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Erscheinungsjahr
- 2011 (15) (entfernen)
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- Englisch (15) (entfernen)
Schlagworte
- Heart failure (2)
- Mortality (2)
- African-americans (1)
- Alpha-galactosidase (1)
- Amino acids (1)
- Antigen 4 (1)
- Autoimmune-Diseases (1)
- CD9 (1)
- Cardiac resynchronization therapy defibrillator (1)
- Cardiovascular hospitalizations (1)
- Chronic Kidney-disease (1)
- Chronic kidney-disease (1)
- Clinical proteomics (1)
- Clinical-trials (1)
- Comorbidities (1)
- Cumulative incidence function (1)
- Dendritic Cells (1)
- Desmoplakin (1)
- Diabetic-nephropathy (1)
- Diastocic Dysfunction (1)
- Discovery (1)
- Eplerenone (1)
- FoxP3 Expression (1)
- Framingham (1)
- General-population (1)
- Gewebedoppler (1)
- Globotriaosylceramide (1)
- Glomerular-filtration-rate (1)
- HIV (1)
- HIV diagnosis and management (1)
- Haemodialysis (1)
- Hazards (1)
- Heart failure with preserved ejection fraction (1)
- Heart failure with reduced ejection fraction (1)
- Hemodialysis-patients (1)
- Home monitoring (1)
- Homoarginine (1)
- Hyperkalemia (1)
- Immune-System (1)
- Immunological Self-Tolerance (1)
- Juvenile biventricular cardiomyopathy (1)
- Mass-spectrometry (1)
- Medicine (1)
- Medizin (1)
- Model (1)
- Morbidity (1)
- Multiparameter predictor (1)
- Multiple-Sclerosis (1)
- Myocardial-Infarction (1)
- Non-Compaction Kardiomyopathie (1)
- Onset hypertrophic cardiomyopathy (1)
- Outcomes (1)
- Palmoplantar keratoderma (1)
- Physical impairment (1)
- Predictors (1)
- Preserved Ejection Fraction (1)
- Prevalence (1)
- Probabilities (1)
- Progression (1)
- Regression (1)
- Remote device monitoring (1)
- Risk (1)
- Sample-sizes (1)
- Sex-Hormones (1)
- Speckle tracking (1)
- Stage renal-disease (1)
- Subdistribution (1)
- Sudden cardiac death (1)
- Suppressive Function (1)
- Systemic-Lupus-Erythematosus (1)
- Tanzania (1)
- Tests (1)
- Ultraschallkardiographie (1)
- Variants (1)
- Young-patients (1)
- adenovirus (1)
- adrenal cortex hormones (1)
- adrenal cortex neoplasms (1)
- antimicrobial resistance (1)
- antiretroviral therapy (1)
- antiretrovirals (1)
- gene-therapy (1)
- identification (1)
- infection (1)
- left ventricular non-compaction (1)
- mass spectrometry (1)
- metabolomics (1)
- mutation databases (1)
- panel (1)
- receptor (1)
- sequence databases (1)
- speckle tracking (1)
- urine (1)
Institut
- Medizinische Klinik und Poliklinik I (15) (entfernen)
EU-Projektnummer / Contract (GA) number
- 259735 (1)
Two sons of a consanguineous marriage developed biventricular cardiomyopathy. One boy died of severe heart failure at the age of 6 years, the other was transplanted because of severe heart failure at the age of 10 years. In addition, focal palmoplantar keratoderma and woolly hair were apparent in both boys. As similar phenotypes have been described in Naxos disease and Carvajal syndrome, respectively, the genes for plakoglobin (JUP) and desmoplakin (DSP) were screened for mutations using direct genomic sequencing. A novel homozygous 2 bp deletion was identified in an alternatively spliced region of DSP. The deletion 5208_5209delAG led to a frameshift downstream of amino acid 1,736 with a premature truncation of the predominant cardiac isoform DSP-1. This novel homozygous truncating mutation in the isoform-1 specific region of the DSP C-terminus caused Carvajal syndrome comprising severe early-onset heart failure with features of non-compaction cardiomyopathy, woolly hair and an acantholytic form of palmoplantar keratoderma in our patient. Congenital hair abnormality and manifestation of the cutaneous phenotype in toddler age can help to identify children at risk for cardiac death.
Background:
Pre- and early clinical studies on patients with autoimmune diseases suggested that induction of regulatory T(T(reg)) cells may contribute to the immunosuppressive effects of glucocorticoids(GCs).
Objective:
We readdressed the influence of GC therapy on T(reg) cells in immunocompetent human subjects and naive mice.
Methods:
Mice were treated with increasing doses of intravenous dexamethasone followed by oral taper, and T(reg) cells in spleen and blood were analyzed by FACS. Sixteen patients with sudden hearing loss but without an inflammatory disease received high-dose intravenous prednisolone followed by stepwise dose reduction to low oral prednisolone. Peripheral blood T(reg) cells were analyzed prior and after a 14 day GC therapy based on different markers.
Results:
Repeated GC administration to mice for three days dose-dependently decreased the absolute numbers of T(reg) cells in blood (100 mg dexamethasone/kg body weight: 2.8 +/- 1.8 x 10(4) cells/ml vs. 33 +/- 11 x 10(4) in control mice) and spleen (dexamethasone: 2.8 +/- 1.9 x 10(5)/spleen vs. 95 +/- 22 x 10(5)/spleen in control mice), which slowly recovered after 14 days taper in spleen but not in blood. The relative frequency of FOXP3(+) T(reg) cells amongst the CD4(+) T cells also decreased in a dose dependent manner with the effect being more pronounced in blood than in spleen. The suppressive capacity of T(reg) cells was unaltered by GC treatment in vitro. In immunocompetent humans, GCs induced mild T cell lymphocytosis. However, it did not change the relative frequency of circulating T(reg) cells in a relevant manner, although there was some variation depending on the definition of the T(reg) cells (FOXP3(+): 4.0 +/- 1.5% vs 3.4 +/- 1.5%*; AITR(+): 0.660.4 vs 0.5 +/- 0.3%, CD127(low): 4.0 +/- 1.3 vs 5.0 +/- 3.0%* and CTLA4+: 13.8 +/- 11.5 vs 15.6 +/- 12.5%; * p < 0.05).
Conclusion:
Short-term GC therapy does not induce the hitherto supposed increase in circulating T(reg) cell frequency, neither in immunocompetent humans nor in mice. Thus, it is questionable that the clinical efficacy of GCs is achieved by modulating T(reg) cell numbers.
Aim
To investigate whether diagnostic data from implanted cardiac resynchronization therapy defibrillators (CRT-Ds) retrieved automatically at 24 h intervals via a Home Monitoring function can enable dynamic prediction of cardiovascular hospitalization and death.
Methods and results
Three hundred and seventy-seven heart failure patients received CRT-Ds with Home Monitoring option. Data on all deaths and hospitalizations due to cardiovascular reasons and Home Monitoring data were collected prospectively during 1-year follow-up to develop a predictive algorithm with a predefined specificity of 99.5%. Seven parameters were included in the algorithm: mean heart rate over 24 h, heart rate at rest, patient activity, frequency of ventricular extrasystoles, atrial–atrial intervals (heart rate variability), right ventricular pacing impedance, and painless shock impedance. The algorithm was developed using a 25-day monitoring window ending 3 days before hospitalization or death. While the retrospective sensitivities of the individual parameters ranged from 23.6 to 50.0%, the combination of all parameters was 65.4% sensitive in detecting cardiovascular hospitalizations and deaths with 99.5% specificity (corresponding to 1.83 false-positive detections per patient-year of follow-up). The estimated relative risk of an event was 7.15-fold higher after a positive predictor finding than after a negative predictor finding.
Conclusion
We developed an automated algorithm for dynamic prediction of cardiovascular events in patients treated with CRT-D devices capable of daily transmission of their diagnostic data via Home Monitoring. This tool may increase patients’ quality of life and reduce morbidity, mortality, and health economic burden, it now warrants prospective studies.
Isolated left ventricular non-compaction cardiomyopathy (LVNC) is a congenital myocardial disease characterized by excessive and prominent trabeculations in the left ventricle with deep intertrabecular recesses. Trabeculation is, however, a non specific finding which is present not only in LVNC but also in other cardiomyopathies like dilated cardiomyopathy (DCM) and even in healthy controls, therefore, differential diagnosis keeps puzzling clinicians. Therefore the present study aimed to comprehensively explore regional myocardial deformation properties in adult patients with isolated LVNC using strain and strain rate imaging derived from tissue Doppler imaging and 2D speckle tracking. It was proposed that the knowledge of deformation properties in LVNC would help to differentiate patients with LVNC and DCM. A total of 14 patients with LVNC, 15 patients with DCM, and 15 healthy controls were included in this study. The groups were matched for age and gender. Standard 2D echocardiography was performed in all subjects, and tissue Doppler imaging (TDI) of all ventricular walls was acquired using parasternal long axis, apical 4-chamber, 2-chamber, and apical long axis views. Deformation imaging data derived from both TDI and grey scale images were analyzed. Clinical and standard echocardiographic findings in patients with LVNC and DCM were similar. In patients with LVNC, hypertrabeculation was mostly located in the apical and mid segments of the left ventricle and strikingly more than in patients with DCM. The extent of non-compaction was poorly related to global left ventricular systolic function (LVEF) as well as regional myocardial function assessed by strain rate imaging. Regional myocardial systolic deformation in patients with LVNC was significantly impaired in the left and right ventricles in both longitudinal and radial direction. There was a striking difference on longitudinal myocardial systolic function between LVNC and DCM patients, i.e., an increasing strain and strain rate gradient from apex to base in patients with LVNC, whereas patients with DCM displayed a homogeneously decreased strain and strain rate in all segments. Results derived from 2D speckle tracking method were consistent with those from TDI method. Analysis of myocardial mechanical asynchrony revealed a lack of myocardial contraction synchrony in the LVNC and DCM patients. The time to systolic peak velocity was obviously delayed in these two patient groups. However, the mechanical asynchrony features were similar in patients with LVNC and DCM and could not serve for differential diagnosis. In conclusion, LVNC and DCM are both cardiomyopathies presenting reduced regional myocardial function and mechanical asynchrony. Nevertheless differential diagnosis can be made by analysis of hypertrabeculation as well as analysis of regional myocardial deformation pattern.
Female patients affected by Fabry disease, an X-linked lysosomal storage disorder, exhibit a wide spectrum of symptoms, which renders diagnosis, and treatment decisions challenging. No diagnostic test, other than sequencing of the alpha-galactosidase A gene, is available and no biomarker has been proven useful to screen for the disease, predict disease course and monitor response to enzyme replacement therapy. Here, we used urine proteomic analysis based on capillary electrophoresis coupled to mass spectrometry and identified a biomarker profile in adult female Fabry patients. Urine samples were taken from 35 treatment-naive female Fabry patients and were compared to 89 age-matched healthy controls. We found a diagnostic biomarker pattern that exhibited 88.2% sensitivity and 97.8% specificity when tested in an independent validation cohort consisting of 17 treatment-naive Fabry patients and 45 controls. The model remained highly specific when applied to additional control patients with a variety of other renal, metabolic and cardiovascular diseases. Several of the 64 identified diagnostic biomarkers showed correlations with measures of disease severity. Notably, most biomarkers responded to enzyme replacement therapy, and 8 of 11 treated patients scored negative for Fabry disease in the diagnostic model. In conclusion, we defined a urinary biomarker model that seems to be of diagnostic use for Fabry disease in female patients and may be used to monitor response to enzyme replacement therapy.
Background
The World Health Organization (WHO) has recommended guidelines for a HIV drug resistance (HIVDR) survey for resource-limited countries. Eligibility criteria for patients include age below 25 years in order to focus on the prevalence of transmitted HIVDR (tHIVDR) in newly-infected individuals. Most of the participating sites across Africa have so far reported tHIVDR prevalences of below 5%. In this study we investigated whether the rate of HIVDR in patients <25 years is representative for HIVDR in the rest of the therapy-naïve population.
Methods and Findings
HIVDR was determined in 88 sequentially enrolled ART-naïve patients from Mwanza, Tanzania (mean age 35.4 years). Twenty patients were aged <25 years and 68 patients were aged 25–63 years. The frequency of HIVDR in the study population was 14.8% (95%; CI 0.072–0.223) and independent of NVP-resistance induced by prevention of mother-to-child transmission programs. Patients >25 years had a significantly higher HIVDR frequency than younger patients (19.1%; 95% CI 0.095–0.28) versus 0%, P = 0.0344). In 2 out of the 16 patients with HIVDR we found traces of antiretrovirals (ARVs) in plasma.
Conclusions
ART-naïve patients aged over 25 years exhibited significantly higher HIVDR than younger patients. Detection of traces of ARVs in individuals with HIVDR suggests that besides transmission, undisclosed misuse of ARVs may constitute a significant factor in the generation of the observed high HIVDR rate. The current WHO tHIVDR survey that is solely focused on the transmission of HIVDR and that excludes patients over 25 years of age may therefore result in substantial underestimation of the prevalence of HIVDR in the therapy-naïve population. Similar studies should be performed also in other areas to test whether the so far reported optimistic picture of low HIVDR prevalence in young individuals is really representative for the rest of the ART-naïve HIV-infected population.
Background: Pre- and early clinical studies on patients with autoimmune diseases suggested that induction of regulatory T(Treg) cells may contribute to the immunosuppressive effects of glucocorticoids(GCs). Objective: We readdressed the influence of GC therapy on Treg cells in immunocompetent human subjects and naı¨ve mice. Methods: Mice were treated with increasing doses of intravenous dexamethasone followed by oral taper, and Treg cells in spleen and blood were analyzed by FACS. Sixteen patients with sudden hearing loss but without an inflammatory disease received high-dose intravenous prednisolone followed by stepwise dose reduction to low oral prednisolone. Peripheral blood Treg cells were analyzed prior and after a 14 day GC therapy based on different markers. Results: Repeated GC administration to mice for three days dose-dependently decreased the absolute numbers of Treg cells in blood (100 mg dexamethasone/kg body weight: 2.861.86104 cells/ml vs. 336116104 in control mice) and spleen (dexamethasone: 2.861.96105/spleen vs. 956226105/spleen in control mice), which slowly recovered after 14 days taper in spleen but not in blood. The relative frequency of FOXP3+ Treg cells amongst the CD4+ T cells also decreased in a dose dependent manner with the effect being more pronounced in blood than in spleen. The suppressive capacity of Treg cells was unaltered by GC treatment in vitro. In immunocompetent humans, GCs induced mild T cell lymphocytosis. However, it did not change the relative frequency of circulating Treg cells in a relevant manner, although there was some variation depending on the definition of the Treg cells (FOXP3+: 4.061.5% vs 3.461.5%*; AITR+: 0.660.4 vs 0.560.3%, CD127low: 4.061.3 vs 5.063.0%* and CTLA4+: 13.8611.5 vs 15.6612.5%; * p,0.05). Conclusion: Short-term GC therapy does not induce the hitherto supposed increase in circulating Treg cell frequency, neither in immunocompetent humans nor in mice. Thus, it is questionable that the clinical efficacy of GCs is achieved by modulating Treg cell numbers.
Background:
To assess heart failure therapies in diabetic patients with preserved as compared to impaired systolic ventricular function.
Methods:
3304 patients with heart failure from 9 different studies were included (mean age 63 +/- 14 years); out of these, 711 subjects had preserved left ventricular ejection fraction (>= 50%) and 994 patients in the whole cohort suffered from diabetes.
Results:
The majority (>90%) of heart failure patients with reduced ejection fraction (SHF) and diabetes were treated with an ACE inhibitor (ACEi) or angiotensin receptor blocker (ARB) or with beta-blockers. By contrast, patients with diabetes and preserved ejection fraction (HFNEF) were less likely to receive these substance classes (p < 0.001) and had a worse blood pressure control (p < 0.001). In comparison to patients without diabetes, the probability to receive these therapies was increased in diabetic HFNEF patients (p < 0.001), but not in diabetic SHF patients. Aldosterone receptor blockers were given more often to diabetic patients with reduced ejection fraction (p < 0.001), and the presence and severity of diabetes decreased the probability to receive this substance class, irrespective of renal function.
Conclusions:
Diabetic patients with HFNEF received less heart failure medication and showed a poorer control of blood pressure as compared to diabetic patients with SHF. SHF patients with diabetes were less likely to receive aldosterone receptor blocker therapy, irrespective of renal function.
Background
Comorbidities negatively affect prognosis more strongly in heart failure with preserved (HFpEF) than with reduced (HFrEF) ejection fraction. Their comparative impact on physical impairment in HFpEF and HFrEF has not been evaluated so far.
Methods and results
The frequency of 12 comorbidities and their impact on NYHA class and SF-36 physical functioning score (SF-36 PF) were evaluated in 1,294 patients with HFpEF and 2,785 with HFrEF. HFpEF patients had lower NYHA class (2.0 ± 0.6 vs. 2.4 ± 0.6, p < 0.001) and higher SF-36 PF score (54.4 ± 28.3 vs. 54.4 ± 27.7, p < 0.001). All comorbidities were significantly (p < 0.05) more frequent in HFrEF, except hypertension and obesity, which were more frequent in HFpEF (p < 0.001). Adjusting for age and gender, COPD, anemia, hyperuricemia, atrial fibrillation, renal dysfunction, cerebrovascular disease and diabetes had a similar (p for interaction > 0.05) negative effect in both groups. Obesity, coronary artery disease and peripheral arterial occlusive disease exerted a significantly (p < 0.05) more adverse effect in HFpEF, while hypertension and hyperlipidemia were associated with fewer (p < 0.05) symptoms in HFrEF only. The total impact of comorbidities on NYHA (AUC for prediction of NYHA III/IV vs. I/II) and SF-36 PF (r 2) in multivariate analyses was approximately 1.5-fold higher in HFpEF, and also much stronger than the impact of a 10% decrease in ejection fraction in HFrEF or a 5 mm decrease in left ventricular end-diastolic diameter in HFpEF.
Conclusion
The impact of comorbidities on physical impairment is higher in HFpEF than in HFrEF. This should be considered in the differential diagnosis and in the treatment of patients with HFpEF.