Thomas M. Behr

Bio: Thomas M. Behr is an academic researcher from University of Würzburg. The author has contributed to research in topics: Heart failure & Muscle hypertrophy. The author has an hindex of 10, co-authored 12 publications receiving 716 citations. Previous affiliations of Thomas M. Behr include GlaxoSmithKline.

Sustained activation of nuclear factor kappa B and activator protein 1 in chronic heart failure

Abstract: Objective: Innate immune response proteins such as inflammatory cytokines, inducible nitric oxide synthase, and toll like receptors are implicated in myocardial depression and left ventricular (LV) remodeling after myocardial infarction (MI). Although all these innate immunity proteins share the downstream activation of the transcription factor NF-κB (nuclear factor kappa B) and activator protein 1 (AP-1), the involvement of NF-κB and AP-1 in LV remodeling has not been demonstrated so far. Methods and results: Nuclear translocation of NF-κB and AP-1 was studied by electrophoretic mobility shift assays and ELISA 10 weeks after large experimental MI in rats, the chronic phase of LV remodeling. In the non-infarcted myocardium of MI rats, NF-κB and AP-1 were significantly activated (2.5-fold) as compared to sham-operated animals. Immunohistochemistry demonstrated NF-κB activation mainly in cardiac myocytes. Treatment with the ACE (angiotensin converting enzyme) inhibitor trandolapril led to a further 2-fold increase in the activation of NF-κB and AP-1 when compared to placebo-treated animals with the same MI size ( P <0.001). Human failing hearts explanted at the time of heart transplantation exhibited marked nuclear translocation of NF-κB in cardiac myocytes when compared to control hearts. NF-κB as well as AP-1 were both significantly activated in congestive heart failure due to ischemic or dilated cardiomyopathy. Conclusion: In experimental and human heart failure, both NF-κB and AP-1 are chronically activated in cardiac myocytes. These findings suggest an important involvement of NF-κB and AP-1 in the cardiac remodeling process.

Detection of humoral rejection in human cardiac allografts by assessing the capillary deposition of complement fragment C4d in endomyocardial biopsies

Abstract: Background: There are no well-established diagnostic criteria to detect humoral rejection in organ transplantation. The value of commonly used markers in immunohistochemistry, such as C1q, C3c, IgG, IgM and fibrinogen, is questioned by some groups. Complement fragment C4d is a more stable marker of complement activation as it is covalently bound to graft capillaries. C4d has been shown to identify clinically relevant, but otherwise undetectable humoral anti-graft reactions in human kidney transplants. Methods Immunohistochemical techniques were used to evaluate 155 endomyocardial biopsies from 56 heart transplant recipients less than 3 months post transplantation for the presence of capillary C4d staining. In a subset of patients, C4d staining was compared with C1q, C3c, IgM and fibrin staining and was correlated with clinical outcome. Results Within 3 months 9 of 56 patients died. Five of these nonsurvivors had prominent C4d staining ( p p Conclusions The capillary deposition of complement split product C4d in human endomyocardial biopsies was significantly associated with graft loss. Determination of fibrin deposition may yield additional information to establish a diagnosis of humoral rejection. The immunohistochemical assessment of capillary deposition of C4d and fibrin appears to be an appropriate tool for the identification of patients, who may require additional or alternative immunosuppressive therapy targeted against the humoral immune system.

Hypertensive End-Organ Damage and Premature Mortality Are p38 Mitogen-Activated Protein Kinase–Dependent in a Rat Model of Cardiac Hypertrophy and Dysfunction

Abstract: Background Numerous pathological mediators of cardiac hypertrophy (eg, neurohormones, cytokines, and stretch) have been shown to activate p38 MAPK. The purpose of the present study was to examine p38 MAPK activation and the effects of its long-term inhibition in a model of hypertensive cardiac hypertrophy/dysfunction and end-organ damage. Methods and Results In spontaneously hypertensive stroke-prone (SP) rats receiving a high-salt/high-fat diet (SFD), myocardial p38 MAPK was activated persistently during the development of cardiac hypertrophy and inactivated during decompensation. Long-term oral treatment of SFD-SP rats with a selective p38 MAPK inhibitor (SB239063) significantly enhanced survival over an 18-week period compared with the untreated group (100% versus 50%). Periodic echocardiographic analysis revealed a significant reduction in LV hypertrophy and dysfunction in the SB239063-treatment groups. Little or no difference in blood pressure was noted in the treatment or vehicle groups. Basal and s...

Monocyte Chemoattractant Protein-1 is Upregulated in Rats With Volume-Overload Congestive Heart Failure

Abstract: Background —Chemokines are potent proinflammatory and immune modulators. Increased expression of chemokines, eg, monocyte chemoattractant protein-1 (MCP-1), has recently been described in clinical and experimental heart failure. The present report is aimed at exploring the expression, localization, and binding site regulation of MCP-1, a member of the C-C chemokine family, in a rat model of volume-overload congestive heart failure (CHF). Methods and Results —An aortocaval fistula was surgically created between the abdominal aorta and inferior vena cava. Rats with CHF were further subdivided into compensated and decompensated subgroups. Northern blot analysis and real-time quantitative polymerase chain reaction demonstrated upregulation of MCP-1 mRNA expression correlating with the severity of CHF (288±22, 502±62, and 826±138 copies/ng total RNA for sham, compensated, and decompensated animals, respectively; n=5, P <0.05). MCP-1 protein was localized by immunohistochemistry in cardiomyocytes, vascular endothelium and smooth muscle cells, infiltrating leukocytes, and interstitial fibroblasts, and its intensity increased with severity of CHF. In addition, rats with CHF displayed a significant decrease of 125I-labeled MCP-1 binding sites to myocardium-derived membranes (384.3±57.0, 181.3±8.8, and 123.3±14.1 fmol/mg protein for sham, compensated, and decompensated animals, respectively). Conclusions —Volume-overload CHF in rats is associated with alterations in the expression, immunohistochemical localization, and receptor binding of the MCP-1 chemokine in the myocardium. These changes were more pronounced in rats with decompensated CHF. The data suggest that activation of the MCP-1 system may contribute to the progressive cardiac decompensation and development of CHF in rats with aortocaval fistula.

Vascular endothelial dysfunction and superoxide anion production in heart failure are p38 MAP kinase-dependent

Abstract: Objective: The mitogen-activated protein (MAP) kinase system, especially the p38 MAP kinase, is activated in chronic heart failure (CHF). However, the role of vascular p38 MAP kinase in CHF has not been analyzed yet. Methods and results: In aortic rings from rats with CHF 10 weeks after myocardial infarction, acetylcholine-induced relaxation was attenuated (maximum relaxation, Rmax: 54F5%) compared to sham-operated animals (Rmax :7 7F5%, p<0.01), while endothelium-independent relaxation elicited by sodium nitroprusside was not significantly changed. Aortic levels of phosphorylated p38 MAP kinase protein were significantly elevated in rats with CHF. In addition, phosphorylation of MAP kinase-activated protein kinase-2 (MAPKAPK-2), an index of p38 MAP kinase activity, was increased. Aortic superoxide anion generation was significantly enhanced in rats with CHF accompanied by elevation of the NAD(P)H oxidase subunit p47 phox protein expression. Inhibition of p38 MAP kinase by treatment with the p38 MAP kinase inhibitor SB239063 (800 ppm in standard rat chow) reduced MAPKAPK-2 phosphorylation, preserved acetylcholine-induced relaxation (Rmax: 80F4%, p<0.01), and reduced vascular superoxide formation. SB239063 treatment did not affect blood pressure and left ventricular enddiastolic pressure. In aortic tissue from CHF animals treated with the angiotensin-converting enzyme (ACE) inhibitor trandolapril, p38 MAP kinase phosphorylation was significantly reduced. Conclusions: Vascular p38 MAP kinase is markedly activated in rats with CHF. Chronic p38 MAP kinase inhibition with SB239063 prevented endothelial vasomotor dysfunction through reduction of superoxide anion production.

The International Society of Heart and Lung Transplantation Guidelines for the care of heart transplant recipients

Abstract: Institutional Affiliations Chair Costanzo MR: Midwest Heart Foundation, Lombard Illinois, USA Task Force 1 Dipchand A: Hospital for Sick Children, Toronto Ontario, Canada; Starling R: Cleveland Clinic Foundation, Cleveland, Ohio, USA; Anderson A: University of Chicago, Chicago, Illinois, USA; Chan M: University of Alberta, Edmonton, Alberta, Canada; Desai S: Inova Fairfax Hospital, Fairfax, Virginia, USA; Fedson S: University of Chicago, Chicago, Illinois, USA; Fisher P: Ochsner Clinic, New Orleans, Louisiana, USA; Gonzales-Stawinski G: Cleveland Clinic Foundation, Cleveland, Ohio, USA; Martinelli L: Ospedale Niguarda, Milano, Italy; McGiffin D: University of Alabama, Birmingham, Alabama, USA; Parisi F: Ospedale Pediatrico Bambino Gesu, Rome, Italy; Smith J: Freeman Hospital, Newcastle upon Tyne, UK Task Force 2 Taylor D: Cleveland Clinic Foundation, Cleveland, Ohio, USA; Meiser B: University of Munich/Grosshaden, Munich, Germany; Baran D: Newark Beth Israel Medical Center, Newark, New Jersey, USA; Carboni M: Duke University Medical Center, Durham, North Carolina, USA; Dengler T: University of Hidelberg, Heidelberg, Germany; Feldman D: Minneapolis Heart Institute, Minneapolis, Minnesota, USA; Frigerio M: Ospedale Niguarda, Milano, Italy; Kfoury A: Intermountain Medical Center, Murray, Utah, USA; Kim D: University of Alberta, Edmonton, Alberta, Canada; Kobashigawa J: Cedar-Sinai Heart Institute, Los Angeles, California, USA; Shullo M: University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Stehlik J: University of Utah, Salt Lake City, Utah, USA; Teuteberg J: University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Uber P: University of Maryland, Baltimore, Maryland, USA; Zuckermann A: University of Vienna, Vienna, Austria. Task Force 3 Hunt S: Stanford University, Palo Alto, California, USA; Burch M: Great Ormond Street Hospital, London, UK; Bhat G: Advocate Christ Medical Center, Oak Lawn, Illinois, USA; Canter C: St. Louis Children Hospital, St. Louis, Missouri, USA; Chinnock R: Loma Linda University Children's Hospital, Loma Linda, California, USA; Crespo-Leiro M: Hospital Universitario A Coruna, La Coruna, Spain; Delgado R: Texas Heart Institute, Houston, Texas, USA; Dobbels F: Katholieke Universiteit Leuven, Leuven, Belgium; Grady K: Northwestern University, Chicago, Illlinois, USA; Kao W: University of Wisconsin, Madison Wisconsin, USA; Lamour J: Montefiore Medical Center, New York, New York, USA; Parry G: Freeman Hospital, Newcastle upon Tyne, UK; Patel J: Cedar-Sinai Heart Institute, Los Angeles, California, USA; Pini D: Istituto Clinico Humanitas, Rozzano, Italy; Pinney S: Mount Sinai Medical Center, New York, New York, USA; Towbin J: Cincinnati Children's Hospital, Cincinnati, Ohio, USA; Wolfel G: University of Colorado, Denver, Colorado, USA Independent Reviewers Delgado D: University of Toronto, Toronto, Ontario, Canada; Eisen H: Drexler University College of Medicine, Philadelphia, Pennsylvania, USA; Goldberg L: University of Pennsylvania, Philadelphia, Pennsylvania, USA; Hosenpud J: Mayo Clinic, Jacksonville, Florida, USA; Johnson M: University of Wisconsin, Madison, Wisconsin, USA; Keogh A: St Vincent Hospital, Sidney, New South Wales, Australia; Lewis C: Papworth Hospital Cambridge, UK; O'Connell J: St. Joseph Hospital, Atlanta, Georgia, USA; Rogers J: Duke University Medical Center, Durham, North Carolina, USA; Ross H: University of Toronto, Toronto, Ontario, Canada; Russell S: Johns Hopkins Hospital, Baltimore, Maryland, USA; Vanhaecke J: University Hospital Gasthuisberg, Leuven, Belgium.

p38 MAP kinases: key signalling molecules as therapeutic targets for inflammatory diseases.

Abstract: The p38 MAP kinases are a family of serine/threonine protein kinases that play important roles in cellular responses to external stress signals. Since their identification about 10 years ago, much has been learned of the activation and regulation of the p38 MAP kinase pathways. Inhibitors of two members of the p38 family have been shown to have anti-inflammatory effects in preclinical disease models, primarily through the inhibition of the expression of inflammatory mediators. Several promising compounds have also progressed to clinical trials. In this review, we provide an overview of the role of p38 MAP kinases in stress-activated pathways and the progress towards clinical development of p38 MAP kinase inhibitors in the treatment of inflammatory diseases.

The pathogenesis of cardiac fibrosis

Abstract: Cardiac fibrosis is characterized by net accumulation of extracellular matrix proteins in the cardiac interstitium, and contributes to both systolic and diastolic dysfunction in many cardiac pathophysiologic conditions. This review discusses the cellular effectors and molecular pathways implicated in the pathogenesis of cardiac fibrosis. Although activated myofibroblasts are the main effector cells in the fibrotic heart, monocytes/macrophages, lymphocytes, mast cells, vascular cells and cardiomyocytes may also contribute to the fibrotic response by secreting key fibrogenic mediators. Inflammatory cytokines and chemokines, reactive oxygen species, mast cell-derived proteases, endothelin-1, the renin/angiotensin/aldosterone system, matricellular proteins, and growth factors (such as TGF-β and PDGF) are some of the best-studied mediators implicated in cardiac fibrosis. Both experimental and clinical evidence suggests that cardiac fibrotic alterations may be reversible. Understanding the mechanisms responsible for initiation, progression, and resolution of cardiac fibrosis is crucial to design anti-fibrotic treatment strategies for patients with heart disease.

Nuclear factor-κB: its role in health and disease

Abstract: Nuclear factor-kappaB (NF-kappaB) is a major transcription factor that plays an essential role in several aspects of human health including the development of innate and adaptive immunity. The dysregulation of NF-kappaB is associated with many disease states such as AIDS, atherosclerosis, asthma, arthritis, cancer, diabetes, inflammatory bowel disease, muscular dystrophy, stroke, and viral infections. Recent evidence also suggests that the dysfunction of NF-kappaB is a major mediator of some human genetic disorders. Appropriate regulation and control of NF-kappaB activity, which can be achieved by gene modification or pharmacological strategies, would provide a potential approach for the management of NF-kappaB related human diseases. This review summarizes the current knowledge of the physiological and pathophysiological functions of NF-kappaB and its possible role as a target of therapeutic intervention

International Society for Heart and Lung Transplantation working formulation of a standardized nomenclature for cardiac allograft vasculopathy—2010

Abstract: The development of cardiac allograft vasculopathy remains the Achilles heel of cardiac transplantation. Unfortunately, the definitions of cardiac allograft vasculopathy are diverse, and there are no uniform international standards for the nomenclature of this entity. This consensus document, commissioned by the International Society of Heart and Lung Transplantation Board, is based on best evidence and clinical consensus derived from critical analysis of available information pertaining to angiography, intravascular ultrasound imaging, microvascular function, cardiac allograft histology, circulating immune markers, non-invasive imaging tests, and gene-based and protein-based biomarkers. This document represents a working formulation for an international nomenclature of cardiac allograft vasculopathy, similar to the development of the system for adjudication of cardiac allograft rejection by histology.