Genetic causes and molecular mechanisms of myocardial fibrosis - Risto Kerkelä and Juhani Junttila

Project description

Cardiovascular pathologies induce accumulation of extracellular matrix in the heart, which results in increased ventricular stiffness and disrupts the normal electrical cell-to-cell coupling and impulse conduction predisposing to arrhythmias and sudden cardiac death (SCD). Currently, there are no useful biomarkers for detecting myocardial fibrosis and no specific therapies exist for treatment of cardiac fibrosis. We have collected a consecutive series of victims of SCD undergoing medico-legal autopsy in the FinGesture study since 1998 until now. Our aim is to study cardiac samples of these victims to identify genetic factors regulating development of cardiac fibrosis. Secondly, we will study the clinical characteristics of mutation carrier family members with ECG, echocardiogram, and cardiac MRI in order to find applicable clinical markers which can be used to identify subjects at risk for SCD. Samples from SCD victims and their first-degree relatives will be studied to identify biomarkers of fibrosis and non-coding RNAs dysregulated in fibrotic hearts. We will then utilize cell models and genetically engineered mice to study the role of the factors identified in regulating cardiac fibrosis. Understanding the signaling mechanisms involved in cardiac fibrosis may provide new diagnostic opportunities and has potential to provide novel targets for therapy of cardiac fibrosis.

Selected publications:

Junttila MJ, Holmström L, Pylkäs K, Mantere T, Kaikkonen K, Porvari K, Kortelainen ML, Pakanen L, Kerkelä R, Myerburg RJ, Huikuri HV. Primary Myocardial Fibrosis as an Alternative Phenotype Pathway of Inherited Cardiac Structural Disorders. Circulation. 2018 Jun 19;137(25):2716-2726.

Vainio LE, Szabó Z, Ulvila J, Yrjölä R,  Alakoski T, Piuhola J, Koch WJ, Ruskoaho H, Lipson KE, Signore P, Gao E, Magga J, Kerkelä R. Connective tissue growth factor inhibition enhances cardiac repair and limits fibrosis after myocardial infarction. JACC Basic to Translational Science. 2019 Feb 25;4(1):83-94.

Magga J, Vainio L, Kilpiö T, Hulmi JJ, Taponen S, Lin R, Räsänen M, Szabo Z, Gao E, Rahtu-Korpela L, Alakoski T, Ulvila J, Laitinen M, Paternack A, Koch WJ, Alitalo K, Kivelä R, Ritvos O, Kerkelä R. Systemic blockade of ACVR2B ligands protects myocardium from acute ischemia-reperfusion injury. Molecular Therapy. 2019 Mar 6;27(3):600-610

Haukilahti MAE, Holmström L, Vähätalo J, Kenttä T, Tikkanen J, Pakanen L, Kortelainen M-L, Perkiömäki J, Huikuri H, Myerburg RJ, Junttila MJ. Sudden Cardiac Death in Women: Causes of Death, Autopsy Findings and Electrocardiographic Risk Markers. Circulation. 2019;139:1012-1021.

Vähätalo JH, Huikuri HV, Holmström LTA, Kenttä TV, Haukilahti MAE, Pakanen L, Kaikkonen KS, Tikkanen J, Perkiömäki JS, Myerburg RJ, Junttila MJ. Silent myocardial infarction and sudden cardiac death. JAMA Cardiol 2019; 2019 Jul 10.

Paavola J, Alakoski T, Ulvila J, Kilpiö T, Sirén J, Perttunen S, Narumanchi S, Wang H, Lin R, Porvari K, Junttila J, Huikuri H, Immonen K, Lakkisto P, Magga J, Tikkanen I, Kerkelä R. Vezf1 regulates cardiac structure and contractile function. EBioMedicine. 2020 Jan 3;51:102608.