Increased Serum Levels of soluble ST2 as a Predictor of Disease Progression in Systemic Sclerosis.

OBJECTIVE: Interleukin-33 (IL-33) has been investigated as a mediator in the pathogenesis of fibrosis in lung, liver, and heart. There is accumulating evidence for the involvement of the IL-33/IL-33 receptor ST2L signalling pathway in systemic sclerosis (SSc). Little is known about the role of serum sST2 in SSc, which is the subject of the present investigation. METHOD: Serum levels of sST2 were measured in 49 patients with SSc, recruited prospectively between November 2017 and March 2019. Patients were divided into those with progressive and those with stable disease. Receiver operating characteristics (ROC) curve analysis was applied to study sST2 as a marker for identifying patients with progressive disease. We used multivariate logistic regression analysis to evaluate the predictive value of sST2 for progressive disease after adjustment for potential confounding factors. RESULTS: Serum sST2 levels in patients with progressive disease were significantly elevated compared with patients with stable disease (mean ± sem: 50.4 ± 4.7 ng/mL vs 29.2 ± 2.97 ng/mL, p < 0.001). ROC curve analysis identified an sST2 cut-off value of 37.8 ng/mL as optimal for discriminating patients with progressive disease from those with stable disease (sensitivity 80.0%, specificity 79.3%, area under the curve 0.80). After controlling for potential confounding factors (age, gender, C-reactive protein, pro-brain natriuretic peptide, and sum of internal medicine comorbidities), sST2 remained predictive of progressive disease (odds ratio 1.070, 95% confidence interval 1.017-1.126, p < 0.009). CONCLUSION: In the present study, sST2 serum levels were predictive of disease progression in patients with SSc.

Implications of prevalent and incident diabetes mellitus on left ventricular geometry and function in the ageing heart: the MONICA/KORA Augsburg cohort study.

BACKGROUND AND AIM: It is unclear to what extent diabetes modulates the ageing-related adaptations of cardiac geometry and function. METHODS AND RESULTS: We examined 1005 adults, aged 25-74 years, from a population-based survey at baseline in 1994/5 and at follow-up in 2004/5. We compared persistently non-diabetic individuals (ND; no diabetes at baseline and at follow-up, n=833) with incident (ID; non-diabetic at baseline and diabetic at follow-up, n=36) and with prevalent diabetics (PD; diabetes at baseline and follow-up examination, n=21). Left ventricular (LV) geometry and function were evaluated by echocardiography. Statistical analyses were performed with multivariate linear regression models. Over ten years the PD group displayed a significantly stronger relative increase of LV mass (+9.34% vs. +23.7%) that was mediated by a more pronounced increase of LV end-diastolic diameter (+0% vs. +6.95%) compared to the ND group. In parallel, LA diameter increased (+4.50% vs. +12.7%), whereas ejection fraction decreased (+3.02% vs. -4.92%) more significantly in the PD group. Moreover, at the follow-up examination the PD and ID groups showed a significantly worse diastolic function, indicated by a higher E/EM ratio compared with the ND group (11.6 and 11.8 vs. 9.79, respectively). CONCLUSIONS: Long-standing diabetes was associated with an acceleration of age-related changes of left ventricular geometry accumulating in an eccentric remodelling of the left ventricle. Likewise, echocardiographic measures of systolic and diastolic ventricular function deteriorated more rapidly in individuals with diabetes.

Quantification of left-to-right shunting in adult congenital heart disease: phase-contrast cine MRI compared with invasive oximetry.

Atrial septum defects (ASDs), ventricular septum defects (VSDs) and patent ductus arteriosus (PDA) are the most common adult congenital heart defects. The degree of left-to-right shunting as assessed by the ratio of flow in the pulmonary (Qp) and systemic circulation (Qs) is crucial in the management of these conditions. This study compared phase-contrast cine magnetic resonance imaging (PC-MRI), a non-invasive imaging technique, with invasive oximetry for the measurement of shunt volumes during cardiac catheterisation in adults with left-to-right shunting. Both invasive oximetry and shunt quantification by PC-MRI (1.5 T scanner; Sonata, Siemens Medical Solutions) were performed on 21 patients with left-to-right shunting (14 ASD, 5 VSD, 2 PDA) and data on Qp/Qs ratios and left-to-right shunt fraction compared. Mean Qp/Qs ratios assessed by PC-MRI and oximetry were 2.10+/-0.76 and 1.96+/-0.77, respectively (p = 0.37). Mean shunt fraction was 46.3+/-19.6% when calculated by PC-MRI and 42.3+/-20.1% when obtained by oximetry (p = 0.12). There was a strong correlation of Qp/Qs ratios and shunt fraction between both methods (r = 0.61, p < 0.01 and r = 0.84, p < 0.0001, respectively). The two methods had a good agreement according to Bland and Altman plots with a small but non-significant overestimation of Qp/Qs-ratios and shunt fraction by PC-MRI. On receiver operating characteristic analysis, the sensitivity and specificity of PC-MRI to detect an oximetry-derived Qp/Qs ratio of > or =1.5:1 were 93% and 100% at a PC-MRI threshold of a Qp/Qs ratio > or =1.75:1 (area under curve (AUC) = 0.99). Quantification of left-to-right shunting can be performed reliably and accurately by PC-MRI and the data obtained by this method correlate closely to those from invasive oximetry.

Safety of the novel atrial-selective K+-channel blocker AVE0118 in experimental heart failure.

Congestive heart failure (CHF) is often associated with atrial fibrillation. The safety of many antiarrhythmic drugs in CHF is limited by proarrhythmic effects. We aimed to assess the safety of a novel atrial-selective K(+)-channel blocker AVE0118 in CHF compared to a selective (dofetilide) and a non-selective IKr blocker (terfenadine). For the induction of CHF, rabbits (n = 12) underwent rapid right ventricular pacing (330-380 bpm for 30 days). AVE0118 (1 mg/kg) dofetilide (0.02 mg/kg) and terfenadine (2 mg/kg) were administered in baseline (BL) and CHF. A six-lead ECG was continuously recorded digitally for 30 min after each drug administration. At BL, dofetilide and terfenadine significantly prolonged QTc interval (218 +/- 30 ms vs 155 +/- 8 ms, p = 0.001 and 178 +/- 23 ms vs. 153 +/- 12 ms, p = 0.01, respectively) while QTc intervals were constant after administration of AVE0118 (p = n.s.). In CHF, dofetilide and terfenadine caused torsades de pointes and symptomatic bradycardia, respectively, and prolonged QTc interval (178 +/- 30 ms vs. 153 +/- 14 ms, p = 0.02 and 157 +/- 7 ms vs. 147 +/- 10 ms, p = 0.02, respectively) even at reduced dosages, whereas no QTc-prolongation or arrhythmia was observed after full-dose administration of AVE0118. In conclusion, atrial-selective K(+)-channel blockade by AVE0118 appears safe in experimental CHF.

Increased aldosterone levels in a model of type 2 diabetes mellitus.

BACKGROUND: Aldosterone is an important mediator of cardiovascular and renal remodeling. Type II diabetes mellitus leads to renal and cardiac end organ damage. We investigated the renin-angiotensin-aldosterone system in a model of type 2 diabetes mellitus with known diabetic nephropathy and cardiac remodeling, the Zucker Diabetic Fatty rat with and without ACE-inhibition (ZDF and ZDF+ACE-I) and its control, the Zucker Lean (ZDL) rat. METHODS: Male animals were studied from an age of 7-24 weeks. At ages 7, 14, 17, 20, and 23 weeks, urinary excretion of aldosterone-glucuronide and potassium was assessed. ACE-inhibition with ramipril was started orally at week 13 (1 mg/kg/d). At the end of the study rats were sacrificed and plasma aldosterone concentration and plasma renin activity were measured. Aldosterone synthase (CYP11B2) mRNA expression in the adrenals, kidney, heart and adipose tissue was assessed by real-time PCR. Urinary albumin excretion as marker for diabetic nephropathy was measured in metabolic cages and correlated to aldosterone. RESULTS: Plasma aldosterone concentration and aldosterone-glucuronide was significantly elevated in ZDF rats, and significantly reduced by ACE-inhibiton. In contrast, plasma renin activity was significantly reduced in ZDF rats and normalized by ACE-inhibition. The urinary aldosterone correlated significantly to albuminuria. Adrenal CYP11B2 expression was not significantly higher in ZDF rats. CYP11B2 mRNA was not detected in the kidney, heart and adipose tissue. CONCLUSION: In ZDF rats, urinary and plasma aldosterone levels were elevated despite reduced plasma renin activity. The reversible effect of ACE-inhibition shows that the up-regulation of aldosterone must be dependent of the renin-angiotensin-system in this type II diabetes model. The correlation between aldosterone and diabetic nephropathy suggests a clinical relevance of this observation.

Extracorporeal pumpless interventional lung assist in clinical practice: determinants of efficacy.

Respiratory acidosis can become a serious problem during protective ventilation of severe lung failure. A pumpless arteriovenous interventional lung assist (iLA) for extracorporeal carbon dioxide removal has been used increasingly to control critical respiratory situations. The present study sought to evaluate the factors determining the efficacy of iLA and calculate its contribution to gas exchange. In a cohort of 96 patients with severe acute respiratory distress syndrome, haemodynamic parameters, oxygen consumption and carbon dioxide production as well as gas transfer through the iLA were analysed. The measurements demonstrated a significant dependency of blood flow via the iLA device on cannula size (mean+/-sd 1.59+/-0.52 L x min(-1) for 15 French (Fr), 1.94+/-0.35 L x min(-1) for 17 Fr, and 2.22 +/-0.45 L x min(-1) for 19 Fr) and on mean arterial pressure. Oxygen transfer capacity averaged 41.7+/-20.8 mL x min(-1), carbon dioxide removal was 148.0+/-63.4 mL x min(-1). Within two hours of iLA treatment, arterial oxygen partial pressure/inspired oxygen fraction ratio increased significantly and a fast improvement in arterial carbon dioxide partial pressure and pH was observed. Interventional lung assist eliminates approximately 50% of calculated total carbon dioxide production with rapid normalisation of respiratory acidosis. Despite limited contribution to oxygen transfer it may allow a more protective ventilation in severe respiratory failure.

Unicuspid aortic valve disease: a magnetic resonance imaging study.

PURPOSE: Congenitally malformed aortic valves are a common finding in adults with aortic valve disease. Most of these patients have bicuspid aortic valve disease. Unicuspid aortic valve disease (UAV) is rare. The aim of our study was to describe valve morphology and the dimensions of the proximal aorta in a cohort of 12 patients with UAV in comparison to tricuspid aortic valve disease (TAV) using magnetic resonance imaging (MRI). MATERIALS AND METHODS/RESULTS: MRI studies were performed on a 1.5 T scanner in a total of 288 consecutive patients with aortic valve disease. 12 aortic valves were retrospectively classified as UAV. Annulus areas and dimensions of the thoracic aorta were retrospectively compared to a cohort of 103 patients with TAV. In UAV, valve morphology was unicuspid unicommissural with a posterior commissure in all patients. Mean annulus areas and mean diameters of the ascending aorta were significantly greater in UAV compared to TAV (12.6 +/- 4.7 cm (2) vs. 8.7 +/- 2.3 cm (2), p < 0.01 and 4.6 +/- 0.7 cm vs. 3.6 +/- 0.5 cm, p < 0.0001, respectively), while no differences were observed in the mean diameters of the aortic arch (2.3 +/- 0.6 cm vs. 2.3 +/- 0.4 cm, p = 0.69). The diameters of the descending aorta were slightly smaller in UAV compared to TAV (2.2 +/- 0.5 cm vs. 2.6 +/- 0.3 cm, p < 0.05). CONCLUSION: In UAV, visualization of valve morphology by MRI is possible with good image quality. Valve morphology was classified as unicuspid unicommissural in all UAV patients. Dilatation of the proximal aorta > 4.5 cm is a frequent finding in UAV. Additional assessment of aortic dimensions is therefore recommended in patients with UAV.

Effects of selective and unselective endothelin-receptor antagonists on prostacyclin synthase gene expression in experimental pulmonary hypertension.

OBJECTIVE: Compared to the unselective endothelin (ET) receptor antagonist (Bosentan), superior effects of selective ET-A-receptor blockage (Ambrisentan) for the treatment of pulmonary hypertension (PH) are expected due to ET-B-receptor mediated beneficial effects. Our hypothesis was that treatment with Ambrisentan leads to an increase in prostacyclin synthase I (PGIS) expression compared to Bosentan. MATERIAL AND METHODS: To test this hypothesis, rats were treated with either monocrotaline (MCT) only, MCT+Ambrisentan or MCT+Bosentan. After 4 weeks, right ventricular systolic pressure (RVSP), pulmonary vascular remodelling and right ventricular hypertrophy (RV/(LV+S)) were measured. RESULTS: In MCT only treated animals, significantly greater expression of PGIS mRNA was found in the lungs compared to control animals, and this was confirmed by immunohistochemical analysis indicating increased staining of PGIS in the very small pulmonary arteries (17 % greater expression of PGIS mRNA in MCT versus control, p = 0.002; Remmele score (RS): 51 versus 102, p = 0.009). Treatment with Bosentan resulted in a significantly lower expression of PGIS mRNA compared to Ambrisentan and MCT only (7 % versus 18 %, p = 0.003 and 7 % versus 17 %, p = 0.004). This observation was also confirmed by immunohistochemical analysis (RS very small arteries: 45 versus 81, p = 0.003; RS small arteries: 45 versus 108, p = 0.014). No difference was observed in RVSP, RV/(LV+S) or pulmonary vascular remodelling between the two treatment groups (RVSP: 28 versus 39 mmHg, p = 0.189; RV/(LV+S) 0.46 versus 0.48, p = 0.818; medial area: 78.3 % versus 75.2 %, p = 0.823). CONCLUSIONS: Treatment with Bosentan leads to lower PGIS expression in pulmonary arteries compared to Ambrisentan, although the greater PGIS expression by Ambrisentan treatment had no benefical effect on pulmonary haemodynamics.

Assessment of the anatomic regurgitant orifice in aortic regurgitation: a clinical magnetic resonance imaging study.

BACKGROUND: The aim of our study was to determine whether planimetry of the anatomic regurgitant orifice (ARO) in patients with aortic regurgitation (AR) by magnetic resonance imaging (MRI) is feasible and whether ARO by MRI correlates with the severity of AR. METHODS AND RESULTS: Planimetry of ARO by MRI was performed on a clinical magnetic resonance system (1.5 T Sonata, Siemens Medical Solutions) in 45 patients and correlated with the regurgitant fraction (RgF) and regurgitant volume (RgV) determined by MRI phase velocity mapping (PVM; MRI-RgF, MRI-RgV, n = 45) and with invasively quantified AR by supravalvular aortography (n = 32) and RgF upon cardiac catheterisation (CATH-RgF, n = 15). Determination of ARO was possible in 98% (44/45) of the patients with adequate image quality. MRI-RgF and CATH-RgF were modestly correlated (n = 15, r = 0.71, p<0.01). ARO was closely correlated with MRI-RgF (n = 44, r = 0.88, p<0.001) and was modestly correlated with CATH-RgF (n = 14, r = 0.66, p = 0.01). Sensitivity and specificity of ARO to detect moderately severe and severe aortic regurgitation (defined as MRI-RgF > or =40%) were 96% and 95% at a threshold of 0.28 cm2 (AUC = 0.99). Of note, sensitivity and specificity of ARO to detect moderately severe and severe AR at catheterisation (defined as CATH-RgF > or =40% or supravalvular aortography > or =3+) were 90% and 91% at a similar threshold of 0.28 cm2 (AUC = 0.95). Lastly, sensitivity and specificity of ARO to detect severe aortic regurgitation (defined as MRI-RgF > or =50% and/or regurgitant volume > or =60 ml) were 83% and 97% at a threshold of 0.48 cm2 (AUC = 0.97). CONCLUSIONS: Visualisation and planimetry of the ARO in patients with AR are feasible by MRI. There is a strong correlation of ARO with RgV and RgF assessed by PVM and with invasively graded AR at catheterisation. Therefore, determination of ARO by MRI is a new non-invasive measure for assessing the severity of AR.

Mechanisms of regional wall motion abnormalities in contrast-enhanced dobutamine stress echocardiography.

BACKGROUND: In the diagnosis of coronary artery disease (CAD) with Dobutamine Stress Echocardiography (DSE), regional wall motion abnormalities (RWMA) are assumed to indicate a perfusion deficit. METHODS AND RESULTS: For a more particular examination of RWMAs, we compared simultaneous echo-contrast (Optisone)-enhanced DSE (0-40 microg/kg Dobutamine, 16-segment- model) and MiBi-SPECT in a prospective double-blinded study design in 69 non-selected consecutive patients (44 male, 25 female, age 64+/-12 years). Additionally, all patients were examined by coronary-angiography. The prevalence of significant CAD (stenosis >50% lumen diameter) was 52%. DSE had a sensitivity of 78% and a specificity of 66% for the detection of significant CAD with a positive and negative predictive value of 72 and 73%, respectively. Among 28 patients with significant CAD and positive DSE study (true positive), 78% displayed a corresponding perfusion deficit in MiBi-SPECT. Among 11 patients with a positive DSE study but no current significant coronary stenosis (false positive), 82% showed stress-induced RWMAs in the inferior/posterior region, 73% displayed left ventricular hypertrophy, 54% resting-ECG abnormalities and 45% resting-RWMA (3 previous MI, 2 previous CABG surgery). Among 8 patients with negative DSE study but significant coronary stenosis (false negative), 75% had a stenosis of the LCX, 63% displayed resting- WMA, 63% displayed left bundle branch block or ST-segment depression, 50% displayed only peripheral coronary stenosis, and DSE visualization was suboptimal in 38%. CONCLUSION: This prospective study in non-selected patients shows that the majority of RWMAs in DSE are matched to a perfusion deficit detectable by nuclear imaging. Nevertheless, pre-existing cardiac abnormalities may also lead to stress-induced RWMA not associated with a perfusion deficit or mask a perfusion deficit upon DSE. Particularly in patients with LV hypertrophy, resting-RWMA, bundle branch block or ST segment depression, the predictive value of DSE may, therefore, be limited.

MRI planimetry for diagnosis and follow-up of valve area in mitral stenosis treated with valvuloplasty.

PURPOSE: We sought to determine whether noninvasive planimetry by magnetic resonance imaging (MRI) is suitably sensitive and reliable for visualizing the mitral valve area (MVA) and for detecting increases in the MVA after percutaneous balloon mitral valvuloplasty (PBMV). MATERIALS AND METHODS: In 8 patients with mitral valve stenosis, planimetry of the MVA was performed before and after PBMV with a 1.5 T MR scanner using a breath-hold balanced gradient echo sequence (True FISP). The data was compared to the echocardiographically determined MVA (ECHO-MVA) as well as to the invasively calculated MVA by the Gorlin formula at catheterization (CATH-MVA). RESULTS: PBMV was associated with an increase of 0.79 +/- 0.30 cm (2) in the MVA (Delta MRI-MVA). The correlation between Delta MRI-MVA and Delta CATH-MVA was 0.92 (p < 0.03) and that between Delta MRI-MVA and Delta ECHO-MVA was 0.90 (p < 0.04). The overall correlation between MRI-MVA and CATH-MVA was 0.95 (p < 0.0001) and that between MRI-MVA and ECHO-MVA was 0.98 (p < 0.0001). MRI-MVA slightly overestimated CATH-MVA by 8.0 % (1.64 +/- 0.45 vs. 1.51 +/- 0.49 cm (2), p < 0.01) and ECHO-MVA by 1.8 % (1.64 +/- 0.45 vs. 1.61 +/- 0.43 cm (2), n. s.). CONCLUSION: Magnetic resonance planimetry of the mitral valve orifice is a sensitive and reliable method for the noninvasive quantification of mitral stenosis and visualization of small relative changes in the MVA. This new method is therefore capable of diagnosing as well as following the course of mitral stenosis. It must be taken into consideration that planimetry by MRI slightly overestimates the MVA as compared to cardiac catheterization.

Delayed hyperenhancement in magnetic resonance imaging of left ventricular hypertrophy caused by aortic stenosis and hypertrophic cardiomyopathy: visualisation of focal fibrosis.

OBJECTIVE: To compare the extent and distribution of focal fibrosis by gadolinium contrast-enhanced magnetic resonance imaging (MRI; delayed hyperenhancement) in severe left ventricular (LV) hypertrophy in patients with pressure overload caused by aortic stenosis (AS) and with genetically determined hypertrophic cardiomyopathy (HCM). METHODS: 44 patients with symptomatic valvular AS (n = 22) and HCM (n = 22) were studied. Cine images were acquired with fast imaging with steady-state precession (trueFISP) on a 1.5 T scanner (Sonata, Siemens Medical Solutions). Gadolinium contrast-enhanced MRI was performed with a segmented inversion-recovery sequence. The location, extent and enhancement pattern of hyperenhanced myocardium was analysed in a 12-segment model. RESULTS: Mean LV mass was 238.6 (SD 75.3) g in AS and 205.4 (SD 80.5) g in HCM (p = 0.17). Hyperenhancement was observed in 27% of patients with AS and in 73% of patients with HCM (p < 0.01). In AS, hyperenhancement was observed in 60% of patients with a maximum diastolic wall thickness >or= 18 mm, whereas no patient with a maximum diastolic wall thickness < 18 mm had hyperenhancement (p < 0.05). Patients with hyperenhancement had more severe AS than patients without hyperenhancement (aortic valve area 0.80 (0.09) cm(2)v 0.99 (0.3) cm(2), p < 0.05; maximum gradient 98 (22) mm Hg v 74 (24) mm Hg, p < 0.05). In HCM, hyperenhancement was predominant in the anteroseptal regions and patients with hyperenhancement had higher end diastolic (125.4 (36.9) ml v 98.8 (16.9) ml, p < 0.05) and end systolic volumes (38.9 (18.2) ml v 25.2 (1.7) ml, p < 0.05). The volume of hyperenhancement (percentage of total LV myocardium), where present, was lower in AS than in HCM (4.3 (1.9)% v 8.6 (7.4)%, p< 0.05). Hyperenhancement was observed in 4.5 (3.1) and 4.6 (2.7) segments in AS and HCM, respectively (p = 0.93), and the enhancement pattern was mostly patchy with multiple foci. CONCLUSIONS: Focal scarring can be observed in severe LV hypertrophy caused by AS and HCM, and correlates with the severity of LV remodelling. However, focal scarring is significantly less prevalent in adaptive LV hypertrophy caused by AS than in genetically determined HCM.

Cardiovascular phenotypes and functional parameters in the general population--results of the MONICA/KORA studies.

The MONICA/KORA surveys are characterized by a careful and broad investigation of multiple cardiovascular phenotypes. Particularly, repeated blinded measurements of blood pressure, comprehensive echocardiographic and electrocardiographic evaluations as well as differentiation between fat and fat-free body mass have led to manifold innovative observations. Specifically, genetic and serological markers of the renin angiotensin system could be associated with high blood pressure and left ventricular hypertrophy. The same applies to the importance of parameters of body composition as obesity and muscular mass. Moreover, the prevalence of heart failure in the general population could be determined for the first time in Germany. Additionally, the prevalence of left ventricular systolic and diastolic dysfunction could be obtained in the region of the survey, exemplarily for the Federal Republic of Germany. Finally, the surveys of the population random sample were used to define normal serum levels of natriuretic peptides. In summary, the evaluation of cardiovascular phenotypes in the MONICA/KORA surveys resulted in a -- in the European region unique -- documentation of cardiovascular functional parameters in the general population. Moreover, multiple epidemiological observations as to pathophysiologically relevant topics of heart and vascular diseases could be studied in extraordinary details.

BNP as a marker of diastolic dysfunction in the general population: Importance of left ventricular hypertrophy.

BNP is a marker of systolic left ventricular dysfunction (LVSD) and heart failure. To assess BNP for the detection of diastolic dysfunction in the general population, we examined 1678 subjects within an age- and sex-stratified survey (MONICA Augsburg). BNP was measured using a commercially available RIA (Shionogi). BNP increased in subjects with diastolic dysfunction (mean 20.3+/-4.7 pg/ml vs. control 9.6+/-0.5 pg/ml, p<0.001), but to a lesser extent than in subjects with LV hypertrophy (LVH, mean 37.3+/-49.1 pg/ml, p<0.001 vs. control) or LVSD (mean 76.2+/-23.2 pg/ml, p<0.001 vs. control). Individuals with sole diastolic abnormality displayed BNP concentrations at the control level (mean 9.7+/-1.7 pg/ml). In univariate analysis, age, BMI, systolic blood pressure, left atrial size, LV mass index, diastolic dysfunction and EF displayed a significant correlation with BNP (p<0.001). However, LV mass index displaced diastolic dysfunction as a significant predictor of BNP in multivariate analysis. Upon ROC analysis, sensitivity and specificity for the detection of diastolic dysfunction by BNP were only 61% and 55%, respectively. Nevertheless, a normal BNP test virtually excluded the presence of diastolic dysfunction and concomitant LVH (NPV 99.9%). Increased BNP concentrations in subjects with diastolic dysfunction are strongly related to LVH. Population-wide screening for diastolic dysfunction with BNP cannot be recommended although a normal BNP test usually excludes diastolic dysfunction and LV hypertrophy.

Interactions between the sympathetic nervous system and the cardiac natriuretic peptide system.

The sympathetic nervous system (SNS) and the cardiac natriuretic peptide system (NPS) are fundamentally important neurohumoral systems for cardiovascular regulation. Their mutual interactions have been subject to numerous experimental and human studies. In the current manuscript, results from in vivo and in vitro studies will be reviewed with a focus on sympathetic outflow on the control of natriuretic peptide release.

NT-proBNP and the diagnosis of heart failure: a pooled analysis of three European epidemiological studies.

Many studies have shown that the B-type natriuretic peptides (BNP and NT-proBNP) are proven diagnostic markers for heart failure due to left ventricular systolic dysfunction. The manner in which they are to be used is still being unravelled; most single centre studies have chosen the best concentration of the peptide on ROC analysis as their cut-point resulting in numerous different values for both BNP and NT-proBNP appearing in the literature. We report a different approach of defining an age and sex corrected abnormal concentration for NT-proBNP, derived from normal individuals within a large sample of 3051 subjects pooled from three European epidemiology studies and applying that to the entire population to detect HF and LVD. Three thousand and fifty one subjects were studied. Of these 10% (305) had significant LVD and 3.1% (94) had HF. The median concentrations of NT-proBNP (IQR) in normals, those with LVD and in heart failure subjects were 20 pg/ml (10.30), 117.3 pg/ml (28.145) and 269.6 pg/ml (54.323), P<0.001, respectively. The area under the ROC curve for NT-proBNP for the detection of 'heart failure' was 0.85 and 0.69 for LVD. NT-proBNP was an independent predictor of the presence of HF on multivariate analysis. An abnormal NT-proBNP was defined as being >95th centile for normals, age and sex corrected, and diagnosed HF with a sensitivity of 75% and a negative predictive value of 99%. In an additional analysis in a breathless subgroup of our population, in 30% a raised NT-proBNP concentration could be explained by HF due to LVD, in another 64% the high BNP level was associated with some other structural of functional cardiac abnormality or renal impairment. We were unable to assign a possible cause to the high NT-proBNP values in 5.9% of this breathless subgroup of the population. An abnormal NT-proBNP concentration is an accurate diagnostic test both for the exclusion of HF in the population and in ruling out LVD in breathless subjects. An elevated NT-proBNP merely indicates the presence of 'cardio-renal distress' and should prompt referral for further investigation.

Clinical applications of B-type natriuretic peptide (BNP) testing.

Many claims have been made in recent years regarding the utility of plasma B-type natriuretic peptide (BNP) concentration measurements in the diagnosis, risk stratification and monitoring of patients with heart failure. This paper summarizes the current evidence and provides guidance for practising clinicians. Overall, plasma BNP testing appears to be of most value in the diagnostic arena, where it is likely to improve the performance of non-specialist physicians in diagnosing heart failure. In clinical practice, BNP testing is best used as a 'rule out' test for suspected cases of new heart failure in breathless patients presenting to either the outpatient or emergency care settings; it is not a replacement for echocardiography and full cardiological assessment, which will be required for patients with an elevated BNP concentration. Although work is ongoing in establishing the 'normal' values of BNP, heart failure appears to be highly unlikely below a plasma concentration of 100 pg/ml. However, as BNP levels rise with age and are affected by gender, comorbidity and drug therapy, the plasma BNP measurement should not be used in isolation from the clinical context.

[Epidemiology of left ventricular systolic dysfunction in the general population of Germany: results of an echocardiographic study of a large population-based sample]. / Epidemiologie der linksventrikulären systolischen Dysfunktion in der Allgemeinbevölkerung Deutschlands. Ergebnisse echokardiografischer Untersuchungen einer grossen Bevölkerungsstichprobe.

The prevalence of left ventricular systolic dysfunction (LVSD) in the general population is poorly defined. Specifically, the number of asymptomatic individuals with LVSD and, thus, the most appropriate strategy to identify and treat such subjects is still unknown. Therefore, the aim of this study was to document LV dysfunction in a middle-aged (25 to 75 years, mean 51.8+/-13.8) population - based sample in Germany (MONICA Augsburg, n=1678; echocardiography technically adequate n=1418) by M-mode and 2D-echocardiography and to analyze the importance of predisposing contributors. The overall prevalence of an ejection fraction (EF) less than 48% (mean minus 2 SD=LVSD) was 2.3% (n=33), with a slightly higher rate in men than in women (2.8% vs 1.9%, n.s.). LVSD rate increased with age: from 1.5% in individuals younger than 40 years to 4.0% among those older than 60 years of age (p<0.05). Of 33 participants with reduced left ventricular systolic function, 20 presented with at least one cardiovascular disease. The most frequent diagnoses were arterial hypertension, obesity and coronary heart disease. Only 13 subjects (0.9%) of the study population were asymptomatic without a history of cardiovascular disease. Furthermore, only 6 subjects (0.4%, 4 male) in this population presented with a moderate impairment of LV function (EF of 30 to 40%) and only 1 subject (0.07%, male) had severe LVSD (EF less than 30%). Almost all subjects with an EF less than 40% (6 of 7 individuals) had a known history of cardiovascular disease. In conclusion, LVSD is a relatively common finding in the general population. However, severe LVSD is rare in subjects without any concomitant cardiovascular disease. Thus, echocardiographic screening cannot be recommended in the unselected, middle-aged population to identify such patients.

[48-year old woman with diffuse pulmonary calcifications after allogeneic kidney transplantation. A rare manifestation of tertiary hyperparathyroidism]. / 48-jährige Patientin mit ausgedehnten pulmonalen Verkalkungen nach allogener Nierentransplantation. Seltene Manifestation eines tertiären Hyperparathyreoidismus.

HISTORY: A 48-year-old woman was hospitalized because of the presence of asymptomatic bilateral pulmonary infiltrates in the conventional chest radiograph. An antibiotic treatment administered 3 months before had been without any effect on the radiological aspect. The patient had had an end-stage renal disease of unknown cause and was on hemodialysis since 1993. 1997 she received a cadaveric renal transplant. INVESTIGATIONS: Computed tomography scan detected the infiltrates as diffuse calcifications mainly at the lung bases. Extended arterial vascular calcifications were also found. Since approximately 4 years calcium-phosphorus product and parathyroid hormone had been increased. TREATMENT AND COURSE: Because of the long-term increased calcium-phosphorus product and the high parathyroid hormone levels we interpreted the pulmonary calcifications as a result of the tertiary hyperparathyroidism. After parathyroidectomy calcium-phosphorus product and PTH levels normalized, but our patient suffered from increasing disturbances of the peripheral blood circulation induced by the vascular calcifications, necessitating amputation of finger and toe tips. CONCLUSION: Patients with renal failure should undergo regular controls of calcium, phosphorus and parathyroid hormone when creatinine clearance is below 50 ml/min/1.73 m2. Only an early medical treatment can prevent the various complications induced by the secondary or tertiary hyperparathyroidism. If medical therapy fails, parathyroidectomy has to be done. Especially before renal transplantation the extent of hyperparathyroidism has to be carefully analyzed and treated aggressively, if necessary by surgery before the date of transplantation.