Evaluation of increased cardiotoxicity risk in patients experiencing statin-associated muscle symptoms

• Grant number: 20/10296-8
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• Start date: January 28, 2021
• End date: January 27, 2022
• Field of knowledge: Health Sciences - Pharmacy
• Principal Investigator: Mario Hiroyuki Hirata
• Grantee: Raul Hernandes Bortolin
• Supervisor: William Tswenching Pu
• Host Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Institution abroad: Harvard University, Boston, United States
• Associated to the scholarship: 17/21055-9 - Toxicogenetic of statins using induced pluripotent stem cells from patients with familial hypercholesterolemia, BP.PD

Abstract

Statins are one of the most prescribed drugs worldwide. Despite being considered safe, they are associated with several side effects, mainly those related to muscle symptoms, which represent up to 65% of low adherence cases. Statin-associated muscle symptoms (SAMS) are largely studied, but molecular mechanisms are not yet fully understood. Most studies focused on skeletal muscle and some have attempted to assess the molecular mechanisms of statin-induced cardiotoxicity. Also, to the best of our knowledge, there is no evidence about the association of SAMS with an increased risk of statin-induced cardiotoxicity. This study aims to evaluate the molecular mechanisms of statin-induced cardiotoxicity by utilizing 3D disease modeling with engineered heart tissue (EHT) and hiPSCs from familial hypercholesterolemic patients experiencing SAMS. To achieve this goal, hiPSCs from patients with (n=3) and without (n=3) SAMS will be differentiated into cardiomyocytes and used to generate EHTs, allowing enhanced maturation of hiPSC-derived cardiomyocytes (hiPSC-CMs) to facilitate the evaluation of drug responses. Functional and molecular methods, such as apoptosis/cell death, cellular membrane integrity and mitochondrial activity assays, as well as transcriptome and protein analysis, will be used. The present project, to the best of our knowledge, is a pioneer in this approach, which links SAMS and increased cardiotoxicity risk by statins. The project will also improve my post-doctoral research knowledge and experience to further strengthen the research team in Brazil, bringing insights of new disease modeling and drug screening technologies. Furthermore, it will contribute to establishing new collaborations with an important international research center in cardiology. (AU)