Mohammed Yusof, Nur Liyana; (2024) Investigation into the Role of Selective Cardiac Myosin Inhibitors in Myocardial Ischaemia-Reperfusion Injury. Doctoral thesis (Ph.D), UCL (University College London).

Text Thesis_Nur Mohammed Yusof (19172637).pdf - Accepted Version Access restricted to UCL open access staff until 1 August 2025. Download (51MB)

Abstract

Background: Cardiomyocyte hypercontracture during the first few minutes of reperfusion is a major cause of cell death, leading to a worse long-term prognosis. While inhibition of hypercontracture demonstrates substantial cardioprotection, the therapies available are non-specific and unsuitable for clinical translation. Recently, cardiac myosin-targeted inhibitors (CMIs) of contraction, known as Mavacamten (MYK-461) and Aficamten (CK-274), have been developed to treat patients with hypertrophic cardiomyopathy. These CMIs are well tolerated and safe in clinical trials; however, they have not been investigated in the setting of ischaemia-reperfusion (IR) injury. // Purpose: Hence, this thesis aimed to explore the effects of CMIs as novel therapeutic strategies in reperfusion-induced hypercontracture following IR, thereby potentially limiting infarct size.// Methods: In vitro experiments were undertaken using primary adult rat cardiomyocytes (ARVCs) to study the ability of CMIs to inhibit hypercontracture following ATP depletion. Acute myocardial infarction (AMI) experiments were conducted in vivo in rats with 30 min of ischaemia followed by 2 h of reperfusion. Prior to reperfusion, CMIs or vehicle were administered intraperitoneally. Subsequently, the hearts were thinly sliced, with alternate slices used for infarct size measurement by tetrazolium chloride staining, or thinly sectioned for histological staining. // Results: Treatment with CMIs inhibited ARVCs hypercontracture in vitro. MYK-461 (2 mg/kg) and CK274 (0.5 mg/kg to 2 mg/kg) significantly reduced infarct size in vivo in comparison to vehicle. Notably, the IR hearts had extensive contraction band necrosis, which was less prominent in MYK-461 and CK-274-treated groups. Finally, GDC-0326, a pharmacological inhibitor of PI3Kα, abrogated CK-274- mediated protection following IR injury. // Conclusion: This thesis establishes the role of CMIs as a novel target for cardioprotection, presenting experimental evidence demonstrating their role as novel reperfusion-induced hypercontracture targets for protecting the heart against IR injury. Protection by CMIs involves the PI3Kα pathway. These findings provide additional information that warrants further exploration of the clinical potential of these CMIs in an AMI setting.

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