natriuretic-peptide--brain and Scleroderma--Systemic

Topics: Biomarkers; Diagnostic Tests, Routine; Humans; Hypertension, Pulmonary; Natriuretic Peptide, Brain; Natriuretic Peptides; Peptide Fragments; Pulmonary Arterial Hypertension; Scleroderma, Systemic

Systemic sclerosis (SSc) heart involvement (SHI) is a leading cause of SSc-associated mortality and once clinically overt, carries a very poor prognosis. There remain no established diagnostic criteria for SHI. This study aimed to systematically review the literature regarding the role of cardiac troponin (cTn) and B-type natriuretic peptide (BNP) or N-terminal B-type natriuretic peptide (NT-proBNP) in the diagnosis of SHI.. A comprehensive search of the MEDLINE (Ovid), EMBASE and Pubmed databases was performed to identify adult human studies of at least 10 SSc patients with a primary focus of SHI that included data on cTn and BNP or NT-proBNP results. Only cohort studies and case-controlled studies were identified and the quality of the evidence presented in each study was assessed according to the Newcastle-Ottawa Quality Assessment Scale.. Of the 2742 studies identified by the database search, 12 articles fulfilled the study inclusion criteria. Three out of four studies evaluating SHI using cardiac magnetic resonance imaging found no association between cardiac biomarkers and imaging changes. By comparison echocardiographic abnormalities, cardiac arrhythmias and congestive cardiac failure were more likely to be associated with elevated cardiac biomarkers. Comparison of results between studies was limited by the highly heterogenous definitions of SHI and inclusion criteria employed across studies.. There are insufficient data to draw definitive conclusions about the role of cTn and BNP / NT-proBNP in the diagnosis of SHI. Currently available literature suggests that cardiac biomarkers may have some role, in conjunction with other diagnostic modalities, in identifying SHI; however, this remains a much-needed area of clinical research.

Topics: Adult; Biomarkers; Humans; Natriuretic Peptide, Brain; Natriuretic Peptides; Peptide Fragments; Scleroderma, Systemic; Troponin

Pulmonary arterial hypertension (PAH) in systemic sclerosis (SSc) is a lethal complication affecting 8-15% of patients. Screening tests such as echocardiography and pulmonary function tests allow for triaging patients for diagnosis by right heart catheterization. Understanding risk factors of SSc-PAH could help differentiate high-risk patients.. A systematic review was conducted to determine associations with SSc-PAH, including clinical/disease characteristics, antibodies, labs and biomarkers. The frequencies of publications featuring each risk/association were reported.. Among 2654 articles, 984 duplicates and 1578 irrelevant articles were removed, leaving 92 articles for manual screening. After excluding 55 papers with small sample sizes, publications from identical cohorts, not English language, or PAH not ascertained by RHC, 37 articles were eligible. A total of 43 factors for SSc-PAH were identified within seven categories. Several associations were due to PAH and risk factors such as dynpnea, right heart failure, and short 6-minute walk distance. Patient characteristics (14), pulmonary physiology (6), antibody profiles (6) and genetics/epigenetics (6) had the most numerous and diverse factors, while biomarkers (4) and other labs (2) features were infrequent. Low carbon monoxide (DLCO) (6), older age (4), longer disease duration (4), positive anticentromere antibodies (ACA) (4), telangiectasias (4), high brain natriuretic peptide (4) were frequent associations.. Risk factors for SSc-PAH such as ACA, older age, longer disease duration limited cutaneous SSc subset and presence of ILD may enrich screening programs. Genes and other antibody profiles are inconsistent and requires further validation.

Topics: Aging; Humans; Natriuretic Peptide, Brain; Pulmonary Arterial Hypertension; Risk Factors; Scleroderma, Systemic

Pulmonary arterial hypertension (PAH) is a major complication of systemic sclerosis (SSc) and screening is recommended for a timely initiation of disease-targeted drug therapy to modify disease progression. Patients with SSc-PAH have a better prognosis when detected and treated early. The PAH can occur in all disease stages and subsets of SSc. Regular screening tests, which are indicative for PAH, e.g. echocardiography, diffusion capacity, brain natriuretic protein (BNP) and a 6-min walking test, are recommended to enhance the suspicion, since clinical symptoms are unspecific and occur late in the course of PAH. In patients with suspected PAH, the diagnosis should be confirmed by right heart catheterization. A multidisciplinary approach in expert centres including rheumatologists and respiratory physicians and cardiologists specialized in pulmonary hypertension is mandatory for management of patients with SSc at risk for or with manifest pulmonary arterial hypertension.

Topics: Cardiac Catheterization; Early Diagnosis; Early Medical Intervention; Echocardiography; Exercise Test; Humans; Hypertension, Pulmonary; Interdisciplinary Communication; Intersectoral Collaboration; Natriuretic Peptide, Brain; Prognosis; Pulmonary Diffusing Capacity; Scleroderma, Systemic

Topics: Biomarkers; Cost-Benefit Analysis; Early Diagnosis; Echocardiography, Doppler; False Positive Reactions; Genetic Testing; Humans; Hypertension, Pulmonary; Mass Screening; Natriuretic Peptide, Brain; Respiratory Function Tests; Scleroderma, Systemic

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

The long-term prognosis for patients with pulmonary arterial hypertension (PAH) remains poor, despite advances in treatment options that have been made in the past few decades. Recent evidence suggests that World Health Organization functional class I or II patients have significantly better long-term survival rates than patients in higher functional classes, thus providing a rationale for earlier diagnosis and treatment of PAH. However, early diagnosis is challenging and there is frequently a delay between symptom onset and diagnosis. Screening programmes play an important role in PAH detection and expert opinion favours echocardiographic screening of asymptomatic patients who may be predisposed to the development of PAH (i.e. those with systemic sclerosis or sickle cell disease), although current guidelines only recommend annual echocardiographic screening in symptomatic patients. This article reviews the currently available screening programmes, including their limitations, and describes alternative screening approaches that may identify more effectively those patients who require right heart catheterisation for a definitive PAH diagnosis.

Topics: Anemia, Sickle Cell; Antihypertensive Agents; Bosentan; Early Diagnosis; Echocardiography, Doppler; Exercise Test; Humans; Hypertension, Pulmonary; Mass Screening; Natriuretic Peptide, Brain; Peptide Fragments; Piperazines; Practice Guidelines as Topic; Purines; Respiratory Function Tests; Risk Factors; Scleroderma, Systemic; Sildenafil Citrate; Sulfonamides; Sulfones; Vasodilator Agents

When present clinically, cardiac involvement in systemic sclerosis (SSc) is a major risk factor for death. It is therefore vitally important to understand the epidemiology, screening, diagnosis, and treatment of the cardiac manifestations of SSc.. The epidemiology of cardiac involvement in SSc has been the subject of several recent studies. Most importantly, the prevalence of overt left ventricular (LV) systolic dysfunction and its associated risk factors have been defined, and patients with diffuse cutaneous SSc appear to be most susceptible to direct cardiac involvement. From a diagnostic and screening standpoint, tissue Doppler echocardiography and natriuretic peptides have provided fresh insight into subclinical cardiac dysfunction in SSc. Newer techniques, such as speckle-tracking echocardiography, diffuse myocardial fibrosis imaging, and absolute myocardial perfusion imaging, are poised to further advance our knowledge. Lastly, there is now consistent observational data to suggest a central role for calcium channel blockers in the treatment of microvascular ischemia and prevention of overt LV systolic dysfunction, although randomized controlled trials are lacking.. Recent studies have improved our understanding of cardiac involvement in SSc. Nevertheless, key questions regarding screening, diagnosis, and treatment remain. Novel diagnostic techniques and multicenter studies should yield important new data, which will hopefully ultimately result in improved outcomes.

Topics: Biomarkers; Echocardiography; Heart Diseases; Humans; Magnetic Resonance Imaging; Natriuretic Peptide, Brain; Peptide Fragments; Risk Factors; Scleroderma, Systemic; Tomography, Emission-Computed, Single-Photon; Tomography, X-Ray Computed; Ventricular Dysfunction, Right

The review provides an update of the epidemiology, pathogenesis, risk factors, screening and treatment of pulmonary arterial hypertension in systemic sclerosis.. Several recent studies have investigated the utility of several noninvasive screening methods and the propagation of new treatments promise the clinician better outcomes than the current median survival time of 1 year for patients with scleroderma-related pulmonary arterial hypertension.. Pulmonary hypertension is a frequent cause of morbidity and mortality in patients with systemic sclerosis. This review discusses the recent changes in the classification of pulmonary hypertension, especially the significance for the rheumatologist. A high clinical suspicion should be maintained, even in early scleroderma. Despite progress in echocardiography and biomarkers, right heart catheterization remains the only test that can diagnose pulmonary hypertension and differentiate pulmonary veno-occlusive disease from pulmonary arterial hypertension. The differentiation of these causes of pulmonary hypertension in the scleroderma patient is essential because the initiation of pulmonary vasodilators in veno-occlusive disease often leads to increased mortality. The role of screening with serum biomarkers and noninvasive testing remains controversial, and in this review we discuss the controversies and new recommendations in detail.

Topics: Biomarkers; Cardiac Catheterization; Echocardiography; Humans; Hypertension, Pulmonary; Natriuretic Peptide, Brain; Peptide Fragments; Prognosis; Respiratory Function Tests; Risk Factors; Scleroderma, Systemic

Vascular disease is present in every patient with scleroderma and is a major source of morbidity and mortality. There is a subset of patients who will develop severe and sometimes life-threatening vascular events. We have good evidence that an insult to the microvasculature occurs early in the disease course, but there is a subset of patients who have an ongoing chronic process, the end result of which are events such as digital loss and pulmonary arterial hypertension. The ability to detect this process at an early stage by simple means would be of great value as our ability to treat these vascular complications improves with time. We have a significant amount of evidence of vascular perturbation from studies of peripheral blood in scleroderma, but know very little about the ability of these biomarkers to predict vascular outcomes. In this review, we will critically assess our current knowledge of the use of biomarkers of vascular disease in scleroderma and the possible directions of future research in this area.

Topics: Biomarkers; Carbon Dioxide; Humans; Hypertension, Pulmonary; Natriuretic Peptide, Brain; Peptide Fragments; Pulmonary Diffusing Capacity; Scleroderma, Systemic; Vascular Endothelial Growth Factor A

SSc is a CTD, which may cause critical organ fibrosis. It has a highly variable clinical presentation and course. While it is more common in females, this heterogeneity has led to significant problems with classification. Biomedical (clinical) and biomolecular markers to identify diagnostic, prognostic and therapeutic response have been elusive in part as a result of difficulties with classification and also due to the rarity of the disease. Existing biomarkers have been identified largely in small cohorts and larger cross-sectional or occasional longitudinal observational cohorts. The nature of biomarkers requires well-defined clinical characteristics and/or defined clinical outcomes and this has been extremely challenging to the international SSc research community. This brief review summarizes the current level of knowledge; however, it most importantly highlights the potential now to find biomarkers through a large, multicentre, international collaborative group approach.

Topics: Acute-Phase Proteins; Biomarkers; Blood Sedimentation; CD40 Ligand; Endothelin-1; Hemoglobins; Humans; Interleukins; Natriuretic Peptide, Brain; Peptide Fragments; Receptors, Interleukin; Scleroderma, Systemic

To evaluate N-terminal pro-brain natriuretic peptide (NT-proBNP) as a marker of early pulmonary artery hypertension (PAH) and to study changes in the levels of this marker following treatment with dihydropyridine-type calcium-channel blocker (DTCCB) in patients with systemic sclerosis (SSc).. We evaluated 40 consecutive SSc patients who had been hospitalized for followup care (mean +/- SD age 56 +/- 11 years and mean +/- SD duration of cutaneous disease 9 +/- 9 years; 27 with limited cutaneous and 13 with diffuse cutaneous disease) but who had no clinical symptoms of heart failure and had a normal left ventricular ejection fraction. At baseline, 10 patients had PAH, defined as a systolic pulmonary artery pressure (sPAP) >40 mm Hg, as measured by echocardiography. Levels of NT-proBNP were determined at baseline (after discontinuation of DTCCB treatment for 72 hours), after taking 3 doses of DTCCB following treatment reinitiation (assessment 1), and after 6-9 months of continuous DTCCB treatment (assessment 2) in the 20 patients who attended regular appointments (including the 10 patients with PAH at baseline).. At baseline, 13 patients had high NT-proBNP values for their ages. High NT-proBNP levels identified patients with PAH with a sensitivity of 90%, a specificity of 90.3%, a positive predictive value of 69.2%, and a negative predictive value of 96%. The NT-proBNP level correlated with the sPAP (r = 0.44; P = 0.006). By assessment 1, the number of patients with PAH and high levels of NT-proBNP had decreased from 9 of 10 to 2 of 10 (P = 0.02). This decrease was partially sustained at assessment 2 (4 of 10 patients; P = 0.06).. NT-proBNP is a useful biologic marker that can be used to diagnose early PAH in SSc patients without clinical heart failure. Measurement of NT-proBNP may be valuable for the evaluation of treatment with DTCCB and vasodilators in patients with PAH.

Topics: Aged; Biomarkers; Calcium Channel Blockers; Calcium Channels, L-Type; Disease Progression; Humans; Hypertension, Pulmonary; Middle Aged; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Peptide Fragments; Prospective Studies; Pulmonary Artery; Scleroderma, Systemic

Topics: Biomarkers; Diagnostic Tests, Routine; Humans; Natriuretic Peptide, Brain; Peptide Fragments; Pulmonary Arterial Hypertension; Scleroderma, Systemic

Pulmonary arterial hypertension (PAH) is a serious complication of SSc with high mortality. Interventricular systolic asynchrony (IVSA) is observed in PAH patients, but the effect of IVSA and its association with long-term mortality and clinical events in SSc-associated PAH are unclear. This study aimed to investigate the impact of IVSA on the prognosis of SSc-associated PAH.. Between March 2010 and July 2018, a total of 60 consecutive patients with SSc-associated PAH were enrolled. The end point was a composite of all-cause mortality and clinical worsening. Asynchrony was assessed by colour-coded tissue Doppler imaging (TDI) echocardiography. The myocardial sustained systole curves (Sm) of the basal portion of the right ventricular (RV) free wall and left ventricular (LV) lateral wall were obtained. IVSA was defined as the time difference from the onset of the QRS complex to the end of Sm between LV and RV.. Patients with greater IVSA time differences presented with advanced pulmonary vascular resistance (PVR). The IVSA time difference was an independent predictive factor (Hazard Ratio (HR) = 1.018, 95% CI: 1.005, 1.031, P =0.005) for the composite end point and was significantly associated with PVR (r = 0.399, R2=0.092, P =0.002). Kaplan-Meier survival curves showed that patients with greater IVSA had worse prognoses (log-rank P =0.001).. In conclusion, IVSA analysed by colour-coded TDI echocardiography provided added value as a noninvasive, easy-to-use approach for assessing the prognosis of patients with SSc-associated PAH. A significant IVSA time difference identifies the subgroup of patients at high risk of a poor prognosis.

Topics: Echocardiography, Doppler, Color; Female; Follow-Up Studies; Heart Ventricles; Humans; Hypertension, Pulmonary; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Prognosis; Scleroderma, Systemic; Systole; Vascular Resistance

Pulmonary arterial hypertension (PAH) is a devastating complication of systemic sclerosis (SSc). Screening for PAH in SSc has increased detection, allowed early treatment for PAH and improved patient outcomes. Blood-based biomarkers that reliably identify SSc patients at risk of PAH, or with early disease, would significantly improve screening, potentially leading to improved survival, and provide novel mechanistic insights into early disease. The main objective of this study was to identify a proteomic biomarker signature that could discriminate SSc patients with and without PAH using a machine learning approach and to validate the findings in an external cohort.Serum samples from patients with SSc and PAH (n=77) and SSc without pulmonary hypertension (non-PH) (n=80) were randomly selected from the clinical DETECT study and underwent proteomic screening using the Myriad RBM Discovery platform consisting of 313 proteins. Samples from an independent validation SSc cohort (PAH n=22 and non-PH n=22) were obtained from the University of Sheffield (Sheffield, UK).Random forest analysis identified a novel panel of eight proteins, comprising collagen IV, endostatin, insulin-like growth factor binding protein (IGFBP)-2, IGFBP-7, matrix metallopeptidase-2, neuropilin-1, N-terminal pro-brain natriuretic peptide and RAGE (receptor for advanced glycation end products), that discriminated PAH from non-PH in SSc patients in the DETECT Discovery Cohort (average area under the receiver operating characteristic curve 0.741, 65.1% sensitivity/69.0% specificity), which was reproduced in the Sheffield Confirmatory Cohort (81.1% accuracy, 77.3% sensitivity/86.5% specificity).This novel eight-protein biomarker panel has the potential to improve early detection of PAH in SSc patients and may provide novel insights into the pathogenesis of PAH in the context of SSc.

Topics: Biomarkers; Humans; Machine Learning; Natriuretic Peptide, Brain; Peptide Fragments; Proteomics; Pulmonary Arterial Hypertension; Scleroderma, Systemic

Asymptomatic cardiac involvement in systemic sclerosis (SSc) has been reported. Long-term follow-up might elucidate the clinical implications of these abnormalities. The aim was to identify the clinical outcomes of asymptomatic cardiac involvement in SSc patients after 2 years of follow-up.. A cohort study was done at Khon Kaen University, Thailand, on adult patients with SSc who completed the preliminary study. Repeated investigations included electrocardiography, chest radiography, echocardiography, and blood tests for creatine kinase-MB, high sensitivity cardiac troponin-T, and N-terminal prohormone of brain natriuretic peptide.. Seventy-four of the 103 patients from the previous study were enrolled. The mean duration of follow-up was 3.1 ± 0.9 years. Five patients developed symptomatic cardiac involvement-all of whom had pulmonary arterial hypertension (PAH). The incidence of symptomatic cardiac involvement for the combined 315 person-years was 1.6 per 100-person-years (95%CI 0.7-3.4). Fourteen patients died resulting in a mortality incidence of 4.4 per 100-person-years (95%CI 4.3-5.4). Persistent cardiac involvement was found in 35 patients for an incidence of 11.1 per 100-person-years (95%CI 8.0-15.5). Two of the patients who had persistent elevated cardiac enzyme developed PAH at a respective 3.7 and 39.4 months after the initial evaluation. None of the clinical parameters were predictive of symptomatic and persistent cardiac involvement. Only male sex was associated with mortality (hazard ratio 3.70; 95%CI 1.22-11.11).. Cardiac involvement in SSc can progress slowly or even be reversed. Based on a previous test, the incidence of symptomatic cardiac involvement after 2 years was low despite its being a persistent involvement. If symptomatic cardiac involvement develops, PAH is the most prevalent symptom.

Topics: Adult; Cohort Studies; Follow-Up Studies; Humans; Male; Natriuretic Peptide, Brain; Scleroderma, Systemic; Thailand

Systemic sclerosis (SSc) is an autoimmune disease characterized by micro/macrovascular damage due to the underlying fibrosis. Markers able to predict the progression of cardiovascular damage, including digital ulcers, in SSc are warranted. We aimed at characterizing the relevance of N-terminal proatrial natriuretic peptide (NT-proANP) and N-terminal probrain natriuretic peptide plasma levels in relation to cardiovascular damage and digital ulcers in a cohort of Italian SSc patients.. Seventy patients were enrolled (64 women and six men; mean age 56.7 ± 14 years) with a disease duration of 11.1 ± 8.3 years. Clinical, instrumental (nailfold videocapillaroscopy, ECG, transthoracic echocardiography, pulmonary function test with diffusion lung CO), NT-proANP and N-terminal probrain natriuretic peptide plasma levels measurement were performed at baseline. The clinical follow-up lasted 24 months. The statistical approach used to achieve the study objectives included multivariate analysis, receiver operating characteristic curve, Kaplan-Meier and Cox regression analyses.. Both NT-proNPs levels correlated with systolic pulmonary arterial pressure, but only the NT-proANP level correlated with right heart dimension. Both NT-proNPs levels were higher in patients experiencing events at follow-up but only the NT-proANP level significantly predicted the progression of cardiovascular damage, including development of pulmonary arterial hypertension (PAH). NT-proANP levels were higher in patients with digital ulcers and strongly predicted their development.. Our results show that the NT-proANP plasma level significantly correlates with disease progression such as new onset of PAH, worsening of pulmonary hypertension and development of digital ulcers in a cohort of SSc Italian patients. If future studies will confirm our findings, the plasma NT-proANP level could be used in clinical practice as a novel sensitive marker for PAH and digital ulcers development in SSc.

Topics: Adult; Aged; Atrial Natriuretic Factor; Biomarkers; Disease Progression; Female; Humans; Italy; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Predictive Value of Tests; Prognosis; Pulmonary Arterial Hypertension; Scleroderma, Systemic; Skin Ulcer; Up-Regulation

The aim of our study was to define the role of high-sensitive cardiac troponin T (hs-cTnT) and NT-proBNP in identifying Systemic Sclerosis (SSc) patients with cardiac involvement and at higher risk of cardiac death.. Plasma hs-cTnT and NT-proBNP concentrations were measured in 245 SSc-patients.. hs-cTnT and NT-proBNP levels were higher in SSc-patients than in healthy controls. Hs-cTnT levels were higher than 0.014 ng/ml in 32.3% SSc-patients, while NT-proBNP was above 125 pg/ml in 31.8% of them, irrespective of classical cardiovascular risk factor and of pulmonary arterial hypertension. Elevated hs-cTnT and NT-proBNP were associated with diffuse skin involvement and directly correlated with the skin score. Patients with increased cardiac markers presented a lower left-ventricular ejection fraction (LVEF) and a higher rate of right bundle branch block (RBBB) on electrocardiogram (ECG) compared to patients with normal cardiac enzymes. During the follow-up, 12 SSc-patients experience a disease-related death; 9 of these were directly related to cardiac involvement (sudden cardiac death or heart failure) and the majority of them occurred among patients with increase of at least one cardiac biomarker. Long-term survival was worse in patients with increase of both cardiac biomarkers.. Evaluation of hs-cTnT and NT-proBNP levels may provide a tool to screen non-invasively SSc-patients for heart involvement. A higher incidence of impaired systolic function, ECG abnormalities and a poor outcome in SSc-patients with elevated cardiac enzymes suggests that they may be valuable screening biomarkers to detect a cardiac damage at early stages and to improve risk stratification.

Topics: Adult; Aged; Biomarkers; Case-Control Studies; Electrocardiography; Female; Heart; Heart Diseases; Humans; Italy; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Prognosis; Prospective Studies; Risk Factors; Scleroderma, Systemic; Severity of Illness Index; Troponin T; Young Adult

This study aimed to evaluate the association between myocardial abnormalities and left ventricular (LV) geometry as assessed using cardiac magnetic resonance imaging (CMRI) in systemic sclerosis (SSc) patients without cardiac symptoms.. SSc patients without cardiac symptoms or cardiovascular risk factors underwent contrast CMRI. CMRI were assessed for structural and functional LV parameters and myocardial fibrosis based on myocardial late gadolinium enhancement (LGE). The correlation between brain natriuretic peptide (BNP) levels and LGE status was evaluated.. Among 49 patients, 27 (55%) showed LGE positivity. The most common identified LGE pattern was a linear pattern. LGE was not consistent with coronary artery distribution. There was no difference in ejection fraction between those with and without LGE. LV morphological changes were observed in 29% of SSc patients. An abnormal LV structure was detected in 44% and 14% of patients in the LGE+ and LGE- groups, respectively. The BNP levels were higher by 57% in the LGE+ group than in the LGE-group. Receiver operating characteristic analysis showed that BNP levels reliably detected myocardial abnormalities (area under the curve, 0.72; 95% confidence interval 0.58-0.88).. Myocardial abnormalities were common in SSc patients without cardiac symptoms. We suggest that LV morphological changes may have resulted from myocardial abnormalities. BNP may be useful as a screening tool for the detection of myocardial abnormalities in SSc patients.

Topics: Asymptomatic Diseases; Biomarkers; Female; Fibrosis; Humans; Hypertrophy, Left Ventricular; Japan; Magnetic Resonance Imaging, Cine; Male; Middle Aged; Myocardium; Natriuretic Peptide, Brain; Predictive Value of Tests; Prevalence; Prognosis; Retrospective Studies; Risk Assessment; Risk Factors; Scleroderma, Systemic; Ventricular Function, Left; Ventricular Remodeling

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

Topics: Aged; Atrial Pressure; Blood Pressure; Comorbidity; Female; Heart Rate; Humans; Incidence; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Prognosis; Pulmonary Arterial Hypertension; Renal Insufficiency; Reproducibility of Results; Risk Assessment; Scleroderma, Systemic; Severity of Illness Index; Survival Rate; Vascular Resistance; Walk Test

Heart failure with preserved ejection fraction (HFpEF) is common in systemic sclerosis (SSc) and implies a worse prognosis therefore non-invasive assessment of left ventricular (LV) filling pressure is pivotal. Besides E/e' the use of maximal left atrial volume (LA Vmax index) is recommended. LA reservoir strain was also reported to be useful. The utility of LA stiffness, however, was never investigated in SSc. Thus we aimed to compare the diagnostic power of LA Vmax index, reservoir strain and stiffness in predicting elevated LV filling pressure in SSc patients. 72 SSc patients (age: 57 ± 11 years) were investigated. LA stiffness was calculated as ratio of E/e' to LA reservoir strain. Elevated LV filling pressure was defined as NT-proBNP > 220 pg/ml. Receiver-operating characteristic (ROC) curves were used to estimate the diagnostic performance of the investigated parameters. Average NT-proBNP level was 181 ± 154 pg/ml. NT-proBNP > 220 pg/ml was found in 21 SSc patients. LA stiffness showed the highest diagnostic performance in predicting NT-pro-BNP > 220 pg/ml, with a cut off value of 0.314 (Area under the curve: 0.719, specificity: 89.4%, sensitivity: 42.1%). AUC values for LA reservoir strain and Vmax index were 0.595 and 0.521, respectively. LA stiffness was superior to Vmax index and reservoir strain in predicting elevated NT-proBNP levels in SSc patients. Although invasive validation studies on larger samples are required, our data suggest, that the use of LA stiffness may significantly contribute to diagnostic precision in populations with a high suspicion of HFpEF.

Topics: Adult; Aged; Atrial Function, Left; Biomarkers; Echocardiography, Doppler; Female; Heart Failure; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Predictive Value of Tests; Prognosis; Risk Factors; Scleroderma, Systemic; Stroke Volume; Up-Regulation; Ventricular Function, Left

Pulmonary arterial hypertension is an important cause of death and disability in patients with systemic sclerosis (SSc). Yearly screening of all SSc patients with transthoracic echocardiography (TTE) is recommended in international guidelines and currently utilised by the Australian Scleroderma Interest Group (ASIG

Topics: Algorithms; Australia; Biomarkers; Cohort Studies; Cost Savings; Early Diagnosis; Echocardiography; Humans; Mass Screening; Natriuretic Peptide, Brain; Peptide Fragments; Pulmonary Arterial Hypertension; Scleroderma, Systemic

Topics: Biomarkers; Cardiovascular Diseases; Cause of Death; Disease Progression; Echocardiography; Humans; Natriuretic Peptide, Brain; Netherlands; Peptide Fragments; Predictive Value of Tests; Progression-Free Survival; Risk Factors; Scleroderma, Systemic; Stroke Volume; Time Factors; Ventricular Function, Left

To identify circulating angiogenic and inflammatory biomarkers with potential in screening for pulmonary arterial hypertension (PAH) in systemic sclerosis (SSc), and in early diagnosis and determination of treatment response in PAH.. Plasma samples were taken at the time of PAH diagnosis and at treatment follow-up after a median (interquartile range) of 4 months (3-9.8 months) in idiopathic (n = 9) and SSc-associated PAH (n = 11). In patients with SSc-associated PAH, plasma samples had also been gathered a median of 2 years (0.8-3 years) before PAH diagnosis (n = 10). Additional plasma samples were retrieved at two time-points separated by a median of 12 years (10-13 years) from SSc patients who did not develop PAH (n = 10) and from controls (n = 8). Angiogenic and inflammatory biomarkers were analysed by multiplex immunoassays.. Plasma levels of placenta growth factor (PlGF), soluble vascular endothelial growth factor receptor-1 (sVEGFR-1), and tumour necrosis factor-α (TNF-α) were higher (p < 0.05) in SSc patients who later developed PAH than in those who did not. Plasma vascular endothelial growth factor (VEGF)-D increased (p < 0.05) in SSc patients as PAH developed. Plasma levels of PlGF, VEGF-A, VEGF-D, sVEGFR-1, interleukin-6, and TNF-α were higher (p < 0.05) in PAH than controls. There were no significant differences in circulating biomarkers between idiopathic and SSc-associated PAH. Plasma sVEGFR-1 decreased (p < 0.05) after initiating PAH-targeted treatments.. Plasma levels of PlGF, sVEGFR-1, TNF-α, and VEGF-D have potential in screening for SSc-associated PAH. Plasma sVEGFR-1 may be a biomarker of treatment response.

Topics: Aftercare; Aged; Biomarkers; Case-Control Studies; Female; Humans; Hypertension, Pulmonary; Inflammation; Interleukin-6; Male; Mass Screening; Middle Aged; Natriuretic Peptide, Brain; Neovascularization, Pathologic; Peptide Fragments; Placenta Growth Factor; Scleroderma, Systemic; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor D; Vascular Endothelial Growth Factor Receptor-1; Vascular Resistance; Walk Test

The aim of this study was to evaluate N-terminal pro-brain natriuretic peptide (NT-proBNP) in patients with systemic sclerosis (SSc)-associated pulmonary arterial hypertension (PAH) and changes after therapy with bosentan.. Twenty-one patients with SSc-PAH on bosentan therapy were enrolled. PAH was diagnosed by right heart catheterization. NT-proBNP levels, 6-min walking test (6MWT), Doppler echocardiography to estimated systolic pulmonary arterial pressure (sPAP), New York Heart Association (NYHA) functional class for dyspnea and carbon monoxide lung diffusion capacity (DLco) were recorded at baseline, and after 1 and 2 years. Fifty-two SSc patients without PAH were also evaluated as controls.. NT-proBNP plasma levels were significantly higher in SSc-PAH at 385 pg/mL (SD ± 427) than in SSc without PAH and 72 pg/mL (SD ± 52, P < 0.001) at baseline, but did not significantly change following bosentan therapy at 1 year (330 pg/mL [SD ± 291] and 2 years (374 pg/mL [SD ± 291]). However, NYHA class significantly improved at 2 years (P = 0.01) as well as 6MWT (P = 0.04). NT-proBNP levels were positively correlated only with sPAP but not with DLco, NYHA class or 6MWT.. NT-proBNP levels were found to be significantly higher in SSc-PAH at baseline. Serial assessment of NT-proBNP in SSc-PAH patients on bosentan therapy showed no relation to the clinical improvement. This suggests that NT-proBNP may lack 'sensitivity to change', but further studies are warranted to assess the role of NT-proBNP as a biomarker of the therapeutic response in larger cohorts of SSc patients.

Topics: Adult; Aged; Antihypertensive Agents; Biomarkers; Blood Pressure; Bosentan; Endothelin Receptor Antagonists; Exercise Tolerance; Female; Humans; Hypertension, Pulmonary; Longitudinal Studies; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Prospective Studies; Recovery of Function; Scleroderma, Systemic; Sulfonamides; Time Factors; Treatment Outcome; Up-Regulation

Pulmonary arterial hypertension (PAH) is one of the most devastating complications in scleroderma (SSc) patients and has a poorer outcome than other PAH subgroups. Tadalafil (Adcirca. We enrolled 10 SSc-PAH subjects who were naïve to PDE5-I treatment, profiled gene expression in whole blood prior to and following treatment with tadalafil, measured changes in genomic profiles before and after treatment with tadalafil, and correlated them with changes in clinical outcomes, such as cardiopulmonary hemodynamics, six-min walk distance (6MWD), Borg Dyspnea Index (BDI), NYHA/WHO functional class (FC), B-type natriuretic peptide (BNP), and cardiac magnetic resonance imaging (cMRI).. Genes associated with IL-12 signaling and extracellular matrix maintenance were coordinately up- or down-regulated with treatment, respectively, across all subjects. Interestingly, we found that genes encoding voltage-gated potassium channels and genes related to innate immunity were coordinately up-regulated in subjects who improved with tadalafil treatment compared to those patients who did not. In contrast, up-regulation of Golgi-related gene sets was associated with clinical worsening during the treatment period.. The results of this pilot study suggest that outcomes of SSc-PAH patients treated with tadalafil are associated with specific changes in gene expression and biological pathways.

Topics: Aged; Down-Regulation; Extracellular Matrix; Female; Golgi Apparatus; Humans; Hypertension, Pulmonary; Immunity, Innate; Interleukin-12; Male; Microarray Analysis; Middle Aged; Natriuretic Peptide, Brain; Phosphodiesterase 5 Inhibitors; Pilot Projects; Potassium Channels, Voltage-Gated; Scleroderma, Systemic; Signal Transduction; Tadalafil; Transcriptome; Treatment Outcome; Up-Regulation; Walk Test

Cardiac manifestations in systemic sclerosis (SSc) are associated with poor prognosis. Few studies have investigated cardiac troponins in SSc. We studied the relationships between echocardiographic abnormalities, cardiac biomarkers, and disease manifestations in a population-based cohort of patients with SSc and controls.. The study comprised 110 patients with SSc and 105 age- and sex-matched population-based controls. We examined ventricular function, heart valves, and estimated pulmonary arterial pressure (ePAP) by echocardiography in all participants. Disease characteristics, manifest ischaemic heart disease (IHD), and measurements of N-terminal prohormone brain natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin I (hs-cTnI) were tabulated.. NT-proBNP and hs-cTnI levels were higher in SSc patients than controls. Both NT-proBNP and hs-cTnI were associated with the presence of echocardiographic abnormalities. Forty-four SSc patients and 23 control subjects had abnormal echocardiograms (p = 0.002). As a group, SSc patients had lower (but normal) left ventricular ejection fraction (LVEF, p = 0.02), more regional hypokinesia (p = 0.02), and more valve regurgitations (p = 0.01) than controls. Thirteen patients and four controls had manifest IHD. Decreased right ventricular (RV) function (n = 7) and elevated ePAP (n = 15) were exclusively detected among SSc patients.. Both NTproBNP and hs-cTnI were associated with echocardiographic abnormalities, which were more prevalent in SSc patients than in controls. Our results thus suggest that hs-cTnI could be a potential cardiac biomarker in SSc. Low RV function and signs of pulmonary hypertension (PH) were uniquely found in the SSc group. SSc patients had more valve regurgitation than controls, an observation that warrants more clinical attention.

Topics: Aged; Aortic Valve Insufficiency; Case-Control Studies; Echocardiography; Female; Heart Valve Diseases; Humans; Male; Middle Aged; Mitral Valve Insufficiency; Myocardial Ischemia; Natriuretic Peptide, Brain; Peptide Fragments; Pulmonary Wedge Pressure; Scleroderma, Systemic; Stroke Volume; Tricuspid Valve Insufficiency; Troponin I; Ventricular Dysfunction, Left

Pulmonary hypertension (PH) is an important cause of morbidity and mortality in patients with SSc. The submaximal heart and pulmonary evaluation (step test) is a non-invasive, submaximal stress test that could be used to identify SSc patients with PH. Our aims were to determine whether change in end tidal carbon dioxide ([Formula: see text]) from rest to end-exercise, and the minute ventilation to carbon dioxide production ratio ([Formula: see text]), both as measured by the step test, differ between SSc patients with and without PH. We also examined differences in validated self-report questionnaires and potential PH biomarkers between SSc patients with and without PH.. We performed a cross-sectional study of 27 patients with limited or dcSSc who underwent a right heart catheterization within 24 months prior to study entry. The study visit consisted of questionnaire completion; history; physical examination; step test performance; and phlebotomy. [Formula: see text], [Formula: see text], self-report data and biomarkers were compared between patients with and without PH.. SSc patients with PH had a statistically significantly lower median (interquartile range) [Formula: see text] than SSc patients without PH [-2.1 (-5.1 to 0.7) vs 1.2 (-0.7 to 5.4) mmHg, P = 0.035], and a statistically significantly higher median (interquartile range) [Formula: see text] [53.4 (39-64.1) vs 36.4 (31.9-41.1), P = 0.035]. There were no statistically significant differences in self-report data or biomarkers between groups.. [Formula: see text] and [Formula: see text] as measured by the step test are statistically significantly different between SSc patients with and without PH. [Formula: see text] and [Formula: see text] may be useful screening tools for PH in the SSc population.

Topics: Aged; Breath Tests; Carbon Dioxide; Cross-Sectional Studies; Exercise Test; Female; Humans; Hypertension, Pulmonary; Hypoxia-Inducible Factor 1, alpha Subunit; Interleukin-6; Lung; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Pulmonary Gas Exchange; Pulmonary Ventilation; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Scleroderma, Diffuse; Scleroderma, Limited; Scleroderma, Systemic; Vascular Endothelial Growth Factor A

Cardiovascular involvement is a major contributor to mortality in systemic sclerosis (SSc). We examined whether N-terminal pro-brain natriuretic peptide (NT-proBNP) is a reliable predictor of mortality in SSc.. This multicentre prospective cohort study included 523 patients presenting with SSc, whose mean age was 54±13years, mean disease duration 8±9years, and diffuse cutaneous form in 168. Plasma NT-proBNP was measured at baseline and the patients were followed yearly. Overall mortality was measured at 3years. At baseline, cardiovascular involvement was present in 37 patients, including 17 with pulmonary artery hypertension (PAH) and 20 with a left ventricular ejection fraction (LVEF) <55%. At 3years, 32 (7%) patients had died. The median [25th-75th percentile] NT-proBNP concentration was 203ng/l [129-514] in patients who died within 3years, versus 88ng/l [47-167] in survivors (P<0.001). NT-proBNP was an independent predictor of 3-years mortality in multivariate analysis (P=0.046). The optimal cut-off derived from the ROC curve was 129ng/l; sensitivity and specificity to predict 3y mortality were 78.1 and 66.7%. Using the previously recommended 125-ng/l concentration as threshold value, NT-proBNP reliably and independently predicted 3year mortality, with a sensitivity of 78.1 and a negative predictive value of 97.6%, respectively (P=0.006). The consideration of SSc patients without PAH or LVEF<55% at baseline yielded similar results.. NT-proBNP appears as a reliable and independent predictor of mortality in patients with SSc.

Topics: Aged; Biomarkers; Female; Follow-Up Studies; France; Germany; Humans; Hungary; Italy; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Predictive Value of Tests; Prognosis; Prospective Studies; ROC Curve; Scleroderma, Systemic; Survival Rate; Time Factors

Cardiac involvement in systemic sclerosis (SSc) is considerably frequent in autopsy, but the early identification is clinically difficult. Recent advantages in cardiac magnetic resonance (CMR) enabled to detect myocardial fibrotic scar as late gadolinium enhancement (LGE). We aimed to examine the prevalence and distribution of LGE in patients with SSc, and associate them with clinical features, electrocardiographic abnormalities and cardiac function. Forty patients with SSc (58 ± 14 years-old, 35 females, limited/diffuse 25/15, disease duration 106 ± 113 months) underwent serological tests, 12-lead electrocardiogram (ECG) and CMR. Seven patients (17.5 %) showed LGE in 26 segments of left ventricle (LV). LGE distributed mainly in the basal to mid inter-ventricular septum and the right ventricular (RV) insertion points, but involved all the myocardial regions. More patients with LGE showed NYHA functional class II and more (71 vs. 21 %, p < 0.05), bundle branch blocks (57 vs. 6 %, p < 0.05), LV ejection fraction (LVEF) < 50 % (72 vs. 6 %, p < 0.01), LV asynergy (43 vs. 0 %, p < 0.01) and RVEF < 40 % (100 vs. 39 %, p < 0.01). There was no difference in disease duration, disease types, or prevalence of positive autoimmune antibodies or high serum NT-proBNP level (>125 pg/ml). When cardiac involvement of SSc was defined as low LVEF, ECG abnormalities or high NT-proBNP, the sensitivity, specificity positive and negative predictive values of LGE were 36, 92, 71 and 72 %, respectively. We could clarify the prevalence and distribution of LGE in Japanese patients with SSc. The presence of LGE was associated with cardiac symptom, conduction disturbance and impaired LV/RV contraction.

Topics: Adolescent; Adult; Aged; Cardiomyopathies; Contrast Media; Electrocardiography; Female; Gadolinium; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Myocardium; Natriuretic Peptide, Brain; Peptide Fragments; Predictive Value of Tests; Scleroderma, Systemic; Ventricular Function, Left; Young Adult

To measure plasma concentrations of high-sensitivity cardiac troponin T (HS-cTnT) and N-terminal pro-brain natriuretic peptide (NT-proBNP) in patients with systemic sclerosis (SSc; scleroderma) and age- and sex-matched healthy control subjects, and to examine the contribution of traditional cardiovascular risk factors and SSc features to the concentrations of these 2 cardiac biomarkers.. Plasma HS-cTnT and NT-proBNP concentrations were measured using the electrochemiluminescence method and sandwich immunoassay, respectively.. The study group comprised 161 unrelated patients with SSc and 213 matched control subjects. HS-cTnT and NT-proBNP plasma levels were significantly increased in SSc patients compared with controls (both P < 0.001). Similar results were observed in the subgroup of patients with SSc who had no cardiovascular risk factors (n = 72). Multivariate logistic regression analysis confirmed diabetes mellitus (P = 0.006), high blood pressure (P = 0.021), precapillary pulmonary hypertension (P = 0.039), and the diffuse cutaneous SSc (P = 0.004) as factors independently associated with an HS-cTnT level of >14 ng/liter. Increased NT-proBNP concentrations were associated only with the presence of precapillary pulmonary hypertension (P < 0.001). Normal concentrations of both HS-cTnT and NT-proBNP had a high negative predictive value for precapillary pulmonary hypertension (92%), and the combination of increased values of these 2 markers had the highest strength of association with precapillary pulmonary hypertension in logistic regression analysis.. HS-cTnT and NT-proBNP concentrations are increased in patients with SSc, even in those who are free of cardiovascular risk factors. These easily obtained biomarkers may be useful for systematic evaluation and stratification of SSc patients, especially to identify those at risk of pulmonary hypertension.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Cardiovascular Diseases; Cross-Sectional Studies; Female; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Risk Factors; Scleroderma, Systemic; Troponin T; Young Adult

Scleroderma-associated pulmonary arterial hypertension (SSc-PAH) is a rare disease characterized by a very dismal response to therapy and poor survival. We assessed the effects of up-front combination PAH therapy in patients with SSc-PAH.. In this prospective, multicenter, open-label trial, 24 treatment-naive patients with SSc-PAH received ambrisentan 10 mg and tadalafil 40 mg daily for 36 weeks. Functional, hemodynamic, and imaging (cardiac magnetic resonance imaging and echocardiography) assessments at baseline and 36 weeks included changes in right ventricular (RV) mass and pulmonary vascular resistance as co-primary endpoints and stroke volume/pulmonary pulse pressure ratio, tricuspid annular plane systolic excursion, 6-minute walk distance, and N-terminal pro-brain natriuretic peptide as secondary endpoints.. At 36 weeks, we found that treatment had resulted in significant reductions in median (interquartile range [IQR]) RV mass (28.0 g [IQR, 20.6-32.9] vs. 32.5 g [IQR, 23.2-41.4]; P < 0.05) and median pulmonary vascular resistance (3.1 Wood units [IQR, 2.0-5.7] vs. 6.9 Wood units [IQR, 4.0-12.9]; P < 0.0001) and in improvements in median stroke volume/pulmonary pulse pressure ratio (2.6 ml/mm Hg [IQR, 1.8-3.5] vs. 1.4 ml/mm Hg [IQR 8.9-2.4]; P < 0.0001) and mean ( ± SD) tricuspid annular plane systolic excursion (2.2 ± 0.12 cm vs. 1.65 ± 0.11 cm; P < 0.0001), 6-minute walk distance (395 ± 99 m vs. 343 ± 131 m; P = 0.001), and serum N-terminal pro-brain natriuretic peptide (647 ± 1,127 pg/ml vs. 1,578 ± 2,647 pg/ml; P < 0.05).. Up-front combination therapy with ambrisentan and tadalafil significantly improved hemodynamics, RV structure and function, and functional status in treatment-naive patients with SSc-PAH and may represent a very effective therapy for this patient population. In addition, we identified novel hemodynamic and imaging biomarkers that could have potential value in future clinical trials. Clinical trial registered with www.clinicaltrials.gov (NCT01042158).

Topics: Drug Therapy, Combination; Female; Heart Ventricles; Humans; Hypertension, Pulmonary; Magnetic Resonance Imaging; Male; Middle Aged; Natriuretic Peptide, Brain; Phenylpropionates; Phosphodiesterase 5 Inhibitors; Prospective Studies; Pyridazines; Scleroderma, Systemic; Stroke Volume; Tadalafil; Ultrasonography; Vascular Resistance

Cardiovascular involvement is recognized as a poor prognostic factor in systemic sclerosis (SSc). The aim of this study was to evaluate the usefulness of nailfold video-capillaroscopy (NVC), brain natriuretic peptide (BNP) blood level and exercise echocardiography to predict the occurrence of cardiovascular events in SSc.. We prospectively enrolled 65 patients with SSc (age 54±14 years, 30% female) followed in CHU Sart-Tilman, Liège, Belgium. All patients underwent graded semi-supine exercise echocardiography. Both baseline resting pulmonary hypertension (PH) and PH during follow-up (FUPH) were defined as systolic pulmonary arterial pressure (sPAP)>35 mmHg, and exercise-induced PH (EIPH) as sPAP>50 mmHg during exercise.. EIPH was present in 21 patients. During FU (27±18 months), 13 patients developed FUPH and 9 presented cardiovascular complications. Patients with cardiovascular events were significantly older (63±14 vs 52±13 years; P=0.03), presented more frequently NVC grade>2 (89 vs 43%; P=0.009), had higher resting and exercise sPAP (30±6 vs 24±6; P=0.007 and 57±13 vs 44±13 vs mmHg; P=0.01, respectively), and higher BNP blood level (112±106 vs 26±19 pg/ml; P=0.0001). After adjustment for age and gender, NVC grade>2 (ß=2.4±1.1; P=0.03), EIPH (ß=2.30±1.13; P=0.04), FUPH (ß=0.24±0.09; P=0.01 and ß=3.52±1.16; P=0.002, respectively;) and BNP (ß=0.08±0.04; P=0.02) were independent predictors of CV events. Beyond age, an incremental value of EIPH, BNP and NVC grade>2 was predictive of cardiovascular events (P<0.001).. Cardiovascular complications are not rare in SSc (18%). NVC, BNP blood level assessment and exercise echocardiography could be useful tools to identify patients at risk of SSc.

Topics: Adult; Aged; Arterial Pressure; Belgium; Biomarkers; Cardiovascular Diseases; Echocardiography, Stress; Exercise Test; Female; Humans; Hypertension, Pulmonary; Male; Microcirculation; Microscopic Angioscopy; Middle Aged; Nails; Natriuretic Peptide, Brain; Predictive Value of Tests; Prognosis; Prospective Studies; Pulmonary Artery; Risk Assessment; Risk Factors; Scleroderma, Systemic

Heart and pulmonary involvement is a leading cause of systemic sclerosis (SSc)-related deaths.. The aim of our study was to assess if biochemical markers of right ventricular (RV) overload, endothelial function and collagen metabolism can predict RV dysfunction assessed by Doppler echocardiography in SSc patients.. We prospectively studied 111 consecutive patients (101 F, 10 M, age 54.2 ± 13.8 years) with diagnosed SSc (mean disease duration 9.4 ± 11.4 years) and a group of 21 age-matched subjects (18 F, 3 M, age 49.3 + 10.5 years). We performed transthoracic echocardiography (Phillips iE 33) and measured serum endothelin-1 (ET-1), N-terminal pro-brain natriuretic peptide (NT-proBNP), asymmetric dimethylarginine (ADMA), endoglin and human tissue inhibitor of matrix metalloproteinase (TIMP-1) concentration.. Median serum NT-proBNP level in SSc patients was 133.5 (range 21.86-17,670 pg/ml) and was significantly higher than in controls (p = 0.0002). Moreover, the median serum ET-1 level of 1.49 (range 0.26-8.75 pg/ml) was higher in SSc patients (p = 0.002). However, no significant differences in ADMA, TIMP-1 and endoglin serum concentration between SSc patients and controls were observed. Serum NT-proBNP concentration correlated positively with echocardiographic signs of RV overload: tricuspid regurgitation pressure gradient (r = 0.38, p = 0.0004) and RV Tei index (r = 0.25, p = 0.01). ET-1 serum level correlated negatively with tricuspid annular plane systolic excursion (r = -0.4, p = 0.01) and positively with inferior vena cava diameter measured at expiration (r = 0.38, p = 0.0002). The echocardiographic signs of RV overload were significantly more pronounced in the highest NT-proBNP tertile (>195 pg/ml) group than in the lowest one (<88 pg/ml).. Serum ET-1 and NT-proBNP, but not endoglin, ADMA and TIMP-1 levels correlating with the echocardiographic parameters of RV overload, can be considered as noninvasive indicators of RV dysfunction in SSc patients.

Topics: Adult; Aged; Antigens, CD; Arginine; Biomarkers; Case-Control Studies; Collagen; Echocardiography; Echocardiography, Doppler; Endoglin; Endothelin-1; Endothelium, Vascular; Female; Fibrosis; Humans; Lung Diseases; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Prospective Studies; Receptors, Cell Surface; Scleroderma, Systemic; Tissue Inhibitor of Metalloproteinase-1; Ventricular Function, Right

SSc is associated with an increased prevalence of atherosclerosis (ATS). This study assessed the prevalence of subclinical ATS as measured by carotid US and explored serum proteins to identify potential biomarkers of SSc-ATS.. Forty-six SSc female patients and 46 age- and ethnicity-matched controls underwent carotid US to assess the presence of plaque and carotid intima media thickness (CIMT). Abstracted data included demographics, ATS risk factors and serum measurements [cholesterol, proinflammatory high-density lipoprotein (piHDL), CRP, lipoproteins]. Serum cytokines/proteins analyses included circulating type I IFN activity by quantifying IFN-inducible genes, soluble junctional adhesion molecule A (sJAM-A) and 100 serum proteins by using a microplate-based multiplex platform. Proteins significant at P < 0.05 on bivariate analyses for the presence of plaque were used to develop a composite measure.. Patients with SSc had more plaque (45.6% vs 19.5%, P = 0.01) but similar CIMT compared with controls. Multiplex analysis detected significant associations between serum proteins of inflammation, vasculopathy and fibrosis with ATS in SSc, including IL-2, IL-6, CRP, keratinocyte growth factor, intercellular adhesion molecule 1, endoglin, plasminogen activator inhibitor 1 and insulin-like growth factor binding protein 3 associated with carotid plaque. Myeloid progenitor inhibitory factor 1, serum amyloid A, thrombomodulin, N-terminal pro-brain natriuretic peptide (BNP), and Clara cell secretory protein 16 kD correlated with CIMT. The median composite score for the plaque group was 6 and for the no plaque group it was 2 (P < 0.0001).. Patients with SSc have a higher prevalence of carotid plaque than matched controls, and patients with SSc-plaque vs patients without plaque have elevated serum proteins implicated in both vasculopathy and fibrosis. Further studies are needed to evaluate the role of these proteins in SSc compared with healthy controls.

Topics: Adult; Antigens, CD; Asymptomatic Diseases; Biomarkers; C-Reactive Protein; Carotid Arteries; Carotid Artery Diseases; Carotid Intima-Media Thickness; Case-Control Studies; Chemokines, CC; Cross-Sectional Studies; Endoglin; Female; Fibroblast Growth Factor 7; Humans; Insulin-Like Growth Factor Binding Protein 3; Intercellular Adhesion Molecule-1; Interleukin-2; Interleukin-6; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Plaque, Atherosclerotic; Plasminogen Activator Inhibitor 1; Receptors, Cell Surface; Risk Factors; Scleroderma, Systemic; Serum Amyloid A Protein; Thrombomodulin; Uteroglobin

The aim of this study was to find a new and less cardiotoxic conditioning regimen for high-dose chemotherapy and autologous stem cell transplantation (aSCT) in patients with severe SSc and pre-existing cardiac involvement.. Six patients with cardiac involvement were treated for SSc with a conditioning regimen including reduced-dose CYC plus the non-cardiotoxic alkylant thiotepa. All patients received an implantable cardioverter defibrillator (ICD) before aSCT. The response at months 6 and 12 was measured according to reduction of the modified Rodnan skin score (mRSS). CT histography was used to monitor pulmonary manifestations, as were echocardiography, N-terminal pro-brain natriuretic peptide (NT-proBNP) and troponin for the cardiac involvement. Cardiac events were defined as death or hospitalisation due to heart failure or appropriate discharge of the ICD.. Between December 2008 and May 2012, four male and two female patients with a median age of 41 years received aSCT. The median mRSS significantly decreased from 26.5 to 18 and 17.5 at month 6 and 12, respectively. The total lung volume also significantly improved. Within the median follow-up of 1.6 years (range 1-3.8) two patients experienced a relapse of SSc, which results in a progression-free survival rate of 66.6%. Three patients experienced ICD discharge.. For patients with SSc and cardiac involvement, the use of thiotepa and reduced-dose CYC is feasible and effective. The rate of ICD discharge underlines the need for protection in these endangered patients. This preliminary experience allowed us to use this regimen for our currently recruiting prospective trial (NCT01895244).

Topics: Adult; Autoimmune Diseases; Comorbidity; Cyclophosphamide; Defibrillators, Implantable; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Follow-Up Studies; Heart Diseases; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Prevalence; Retrospective Studies; Risk Factors; Scleroderma, Systemic; Stem Cell Transplantation; Thiotepa; Treatment Outcome; Troponin

Pulmonary hypertension (PH) causes mortality in systemic sclerosis (SSc). Pulmonary arterial hypertension (PAH) and left heart disease (LHD) are frequent causes of PH. Therefore, we studied PAH and LHD in early PH.. A total of 432 French Canadian SSc patients were studied retrospectively. All underwent screening for PH. We analysed clinical, serological, and radiographic data from 26 patients with early PH diagnosed by right heart catheterization (RHC). SSc patients with (n = 21) and without PH (n = 19) were prospectively re-evaluated by cardiac magnetic resonance imaging (MRI) and serial measurements of N-terminal pro-brain natriuretic peptide (NT-proBNP) and the haemodynamic biomarkers mid-regional pro-atrial natriuritic peptide (MR-proANP) and mid-regional pro-adrenomedullin (MR-proADM).. The most frequent cause of early PH was LHD (58%). PAH was seen in 34% of patients. No association was found between the type of PH and autoantibodies. Early LHD-PH, but not early PAH, was associated with lower NT-proBNP (p = 0.024), but MR-proANP and MR-proADM levels were higher in early LHD-PH than in patients without PH (p = 0.014 and p = 0.012, respectively). Only one patient had abnormal cardiac MRI explaining LHD-PH.. Early PH in SSc, like late PH, is heterogeneous and RHC is essential for determining its underlying cause. The most frequent cause of early PH was LHD. Levels of MR-proANP and MR-proADM, but not NT-proBNP, were increased in early LHD-PH, and may be more reliable than NT-proBNP as a biomarker of early PH in this subgroup of patients. Cardiac MRI did not explain LHD-PH. This study is the first to identify a high frequency of LHD in early PH correlating with normal NT-proBNP levels but increased MR-proANP and MR-proADM levels in SSc patients.

Topics: Adrenomedullin; Adult; Aged; Biomarkers; Canada; Female; Fibrosis; Heart Diseases; Humans; Hypertension, Pulmonary; Magnetic Resonance Imaging, Cine; Male; Middle Aged; Myocardium; Natriuretic Peptide, Brain; Peptide Fragments; Retrospective Studies; Scleroderma, Systemic

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

To explore the relationship between IL-6 levels and echocardiographic abnormalities, and N-terminal probrain natriuretic peptide (NT-proBNP) levels in SSc patients and to correlate tested parameters with European Scleroderma Activity (EUSTAR) score.. This case-control study included 31 SSc patients with preserved left ventricular ejection fraction (LVEF) and 32 matched healthy controls. Serum IL-6 and NT-proBNP levels were measured and subjects were evaluated by conventional and pulsed-wave tissue Doppler echocardiography.. The level of IL-6 was significantly increased in patients with SSc (3.2 vs 2.2 pg/ml, P < 0.001). SSc patients had significantly lower values of LV systolic (7.7 vs 9.25 cm/s, P < 0.001) and early diastolic (8.7 vs 10.3 cm/s, P = 0.014) myocardial velocities and higher E/e' (9.04 vs 7.37, P = 0.001) ratio, although there was no between-group difference according to LVEF (68% vs 65%, P = 0.248). On evaluating the right ventricle there was no significant between-group difference in systolic tricuspid annular velocity (13 vs 13.9 cm/s, P = 0.105), but the peak early diastolic velocity was significantly lower (11.7 vs 13.6, P = 0.044) and E/e' was significantly higher (4.3 vs 3.38, P = 0.008) in SSc patients. IL-6 level showed correlation with LV mean e' (r = -0.57, P = 0.001), E/e' (r = 0.55, P = 0.001) and NT-proBNP (r = 0.52, P = 0.003). EUSTAR score correlated with LV E/e' (r = 0.48, P = 0.006), mean e' (r = -0.67, P < 0.001), mean s' (r = -0.51, P = 0.004), NT-proBNP (r = 0.60, P < 0.001) and IL-6 (r = 0.79, P < 0.001).. IL-6 level is increased in patients with SSc and significantly correlates with LV diastolic dysfunction, NT-proBNP and EUSTAR score. These results support the role of IL-6 in the development of cardiac disease in SSc patients.

Topics: Aged; Biomarkers; Case-Control Studies; Echocardiography, Doppler; Female; Humans; Interleukin-6; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Scleroderma, Systemic; Severity of Illness Index; Ventricular Dysfunction, Left; Ventricular Function, Left; Ventricular Function, Right

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 evaluate the relationship between pulmonary and myocardial fibrosis in patients with systemic sclerosis (SS).. Eighteen patients with SS prospectively underwent cardiac magnetic resonance imaging (CMR) and high-resolution computed tomography (HRCT) of the chest. Cardiac biomarkers (N-terminal pro B-type natriuretic peptide) and quality-of-life measures (SF-36 and SS health assessment questionnaires) were assessed. Two readers blinded to other test results evaluated the CMRs in consensus for functional left and right ventricular parameters and for myocardial late enhancement. HRCT images were reviewed at 5 levels and scored for total disease extent, extent of reticulation, proportion of ground-glass opacities (GGO), and coarseness of reticulation.. Right ventricular ejection fraction correlated significantly with the percentage of late enhancement of the myocardium (R=0.63, P<0.01), extent of pulmonary fibrosis (R=0.57, P<0.01), and extent of GGO (R=0.53, P<0.05). Significant correlations were also found between the percentage of late enhancement of the myocardium and the extent of overall pulmonary fibrosis (R=0.59, P<0.05) and the extent of the ground-glass subcomponent (R=0.58, P<0.05). N-terminal pro B-type natriuretic peptide correlated significantly with the number of myocardial segments with late enhancement (R=0.64, P<0.05). Stepwise multiple linear regression revealed the extent of pulmonary GGO to be the only independent predictor of the percentage of myocardial enhancement (R2=0.61, P<0.0001).. In patients with SS with pulmonary fibrosis on HRCT images, CMR may be a useful test to detect early-stage myocardial fibrosis.

Topics: Adult; Aged; Analysis of Variance; Biomarkers; Cardiomyopathies; Case-Control Studies; Contrast Media; Endomyocardial Fibrosis; Female; Gadolinium DTPA; Humans; Linear Models; Magnetic Resonance Imaging; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Pulmonary Fibrosis; Quality of Life; Regression Analysis; Scleroderma, Systemic; Surveys and Questionnaires; Tomography, X-Ray Computed

The aim of the present study was non-invasive evaluation of the cardiovascular system in asymptomatic young adult patients with juvenile localized scleroderma (JLS) and juvenile systemic sclerosis (JSS).. A group of 34 consecutive children with scleroderma were prospectively observed in the study. The control group (CG) consisted of 20 healthy subjects. In each subject 12-lead electrocardiographic, echocardiographic, ECG Holter, and ambulatory blood pressure monitoring examinations were performed at the baseline visit and after 10 years. Additionally, B-type natriuretic peptide (BNP) concentrations were measured after 10 years.. Examinations were performed in 13 patients with JLS and 15 with JSS at the final visit. Two children had died (one from each group). Four patients were alive but refused the final visit. After 10 years, a higher prevalence of ventricular extrasystoles (p = 0.01) and an elevated pulmonary arterial pressure (JLS: p = 0.04, JSS: p = 0.03) were observed in both groups, but in comparison with the controls there was no significant difference at the final visit. In JLS patients more cases of left ventricle diastolic dysfunction, hypertension, and sinus tachycardia were diagnosed at the final visit (p ≤ 0.05). More atrioventricular block episodes in both groups of scleroderma patients were observed. Over the 10 years, arterial hypertension was diagnosed in three patients from the JLS group and in two with JSS. There were no significant differences in BNP concentrations at the final visit.. The results of the present study show that juvenile scleroderma seems to be more benign than adult-onset disease. This observational study shows subclinical, not severe, cardiac abnormalities in adult patients with juvenile-onset disease.

Topics: Adolescent; Adult; Asymptomatic Diseases; Blood Pressure; Cardiomegaly; Case-Control Studies; Child; Echocardiography; Electrocardiography; Female; Follow-Up Studies; Heart Diseases; Heart Valve Diseases; Humans; Male; Natriuretic Peptide, Brain; Prospective Studies; Scleroderma, Localized; Scleroderma, Systemic; Tachycardia, Sinus; Young Adult

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

The REgistry of Pulmonary Hypertension Associated with Rheumatic Disease (REOPARD) was established in Korea. The baseline data are described from the second year of the registry's operation.. Patients with a connective tissue disease (CTD) who met the modified definition of the WHO group I pulmonary arterial hypertension (PAH) were enrolled. PAH was defined as a systolic pulmonary arterial pressure> 40 mmHg by echocardiography or mean pulmonary arterial pressure> 25 mmHg by right heart catheterization. Hemodynamic parameters and clinical data such as demographics, functional class, underlying disease, organ involvement, laboratory tests and current treatment were recorded.. A total of 321 patients were enrolled during the 2-year study period from 2008 to 2010. The mean age of the patients at registration was 51.9 years and 87.5% were female. Most patients were diagnosed by echocardiography and only 24 patients (7.5%) underwent cardiac catheterization. Exertional dyspnea was present in 63.6% of patients and 31.8% were New York Heart Association class III or IV. Among the patients, systemic lupus erythematosus accounted for 35.3%, systemic sclerosis 28.3%, rheumatoid arthritis 7.8%, overlap syndrome 9.0%, and mixed connective tissue disease 5.9%. There were no significant differences in hemodynamics, functional class, diffusing capacity and N-terminal pro-brain natriuretic peptide levels between the disease subgroups. Treatments consisted of calcium antagonists (57.0%), endothelin antagonists (32.7%), prostanoids (27.1%), phosphodiesterase-5 inhibitors (14.3%) and combinations (37.4%).. Compared with previous studies, the results showed some differences: underlying diseases, functional status and treatments. This may be due to differences in ethnic background and diagnostic methods of our study.

Topics: Adult; Aged; Arthritis, Rheumatoid; Data Collection; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Lupus Erythematosus, Systemic; Male; Middle Aged; Mixed Connective Tissue Disease; Natriuretic Peptide, Brain; Peptide Fragments; Pulmonary Diffusing Capacity; Registries; Republic of Korea; Retrospective Studies; Rheumatic Diseases; Scleroderma, Systemic

To describe the survival rate in a cohort of systemic sclerosis (SSc) patients with pulmonary arterial hypertension (PAH) and to evaluate possible predictors for SSc-PAH in a cohort of SSc patients.. Thirty patients with SSc-PAH and 150 SSc patients without PAH were included. Survival and survival on therapy were calculated. Clinical features at baseline were correlated to the risk for development of PAH during follow-up.. The 1-, 2-, 3-, and 4-year survival rates were 86, 59, 39, and 22%, respectively, from diagnosis of PAH. The hazard ratio for total mortality in the SSc-PAH group was 3.2 [95% confidence interval (CI) 1.8-5.7] compared to SSc without PAH (p < 0.001). Risk factors at baseline for the development of PAH were: limited skin involvement, low diffusing capacity of the lung for carbon monoxide (DL(CO)), high N-terminal pro-brain natriuretic peptide (NTProBNP), increased estimated systolic pulmonary arterial pressure (ESPAP), and the presence of teleangiectases. Severe peripheral vascular disease requiring iloprost treatment during follow-up was associated with an eightfold increased risk of PAH.. Despite modern treatment and yearly screening by echocardiography, the survival in SSc-PAH is still low in our cohort. The identified risk factors should be assessed to select patients eligible for right heart catheterization (RHC) to make an earlier diagnosis.

Topics: Adult; Aged; Blood Pressure; Carbon Monoxide; Case-Control Studies; Female; Humans; Hypertension, Pulmonary; Lung; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Predictive Value of Tests; Prognosis; Scleroderma, Systemic; Survival Rate; Sweden

Topics: Aged; Amyloidosis; Antibodies, Antinuclear; Antirheumatic Agents; Arthritis, Rheumatoid; Benzimidazoles; Biphenyl Compounds; Carbazoles; Carvedilol; Drug Therapy, Combination; Dyspnea; Etanercept; Female; Furosemide; Glucocorticoids; Hand; Heart Failure; Humans; Immunoglobulin G; Lung Diseases, Interstitial; Natriuretic Peptide, Brain; Propanolamines; Radiography; Receptors, Tumor Necrosis Factor; Rheumatoid Factor; Ribonucleosides; Scleroderma, Systemic; Spironolactone; Sulfasalazine; Tetrazoles; Treatment Outcome

N-terminal pro-brain natriuretic peptide (NT-proBNP) is a marker of neurohormonal activation that is useful in the diagnosis and prognosis of various forms of pulmonary arterial hypertension (PAH). We sought to characterise and compare NT-proBNP in a cohort of PAH related to systemic sclerosis (PAH-SSc) and idiopathic PAH (IPAH) patients. NT-proBNP levels, collected from PAH-SSc and IPAH patients followed prospectively, were compared and correlated with haemodynamic variables. Cox proportional hazard models were created to assess the predictive value of NT-proBNP. 98 patients (55 PAH-SSc, 43 IPAH) were included. Haemodynamics were similar, except for lower mean pulmonary arterial pressure in PAH-SSc. NT-proBNP levels were significantly higher in PAH-SSc (3,419+/-3,784 versus 1,393+/-1,633 pg x mL(-1); p<0.01) and were more closely related to haemodynamics in PAH-SSc than IPAH. 28 patients died. NT-proBNP predicted survival (hazard ratio (HR) 3.18; p<0.01) in the overall cohort; however, when stratified by group, predicted survival only in PAH-SSc (HR 3.07, p<0.01 versus 2.02, p = 0.29 in IPAH). This is the first description showing NT-proBNP levels are 1) significantly higher in PAH-SSc than IPAH despite less severe haemodynamic perturbations, and 2) stronger predictors of survival in PAH-SSc, suggesting that neurohormonal regulation may differ between PAH-SSc and IPAH. Future studies to define pertinent mechanisms are warranted.

Topics: Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Prospective Studies; Scleroderma, Systemic

Cardiopulmonary complications are common in patients with systemic sclerosis (SSc). We assessed cardiac involvement in patients with SSc using echocardiography and investigated the association of N-terminal pro-brain natriuretic peptide (NT-proBNP) and asymmetric dimethylarginine (ADMA) with echocardiographic measures of myocardial function in sera of patients with SSc who had no symptoms of heart failure.. We prospectively studied 52 patients with SSc (mean age 55.7 +/- 10.1 yrs, 51 women), with conventional and tissue-Doppler echocardiography. Plasma NT-proBNP and ADMA levels were measured in all patients. Data were compared with those obtained from 25 healthy controls comparable for age and sex.. Patients with SSc had impaired left ventricular (LV) and right ventricular diastolic function expressed by inverted ratio of peak early to peak late transmitral (Mit E/A) and transtricuspid velocity and increased left atrial diameter compared with controls. Peak systolic mitral lateral annular motion velocity and peak early diastolic mitral lateral annular motion velocity (LV Em) were lower, while LV E/Em ratio was higher, in patients with SSc compared to controls. ADMA was significantly related with LV Em and E/Em ratio. NT-proBNP was associated with Mit E, Mit E/A ratio and mitral deceleration time. Significant correlation was also observed between NT-proBNP and ADMA levels.. Depressed cardiac function is common, even in asymptomatic patients with SSc. NT-proBNP and ADMA are significantly correlated with echocardiographic abnormalities, providing a potent link for cardiac function, neuroendocrine derangement, and endothelial dysfunction in patients with SSc who have cardiac disease.

Topics: Adult; Aged; Analysis of Variance; Arginine; Blood Flow Velocity; Echocardiography, Doppler; Endothelium, Vascular; Female; Humans; Immunoenzyme Techniques; Male; Middle Aged; Myocardial Contraction; Natriuretic Peptide, Brain; Peptide Fragments; Prospective Studies; Scleroderma, Systemic; Ventricular Dysfunction, Left

To identify factors related to NT-proBNP levels in systemic sclerosis (SSc).. NT-proBNP was measured in 119 patients with SSc and 20 controls. Patients with transtricuspid gradient (TG) > or =36 mm Hg or > or =31 mmHg plus dyspnea were considered to have suspected systemic sclerosis-associated pulmonary arterial hypertension (SScPAH).. Increasing age, NYHA functional class, skin score, history of systemic arterial hypertension (SAH), anticentromere antibodies, diastolic dysfunction, reduced pulmonary diffusing capacity, and TG were positively associated with NT-proBNP. In multivariable linear regression, TG, age, and SAH were independently associated to NT-proBNP levels. An ROC curve analysis (with an area under the curve of 0.89, 95% CI: 0.83-0.95) suggested a cutoff of 157.8pg/mL to identify patients with suspected SScPAH, presenting a sensitivity of 100% (78.1-100) and specificity of 72.3% (62.3-80.5).. NT-proBNP levels are related to clinical and laboratory abnormalities in SSc. The results indicate that NT-proBNP may be a useful tool in the evaluation of SScPAH.

Topics: Adult; Age Factors; Case-Control Studies; Female; Humans; Hypertension; Hypertension, Pulmonary; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; ROC Curve; Scleroderma, Systemic; Sensitivity and Specificity; Triglycerides

Primary myocardial involvement is common in systemic sclerosis (SSc). We evaluated the atrial and ventricular electromechanical characteristics by using tissue Doppler echocardiography in SSc patients with subclinical cardiac involvement. Twenty-seven consecutive patients (24 women; mean age +/- SD 49.9 +/- 11.3 years) presenting with SSc without pulmonary arterial hypertension or symptomatic heart failure were prospectively studied. Electrocardiographic P-wave dispersion (Pd), corrected QT dispersion (QTcd), interatrial, intra-atrial, interventricular, and intraventricular electromechanical delays were analyzed by tissue Doppler echocardiography, and brain natriuretic peptide levels were measured. Results were compared with 17 healthy controls. There was no difference in conventional and tissue Doppler parameters between the two groups. However, patients with SSc had higher mean Pd (mean [+/-SD] 46.8 +/- 15 and 36 +/- 8 ms, respectively, P = 0.004) and mean interatrial electromechanical delay time (DT) (mean [+/-SD] 32.2 +/- 9.2 and 24.7 +/- 9.7 ms, respectively, P = 0.01), mean electromechanical delay time for all segments (Mean Ts) (mean [+/-SD] 148.8 +/- 18.8 and 129.3 +/- 13.4 ms, respectively, P < 0.001), and intraventricular DT (mean [+/-SD] 27.6 +/- 12.5 and 16.2 +/- 7.2 ms, respectively, P < 0.001). Intraventricular DT was the only parameter that correlated significantly with the Mean Ts. Brain natriuretic peptide levels were within normal limits in both groups; however, they were higher in patients with SSc than in controls (mean [+/-SD] 37.5 +/- 28.5 and 23.1 +/- 16.0 pg/ml, respectively, P = 0.03). The evaluation of atrial and ventricular electromechanical parameters by using tissue Doppler echocardiography seems to be useful for detection of subclinical cardiac involvement in SSc patients with normal conventional echocardiographic findings.

Topics: Adult; Aged; Arrhythmias, Cardiac; Atrial Function; Biomarkers; Case-Control Studies; Echocardiography, Doppler; Electrocardiography; Female; Heart Conduction System; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Prospective Studies; Scleroderma, Systemic; Time Factors; Ventricular Function; Young Adult

Early detection of pulmonary hypertension (PH) in patients with systemic sclerosis (SSc) is essential as it leads to substantial morbidity and mortality irrespective of its etiology. The aim of our study was to determine whether noninvasive biochemical and/or echocardiographic indices can predict the presence of PH in these patients. We prospectively studied 66 patients (mean age of 57.7 +/- 12.1 years, 63 women) with SSc without clinical manifestations of heart failure. All patients underwent standard and tissue Doppler echocardiography. Plasma N-terminal pro-B type natriuretic peptide (NT-proBNP) and asymmetric dimethylarginine (ADMA) levels were also measured. In 24 (36%) patients, the diagnosis of PH was established by echocardiography (systolic pulmonary artery pressure value > or =40 mmHg). Left atrial (LA) volume, NT-proBNP, ADMA, ratio of early transmitral filling velocity to early diastolic velocity of the mitral annulus (mitral E/E (m)), and right ventricular myocardial performance index (MPI) were univariate predictors of PH. In multivariate analysis, NT-proBNP, LA volume, and right ventricular MPI were independent predictors of PH in SSc patients. LA volume and NT-proBNP may be useful noninvasive markers for the prediction of elevated pulmonary artery pressure in patients with SSc. These parameters should be considered when assessing this population for risk stratification and for identification of patients demanding further investigation and institution of specific therapy for the disease at the time when it is most likely to be effective.

Topics: Aged; Arginine; Biomarkers; Blood Pressure; Cross-Sectional Studies; Female; Follow-Up Studies; Heart Atria; Humans; Hypertension, Pulmonary; Male; Middle Aged; Multivariate Analysis; Natriuretic Peptide, Brain; Peptide Fragments; Predictive Value of Tests; Prospective Studies; Pulmonary Artery; Scleroderma, Systemic; Ultrasonography; Ventricular Dysfunction, Right

To compare the performance of brain natriuretic peptide (BNP) and N-terminal pro-brain natriuretic peptide (NT-proBNP) in screening for pulmonary arterial hypertension (PAH) in systemic sclerosis (SSc).. Between January 2008 and March 2009, outpatients referred to our unit and satisfying LeRoy criteria for SSc were assessed for PAH. Doppler echocardiography, BNP measurement, and NT-proBNP measurement were done concomitantly for a complete clinical, instrumental, and biochemical evaluation. Right-heart catheterization was carried out in cases of suspected PAH [estimated pulmonary arterial pressure (PAP) ≥ 36 mm Hg; diffusion capacity for carbon monoxide (DLCO) ≤ 50% of predicted value; 1-year DLCO decline ≥ 20% in absence of pulmonary fibrosis; unexplained dyspnea].. One hundred thirty-five patients were enrolled (124 women, 11 men; 96 limited SSc, 39 diffuse SSc); precapillary PAH was found in 20 patients (15 limited SSc, 5 diffuse SSc). The estimated PAP correlated with both BNP (R = 0.3; 95% CI 0.14-0.44) and NT-proBNP (R = 0.3, 95% CI 0.14-0.45). BNP [area under the curve (AUC) 0.74, 95% CI 0.59-0.89] was slightly superior to NT-proBNP (AUC 0.63, 95% CI 0.46-0.80) in identification of PAH, with diagnosis cutoff values of 64 pg/ml (sensitivity 60%, specificity 87%) and 239.4 pg/ml (sensitivity 45%, specificity 90%), respectively. BNP (log-transformed, p = 0.032) and creatinine (p = 0.049) were independent predictors of PAH, while NT-proBNP was not (p = 0.50).. In our single-center study, the performance of BNP was slightly superior to that of NT-proBNP in PAH screening of patients with SSc, although normal levels of these markers do not exclude diagnosis. We observed that impaired renal function is associated with an increased risk of PAH in SSc. Further multicenter studies are needed to confirm our results (ClinicalTrials.gov ID NCT00617487).

Topics: Adult; Aged; Area Under Curve; Biomarkers; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Protein Precursors; Scleroderma, Systemic; Sensitivity and Specificity

Topics: Antihypertensive Agents; Bosentan; Humans; Hypertension, Pulmonary; Models, Biological; Natriuretic Peptide, Brain; Peptide Fragments; Scleroderma, Systemic; Sulfonamides

Topics: Adult; Aged; Biomarkers; Female; Fibrosis; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Scleroderma, Systemic; Severity of Illness Index; Skin

Cardiac involvement, a common and often fatal complication of systemic sclerosis (SSc), is currently detected by standard echocardiography enhanced by tissue Doppler echocardiography (TDE).. The performance of the biomarker of cardiovascular disease, N-terminal pro-brain natriuretic peptide (NT-proBNP), in the detection of cardiac involvement by SSc was examined.. A total of 69 consecutive patients with SSc (mean (SD) age 56 (13) years, 56 women) were prospectively studied with standard echocardiography and TDE measurements of longitudinal mitral and tricuspid annular velocities. Plasma NT-proBNP was measured in all patients.. Overall, 18 patients had manifestations of cardiac involvement, of whom 7 had depressed left ventricular and 8 depressed right ventricular myocardial contractility, and 8 had elevated systolic pulmonary arterial pressure. Patients with reduced contractility had increased mean (SD) NT-proBNP (704 (878) pg/ml versus 118 (112) pg/ml in patients with normal myocardial contractility, p<0.001). Similarly, NT-proBNP was higher in patients with (607 (758) pg/ml) than in patients without (96 (78) pg/ml) manifestations of overall cardiac involvement (p<0.001). Receiver operating characteristic analysis showed NT-proBNP reliably detected depressed myocardial contractility and overall cardiac involvement (area under the curve 0.905 (95% CI 0.814 to 0.996) and 0.935 (95% CI 0.871 to 0.996), respectively). Considering patients with SSc with normal echocardiography and TDE as controls, and using a 125 pg/ml cut-off concentration, sensitivity and specificity were 92% and 71% in the detection of depressed myocardial contractility, and 94% and 78% for overall cardiac involvement.. NT-proBNP reliably detected the presence of cardiac involvement and appears to be a very useful marker to risk stratify patients presenting with SSc.

Topics: Adolescent; Adult; Aged; Biomarkers; Echocardiography, Doppler; Female; Heart Diseases; Humans; Male; Middle Aged; Myocardial Contraction; Natriuretic Peptide, Brain; Peptide Fragments; Prospective Studies; Scleroderma, Systemic; Sensitivity and Specificity; Young Adult

Topics: Biomarkers; Cohort Studies; Female; Humans; Hypertension, Pulmonary; Male; Natriuretic Peptide, Brain; Peptide Fragments; Scleroderma, Systemic

Pulmonary arterial hypertension (PAH) is a complication of scleroderma (systemic sclerosis, SSc); as soon as PAH develops, the patient's prognosis deteriorates rapidly. Early detection of PAH ensures timely treatment. We investigated the prevalence of exercise-induced PAH in a cohort of patients with SSc, and examined the relation between exercise-induced PAH and clinical characteristics and biochemical markers.. Patients with SSc and normal resting systolic pulmonary arterial pressure (sPAP) were studied. Eligible patients were asked to perform cycloergometer exercise until exhaustion, and exercise sPAP was measured. All patients had their pulmonary function tested and underwent echocardiography at rest. Brain natriuretic peptide (BNP) was also determined.. Forty-one patients with SSc were studied. Mean sPAP at rest was 29.7 mm Hg, rising to a mean of 41.4 mm Hg on exercise. Eleven of 41 patients (26.8%) had sPAP post-exercise > 50 mm Hg and 8/41 (19.5%) > 55 mm Hg. A significant correlation was found between exercise sPAP and DLCO (p = 0.008) and between sPAP and BNP levels (p = 0.04). Pre-existing severe Raynaud's phenomenon was more prevalent (50% vs 20%), DLCO levels lower (78.9 vs 92.7 % predicted), and BNP levels higher (72.6 vs 42.1 pmol/ml) in patients with exercise sPAP > 55 mm Hg.. The prevalence of exercise-induced PAH in patients with scleroderma is high. Patients with lower DLCO and higher levels of BNP are at higher risk of developing higher sPAP. Studies with longterm followup are required to evaluate the risk of developing resting PAH in these patients.

Topics: Blood Pressure Determination; Cross-Sectional Studies; Disease Progression; Echocardiography, Doppler; Exercise; Exercise Test; Exercise Tolerance; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Natriuretic Peptide, Brain; Prevalence; Respiratory Function Tests; Scleroderma, Systemic; Spain

Pulmonary arterial hypertension (PAH) is a term used to define a variety of progressive conditions that have in common, increased pulmonary vascular resistance leading to right heart failure and death. There has been considerable decrease in mortality and morbidity with the advances in PAH treatment over the past decade. However, since there is no epidemiologic study in Turkey, the prevalence of PAH and its importance is not known yet. This study aimed to evaluate the diagnostic clinical experience of Ege University Medical School Cardiology Department with PAH patients.. We evaluated the diagnostic approach to patients referred to our department with the diagnosis of PAH since 2000 by retrospective analysis method.. The diagnosis of pulmonary hypertension was definite in 70 patients (mean age 47+/-16 years, 61% women). Etiology from most prevalent to least was as following: congenital heart diseases (27%), chronic thromboembolic pulmonary hypertension (24%), connective tissue diseases-scleroderma (14%), idiopathic PAH (8%), diastolic dysfunction (3%), pulmonary disease (3%), pulmonary veno-occlusive disease (2%), hepatopulmonary hypertension (1%), and HIV-infection associated PAH (1%). At diagnosis, 68% of patients were in NYHA functional class-III or IV. Six-minute walk test was 263+/-127 m. Mean pulmonary artery pressure was 65+/-20 mmHg. The prognostic marker pro-BNP (brain natriuretic peptide) level was 3208+/-4145 pg/ml.. Our practice shows that PAH is diagnosed late in the course of the disease in Turkey. This can be overcome with structured management in designated centers with multidisciplinary team-working in a shared care approach. There is also an urgent need for an epidemiological registry in order to determine the burden of PAH in Turkey and increase the awareness of doctors.

Topics: Biomarkers; Exercise Tolerance; Female; Heart Defects, Congenital; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Middle Aged; Natriuretic Peptide, Brain; Prevalence; Prognosis; Retrospective Studies; Scleroderma, Systemic; Turkey

We evaluated the clinical significance of serum N-terminal pro-brain natriuretic peptide (NT-proBNP) level in systemic sclerosis (SSc). We studied 45 SSc patients (30 with limited and 15 with diffuse cutaneous SSc) of mean age +/- SD 47.1 +/- 12.9 years, mean duration of disease 10.2 +/- 6.0 years, and 45 age- and sex-matched healthy controls. Pulmonary artery pressure was measured by echocardiography. Lung involvement was evaluated by pulmonary function testing and by using high-resolution computed tomography scores. Serum NT-proBNP levels were measured using a sandwich electrochemiluminescent immunoassay. Serum NT-proBNP levels were significantly higher in patients with SSc compared to healthy controls. When the patients were divided into clinical subsets, serum NT-proBNP was higher in diffuse SSc than in limited SSc. Serum NT-proBNP levels were found to be positively correlated with age, skin thickness score, and systolic pulmonary artery pressure and negatively correlated with percentage of carbon monoxide diffusion capacity (DLco). Multivariate analysis showed that serum NT-proBNP levels were positively correlated with age (p = 0.010), skin thickness score (p = 0.000), and blood pressure (p = 0.021) and negatively correlated with %DLco (p = 0.016). Fifty-seven percent of the variation in log (proBNP) can be explained by the multivariate model (R (2) = 0.57). Serum NT-proBNP levels were higher in SSc patients (particularly the diffuse subset) than in healthy controls and were found to be correlated with skin thickness and %DLco. We conclude that serum NT-proBNP may be a biologic marker of skin fibrosis and pulmonary vascular involvement in SSc.

Topics: Adult; Biomarkers; Blood Pressure; Carbon Monoxide; Case-Control Studies; Female; Humans; Male; Middle Aged; Multivariate Analysis; Natriuretic Peptide, Brain; Peptide Fragments; Pulmonary Artery; Respiratory Function Tests; Scleroderma, Systemic; Skin

Systemic sclerosis (SSc) is characterized by vascular dysfunction that may lead to pulmonary artery hypertension (PAH). The N-terminal pro-B type natriuretic peptide (NT-proNBP), a marker of cardiac failure, is a diagnostic marker of early PAH in patients with SSc without heart failure. Our aim was to determine whether NT-proBNP levels may be a useful tool to evaluate the response to bosentan therapy in patients with PAH secondary to SSc. Ten patients with symptomatic, severe PAH secondary to SSc, received bosentan, 62.5 mg twice a day for 4 weeks followed by 125 mg twice a day for 7 months. Ten patients with SSc without PAH served as controls for basal level of NT-proBNP. Blood samples were obtained before the beginning of the therapy and after 3 and 7 months of treatment. SSc patients with PAH had significantly higher serum levels of NT-proBNP than those without PAH, at baseline. After 3 and 7 months of therapy, NT-proBNP concentration showed a progressive decrease, nearly approaching statistical difference at 7 months when compared to baseline levels (P=0.953 and P=0.600). Our results show that serum NT-proBNP levels may be a useful marker for the response to bosentan therapy in patients with PAH secondary to SSc.

Topics: Adult; Aged; Bosentan; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Scleroderma, Systemic; Sulfonamides

To evaluate predictors of pulmonary arterial hypertension (PAH) in a prospective cohort of patients with systemic sclerosis (SSc).. Routine clinical assessments as well as measurements of the diffusing capacity for carbon monoxide/alveolar volume (DLCO/VA) ratio and N-terminal pro-brain natriuretic peptide (NT-proBNP) level were performed in a prospective cohort of 101 SSc patients who did not have PAH or severe comorbidities. After a planned 36-month followup, we evaluated the predictive value of these parameters for the development of precapillary PAH, as demonstrated by cardiac catheterization, disease progression, and death. Criteria for cardiac catheterization were a systolic pulmonary artery pressure (PAP) of >40 mm Hg on echocardiography, a DLCO value of <50% without pulmonary fibrosis, and unexplained dyspnea.. Eight patients developed PAH, 29 had disease progression, and 10 died during a median followup of 29 months. Kaplan-Meier analysis identified the following baseline parameters as being predictors of PAH: DLCO/VA ratio <70% or <60% (P<0.01 for each comparison), elevated plasma NT-proBNP level (>97th percentile of normal; P = 0.005), echocardiographically estimated systolic PAP >40 mm Hg (P=0.08), and erythrocyte sedimentation rate >28 mm/hour (P=0.015). In multivariate analyses, an elevated baseline NT-proBNP level (hazard ratio [HR] 9.97 [95% confidence interval (95% CI) 1.69-62.42]) and a DLCO/VA ratio <60% (HR 36.66 [95% CI 3.45-387.6]) were predictors of the occurrence of PAH during followup. An increased NT-proBNP level together with a decreased DLCO/VA ratio of <70% was highly predictive of the occurrence of PAH during followup (HR 47.20 [95% CI 4.90-450.33]).. This prospective study identified a decreased DLCO/VA ratio and an increased NT-proBNP as predictors of PAH in SSc. Use of these markers should result in improved PAH risk stratification and allow earlier initiation of therapy.

Topics: Adult; Aged; Biomarkers; Capillaries; Carbon Monoxide; Comorbidity; Diffusion; Disease Progression; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Incidence; Male; Middle Aged; Multivariate Analysis; Natriuretic Peptide, Brain; Peptide Fragments; Predictive Value of Tests; Prospective Studies; Risk Factors; Scleroderma, Systemic; Severity of Illness Index

The purpose of our study was to investigate the effect of bosentan treatment on surrogate markers in patients with systemic-sclerosis-related pulmonary arterial hypertension (SScPAH). We studied ten SScPAH patients (nine female, median age 58 years, median duration of disease 9 years). Six-minute walk test (SMWT) and plasma N-terminal probrain natriuretic peptide (NT-proBNP) levels were recorded from patients at baseline and after 20 weeks under bosentan treatment. Wilcoxon paired signed rank test was applied in order to compare NT-proBNP levels and SMWT at baseline and week 20. At week 20, NT-proBNP levels were decreased from a median of 474 fmol/ml (range, 212-1407 fmol/ml) at baseline to 238 fmol/ml (range, 198-335 fmol/ml; p=0.002). Mean SMWT distance increased from a baseline median value of 323 m (range, 224-368 m) to 372 m (range, 232-530 m), representing a nonsignificant increase. Our results suggest that NT-proBNP is a biochemical surrogate marker, which could be used to evaluate the effects of bosentan or other vasodilation therapy in SScPAH.

Topics: Adult; Aged; Antihypertensive Agents; Biomarkers; Bosentan; Exercise Test; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Scleroderma, Systemic; Sulfonamides

A 42-year-old woman with limited cutaneous systemic sclerosis presented with rapid-onset dyspnea on exertion, which had developed over the previous 8 weeks. She had not experienced any dyspnea before this period. Transthoracic Doppler echocardiography performed 6 months before presentation demonstrated an estimated right ventricular systolic pressure of 32 mmHg. Lung function tests also performed at that time revealed a decreased diffusion capacity for carbon monoxide of 54% and normal lung volumes, and high-resolution CT scan of the lungs was normal.. Physical investigation, CBC, analysis of C-reactive protein and pro-brain natriuretic peptide, transthoracic Doppler echocardiography, six-minute walk test, lung function tests including diffusion capacity for carbon monoxide, right heart catheter, high-resolution CT scan, and ventilation/perfusion scan.. Pulmonary arterial hypertension associated with limited cutaneous systemic sclerosis.. Treatment with oral anticoagulation therapy and the endothelin-receptor antagonist bosentan. Monitoring of adverse effects of bosentan therapy was performed using liver function tests.

Topics: Adult; Antihypertensive Agents; Bosentan; Dyspnea; Echocardiography; Exercise Test; Female; Humans; Hypertension, Pulmonary; Natriuretic Peptide, Brain; Respiratory Function Tests; Scleroderma, Systemic; Sulfonamides

Elevated serum brain natriuretic peptide (BNP) released from myocytes of ventricles upon stretch have been found in patients with isolated right ventricular (RV) pressure overload. However, limited data suggest that serum BNP may be elevated in systemic sclerosis (SSc) patients, especially with RV dysfunction. We assessed serum N-terminal proBNP (NT-proBNP) in SSc and evaluated whether it reflects the severity of RV overload. We prospectively studied 51 consecutive patients (47F, mean age 53.3 +/- 15.2 years) with SSc (mean disease duration 9 +/- 12.4 years). The control group formed 31 healthy subjects (27F, mean age 52.6 +/- 12.1 years). NT-proBNP level, 6-minute walking test (6MWT), and transthoracic echocardiography (TTE) for the assessment of RV overload were performed. Serum NT-proBNP exceeded the reference value of 125 pg/mL in 31 (61%) SSc patients. The mean serum log NT-proBNP concentration in SSc was higher than in controls (2.138 +/- 0.527 vs. 1.634 +/- 0.420 pg/mL, p < 0.001). 13 (25%) SSc patients have tricuspid regurgitation peak gradient (TRPG) exceeding 31 mmHg reflecting pulmonary arterial hypertension (PAH). The SSc presented other echocardiographic signs of RV overload. Mean 6MWT distance was shorter in SSc than in controls (528 +/- 100 vs. 617 +/- 80 m, p < 0.001). NT-proBNP level correlated positively with TRPG, RV diameter, RV Tei index and negatively with 6MWT distance. ROC analysis identified >115 pg/ml as the best NT-proBNP threshold predicting PAH for SSc patients (sensitivity 92%, specificity 44%). Results of our study suggest that NT-proBNP measurement is a useful screening method for PAH in SSc patients. Since elevated plasma NT-proBNP level reflects the degree of right ventricular overload and limitation of exercise capacity, abnormal NT-proBNP levels should imply further evaluation including echocardiography.

Topics: Adult; Aged; Biomarkers; Case-Control Studies; Echocardiography; Exercise Test; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Natriuretic Peptide, Brain; Prospective Studies; Scleroderma, Systemic; Ventricular Dysfunction, Right

Systemic sclerosis (SSc) is a connective tissue disease, which may lead to pulmonary artery hypertension (PAH). N-terminal pro-brain natriuretic peptide (NT-proBNP) is a biologic marker for the diagnosis and treatment of congestive heart failure. The aim of our study was to investigate the potential role of the plasma NT-proBNP assay in the assessment of functional status and right heart performance in systemic sclerosis-related pulmonary hypertension (SScPAH). Systolic pulmonary artery pressure (sPAP) assessed by echocardiography, six-minute walk test (SMWT) and plasma NT-proBNP levels were recorded from 45 SSc patients. Mean value of NT-proBNP for SSc patients with PAH (n=14) was 691.7+/-325.7 fmol/L compared to 417.4+/-167.1 fmol/L for patients without PAH (n=31) (p=0.0007). In SSc patients we found a statistically significant correlation between NT-proBNP values and sPAP (r=0.32, p=0.03). Amongst SScPAH patients, NT-proBNP values were significantly correlated with sPAP (r=0.73, p=0.003) and inversely correlated with the SMWT (r=-0.60, p=0.02). These results suggest NT-proBNP as a useful additional biological tool in the evaluation and management of SScPAH patients.

Topics: Biomarkers; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Prospective Studies; Scleroderma, Systemic; Severity of Illness Index; Ultrasonography

Topics: Humans; Hypertension, Pulmonary; Natriuretic Peptide, Brain; Scleroderma, Systemic

We describe two systemic sclerosis (SSc) patients with isolated pulmonary arterial hypertension (PAH) who were given treatment with 50 mg oral sildenafil per day. We evaluated the efficacy of oral sildenafil for isolated PAH in SSc patients by direct assessment with cardiac catheterization before and 6 months after the initiation of sildenafil. Right-heart catheterization demonstrated decreased mean pulmonary artery pressure, decreased pulmonary vascular resistance, and increased cardiac output after treatment with sildenafil. Brain natriuretic peptide levels were gradually decreased. The 6-min walking distance was greatly extended. Moreover, the physical conditions of both patients were much improved. We recognized no adverse events. We propose that oral sildenafil may be beneficial as a selective pulmonary vasodilator and as long-term treatment in SSc patients with isolated PAH.

Topics: Female; Hemodynamics; Humans; Hypertension, Pulmonary; Middle Aged; Natriuretic Peptide, Brain; Piperazines; Purines; Scleroderma, Systemic; Sildenafil Citrate; Sulfones; Vasodilator Agents

The aims of this study were to evaluate the diagnostic value and to explore the prognostic value of N-terminal brain natriuretic peptide (N-TproBNP) in patients with systemic sclerosis (SSc) both with and without pulmonary arterial hypertension (PAH).. N-TproBNP, six-minute walk distance (SMWD), haemodynamics (at right heart catheterization) or tricuspid gradient (by echocardiography), and survival were assessed in 109 patients with SSc. The study population included 68 individuals with PAH [mean pulmonary artery pressure (PAP) >25 mmHg and pulmonary capillary wedge pressure <15 mmHg] and 41 individuals without PAH. In patients with PAH, the prognostic value of baseline and change in WHO functional class, N-TproBNP levels, and SMWD were compared using Kaplan-Meier survival curves and Cox proportional hazard analysis. The mean duration of follow-up was 10 months (range 1-18 months). One year survival in patients with normal PAP was 100% when compared with 83.5% in those with SSc-PAH (P < 0.05). The patients without PAH had a mean N-TproBNP level of 139 pg/mL (SD 151); those with SSc-PAH had a significantly higher mean N-TproBNP level of 1474 pg/mL (SD 2642) (P = 0.0002). Among patients with PAH for every order of magnitude increase in N-TproBNP level there was a four-fold increased risk of death (P = 0.002 for baseline level and P = 0.006 for follow-up level). Baseline N-TproBNP levels were correlated positively with mean PAP (r = 0.62; P < 0.0001), pulmonary vascular resistance (PVR) (r = 0.81; P < 0.0001), and inversely with SMWD (r = -0.46; P < 0.0001). Among patients with SSc-PAH, 13 patients (19%) were in WHO functional classes II and had mean N-TproBNP levels of 325 pg/mL (SD 388). Fifty-three patients (78%) were in WHO classes III and IV and had significantly higher mean N-TproBNP levels of 1677 pg/mL (SD 2835) (P = 0.02). At an N-TproBNP level of 395 pg/mL, the sensitivity and specificity for predicting the presence of SSc-PAH were 56 and 95% respectively.. Raised N-TproBNP levels are directly related to the severity of PAH. In screening programs, SSc patients with an N-TproBNP in excess of 395 pg/mL have a very high probability of having pulmonary hypertension. Baseline and serial changes in N-TproBNP levels are highly predictive of survival. A 10-fold increase in N-TproBNP level on therapy is associated with a greater than three-fold increase in mortality, and may indicate therapeutic failure.

Topics: Echocardiography; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Predictive Value of Tests; Prognosis; Scleroderma, Systemic; Survival Analysis; Ventricular Function, Right

Myocardial involvement is frequent in systemic sclerosis, but symptoms are usually delayed and non-specific, thus often misrecognized. The aim of this study was the evaluation of the early subclinical cardiac involvement in patients with systemic sclerosis by means of non-invasive laboratory cardiac markers.. Cardiac troponin T (cTnT), ischemia modified albumin (IMA) and NT-prohormone-brain natriuretic peptide (NT-proBNP) were measured in 40 female patients with systemic sclerosis and in 40 matched healthy controls.. Patients with systemic sclerosis displayed significantly increased concentrations of serum IMA (106 versus 93.5 kunits/l, P < 0.0001) and NT-proBNP (89 versus 37 pg/ml, P < 0.0001), whereas no significant differences could be observed in both IMA and NT-proBNP values in limited versus diffuse pattern of disease.. The increased levels of NT-proBNP and IMA could be considered a sign of early myocardial involvement, warranting further heart examination and a regular follow-up.

Topics: Aged; Biomarkers; Cohort Studies; Female; Humans; Middle Aged; Myocardium; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Protein Precursors; Scleroderma, Systemic; Serum Albumin

To evaluate the longitudinal development of the tricuspid gradient (TG) for screening for pulmonary arterial hypertension (PAH) in systemic sclerosis (SSc).. Doppler echocardiography was performed 506 times in order to estimate TG in 227 consecutive patients with SSc. The value of biochemical markers for predicting TG levels and development was assessed through analyses of pro-brain natriuretic peptide (proBNP), calcitonin-gene related peptide, thrombomodulin and von Willebrand factor in 76 patients with a borderline increase in TG, defined as TG 24-38 mmHg, and for the purpose of comparison also in 10 patients with a normal TG (< 23 mmHg) and in 10 patients with increased TG (TG > 38 mmHg).. TG > 23 mmHg was found in 102 patients (44.9%) at the first assessment point and in 139 patients (61.2%) respectively, cumulatively at follow-up. TG values > 33 mmHg were measured in 24 patients (10.6%) initially and in 38 patients (16.7%) cumulatively in a subsequent assessment. Age and the presence of interstitial lung disease (ILD) were associated with more frequent occurrence of TG > 23 and > 33 mmHg initially and at follow-up, but were not associated with progression rate. The change in TG (mean +/- S.D.) was 1.34 +/- 4.55 mmHg/yr. ProBNP correlated to TG.. An increased TG, indicating possible PAH, is common and progressive in SSc. Age and ILD increase the risk of increased TG. Patients with or without ILD have similar progression of TG. ProBNP has potential as an adjunct to TG in selecting patients eligible for invasive treatment.

Topics: Age Factors; Blood Pressure; Calcitonin Gene-Related Peptide; Carbon Monoxide; Echocardiography, Doppler; Humans; Hypertension, Pulmonary; Lung Diseases, Interstitial; Middle Aged; Natriuretic Peptide, Brain; Scleroderma, Systemic; Thrombomodulin; Tricuspid Valve; Tricuspid Valve Insufficiency; von Willebrand Factor

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Aged; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Natriuretic Peptide, Brain; Piperazines; Pulmonary Fibrosis; Purines; Raynaud Disease; Scleroderma, Systemic; Sildenafil Citrate; Sulfones