title: Myocardial expression of Toll-like receptor 4 predicts the response to immunosuppressive therapy in patients with virus-negative chronic inflammatory cardiomyopathy.
abstract: We sought to determine whether myocardial expression of Toll-like receptor 4 (TLR4) may predict the response to immunosuppression.
  
  
  
  Endomyocardial biopsies from 237 patients with virus-negative inflammatory cardiomyopathy treated with immunosuppression were retrospectively examined for the expression of TLR4, differentiating those patients responding to immunosuppression (n = 193) from non-responder patients (n = 44). A semiquantitative evaluation of the immunoreactivity (grading from 0 to 4) for TLR4 and human leucocyte antigen (HLA)-DR was performed together with real-time PCR and western blot for TLR4. Cardiomyocyte apoptosis and necrosis was evaluated by in situ ligation with hairpin probes. A focal intense positive cytoplasmic immunostaining for TLR4 was observed in cardiomyocytes of all responders (P < 0.001 vs. non-responders). A grading 2 or above (2+) at baseline showed a sensitivity of 100% and 90.9% specificity with a positive predictive value of 98% as a predictor of an immunosuppression-positive response. Real-time PCR and western blot analysis for TLR4 were 4.3-fold and 4.6-fold higher, respectively, in responders vs. non-responders. Correlation between TLR4 grading and TLR4 mRNA molecular and protein expression was highly significant. HLA-DR did not discriminate between the two groups. Cardiomyocyte death by apoptosis was 3.7-fold higher in responders vs. non-responders and significantly correlated with TLR4 expression, while necrosis was comparable. Intensity of baseline TLR4 expression correlated with the variation in ejection fraction after 6 months of immunosuppression.
  
  
  
  TLR4 is highly expressed in human myocarditis responding to immunosuppression. It can be considered as a new sensitive marker in patient selection predicting a good response to immunosuppressive therapy.
authors.affiliation: Cardiovascular, Respiratory, Nephrologic, Anesthesiologic and Geriatric Sciences, La Sapienza University, Rome, Italy.|Cellular and Molecular Cardiology Laboratory, IRCCS INMI L. Spallanzani, Rome, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Chimenti
authors.affiliation: Cellular and Molecular Cardiology Laboratory, IRCCS INMI L. Spallanzani, Rome, Italy.
authors.forename: Romina
authors.initials: R
authors.lastname: Verardo
authors.affiliation: 'Bambino Gesù' Children's Hospital, Rome, Italy.
authors.forename: Fernanda
authors.initials: F
authors.lastname: Scopelliti
authors.affiliation: Cardiovascular, Respiratory, Nephrologic, Anesthesiologic and Geriatric Sciences, La Sapienza University, Rome, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Grande
authors.affiliation: Clinical and Research Department, IRCCS INMI L. Spallanzani, Rome, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Petrosillo
authors.affiliation: Unit of Clinical Epidemiology, IRCCS INMI L. Spallanzani, Rome, Italy.
authors.forename: Pierluca
authors.initials: P
authors.lastname: Piselli
authors.affiliation: Department of Cardiac Surgery, European Hospital, Rome, Italy.
authors.forename: Ruggero
authors.initials: R
authors.lastname: De Paulis
authors.affiliation: Cardiovascular, Respiratory, Nephrologic, Anesthesiologic and Geriatric Sciences, La Sapienza University, Rome, Italy.|Cellular and Molecular Cardiology Laboratory, IRCCS INMI L. Spallanzani, Rome, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Frustaci
mesh_terms: D000328:Adult; D017209:Apoptosis; D001706:Biopsy; D009202:Cardiomyopathies / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D002908:Chronic Disease; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007249:Inflammation / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D012333:RNA, Messenger; D060888:Real-Time Polymerase Chain Reaction; D051197:Toll-Like Receptor 4 / Q000096:biosynthesis / Q000235:genetics*; D014780:Viruses
chemical_list: D007166:Immunosuppressive Agents; D012333:RNA, Messenger; D051197:Toll-Like Receptor 4
keywords: Heart failure; Immunosuppressive therapy; Myocarditis; Toll-like receptor 4; Viruses