Daily Living; Adult; Aged; Analysis of Variance; Biomarkers; Case-Control Studies; Chi-Square Distribution; Exercise Test; Exercise Tolerance; Familial Primary Pulmonary Hypertension; Female; Heart Rate; Humans; Hypertension, Pulmonary; Linear Models; Lung; Male; Middle Aged; Motor Activity; Natriuretic Peptide, Brain; Oximetry; Oxygen; Peptide Fragments; Predictive Value of Tests; Signal Processing, Computer-Assisted; Walking

We sought to investigate the experimental therapeutic effects and mechanisms of iptakalim, a new adenosine triphosphate (ATP)-sensitive potassium channel (K(ATP)) opener, on monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH) and right heart ventricle remodeling in rats.. Rats were injected with a single dose (50 mg/kg, ip) of MCT and given iptakalim (1, 3, and 9 mg/kg·per d, orally [po]) or saline for 28 days. The hemodynamic and morphometric parameters were assessed. Tissue and plasma samples were collected for histological and molecular analysis.. Treatment with iptakalim at daily oral doses of 1, 3, and 9 mg/kg from the day of MCT injection attenuated the high right ventricle systolic pressure (RVSP) and the increased weight ratio of right ventricle (RV) to left ventricle (LV) plus septum (S) (RV/(LV+S)), decreased heart rate (HR) and decreased mean arterial pressure (MAP), inhibited the RV myocardial tissue cell apoptosis, and the RV myocardial cell B-type natriuretic peptide (BNP) protein expression. Iptakalim also decreased the serum levels of nitric oxide (NO), endothelin 1 (ET-1), BNP, and the levels of NO, ET-1, and tumor necrosis factor-alpha (TNF-α) in the lung tissue.. These results indicate that iptakalim prevents MCT-induced PAH and RV remodeling and its mechanisms are related to inhibiting the pathological increases in NO, ET-1, BNP, and TNF-α, and Iptakalim may be a promising candidate for the treatment of PAH.

Topics: Animals; Endothelin-1; Familial Primary Pulmonary Hypertension; Hemodynamics; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; KATP Channels; Lung; Male; Monocrotaline; Natriuretic Peptide, Brain; Nitric Oxide; Propylamines; Rats; Rats, Wistar

Topics: Exercise Test; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Male; Natriuretic Peptide, Brain; Walking

Current guidelines for the treatment of patients with idiopathic pulmonary arterial hypertension (IPAH) recommend basing therapeutic decision-making on haemodynamic, functional and biochemical variables. Most of these parameters have been evaluated as risk predictors at the time of diagnosis. The aim of the present study was to assess the prognostic impact of changes in these parameters after initiation of targeted therapy. A cohort of 109 patients with IPAH who had undergone haemodynamic, functional and biochemical assessments at baseline and 3-12 months after initiation of pulmonary arterial hypertension (PAH)-targeted therapy, were followed for a median 38 months in order to determine predictors of mortality at baseline and during the course of their disease. Within the observation period, 53 (48.6%) patients died and four (3.7%) underwent lung transplantation. Kaplan-Meier estimates for transplantation-free survival were 92%, 67%, and 51% at 1, 3, and 5 yrs, respectively. Among baseline variables, 6-min walk distance, right atrial pressure, cardiac index, mixed-venous oxygen saturation (S(v,O(2))) and N-terminal-pro brain natriuretic peptide (NT-proBNP) were independent predictors of survival. During follow-up, changes in World Health Organization functional class, cardiac index, S(v,O(2)) and NT-proBNP proved significant predictors of outcome. When assigned to prognostic groups, improvements as well as deteriorations in these parameters after initiation of PAH-targeted therapy had a strong impact on survival. Measurements obtained at follow-up had a higher predictive value than variables obtained at baseline. Changes in established predictors of outcome during the course of the disease provide important prognostic information in patients with IPAH.

Topics: Adult; Aged; Atrial Function, Right; Cohort Studies; Endothelin Receptor Antagonists; Epoprostenol; Exercise Test; Familial Primary Pulmonary Hypertension; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Lung Transplantation; Male; Middle Aged; Natriuretic Peptide, Brain; Oxygen; Peptide Fragments; Phosphodiesterase 5 Inhibitors; Prognosis; Prostaglandins; Retrospective Studies; Severity of Illness Index; Treatment Outcome

Circulating cardiac troponins are markers of myocardial injury. We sought to determine whether cardiac troponin I (cTnI), measured by a sensitive assay, is associated with disease severity and prognosis in pulmonary arterial hypertension (PAH). cTnI was measured in 68 patients with PAH diagnostic category 1 in a research-based sensitive immunoanalyser with a lower limit of detection of 0.008 ng · mL(-1). The associations between cTnI and PAH severity and clinical outcomes were assessed using Chi-squared and Wilcoxon rank sum tests, Kaplan-Meier analysis and Cox regression models. cTnI was detected in 25% of patients. Patients with detectable cTnI had more advanced functional class symptoms, a shorter 6-min walk distance, more pericardial effusions, larger right atrial area, and higher B-type natriuretic peptide and C-reactive protein levels. 36-month transplant-free survival was 44% in patients with detectable cTnI versus 85% in those with undetectable cTnI. cTnI was associated with a 4.7-fold increased risk of death related to right ventricular failure or transplant (hazard ratio 4.74, 95% CI 1.89-11.89; p<0.001), even when adjusted individually for known parameters of PAH severity. Elevated plasma cTnI, even at subclinically detectable levels, is associated with more severe disease and worse outcomes in patients with PAH.

Topics: Adult; Biomarkers; C-Reactive Protein; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Kaplan-Meier Estimate; Male; Middle Aged; Natriuretic Peptide, Brain; Pericardial Effusion; Predictive Value of Tests; Prognosis; Proportional Hazards Models; Risk Factors; Sensitivity and Specificity; Severity of Illness Index; Troponin I

Submaximal exercise gas analysis may be a useful method to assess and track pulmonary arterial hypertension (PAH) severity. The aim of the present study was to develop an algorithm, using exercise gas exchange data, to assess and monitor PAH severity. Forty patients with PAH participated in the study, completing a range of clinical tests and a novel submaximal exercise step test, which lasted 6 minutes and incorporated rest (2 minutes), exercise (3 minutes), and recovery (1 minute) ventilatory gas analysis. Using gas exchange data, including breathing efficiency, end-tidal carbon dioxide, oxygen saturation, and oxygen pulse, a pulmonary hypertension gas exchange severity (PH-GXS) score was developed. Patients were retested after about 6 months. There was significant separation between healthy controls and patients with moderate PAH (World Health Organization [WHO] class I/II) and those with more severe PAH (WHO class III/IV) for breathing efficiency, end-tidal carbon dioxide, oxygen saturation, and oxygen pulse. The PH-GXS score was significantly correlated with WHO class (r = 0.51), 6-minute walking distance (r = -0.59), right ventricular systolic pressure (r = 0.49), log N-terminal pro-B-type natriuretic peptide (r = 0.54), and pulmonary vascular resistance (r = 0.71). The PH-GXS score remained unchanged in 22 patients retested (1.50 ± 0.92 vs 1.48 ± 0.94), as did WHO class (2.3 ± 0.8 vs 2.3 ± 0.8) and 6-minute walking distance (455 ± 120 vs 456 ± 103 m). Small individual changes were observed in the PH-GXS score, with 8 patients improving and 8 deteriorating. In conclusion, the PH-GXS score differentiated between patients with PAH and was correlated with traditional clinical measures. The PH-GXS score was unchanged in our cohort after 6 months, consistent with traditional clinical metrics, but individual differences were evident. A PH-GXS score may be a useful way to track patient responses to therapy.

Topics: Adult; Aged; Algorithms; Antihypertensive Agents; Biomarkers; Carbon Dioxide; Case-Control Studies; Cohort Studies; Drug Therapy, Combination; Endothelin Receptor Antagonists; Epoprostenol; Exercise Test; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Natriuretic Peptide, Brain; Oxygen; Phosphodiesterase 5 Inhibitors; Pulmonary Gas Exchange; Risk Assessment; Severity of Illness Index; Treatment Outcome; Walking

Because few have reported the prognostic significance of cardiac magnetic resonance imaging (CMR) for idiopathic pulmonary arterial hypertension (IPAH), in this study we evaluated the value of CMR measurements as a prognostic predictor of IPAH before starting intravenous prostacyclin therapy.. A total of 121 consecutive CMR studies for evaluating right ventricular (RV) function were reviewed. Forty-one patients were diagnosed with IPAH and served as the study group. Factors, such as age, sex, New York Heart Association functional class (NYHAFC), 6-min walk test, plasma brain natriuretic peptide level, serum uric acid level and CMR measurements were analyzed as predictors of first hospitalization and death. The mean follow-up period was 1,350±769 days. Nine patients were hospitalized because of heart failure, and 4 patients died from cardiopulmonary causes. The univariate analyses suggested that the left ventricular (LV) mass index, the left and right ventricular end-diastolic volume indices (LVEDVI, RVEDVI), the LV and RV end-systolic volume indices (LVESVI, RVESVI) and NYHAFC predicted the risk for hospitalization and that RVEDVI, RVESVI and NYHAFC predicted mortality. The multivariate analyses suggested that RVEDVI and NYHAFC are independent predictors of both hospitalization and mortality. The effects of RVEDVI and NYHAFC on hospitalization were not substantially affected by the concomitant medication.. In IPAH patients, the RVEDVI predicts both hospitalization for right heart failure and mortality before initiating intravenous prostacyclin therapy.

Topics: Adult; Antihypertensive Agents; Biomarkers; Epoprostenol; Exercise Test; Exercise Tolerance; Familial Primary Pulmonary Hypertension; Female; Heart Failure; Hospitalization; Humans; Hypertension, Pulmonary; Japan; Magnetic Resonance Imaging; Male; Middle Aged; Multivariate Analysis; Natriuretic Peptide, Brain; Predictive Value of Tests; Prognosis; Proportional Hazards Models; Retrospective Studies; Risk Assessment; Risk Factors; Time Factors; Uric Acid; Vasodilator Agents; Ventricular Function, Left; Ventricular Function, Right; Young Adult

The information needed to diagnose pulmonary arterial hypertension (PAH) in dogs based on N-terminal pro B-type natriuretic peptide (NT-proBNP) and atrial natriuretic peptide (ANP) levels is unclear. In this study, serial changes in plasma NT-proBNP and ANP concentrations were evaluated in association with the development of chronic embolic pulmonary hypertension (CEPH). Six Beagle dogs underwent percutaneous pulmonary artery catheterization. CEPH was induced by the repeated injection of 300 μm microspheres into the pulmonary artery via the catheter. Measured peak systolic pulmonary arterial pressure (PAPs) was elevated up to 80 mm Hg at 90 days by repeated injection of microspheres. Echocardiographic examination showed significant increase in the main pulmonary artery enlargement, right ventricular dilation, transtricuspid late diastolic flow, and ventricular late diastolic myocardial velocity. Plasma concentrations of NT-proBNP and ANP were significantly increased by microsphere-induced severe CEPH, but not by mild CEPH. Measured PAPs correlated weakly with plasma NT-proBNP and ANP concentrations (r=0.63 and 0.69, respectively) and with several echocardiographic variables. Our results indicated that plasma ANP and NT-proBNP responded to severe PAH, but that they were not sensitive for mild PAH.

Topics: Animals; Atrial Natriuretic Factor; Disease Models, Animal; Dog Diseases; Dogs; Familial Primary Pulmonary Hypertension; Female; Hypertension, Pulmonary; Male; Microspheres; Natriuretic Peptide, Brain; Peptide Fragments; Pulmonary Artery; Pulmonary Embolism; Ultrasonography

We present the case of a 72-year-old male with chronic phase myeloid leukemia. Elevation of the pulmonary artery pressure due to nilotinib therapy was noted. This effect on pulmonary artery pressure was nilotinib dose dependent.

Topics: Aged; Antineoplastic Agents; Echocardiography, Doppler; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Natriuretic Peptide, Brain; Peptide Fragments; Pyrimidines

Brain natriuretic peptide (BNP) levels are lower in obese patients with left ventricular failure than in their comparably ill, leaner counterparts. The effect of obesity on BNP in patients with pulmonary arterial hypertension (PAH) is unknown. We reviewed our prospective PAH registry data collected from November 2001 to December 2007 for patients undergoing right heart catheterization who met the criteria for PAH and had the BNP level and body mass index determined at baseline. The median BNP level for the lean, overweight, and obese patients was 285 pg/ml (interquartile range 131 to 548), 315 pg/ml (interquartile range 88 to 531), and 117 pg/ml (interquartile range 58 to 270), respectively (p = 0.029). A greater body mass index was associated with a lower BNP level, adjusted for age, gender, New York Heart Association functional class, hypertension, coronary artery disease, and mean right atrial and pulmonary arterial pressures (p <0.001). No statistically significant differences were found among the groups in age, race, medical co-morbidities, underlying etiology of PAH, use of vasoactive medications, New York Heart Association functional class, echocardiographic parameters, or pulmonary function. Obese patients had greater right atrial and pulmonary artery pressures. Increased BNP was associated with worse survival in the lean and overweight patients only. In conclusion, the BNP levels are attenuated in obese patients with PAH despite similar or worse hemodynamics or functional class compared to lean or overweight patients and should therefore be interpreted with caution.

Topics: Body Mass Index; Cardiac Catheterization; Echocardiography; Familial Primary Pulmonary Hypertension; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Male; Middle Aged; Natriuretic Peptide, Brain; Obesity; Overweight; Prospective Studies; Survival Analysis; Thinness

Pulmonary arterial hypertension is a major cause of mortality in systemic sclerosis. N-terminal pro-brain natriuretic peptide (NT-proBNP) has emerged as a candidate biomarker that may enable the early detection of systemic sclerosis-related pulmonary arterial hypertension (SSc-PAH). The objective of our study was to incorporate NT-proBNP into a screening algorithm for SSc-PAH that could potentially replace transthoracic echocardiography (TTE) as a more convenient and less costly "first tier" test.. NT-proBNP levels were measured in patients from four clinical groups: a group with right heart catheter (RHC)-diagnosed SSc-PAH before commencement of therapy for PAH; a group at high risk of SSc-PAH based on TTE; a group with interstitial lung disease; and systemic sclerosis (SSc) controls with no cardiopulmonary complications. NT-proBNP levels were compared by using ANOVA and correlated with other clinical variables by using simple and multiple linear regression. ROC curve analyses were performed to determine the optimal cut point for NT-proBNP and other clinical variables in prediction of PAH.. NT-proBNP was highest in the PAH group compared with other groups (P < 0.0001), and higher in the risk group compared with controls (P < 0.0001). NT-proBNP was positively correlated with systolic pulmonary artery pressure (PAP) on TTE (P < 0.0001), and mean PAP (P = 0.013), pulmonary vascular resistance (P = 0.005), and mean right atrial pressure (P = 0.006) on RHC. A composite model wherein patients screened positive if NT-proBNP was ≥ 209.8 pg/ml, and/or DLCOcorr was < 70.3% with FVC/DLCOcorr ≥ 1.82, had a sensitivity of 100% and specificity of 77.8% for SSc-PAH.. We have proposed a screening algorithm for SSc-PAH, incorporating NT-proBNP level and PFTs. This model has high sensitivity and specificity for SSc-PAH and, if positive, should lead to TTE and confirmatory testing for PAH. This screening algorithm must be validated prospectively.

Topics: Adult; Age of Onset; Aged; Algorithms; Area Under Curve; Biomarkers; Case-Control Studies; Early Diagnosis; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; ROC Curve; Scleroderma, Systemic; Sensitivity and Specificity

Radiofrequency ablation is first-line therapy for atrial flutter (AFL). There are no studies of ablation in patients with severe pulmonary arterial hypertension (PAH).. Consecutive patients with severe PAH (systolic pulmonary artery pressure >60 mmHg) and AFL referred for ablation were evaluated. Patients with complex congenital heart disease were excluded.. A total of 14 AFL ablation procedures were undertaken in 12 patients. A total of 75% of patients were female; mean age 49 ± 12 years. SPAP prior to ablation was 99 ± 35 mmHg. Baseline 6-minute walk distance was 295 ± 118 m. ECG demonstrated a typical AFL pattern in only 42% of cases. Baseline AFL cycle length was longer in PAH patients compared to controls (295 ± 53 ms vs 252 ± 35 ms, P = 0.006). Cavotricuspid isthmus dependence was verified in 86% of cases. Acute success was obtained in 86% of procedures. SPAP decreased from 114 ± 44 mmHg to 82 ± 38 mmHg after ablation (P = 0.004). BNP levels were lower postablation (787 ± 832 pg/mL vs 522 ± 745 pg/mL, P = 0.02). Complications were seen in 14%. A total of 80% (8/10) of patients were free of AFL at 3 months; 75% (6/8) at 1 year.. Ablation of AFL in severe PAH patients is feasible, with good short- and intermediate-term success rates. The ECG pattern is not a reliable marker of isthmus dependence. The SPAP and BNP levels may decrease postablation. AFL may be a marker of poor outcomes in patients with PAH with a 1-year mortality rate of 42% in this study. This rate is higher than expected in the general PAH population.

Topics: Adult; Aged; Arterial Pressure; Atrial Flutter; Biomarkers; Catheter Ablation; Chi-Square Distribution; Electrocardiography; Electrophysiologic Techniques, Cardiac; Exercise Test; Exercise Tolerance; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Kaplan-Meier Estimate; Male; Middle Aged; Natriuretic Peptide, Brain; Predictive Value of Tests; Pulmonary Artery; Recurrence; Retrospective Studies; Severity of Illness Index; Time Factors; Treatment Outcome

To evaluate the efficiency and safety of intravenous infusion of levosimendan in patients with idiopathic pulmonary hypertension (IPH) and its clinical, hemodynamic, and neurohumoral effects.. The study included 9 patients (mean age 31.8 +/- 8.7 years) with Functional Class III and IV IPH and severe right ventricular failure (RVF). Levosimendan was administered as dropwise intravenous infusion. The patients' general condition, blood pressure, heart rate, and 6-minute walk test results were assessed at baseline and 24 hours after levosimendan infusion, and then following 12 weeks. The time course of changes in blood neurohumoral mediators was determined and transthoracic echocardiography performed.. At 24 hours after initiation of levosimendan infusion, there were substantial reductions in pulmonary artery systolic pressure, mean pulmonary artery pressure, mean right atrial pressure, and pulmonary vascular resistance. There was a significant increase in exercise tolerance. The blood exhibited lower norepinephrine and NT-proBNP and higher epinephrine concentrations. At 12 weeks after termination of levosimendan infusion, the improved functional status was preserved in the patients with IPH. There were no noticeable changes in the achieved key hemodynamic parameters. Only one patient needed re-administration of the drug 12 weeks later. The achieved changes in vasoactive mediators were retained 12 weeks following levosimendan infusion. Levosimendan treatment was not followed by clinically relevant adverse reactions requiring infusion termination and therapy discontinuation.. 24-hour intravenous levosimendan infusion in patents with FC III-IV IPH and severe RVF causes positive changes in the key hemodynamic parameters and neurohumoral status of the patients and promotes stabilization in those with IPH at 12-week follow-up.

Topics: Adult; Blood Pressure; Cardiotonic Agents; Echocardiography; Epinephrine; Exercise Test; Familial Primary Pulmonary Hypertension; Female; Follow-Up Studies; Heart Rate; Humans; Hydrazones; Hypertension, Pulmonary; Infusions, Intravenous; Male; Natriuretic Peptide, Brain; Norepinephrine; Peptide Fragments; Pyridazines; Severity of Illness Index; Simendan; Ventricular Dysfunction, Right; Young Adult

Chronic thromboembolic pulmonary hypertension leads to pulmonary hypertension and right-sided heart failure. The purpose of this study was to investigate the efficacy of percutaneous transluminal pulmonary angioplasty (PTPA) for the treatment of chronic thromboembolic pulmonary hypertension.. Twenty-nine patients with chronic thromboembolic pulmonary hypertension underwent PTPA. One patient had a wiring perforation as a complication of PTPA and died 2 days after the procedure. In the remaining 28 patients, PTPA did not produce immediate hemodynamic improvement at the time of the procedure. However, after follow-up (6.0 ± 6.9 months), New York Heart Association functional classifications and levels of plasma B-type natriuretic peptide significantly improved (both P<0.01). Hemodynamic parameters also significantly improved (mean pulmonary arterial pressure, 45.3 ± 9.8 versus 31.8 ± 10.0 mm Hg; cardiac output, 3.6 ± 1.2 versus 4.6 ± 1.7 L/min, baseline versus follow-up, respectively; both P<0.01). Twenty-seven of 51 procedures in total (53%), and 19 of 28 first procedures (68%), had reperfusion pulmonary edema as the chief complication. Patients with severe clinical signs and/or severe hemodynamics at baseline had a high risk of reperfusion pulmonary edema.. PTPA improved subjective symptoms and objective variables, including pulmonary hemodynamics. PTPA may be a promising therapeutic strategy for the treatment of chronic thromboembolic pulmonary hypertension.. URL: http://www.umin.ac.jp. Unique identifier: UMIN000001572.

Topics: Aged; Angioplasty, Balloon; Arterial Pressure; Biomarkers; Chronic Disease; Familial Primary Pulmonary Hypertension; Female; Hospital Mortality; Humans; Hypertension, Pulmonary; Japan; Male; Middle Aged; Natriuretic Peptide, Brain; Pulmonary Artery; Pulmonary Edema; Pulmonary Embolism; Recovery of Function; Reperfusion Injury; Risk Factors; Time Factors; Tomography, X-Ray Computed; Treatment Outcome

To explore the potential role of brain natriuretic peptide (BNP) and N-terminal pro-brain natriuretic peptide (NT-proBNP) in the assessment of patients with connective tissue diseases (CTD) associated pulmonary arterial hypertension (PAH).. Thirty patients with CTD associated PAH were evaluated by WHO function, echocardiography, right heart catheterization and blood biomarkers. All the clinical data was analyzed statistically.. All patients [age (39.5 ± 11.6) yr] were female. Both NT-proBNP and BNP were significantly increased and significantly correlated (all P < 0.05) respectively with mean pulmonary arterial pressure (r = 0.53 and r = 0.40), right arterial pressure (r = 0.55 and r = 0.42), pulmonary vascular resistance (r = 0.69 and r = 0.61), cardiac index (r = -0.58 and r = -0.46), mixed venous blood oxygen saturation (r = -0.62 and r = -0.54), pericardial effusion (r = 0.46 and r = 0.43), right atrial sizes (r = 0.40 and 0.53, and r = 0.39 and 0.45) and right ventricular size (r = 0.55 and r = 0.37). Furthermore, NT-proBNP, but not BNP, significantly correlated with WHO function class (r = 0.55).. Blood NT-proBNP and BNP were elevated in patients with CTD associated PAH and paralleled the extent of function class, pulmonary hemodynamic changes and right ventricular remodeling.

Topics: Adult; Connective Tissue Diseases; Familial Primary Pulmonary Hypertension; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Vascular Resistance; Ventricular Remodeling

Currently available endothelin receptor antagonists for treating pulmonary arterial hypertension block either the endothelin (ET) receptor A or both A and B receptors. Transition from one endothelin receptor antagonist to another may theoretically alter side-effects or efficacy. We report our experience of a transition from sitaxsentan to ambrisentan, both predominant ET(A) receptor antagonists, in pulmonary arterial hypertension patients.. At Baylor Pulmonary Hypertension Center, 18 patients enrolled in the open-label extension phase of the original sitaxsentan studies (Sitaxsentan To Relieve ImpaireD Exercise) were transitioned to ambrisentan (from July 2007 to September 2007) at the time of study closure. Pre-transition (PreT), 1 month (1Mth) and 1 year (1Yr) post-transition assessments of 6-minute walk distance (6MWD), brain naturetic peptide (BNP) levels, WHO functional class (WHO FC), Borg dyspnea score (BDS), oxygen saturation, liver function, and peripheral edema were compared.. 6MWD was 356 ± 126 m at PreT, 361 ± 125 m at 1Mth, and 394 ± 114 m at 1Yr (mean ± SD). There was no difference in the walk distance at 1Mth and 1Yr post transition compared with PreT (P=0.92, 0.41 respectively). Oxygen saturation was no different at 1Mth and 1Yr to PreT level (P=0.49 and P=0.06 respectively). BNP was 178 ± 44 pg/mL at PreT, 129 ± 144 pg/mL at 1Mth and 157 ± 201 at 1Yr. Peripheral edema was present in 7/18 patients at PreT, in 8/16 patients at 1Mth, and in 6/13 patients at 1Yr post transition. Proportions of patients with edema over these 3 time points did not change significantly (P=0.803). At 1Yr, 2 patients had died, 1 had undergone lung transplantation, 1 had relocated, and 1 patient was started on intravenous prostacyclin therapy. Over 3 points (baseline, 1 month, and 1 year), there was no significant change in function class (P=0.672).. Our limited data suggest that ET(A) receptor antagonists can be switched from one to another with sustained exercise capacity and maintained WHO FC with no increase in incidence of peripheral edema.

Topics: Adult; Aged; Antihypertensive Agents; Blood Pressure; Drug Substitution; Dyspnea; Edema; Endothelin A Receptor Antagonists; Exercise Test; Exercise Tolerance; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Isoxazoles; Liver Function Tests; Male; Middle Aged; Natriuretic Peptide, Brain; Oxygen; Phenylpropionates; Pyridazines; Retrospective Studies; Texas; Thiophenes; Time Factors; Treatment Outcome; Walking

Soluble TWEAK is a member of the TNF-alpha family of cytokines that has been shown to predict mortality in patients with heart failure. Pulmonary artery hypertension is a devastating disease, in which right ventricular function has been shown to be the major determinant of prognosis. In this hypothesis-generating study, we sought to evaluate the potential usefulness of sTWEAK in the prediction of disease severity in patients with pulmonary artery hypertension. We therefore conducted a retrospective analysis of sTWEAK serum levels in 95 stable patients with PAH. For all patients data on hemodynamic parameters, biomarkers and functional exercise tests were available. Compared to controls, patients with PAH showed significantly decreased levels of sTWEAK [median 314 pg/ml (interquartile range 217-473 pg/ml) vs. 405 (321-496 pg/ml); PAH vs. controls; P < 0.0001]. Soluble TWEAK levels were inversely correlated with NYHA class, pulmonary artery pressure, pulmonary vascular resistance, NT-proBNP, and troponin T levels and directly correlated with cardiac index, reduced 6-min walk test distances, and peak oxygen consumption. ROC curve analysis of sTWEAK levels in PAH patients revealed a cutoff value of 306 pg/ml for sTWEAK to be predictive of a reduced exercise capacity (6-min walk test <300 m) in patients with PAH with a similar predictive value compared to NT-proBNP. Intraindividual serial evaluation of sTWEAK revealed the potential of sTWEAK as follow-up marker in patients with PAH. In our hypothesis-generating study, sTWEAK was closely correlated to hemodynamic, functional, and serological indices of outcome in patients with PAH. Further prospective studies are needed to determine the role of sTWEAK as potential biomarker in patients with PAH.

Topics: Biomarkers; Blood Pressure; Cytokine TWEAK; Down-Regulation; Exercise Test; Exercise Tolerance; Familial Primary Pulmonary Hypertension; Female; Germany; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Middle Aged; Natriuretic Peptide, Brain; Oxygen Consumption; Peptide Fragments; Predictive Value of Tests; Prognosis; Pulmonary Artery; Retrospective Studies; ROC Curve; Severity of Illness Index; Troponin T; Tumor Necrosis Factors; Vascular Resistance

In addition to N-terminal pro-brain natriuretic peptide (NT-proBNP), red cell distribution width (RDW), growth differentiation factor (GDF)-15, interleukin (IL)-6 and creatinine are all potential circulating prognostic biomarkers in pulmonary arterial hypertension (PAH).. To establish the relative prognostic utility of these biomarkers in patients with idiopathic PAH (IPAH) and to identify independent prognostic markers in this disease.. Circulating RDW, GDF-15, IL-6, creatinine and NT-proBNP levels were determined in 139 patients with IPAH (mean follow-up 4.0±2.4 years) and 40 age- and sex-matched healthy volunteers. Coincident clinical data and baseline haemodynamic measurements were also analysed.. All the biomarkers except creatinine correlated with a 6 min walk distance (6MWD; p<0.05), and all but NT-proBNP correlated with WHO functional class (p<0.01). GDF-15, creatinine and NT-proBNP correlated with mean right atrial pressures and cardiac index. RDW outperformed other biomarkers in receiver operating characteristic (ROC) analysis (area under the curve 0.820). Sensitive (>80%) ROC-derived cut-off points of RDW (15.7%, p=0.001), GDF-15 (779 pg/ml, p<0.001), IL-6 (2.5 pg/ml, p=0.019), creatinine (80.5 μmol/l, p=0.010) and NT-proBNP (491 fmol/ml, p<0.001), all predicted survival in patients with IPAH over time. All the plasma biomarkers analysed predicted survival in Cox regression analysis, as did clinical and haemodynamic parameters. However, only RDW predicted survival independently of NT-proBNP and 6MWD.. Circulating RDW, GDF-15, IL-6, creatinine and NT-proBNP levels are all related to disease severity and may be used to predict survival in patients with IPAH. RDW added significant prognostic value to measurements of NT-proBNP and exercise capacity and may prove valuable in a multiple biomarker approach to disease stratification.

Topics: Adult; Antihypertensive Agents; Biomarkers; Cell Size; Creatinine; Epidemiologic Methods; Erythrocytes; Familial Primary Pulmonary Hypertension; Female; Growth Differentiation Factor 15; Hemodynamics; Humans; Hypertension, Pulmonary; Interleukin-6; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Prognosis; Treatment Outcome

The aim of this study was to prospectively evaluate the prevalence of pulmonary hypertension (PH) in patients with idiopathic pulmonary fibrosis (IPF). One hundred thirty-nine patients (101 male, mean age = 68.6 ± 9 years), with confirmed IPF and who were admitted to eight Pulmonary Departments in Greece between November 2005 and December 2006 were included in the study. Pulmonary artery systolic pressure (PASP) was estimated by echocardiography, and PH was defined as PASP > 36 mmHg. We compared demographics, pulmonary function tests, NYHA functional status, 6-min walk distance (6MWD), B-type natriuretic peptide (BNP), PaO(2), and P(A-a)O(2) at rest data between patients with PH and without PH (PASP ≤ 36 mmHg). Increased estimated right ventricular systolic pressure was present in 55% of patients (mean PASP = 47.1 ± 11.2 mmHg vs. 30.3 ± 3.8 mmHg, respectively). Patients with PH had a lower but not statistically significant DL(CO) (47.1 ± 18.8 vs. 52.5 ± 20.1), lower PaO(2) at rest (64.6 ± 12.2 vs. 71.1 ± 11.3, P = 0.004), and lower mean 6MWD (282 ± 118 vs. 338 ± 91, P = 0.007). Significant differences were also observed in the NYHA functional status between the two groups (P = 0.02). Statistically significant correlations were observed between PASP and PaO(2) at rest (r = -0.331, P = 0.00), P(A-a)O(2) at rest (r = 0.494, P = 0.00)(,) 6MWD (r = -0.264, P = 0.01), SpO(2) at rest (r = -0.293, P = 0.00), SpO(2) at the end of exercise (r = -0.364, P = 0.00), and also BNP values (r = 0.319, P = 0.01). Moreover, PaO(2) (P = 0.02), P(A-a)O(2) (P = 0.005), and SpO(2) at the end of exercise (P = 0.023) were independent predictors of the presence of estimated PH. Using Doppler echocardiography as a screening tool for the estimation of PH, we found that PH is common in patients with IPF. Gas exchange parameters at rest and exercise desaturation might indicate underlying PH in IPF.

Topics: Aged; Echocardiography; Echocardiography, Doppler; Exercise Test; Familial Primary Pulmonary Hypertension; Female; Greece; Humans; Hypertension, Pulmonary; Idiopathic Pulmonary Fibrosis; Lung; Male; Middle Aged; Natriuretic Peptide, Brain; Oxygen; Prevalence; Prospective Studies; Respiratory Function Tests; Walking

Topics: Adult; Aged; Coronary Sinus; Echocardiography; Familial Primary Pulmonary Hypertension; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Middle Aged; Natriuretic Peptide, Brain; Risk Factors

Previous studies have shown the prognostic benefit of N-terminal pro-brain natriuretic peptide (NT-pro-BNP) in pulmonary arterial hypertension (PAH) at time of diagnosis. However, there are only limited data on the clinical utility of serial measurements of the inactive peptide NT-pro-BNP in PAH. This study examined the value of serial NT-pro-BNP measurements in predicting prognosis PAH. We retrospectively analyzed all available NT-pro-BNP plasma samples in 198 patients who were diagnosed with World Health Organization group I PAH from January 2002 through January 2009. At time of diagnosis median NT-pro-BNP levels were significantly different between survivors (610 pg/ml, range 6 to 8,714) and nonsurvivors (2,609 pg/ml, range 28 to 9,828, p <0.001). In addition, NT-pro-BNP was significantly associated (p <0.001) with other parameters of disease severity (6-minute walking distance, functional class). Receiver operating curve analysis identified ≥1,256 pg/ml as the optimal NT-pro-BNP cutoff for predicting mortality at time of diagnosis. Serial measurements allowed calculation of baseline NT-pro-BNP (i.e., intercept obtained by back-extrapolation of concentration-time graph), providing a better discrimination between survivors and nonsurvivors than NT-pro-BNP at time of diagnosis alone (p = 0.010). Furthermore, a decrease of NT-pro-BNP of >15%/year was associated with survival. In conclusion, a serum NT-pro-BNP level ≥1,256 pg/ml at time of diagnosis identifies poor outcome in patients with PAH. In addition, a decrease in NT-pro-BNP of >15%/year is associated with survival in PAH.

Topics: Familial Primary Pulmonary Hypertension; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Immunoassay; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Predictive Value of Tests; Prognosis; Protein Precursors; Retrospective Studies; ROC Curve; Severity of Illness Index

To determine the diagnostic utility of circulating angiopoietin-1 (Ang-1) and its antagonist angiopoietin-2 (Ang-2) as potential biomarkers of disease severity or response to treatment in idiopathic pulmonary arterial hypertension (IPAH). Imbalances in angiogenic factors including vascular endothelial cell growth factor (VEGF) and the angiopoetin-Tie2 receptor system have been implicated in the pathogenesis of IPAH.. Plasma Ang-1, Ang-2, soluble Tie2 (sTie2), and VEGF were determined by in-house immunoassays in two cohorts of IPAH patients: a retrospective cohort (n = 81) and a prospective cohort (n = 25). Ten patients with normal pulmonary artery pressures and 14 apparently healthy subjects served as controls. Plasma levels of all angiogenic factors were elevated in IPAH patients compared with controls (all P < 0.005). Angiopoietin-2, but not Ang-1, sTie2, and VEGF correlated with cardiac index (r = -0.53, P < 0.001), pulmonary vascular resistance (PVR) (r= 0.60, P < 0.001), and mixed venous oxygen saturation (SvO(2)) (r= -0.63, P < 0.001). In multivariate analysis, elevated Ang-2 was an independent risk factor of mortality (P = 0.004). The patients in the prospective cohort were studied longitudinally at baseline and 3 months after initiation of therapy. Changes in Ang-2 after initiation of therapy correlated with changes in mean right atrial pressure (r = 0.6, P = 0.008), PVR (r = 0.51, P = 0.04), and inversely related to changes in SvO(2) (r = -0.75, P < 0.001). Histological studies showed that the expression of Ang-2 mRNA and protein was up-regulated in plexiform lesions from IPAH lung tissue samples.. Ang-2 may be involved in the pathogenesis of IPAH, and plasma Ang-2 might serve as a promising new biomarker of disease severity and response to treatment in patients with IPAH.

Topics: Adult; Angiopoietin-1; Angiopoietin-2; Biomarkers; Case-Control Studies; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Immunohistochemistry; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Prospective Studies; Retrospective Studies; Vascular Endothelial Growth Factor A