Objective The aim of this study was to evaluate cardiac autonomic nervous system function using Holter-derived and standard electrocardiographic parameters in patients with myotonic dystrophy (dystrophia myotonica, DM) and no clinically overt heart involvement. Methods Eighty-four DM patients without conditions potentially influencing cardiac autonomic function were enrolled in the study: 44 with DM type 1 and 40 with DM type 2 (mean age 34.9 +/- 11.5 and 47.8 +/- 13.5 years, respectively). Two corresponding control groups of aged-matched healthy subjects were selected for DM1 (n =3D 35) and for DM2 (n =3D 30). Standard electrocardiography for QT interval dispersion and 24-h Holter monitoring with time-domain heart rate variability and heart rate turbulence were performed. Results No significant differences in time-domain heart rate variability parameters between DM1 or DM2 subjects and controls were observed. However, heart rate turbulence parameters were significantly impaired in DM1 patients as compared to their controls: turbulence onset (p =3D 0.025), and turbulence slope (p =3D 0.018). Moreover, turbulence slope was also impaired in DM2 patients (p =3D 0.042). As compared to controls, we observed an increased QT dispersion, both in DM1 (p =3D 0.003) and also in DM2 patients (p < 0.0001). No relationship between disease duration or neurological status and time-domain heart rate variability, heart rate turbulence, and QT dispersion was observed. Interpretation Despite normal time-domain heart rate parameters, impaired heart rate turbulence and increased QT dispersion may suggest cardiac autonomic nervous system dysfunction in DM patients. The present study is the first one in which heart rate turbulence and QT dispersion assessment were examined both in DM1 and DM2 patients.

Introduction: There are limited data on left (LV) and right ventricular (RV) diastolic function in systemic sclerosis (SSc) patients especially in relation to biomarkers of matrix remodeling. The aim of the study was to analyze LV and RV myocardial diastolic function in SSc patients at baseline and after at least 1 year of follow-up and its relation to serum tissue inhibitors of metalloproteinase 1 (TIMP-1) level. Material and methods: We prospectively studied 111 SSc patients (101 female, 10 male, age 54.2+/-13.8 years) and 21 age-matched controls (18 female, 3 male, age 49.3+/-10.5 years). After at least 1 year of observation (3.0+/-1.1 years) we reevaluated 69 of the SSc patients. Transthoracic echocardiography (Philips, iE33) for assessment of LV and RV diastolic function was performed and TIMP-1 serum level was measured. Results: Impaired LV relaxation was observed in 38 (34%) SSc patients and in 1 (5%) of the controls (p < 0.001). The mean E/A ratio was lower in patients with SSc than in controls (p = 0.002) and significantly decreased after the follow-up period (p = 0.02). Impaired RV relaxation was detected in 25 (22.5%) SSc patients and in 1 (5%) control subject (p < 0.001) but did not deteriorate after follow-up. Mean serum level of TIMP-1 was significantly elevated in the follow-up group compared to baseline examination (p = 0.0001). Serum TIMP-1 level correlated positively with E/E', both septal and lateral (r = 0.4, p = 0.002 and r = 0.32, p = 0.01). Conclusions: The LV and RV relaxation is impaired in SSc patients. Moreover, left ventricular diastolic function deteriorated after the follow-up period. The TIMP-1 serum levels correlate with echocardiographic parameters, providing a potent link for LV diastolic function and matrix remodeling in patients with SSc.

To externally validate the prognostic impact of copeptin, either alone or integrated in risk stratification models, in pulmonary embolism (PE), we performed a post hoc analysis of 843 normotensive PE patients prospectively included in three European cohorts. Within the first 30 days, 21 patients (2.5%, 95% CI 1.5-3.8) had an adverse outcome and 12 (1.4%, 95% CI 0.7-2.5) died due to PE. Patients with copeptin. 24 pmol.L-1 had a 6.3-fold increased risk for an adverse outcome (95% CI 2.6-15.5, p<0.001) and a 7.6-fold increased risk for PE-related death (95% CI 2.3-25.6, p=3D0.001). Risk classification according to the 2014 European Society of Cardiology (ESC) guideline algorithm identified 248 intermediate-high-risk patients (29.4%) with 5.6% (95% CI 3.1-9.3) at risk of adverse outcomes. A stepwise biomarker-based risk assessment strategy (based on high-sensitivity troponin T, N-terminal pro-brain natriuretic peptide and copeptin) identified 123 intermediate-high-risk patients (14.6%) with 8.9% (95% CI 4.5-15.4) at risk of adverse outcomes. The identification of patients at higher risk was even better when copeptin was measured on top of the 2014 ESC algorithm in intermediate-high-risk patients (adverse outcome OR 11.1, 95% CI 4.6-27.1, p<0.001; and PE-related death OR 13.5, 95% CI 4.2-43.6, p<0.001; highest risk group versus all other risk groups). This identified 85 patients (10.1%) with 12.9% (95% CI 6.6-22.0) at risk of adverse outcomes and 8.2% (95% CI 3.4-16.2) at risk of PE-related deaths. Copeptin improves risk stratification of normotensive PE patients, especially when identifying patients with an increased risk of an adverse outcome.

BAG3 belongs to BAG family of molecular chaperone regulators interacting with HSP70 and anti-apoptotic protein Bcl-2. It is ubiquitously expressed with strong expression in skeletal and cardiac muscle, and is involved in a panoply of cellular processes. Mutations in BAG3 and aberrations in its expression cause fulminant myopathies, presenting with progressive limb and axial muscle weakness, and respiratory insufficiency and neuropathy. Herein, we report a sporadic case of a 15-years old girl with symptoms of myopathy, demyelinating polyneuropathy and asymptomatic long QT syndrome. Genetic testing demonstrated heterozygous mutation Pro209Leu (c.626C>T) in exon 3 of BAG3 gene causing severe myopathy and neuropathy, often associated with restrictive cardiomyopathy. We did not find a mutation in any known LQT syndrome genes. Analysis of muscle biopsy revealed profound disintegration of Z-discs with extensive accumulation of granular debris and large inclusions within fibers. We demonstrated profound alterations in BAG3 distribution as the protein localized to long filamentous structures present across the fibers that were positively stained not only for alpha-actinin but also for desmin and filamin indicating that those disintegrated Z-disc regions contained also other sarcomeric proteins. The mutation caused a decrease in the content of BAG3 and HSP70, and also of alpha-actinin desmin, filamin and fast myosin heavy chain, confirming its severe effect on the muscle fiber morphology and thus function. We provide further evidence that BAG3 is associated with Z-disc maintenance, and the Pro209Leu mutation may occur worldwide. We also provide a summary of cases associated with this mutation reported so far. =20

Introduction: In acute pulmonary embolism (APE) the increase of pulmonary vascular resistance depends on the thromboli load and potentially on the pulmonary bed contraction caused by neurohormonal reaction. Plasma levels of endothelin were reported to be elevated in pulmonary arterial hypertension. However, there are only a few studies assessing endothelin in patients with APE.Materials & Methods: Therefore in our study we evaluated endothelin concentration in 55 patients (29M, 26F, age 57 +/- 19 yrs) with confirmed APE for potential value in risk stratification. Patients were compared with 24 healthy volunteers at similar age. On admission blood samples were collected for plasma endothelin concentration. The quantitative assessment of right ventricular (RV) function was performed by echocardiography.Results: endothelin concentrations were similar in APE patients and in control group (1.41(0.22-9.68)pg/mL vs. 1.62(0.27-8.92)pg/mL; p = NS). There was no differences in endothelin levels between APE patients with and without RV dysfunction (1.46(0.38-4.54)pg/mL vs. 1.41(0.22-9.68)pg/mL; p = NS). Endothelin concentration did not differ between patients with serious adverse events and APE group with event-free clinical course (3.19(0.38-4.27)pg/mL vs. 1.38(0.22-9.68)pg/mL; p = NS). There was no significant correlation between endothelin levels and blood saturation, time from the first symptoms, heart rate, blood pressure, tricuspid valve regurgitation pressure gradient and other echocardiographic parameters.Conclusions: We concluded that plasma endothelin concentrations assessed on admission are not elevated in patients with APE and it does not play as important role in acute phase of increase of pressure in pulmonary arteries as in chronic pulmonary hypertension. (C) 2008 Elsevier Ltd. All rights reserved.

OBJECTIVES The goal of the study was to evaluate the prognostic value of echocardiographic indices of right ventricular dysfunction (RVD) for prediction of pulmonary embolism related 30-day mortality or need for rescue thrombolysis in initially normotensive patients with acute pulmonary embolism (APE). BACKGROUND There is no generally accepted echocardiographic definition of RVD used for prognosis in APE. METHODS We studied the prognostic value of a set of echocardiographic parameters in 411 consecutive patients (234 women, age 64 +/- 18 years) with APE hemodynamically stable at admission. RESULTS Thirty-day APE-related mortality was 3% (14 patients), all-cause mortality was 5% (21 patients). Nine patients received thrombolysis as a result of hemodynamic deterioration, and 7 of them survived. The clinical endpoint (CE), which included APE-related death or thrombolysis, occurred in 21 patients. At univariable Cox analysis, the hazard ratio (HR) for CE of the right ventricular (RV)/left ventricular (LV) ratio was 7.3 (95% confidence interval [Cl]: 2.0 to 27.3; p = 0.003). However, multivariable analysis showed that tricuspid annulus plane systolic excursion (TAPSE) was the only independent predictor (HR: 0.64, 95% Cl: 0.54 to 0.7; p < 0.0001). Moreover, the area under the curve (AUC) in receiver-operating characteristic analysis for TAPSE (0.91, 95% Cl: 0.856 to 0.935; p = 0.0001) in CE prediction was higher (p < 0.001) than AUC of RV/LV ratio (0.638, 95% Cl: 0.589 to 0.686; p = 0.001). TAPSE <= 15 mm had a HR of 27.9 (95% Cl: 6.2 to 124.6; p < 0.0001) and a positive predictive value (PPV) of 20.9% for CE with a 99% negative predictive value (NPV), whereas TAPSE <= 20 mm had a PPV of 9.2 with a 100% NPV. RV/LV ratios of >0.9 and >1.0 had a PPV of 13.2% and 14.4% and a NPV of 97% and 94.3%, respectively. CONCLUSIONS TAPSE is preferable to the RV/LV ratio for risk stratification in initially normotensive patients with APE. TAPSE <= 15 mm identifies patients with an increased risk of 30-day APE-related mortality, whereas TAPSE >20 mm can be used for identification of a very low-risk group. (C) 2014 by the American College of Cardiology Foundation

Myocardial stretch leads to the natriuretic peptides release in acute or chronic left ventricular dysfunction. However, there is an accumulating evidence that B-type natriuretic peptide (BNP) and its N-terminal fragment (NT-proBNP) may originate from right ventricle and their concentrations elevated in patients with acute pulmonary embolism (APE) especially when resulting in right ventricular dysfunction (RVD). Recently it is underlined that severity assessment of APE as well as the risk stratification and therapy selection is based both on patients' hemodynamic status and markers of myocardial injury and RVD. BNP and NT-proBNP are helpful in identifying patients with RVD in APE, emerging as an adjunctive tool to echocardiography. Elevated BNP or NT-proBNP levels are also significant predictors of death and/or complicated clinical course in APE. (C) 2008 Elsevier B.V. All rights reserved.

Right ventricular (RV) overload and hypoxia in acute pulmonary embolism (APE) may lead to RV myocardium injury reflected by elevated cardiac troponin levels. We studied 26 patients aged 57.2 +/- 17.8 years with first episode of APE. On admission troponin T (TnT) was measured. Transthoracic echocardiography was performed after 6 months of anticoagulation. Myocardial injury (TnT >= 0.03 ng/ml) was observed in 8 (30.8%) patients at the diagnosis. At follow up RV diastolic area tended to be larger in group with myocardial injury (25.0 (20.8-38.6) vs 18.4 (17.7-23.3) cm(2), p=0.06). Tricuspid annulus systolic velocity at tissue Doppler was lower in group with myocardial injury (0.12 (0.11-0.13) vs 0.15 (0.13-0.21) m/s, p=0.04), while no such a relationship was found for mitral annulus systolic velocity. TnT concentration correlated with RV diastolic area (r=0.61) and tricuspid annulus systolic velocity (r=-0.58) although not significantly (p=0.08 and p=0.09. respectively). Our data suggest that RV injury in acute phase of PE may lead to its remodeling. (c) 2007 Elsevier Ireland Ltd. All rights reserved.

Aims: Low levels of brain natriuretic peptides on admission identify low-risk patients with acute pulmonary embolism (APE) through their high NPV for mortality. However, increased natriuretic peptide values on admission are less helpful for identifying high-risk patients due to their low PPV The aim of the study was to test whether the PPV for mortality can be improved by performing serial NT-proBNP measurements on admission, at 12 h, and at 24 h. Methods and results: We prospectively included 113 consecutive patients with APE (mean age 63 +/- 18 years), of whom 10 had clinically massive APE. Thirty-day mortality was 15% (95% CI: 8%-22%). In survivors, median NT proBNP levels decreased within 24 h from 1895 ng/L (range: 16-33,340) to 1007 ng/L (range: 9-33,243) (p<0.001). In non-survivors, median NT-proBNP levels at baseline (11,491 ng/L, range: 618-60,958) remained elevated at 24 h (8139 ng/L, range: 35-70,018; p=NS). The 30-day mortality rate in the group of 18 patients with NT proBNP >7500 ng/L and less than 50% decrease of NT proBNP within 24 h was 61% (95% CI: 39%-84%). PPV and NPV of NT-proBNP >7500 ng/L on admission and less than 50% decrease of NT proBNP within 24 h were 61% and 94%, respectively. Conclusion: Persistent elevation of plasma NT-proBNP levels within 24 h after APE diagnosis indicates ongoing right ventricular dysfunction with a poor prognosis. These critically ill patients may be candidates for rapid aggressive intervention, including thrombolysis, catheter thrombectomy, or surgical embolectomy. (c) 2007 Elsevier B.V. All rights reserved.

Background: Risk factors for atherosclerosis and venous thromboembolism(VTE) overlap and are mostly associated with endothelial dysfunction (ED). We hypothesized that ED is present in patients after the first episode of acute pulmonary embolism(APE) and predicts the risk of VTE recurrence. Design and Methods: Patients, at least 6 months after the first episode of symptomatic, confirmed APE were included in this case-control study. The exclusion criteria were risk factors for cardiovascular diseases and other conditions associated with endothelial dysfunction. Eighty two patients (aged 38 +/- 11 years; 44 M; 38 F) were enrolled in the study, 39 after provoked APE, 43 after unprovoked APE, and 30 controls (C) (aged 38 +/- 12 years; 15 M, 15 F). In order to evaluate the endothelial function in patients with a history of APE flow-mediated dilation (FMD) of the brachial artery and biomarkers of endothelial dysfunction (sVCAM-1, sICAM-1, ADMA, E-selectin) were measured. Subsequently all patients were followed up in an outpatient clinic for VTE recurrence. Results: FMD was more often impaired in APE patients than in controls (5.3% (0.8-20.3) vs. 13.8% (4.1-24.3); p < 0.0001). Biomarker levels differed between APE and C groups: sVCAM-1 (631 ng/ml (105-2382) vs. 495 ng/ml (348-934); p =3D 0.04) and sICAM-1 (679 ng/ml (279-1006) vs. 600 ng/ml (394-766); p =3D 0.002). There were 19 recurrences of VTE during the at least 12-month follow-up (15 with history of unprovoked-APE and 4 after provoked-APE). E-selectin =3D 39 ng/ml and sICAM-1 =3D 655 ng/ml indicated the group without recurrence of VTE. In a group of 43 unprovoked APE patients both E-selectin < 39 ng/ml and sICAM-1 > N 655 ng/ml were found in 17 subjects. Eleven of them (65%) were diagnosed with recurrent VTE. Conclusions: Endothelial function is significantly impaired in patients after an episode of APE as indicated by FMD assessment and biomarker levels. Low concentrations of E-selectin and high levels of sICAM-1 are associated with a high risk of recurrent thromboembolism. (C) 2017 Elsevier Ltd. All rights reserved.