Background: Myocarditis is an inflammatory disease of myocardium that frequently lead to heart failure as results of an immune mediated cardiac damage. Toll-like receptor (TLR)-4, a molecular component that regulates the innate immune system, plays an important role in the induction and perpetuation of inflammation in autoimmune diseases. We recently demonstrated that myocardial expression of TLR-4 is increased in autoimmune myocarditis and can predict the response to immunosuppression.
Aim of the present study is to determine whether TLR-4 expression on PBMC of patients with autoimmune myocarditis is a biomarker to identify patients who will benefit from immunosuppressive therapy and to predict the resolution or recurrence of the myocardial inflammatory disease at follow-up.
Methods: In our center from January 2016 to January 2018 45 patients with histological and molecular diagnosis of virus negative inflammatory cardiomyopathy were treated for six-months with immunosuppression. PBMC isolated from whole blood at the time of the baseline endomyocardial biopsy will be examined for the expression of TLR4, differentiating those patients responding to immunosuppression with non-responder patients. A semiquantitative evaluation of the myocardial immunoreactivity (grading from 0 to 4) for TLR4 at baseline will be performed and correlated with the protein expression on PBMC. All patients will be submitted to a clinical follow-up, including a cardiac magnetic resonance. Follow-up PBMC assessment of TLR-4 will be also performed to evaluate if TLR-4 upregulation can be reverted within normal limits in parallel with improvement in cardiac dimension and function.
Expected results: The expected result of this project is to validate TLR-4 expression on PBMC as a reliable biomarker to guide the prompt instauration of immunosuppressive therapy in virus-negative myocarditis, with an improvement in patients prognosis.
Myocarditis is an important problem for the Health Care System, being responsible of up to 67% of heart failure of unknown origin, with increasing economic and social costs. Most patients with chronic inflammatory cardiomyopathy are characterized by the absence of viral genomes in the myocardium. These patients, often with a several months or even years of clinical history, are usually treated with the maximal tolerated dosage of supportive therapy, including ACE-inhibitors, diuretics, carvedilol, digitalis. However, in presence of still active cell damage and a progressive muscle impairment, they could benefit from a specific treatment able to counteract the mechanisms responsible of persisting cardiomyocyte inflammation and death. Despite that, immunosuppressive treatment of inflammatory cardiomyopathy is still not widely adopted, mainly because of the absence of validated and easily available circulating biomarkers able to predict the efficacy of this treatment.
The increased expression of TLR-4 on peripheral circulating leukocytes of patients with virus-negative inflammatory cardiomyopathy responding to immunosuppressive therapy could represent a new biomarker able to identify patients with autoimmune myocarditis susceptible of a specific treatment, with important prognostic and social implications.
The possibility to identify from peripheral blood patients who will benefit from this treatment will increase the number of patients treated, being the dosage easy and, differently from genetic and molecular biology biomarkers, not requiring particular technical skills, so that it can be universally adopted in pathology labs. The healthcare system would save substantial money with overall reduction in mortality and rate of hospitalization, instead of paying an expensive symptomatic approach over years, including heart transplantation. Moreover it will open the field of research on inhibitors of TLR4 as future therapeutic agents for the treatment of myocarditis, especially in patients in which steroids or immunosuppressive drugs are a limited option or even contraindicated.