Publications by authors named "Felix Mehrhof"

17 Publications

  • Page 1 of 1

External application of liver compresses to reduce fatigue in patients with metastatic cancer undergoing radiation therapy, a randomized clinical trial.

Radiat Oncol 2021 Apr 19;16(1):76. Epub 2021 Apr 19.

Division of Oncology and Hematology, Department of Pediatrics, Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany.

Background: Liver compresses are frequently used in integrative medicine as supportive therapy during cancer treatment in order to reduce fatigue. We performed a pilot study to test whether the external application of yarrow liver compresses impacts fatigue in patients with metastatic cancer undergoing radiation therapy.

Methods: A randomized prospective pilot trial was performed including patients with brain metastasis or bone metastasis of solid tumors. Patients underwent either palliative radiation therapy (RT) of the metastatic lesions (control group) over two weeks or the same RT with additional external application of yarrow liver compresses once daily during RT. The primary objective was improvement on the general fatigue subscale of the multidimensional fatigue inventory (MFI-20) at the end of treatment, where a mean difference of two points is considered clinically relevant. Secondary objectives included psychological distress, quality of life and qualitative analysis with self-established visual analogue scales (VAS). Mean differences in general fatigue at the end of treatment compared to baseline were analyzed using the ANCOVA test.

Results: From 09/2017 to 08/2019 a total of 39 patients were randomized. Due to drop outs 24 patients (12 per group) were available for analysis. Patients in the intervention group received a mean number of 10.5 (range, 7-14) applications of yarrow liver compresses. The mean improvement at the end of therapy on the general fatigue subscale of the MFI-20 was 2 points in favor of the intervention group (p = 0.13), and all other MFI-20 subscales showed at least a trend towards improvement in favor of the intervention group. Likewise, psychological distress and VAS data was improved, the latter reaching statistical significance for the symptoms fatigue, tension and lack of drive. Major toxicities were not observed.

Conclusions: External application of liver compresses appears to reduce fatigue within a clinical relevant range in patients with metastatic cancer undergoing radiation therapy.

Trial Registration: ISRCTN, ICTRP DRKS00012999.
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April 2021

Salvage-Radiation Therapy and Regional Hyperthermia for Biochemically Recurrent Prostate Cancer after Radical Prostatectomy (Results of the Planned Interim Analysis).

Cancers (Basel) 2021 Mar 6;13(5). Epub 2021 Mar 6.

Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Radiation Oncology, 13353 Berlin, Germany.

Efforts to improve the outcome of prostate cancer (PC) patients after radical prostatectomy (RP) include adjuvant or salvage radiation therapy (SRT), but still up to 50% of patients develop a disease progression after radiotherapy (RT). Regional hyperthermia (HT) is well-known to improve tumor sensitivity to RT in several entities. Here we report on a planned interim analysis of tolerability and feasibility after recruitment of the first 50 patients of a trial combining SRT and HT. We conducted a prospective multicenter non-randomized Phase-II-Trial (HTProstate-NCT04159051) investigating the implementation of combined moderate-dose escalated SRT (70 Gy in 35 fractions) and locoregional deep HT (7-10 HT sessions). The primary endpoints were the rate of acute genitourinary (GU), gastrointestinal (GI), and HT-related toxicities, completed HT sessions (≥7), and SRT applications per protocol (≥95% of patients). The two-step design included a planned interim analysis for acute GU-, GI- and HT-specific toxicities to ensure patients' safety. Between November 2016 and December 2019, 52 patients entered into the trial. After 50 patients completed therapy and three months of follow-up, we performed the planned interim analysis. 10% of patients developed acute grade 2 GU and 4% grade 2 GI toxicities. No grade ≥3 GU or GI toxicities occurred. HT-specific symptoms grade 2 and 3 were observed in 4% and 2% of all patients. Thus, the pre-specified criteria for safety and continuation of recruitment were met. Moreover, ≥7 HT treatments were applicable, indicating the combination of SRT + HT to be feasible. Evaluation of early QoL showed no significant changes. With its observed low rate of GU and GI toxicities, moderate and manageable rates of HT-specific symptoms, and good feasibility, the combined SRT + HT seems to be a promising treatment approach for biochemical recurrence after RP in PC patients.
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March 2021

Fever range whole body hyperthermia for re-irradiation of head and neck squamous cell carcinomas: Final results of a prospective study.

Oral Oncol 2021 Feb 21;116:105240. Epub 2021 Feb 21.

Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Radiation Oncology, Berlin, Germany.

Objectives: Fever-range whole body hyperthermia (FRWBH) has been shown to improve tumor oxygenation in vivo. A prospective pilot study addressed the question if addition of FRWBH to re-irradiation is feasible in recurrent head and neck squamous cell carcinomas (HNSCC) with unfavorable prognostic features.

Materials And Methods: The study completed accrual with the recruitment of ten patients between April 2018 and March 2020. Re-irradiation was administered using volumetric arc hyperfractionated radiotherapy with bi-daily 1.2 Gray (Gy) single fractions and a total dose of 66 Gy to all macroscopic tumor lesions. Concomitant chemotherapy consisted mostly of cisplatin (7 patients). FRWBH was scheduled weekly during re-irradiation. The study was registered in the database (NCT03547388).

Results: Only five patients received all cycles of FRWBH. Poor patient compliance, active infections during treatment and study restrictions due to the Covid-19 pandemic were the main reasons for omitting FRWBH. No increase of acute toxicity was observed by FRWBH. Exploratory evaluation of outcome data suggests that FRWBH treatment according to protocol does not seem to have a detrimental effect on tumor control or survival and might even increase treatment efficacy.

Conclusion: FRWBH is difficult to apply concomitant to re-irradiation in HNSCC. No excess toxicity was observed in patients receiving FRWBH and exploratory analyses suggest potential anti-tumor activity and decreased patient-reported depression scores after FRWBH.
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February 2021

Interdisciplinary Clinical Target Volume Generation for Cardiac Radioablation: Multicenter Benchmarking for the RAdiosurgery for VENtricular TAchycardia (RAVENTA) Trial.

Int J Radiat Oncol Biol Phys 2021 Jan 27. Epub 2021 Jan 27.

I. Medizinische Klinik, Universitätsklinikum Mannheim and German Center for Cardiovascular Research (DZHK), Partner Site Heidelberg/Mannheim, Mannheim, Germany.

Purpose: Cardiac radioablation is a novel treatment option for therapy-refractory ventricular tachycardia (VT) ineligible for catheter ablation. Three-dimensional clinical target volume (CTV) definition is a key step, and this complex interdisciplinary procedure includes VT-substrate identification based on electroanatomical mapping (EAM) and its transfer to the planning computed tomography (PCT). Benchmarking of this process is necessary for multicenter clinical studies such as the RAVENTA trial.

Methods And Materials: For benchmarking of the RAVENTA trial, patient data (epicrisis, electrocardiogram, high-resolution EAM, contrast-enhanced cardiac computed tomography, PCT) of 3 cases were sent to 5 university centers for independent CTV generation, subsequent structure analysis, and consensus finding. VT substrates were first defined on multiple EAM screenshots/videos and manually transferred to the PCT. The generated structure characteristics were then independently analyzed (volume, localization, surface distance and conformity). After subsequent discussion, consensus structures were defined.

Results: VT substrate on the EAM showed visible variability in extent and localization for cases 1 and 2 and only minor variability for case 3. CTVs ranged from 6.7 to 22.9 cm, 5.9 to 79.9 cm, and 9.4 to 34.3 cm; surface area varied from 1087 to 3285 mm, 1077 to 9500 mm, and 1620 to 4179 mm, with a Hausdorff-distance of 15.7 to 39.5 mm, 23.1 to 43.5 mm, and 15.9 to 43.9 mm for cases 1 to 3, respectively. The absolute 3-dimensional center-of-mass difference was 5.8 to 28.0 mm, 8.4 to 26 mm, and 3.8 to 35.1 mm for cases 1 to 3, respectively. The entire process resulted in CTV structures with a conformity index of 0.2 to 0.83, 0.02 to 0.85, and 0.02 to 0.88 (ideal 1) with the consensus CTV as reference.

Conclusions: Multicenter efficacy endpoint assessment of cardiac radioablation for therapy-refractory VT requires consistent CTV transfer methods from the EAM to the PCT. VT substrate definition and CTVs were comparable with current clinical practice. Remarkable differences regarding the degree of agreement of the CTV definition on the EAM and the PCT were noted, indicating a loss of agreement during the transfer process between EAM and PCT. Cardiac radioablation should be performed under well-defined protocols and in clinical trials with benchmarking and consensus forming.
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January 2021

Radiosurgery for ventricular tachycardia: preclinical and clinical evidence and study design for a German multi-center multi-platform feasibility trial (RAVENTA).

Clin Res Cardiol 2020 Nov 18;109(11):1319-1332. Epub 2020 Apr 18.

Klinik für Innere Medizin III, Abteilung für Elektrophysiologie und Rhythmologie, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Kiel, Germany.

Background: Single-session high-dose stereotactic radiotherapy (radiosurgery) is a new treatment option for otherwise untreatable patients suffering from refractory ventricular tachycardia (VT). In the initial single-center case studies and feasibility trials, cardiac radiosurgery has led to significant reductions of VT burden with limited toxicities. However, the full safety profile remains largely unknown.

Methods/design: In this multi-center, multi-platform clinical feasibility trial which we plan is to assess the initial safety profile of radiosurgery for ventricular tachycardia (RAVENTA). High-precision image-guided single-session radiosurgery with 25 Gy will be delivered to the VT substrate determined by high-definition endocardial electrophysiological mapping. The primary endpoint is safety in terms of successful dose delivery without severe treatment-related side effects in the first 30 days after radiosurgery. Secondary endpoints are the assessment of VT burden, reduction of implantable cardioverter defibrillator (ICD) interventions [shock, anti-tachycardia pacing (ATP)], mid-term side effects and quality-of-life (QoL) in the first year after radiosurgery. The planned sample size is 20 patients with the goal of demonstrating safety and feasibility of cardiac radiosurgery in ≥ 70% of the patients. Quality assurance is provided by initial contouring and planning benchmark studies, joint multi-center treatment decisions, sequential patient safety evaluations, interim analyses, independent monitoring, and a dedicated data and safety monitoring board.

Discussion: RAVENTA will be the first study to provide the initial robust multi-center multi-platform prospective data on the therapeutic value of cardiac radiosurgery for ventricular tachycardia.

Trial Registration Number: NCT03867747 ( Registered March 8, 2019. The study was initiated on November 18th, 2019, and is currently recruiting patients.
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November 2020

ARC is a novel therapeutic approach against acetaminophen-induced hepatocellular necrosis.

J Hepatol 2013 Feb 6;58(2):297-305. Epub 2012 Oct 6.

Max-Delbrück Center for Molecular Medicine, Berlin, Germany.

Background & Aims: Acetaminophen (AAP) overdose is the most frequent cause of drug-induced liver failure. c-Jun N-terminal kinase (JNK) is thought to play a central role in AAP-induced hepatocellular necrosis. The apoptosis repressor with caspase recruitment domain (ARC) is a death repressor that inhibits death receptor and mitochondrial apoptotic signaling. Here, we investigated ARC's therapeutic effect and molecular mechanisms on AAP-induced hepatocellular necrosis.

Methods: We tested the in vivo and in vitro effects of ARC fused with the transduction domain of HIV-1 (TAT-ARC) on murine AAP hepatotoxicity.

Results: Treatment with TAT-ARC protein completely abrogated otherwise lethal liver failure induced by AAP overdose in C57BL/6 mice. AAP triggered caspase-independent necrosis, as evidenced by liver histology, elevated serum transaminases, and secreted HMGB1 that was inhibited by ARC. ARC-mediated hepatoprotection was not caused by an alteration of AAP metabolism, but resulted in reduced oxidative stress. AAP overdose led to induction of RIP-dependent signaling with subsequent JNK activation. Ectopic ARC inhibited JNK activation by specific interactions between ARC and JNK1 and JNK2. Importantly, survival of mice was even preserved when ARC therapy was initiated in a delayed manner after AAP administration.

Conclusions: This work identifies for the first time ARC-JNK-binding with subsequent inhibition of JNK signaling as a specific mechanism of ARC to interfere with AAP-dependent necrosis. Our data suggests that AAP-mediated induction of RIP signaling serves as a critical switch for hepatocellular necrosis. The efficacy of TAT-ARC protein transduction in murine AAP hepatotoxicity suggests its therapeutic potential for reversing AAP intoxication also in humans.
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February 2013

Vorapaxar for secondary prevention of thrombotic events for patients with previous myocardial infarction: a prespecified subgroup analysis of the TRA 2°P-TIMI 50 trial.

Lancet 2012 Oct 26;380(9850):1317-24. Epub 2012 Aug 26.

Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.

Background: Vorapaxar inhibits platelet activation by antagonising thrombin-mediated activation of the protease-activated receptor 1 on human platelets. The effect of adding other antiplatelet drugs to aspirin for long-term secondary prevention of thrombotic events in stable patients with previous myocardial infarction is uncertain. We tested this effect in a subgroup of patients from the Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events (TRA 2°P)-TIMI 50 trial.

Methods: In TRA 2°P-TIMI 50--a randomised, placebo-controlled, parallel trial--we randomly assigned patients with a history of atherothrombosis to receive vorapaxar (2·5 mg daily) or matching placebo in a 1:1 ratio. Patients, and those giving treatment, assessing outcomes, and analysing results were masked to treatment allocation. Patients with a qualifying myocardial infarction within the previous 2 weeks to 12 months were analysed as a pre-defined subgroup. The primary efficacy endpoint was cardiovascular death, myocardial infarction, or stroke, analysed by intention to treat. We analysed events by Kaplan-Meier analysis and compared groups with a Cox proportional hazard model. TRA 2°P-TIMI 50 is registered at (NCT00526474).

Findings: 17,779 of 26,449 patients had a qualifying myocardial infarction and were assigned treatment (8898 to vorapaxar and 8881 to placebo). Median follow-up was 2·5 years (IQR 2·0-2·9). Cardiovascular death, myocardial infarction, or stroke occurred in 610 of 8898 patients in the vorapaxar group and 750 of 8881 in the placebo group (3-year Kaplan-Meier estimates 8·1%vs 9·7%, HR 0·80, 95% CI 0·72-0·89; p<0·0001). Moderate or severe bleeding was more common in the vorapaxar group versus the placebo group (241/8880 [3·4%, 3-year Kaplan-Meier estimate] vs 151/8849 [2·1%, 3-year Kaplan-Meier estimate], HR 1·61, 95% CI 1·31-1·97; p<0·0001). Intracranial haemorrhage occurred in 43 of 8880 patients (0·6%, 3-year Kaplan-Meier estimate) with vorapaxar versus 28 of 8849 (0·4%, 3-year Kaplan-Meier estimate) with placebo (p=0·076). Other serious adverse events were equally distributed between groups.

Interpretation: For patients with a history of myocardial infarction, inhibition of protease-activated receptor 1 with vorapaxar reduces the risk of cardiovascular death or ischaemic events when added to standard antiplatelet treatment, including aspirin, and increases the risk of moderate or severe bleeding.

Funding: Merck.
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October 2012

Titration to target dose of bisoprolol vs. carvedilol in elderly patients with heart failure: the CIBIS-ELD trial.

Eur J Heart Fail 2011 Jun 23;13(6):670-80. Epub 2011 Mar 23.

Department of Internal Medicine-Cardiology, Charité-Universitätsmedizin, Competence Network Heart Failure, Campus Virchow-Klinkum, Berlin, Germany.

Aims: Various beta-blockers with distinct pharmacological profiles are approved in heart failure, yet they remain underused and underdosed. Although potentially of major public health importance, whether one agent is superior in terms of tolerability and optimal dosing has not been investigated. The aim of this study was therefore to compare the tolerability and clinical effects of two proven beta-blockers in elderly patients with heart failure.

Methods And Results: We performed a double-blind superiority trial of bisoprolol vs. carvedilol in 883 elderly heart failure patients with reduced or preserved left ventricular ejection fraction in 41 European centres. The primary endpoint was tolerability, defined as reaching and maintaining guideline-recommended target doses after 12 weeks treatment. Adverse events and clinical parameters of patient status were secondary endpoints. None of the beta-blockers was superior with regards to tolerability: 24% [95% confidence interval (CI) 20-28] of patients in the bisoprolol arm and 25% (95% CI 21-29) of patients in the carvedilol arm achieved the primary endpoint (P= 0.64). The use of bisoprolol resulted in greater reduction of heart rate (adjusted mean difference 2.1 b.p.m., 95% CI 0.5-3.6, P= 0.008) and more, dose-limiting, bradycardic adverse events (16 vs. 11%; P= 0.02). The use of carvedilol led to a reduction of forced expiratory volume (adjusted mean difference 50 mL, 95% CI 4-95, P= 0.03) and more, non-dose-limiting, pulmonary adverse events (10 vs. 4%; P < 0.001).

Conclusion: Overall tolerability to target doses was comparable. The pattern of intolerance, however, was different: bradycardia occurred more often in the bisoprolol group, whereas pulmonary adverse events occurred more often in the carvedilol group. This study is registered with, number ISRCTN34827306.
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June 2011

Heart failure therapy in diabetic patients-comparison with the recent ESC/EASD guideline.

Cardiovasc Diabetol 2011 Feb 8;10:15. Epub 2011 Feb 8.

Department of Cardiology and Pneumology, University of Göttingen, Göttingen, Germany.

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.
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February 2011

Innovative strategy for implementing chronic heart failure guidelines among family physicians in different healthcare settings in Berlin.

Eur J Heart Fail 2011 Jan 14;13(1):93-9. Epub 2010 Oct 14.

Institute of General Practice & Family Medicine, Charité-Universitätsmedizin, Berlin.

Aims: The aim of this study was to improve drug therapy for chronic heart failure (CHF) patients.

Methods And Results: This prospective interventional pilot study was performed with cross-sectional comparative analysis before and after the intervention. Usual pharmacotherapy was observed for 8 months in two different outpatient healthcare settings in Berlin [11 family physicians from individual GP (IGP) practices and 12 working in a medical care centre (MCC)]. Medical care centres provide a novel structure for outpatient care and have recently been introduced in Germany. The subsequent intervention entailed implementation of heart failure guidelines via a computer-based reminder system, followed by renewed cross-sectional observation of prescription behaviour for 1 year. Family physicians recruited patients, assessed CHF severity according to the NYHA class, and referred patients for echocardiography. The study included 190 patients in the baseline phase and 209 in the intervention phase. Longitudinal follow-up was performed in 172 cases. Echocardiography was ordered by 94.6% of MCC-physicians and 79.9% of IGP's. Undermedication was observed in both settings. Guideline-based beta-blocker therapy was prescribed for 46.3% of patients (44.8% of IGPs and 48.5% of MCC-GPs). Prescription improved by 12.3% after the intervention. There were marked deficiencies in the prescription of aldosterone antagonists (35%) for severe heart failure, which improved to 44.2% after the intervention.

Conclusion: The problem of inadequate implementation of evidence-based therapy for CHF was partially overcome by using the reminder system, which provided participating physicians with short guideline recommendations during the intervention phase.
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January 2011

Autoantibodies against cardiac troponin I in patients with congestive heart failure.

Eur J Heart Fail 2010 Jul 31;12(7):668-75. Epub 2010 May 31.

Department of Cardiology, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, Berlin 13353, Germany.

Aims: In this randomized, double-blind clinical study, we investigated the relationship between autoantibodies against cardiac troponin I (cTnI) and disease severity in elderly congestive heart failure (CHF) patients before and after titration of beta-blocker therapy.

Methods And Results: Anti-cTnI, cTnI, and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels in blood from 138 patients (73 +/- 5.6 years, 48% male) with CHF in American Heart Association stages A-C were measured at baseline and after titration of beta-blockers to maximal tolerated dose. Median follow-up period was 85 days. Anti-cTnI was measured using an experimental assay (Abbott Diagnostics) and is expressed as a relative value unit (RVU) in relation to the mean value of a low-level control sample. Anti-cTnI values in CHF patients were also compared with measurements taken in a normal reference population of 300 healthy individuals (50% male). Cardiac troponin I and NT-proBNP levels were measured using routine assays (Architect Abbott Diagnostics and Roche Diagnostics). Median anti-cTnI was 0.53 and 0.56 RVU in healthy and CHF subjects, respectively (P = n.s.), and increased significantly to 0.67 RVU (P < 0.001) after beta-blocker titration. Mean cTnI values were 0.021 microg/L at baseline and fell significantly to 0.0046 microg/L at follow-up (P < 0.001). Median NT-proBNP values were 352 ng/L at baseline and 414 ng/L after titration (P = n.s.). In contrast to NT-proBNP and cTnI, anti-cTnI was not associated with the severity of CHF at baseline or follow-up.

Conclusion: Levels of anti-cTnI tend to increase in elderly patients with CHF following titration of beta-blocker therapy but do not correlate with disease severity. Anti-cTnI is not a useful biomarker for heart failure diagnosis, prognosis, or monitoring. In contrast, levels of cTnI decreased following therapy and did correlate with disease severity.
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July 2010

A network against failing hearts--introducing the German "Competence Network Heart Failure".

Int J Cardiol 2010 Nov 13;145(1):135-8. Epub 2009 Aug 13.

Heart failure (HF) has been identified as one of the most threatening diseases for the western civilisation, posing a risk to health for a rising number of patients. Acknowledging the medical problem of HF to be both economically and socially threatening the German Federal Ministry of Research and Education (BMBF) initiated a nationwide research network aiming to find new ways in prevention, alleviation and treatment of the widespread disease. The "Competence Network Heart Failure" (CNHF), initiated in 2003, bundles the scientific expertise in a large-scale research network; its aims are the coordination of basic and applied clinical research as well as dissemination of findings into clinical practice in order to consolidate and perpetuate the achieved improvements. The scope of this paper is to introduce the CNHF and to provide an overview of the tasks and hitherto attained achievements to a broad spectrum of health care providers.
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November 2010

Ventricular tachycardia as the first manifestation of cardiac sarcoidosis.

BMJ Case Rep 2009 28;2009. Epub 2009 Apr 28.

Charité University Medicine Berlin, Cardiology, Augustenburger Platz 1, Berlin, 13353, Germany.

The case of a 32-year-old man with sustained ventricular tachycardia and hypotension is described. Following pharmacological treatment the patient switched to a sinus rhythm and was transferred to a university hospital for further diagnostic procedures and treatment. Cardiac catherisation ruled out underlying coronary artery disease, and cardiac MRI as well as echocardiography demonstrated a moderately reduced left ventricular ejection fraction, marked thickening of the interventricular septum and extensive intramural and epicardial infiltration of both ventricles. Endomyocardial biopsies were inconclusive; an implantable cardioverter defibrillator (ICD) was implanted in order to prevent a fatal arrhythmic event. Only repeated lymph node biopsies revealed typical findings of granulomatous disease, which together with the clinical course and the cardiac MRI findings strongly supported cardiac sarcoidosis. A few days after initiation of therapy with corticosteroids, the patient experienced the first of a number of ICD discharges, demanding aggressive anti-arrhythmic treatment regimen for the future.
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November 2011

Beta-blocker tolerability in elderly heart failure patients.

Int J Cardiol 2009 Jul 7;136(1):93-4; author reply 94-5. Epub 2008 Jul 7.

Beta-blocker therapy is well established for patients with chronic heart failure. In clinical practice, questions of tolerability and recommended target dose therapy remain important topics.
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July 2009

Survivin determines cardiac function by controlling total cardiomyocyte number.

Circulation 2008 Mar 10;117(12):1583-93. Epub 2008 Mar 10.

Institut für Pathophysiologie, Universitätsklinikum Essen, Essen Germany.

Background: Survivin inhibits apoptosis and regulates cell division in many organs, but its function in the heart is unknown.

Methods And Results: We show that cardiac-specific deletion of survivin resulted in premature cardiac death. The underlying cause was a dramatic reduction in total cardiomyocyte numbers as determined by a stereological method for quantification of cells per organ. The resulting increased hemodynamic load per cell led to progressive heart failure as assessed by echocardiography, magnetic resonance imaging, positron emission tomography, and invasive catheterization. The reduction in total cardiomyocyte number in alpha-myosin heavy chain (MHC)-survivin(-/-) mice was due to an approximately 50% lower mitotic rate without increased apoptosis. This occurred at the expense of DNA accumulation because survivin-deficient cardiomyocytes displayed marked DNA polyploidy indicative of consecutive rounds of DNA replication without cell division. Survivin small interfering RNA knockdown in neonatal rat cardiomyocytes also led to polyploidization and cell cycle arrest without apoptosis. Adenoviral overexpression of survivin in cardiomyocytes inhibited doxorubicin-induced apoptosis, induced DNA synthesis, and promoted cell cycle progression. The phenotype of the alphaMHC-survivin(-/-) mice also allowed us to determine the minimum cardiomyocyte number sufficient for normal cardiac function. In human cardiomyopathy, survivin was potently induced in the failing heart and downregulated again after hemodynamic support by a left ventricular assist device. Its expression positively correlated with the mean cardiomyocyte DNA content.

Conclusions: We suggest that the ontogenetically determined cardiomyocyte number may be an independent factor in the susceptibility to cardiac diseases. Through its profound impact on both cardiomyocyte replication and apoptosis, survivin may emerge as a promising new target for myocardial regeneration.
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March 2008

Regulation of vascular smooth muscle cell proliferation: role of NF-kappaB revisited.

Circ Res 2005 May 14;96(9):958-64. Epub 2005 Apr 14.

Medizinische Klinik mit Schwerpunkt Kardiologie, Universitätsklinikum Charité, Campus Virchow Klinikum, Berlin, Germany.

The transcription factor NF-kappaB regulates cell cycle progression and proliferation in a number of cell types. An important unresolved issue is the potential role of NF-kappaB in the proliferation of vascular smooth muscle cells (VSMCs) as a basis for the development of vascular disease. To investigate the contribution of NF-kappaB to mitogen-induced proliferation of VSMCs, a knock-in mouse model expressing the NF-kappaB superrepressor IkappaBalphaDeltaN (c(IkappaBalphaDeltaN)) was used. Comparing wild-type and IkappaBalphaDeltaN-expressing VSMCs, we found that proliferation rates did not differ after mitogenic stimulation by platelet-derived growth-factor-BB (PDGF-BB) or serum. In line with this, NF-kappaB activation was not observed in VSMCs derived from transgenic mice expressing an NF-kappaB-dependent lacZ reporter (c((Igk)3conalacZ)). We further show, that classical mitogenic signaling pathways (namely mitogen-activated protein kinase [MAPK] and the phosphatidyl-inositol-3-OH-kinase [PI3K] pathways) control VSMC proliferation, but independently of NF-kappaB activation. In contrast to VSMCs, mouse embryonic fibroblasts (MEFs) derived from IkappaBalphaDeltaN-expressing mice showed significantly impaired proliferation rates after mitogenic stimulation. This was reflected by strongly impaired cyclin D1 expression in serum-stimulated MEFs derived from (c(IkappaBalphaDeltaN)) mice. These results implicate that essential pathogenetic functions of NF-kappaB in the development of atherosclerosis involve apoptotic and inflammatory signaling of VSMCs rather than proliferation. They further provide genetic evidence for a cell-type restricted requirement of NF-kappaB in the control of cellular proliferation.
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May 2005