![]() Informed written consent for use of post-mortem tissue was obtained from the patient’s next-of-kin. Human cardiac tissue specimens were obtained from post-mortem samples of patients with heart failure and advanced stages of LVH. The human heart tissue part of the study was approved by the Ethics Committee from Medical Faculty, Rheinisch–Westfälische Technische Hochschule Aachen, Germany (reference number BUS EK 062/13). Study participants gave informed consent prior to their inclusion in the study and all investigations conformed with the principles outlined in the Declaration of Helsinki. The iPSC part of the study was approved by the SingHealth Centralized Institutional Review Board, reference number 2015/2521. Importantly, we also demonstrated MPO protein expression in cardiomyocytes from healthy and diseased hypertrophied adult murine and human hearts. Importantly, treatment of HCM-CMs with the MPO inhibitor AZD5904 13 restored phosphorylation of MYBPC3, and alleviated the cardiomyocyte relaxation defect, highlighting MPO inhibition as a novel therapy for improving diastolic function in HCM patients. 1 We show for the first time the presence of functional MPO within iPSC-CMs, and have demonstrated that in iPSC-CMs from HCM patients (HCM-CMs), it reduced the phosphorylation of 3-chlorotyrosine-modified cardiac myosin binding protein-C (MYBPC3) protein and delayed cardiomyocyte relaxation. We evaluated cardiomyocytes derived from induced pluripotent stem cells (iPSC-CMs) from patients with mutations in MYH7 and MYBPC3, the two most common gene mutations associated with HCM. In this study, we hypothesized that MPO is expressed in cardiomyocytes, and is up-regulated under conditions of cellular stress such as HCM, where it modifies sarcomere proteins and contributes to diastolic dysfunction. 10 Although MPO is predominantly found in neutrophils and monocytes, it has also been shown to be expressed in other cell types including neurons 11 and endothelial cells. Elevated circulating MPO levels have been associated with poor prognosis and increased risk of CVD-related mortality. 8, 9 Increased circulating levels of MPO are indicative of underlying inflammation and oxidative stress, and have been associated with a wide variety of cardiovascular diseases (CVDs) including coronary artery disease, congestive heart failure, arterial hypertension, peripheral arterial disease, and cardiac arrhythmias. 7 Dysregulated MPO release can lead to tissue damage in various diseases. MPO is secreted upon leucocyte activation, and through enzymatic production of hypohalous acids and other reactive species, it post-translationally modifies different target proteins, 6 and plays an important role in antimicrobial activity and innate immunity. Myeloperoxidase (MPO) is a member of the superfamily of haem peroxidases that is mainly expressed in neutrophils and monocytes, where it is stored in azurophilic granules. Hence, there is an unmet need to identify novel therapeutic targets that can alleviate diastolic dysfunction and improve symptoms in patients with HCM. 5 However, these treatments do not directly address the underlying contractile impediment of diastolic dysfunction. 4 HCM patients with limiting symptoms of exercise intolerance, angina, and dyspnoea, are often managed with β-blockers and L-type calcium channel blockers. 2, 3 HCM is also the leading cause of sudden cardiac death in adolescents, young adults, and athletes, and this is mediated primarily by ventricular tachycardia and fibrillation due to the underlying arrhythmogenic substrate. It is characterized by cardiomyocyte hypertrophy and disorganization, myofibre disarray, and interstitial fibrosis, which result in increased left ventricular (LV) stiffness, impaired LV filling and diastolic dysfunction, and manifests as dyspnoea and exercise intolerance. 1 It is defined as left ventricular hypertrophy (LVH) without chamber dilation, which develops in the absence of an identifiable cause. Hypertrophic cardiomyopathy (HCM) is one of the most common inherited cardiac disease, affecting ∼1 in 500 individuals. Myeloperoxidase, Hypertrophic cardiomyopathy (HCM), Diastolic dysfunction, Human-induced pluripotent stem cells (hiPSCs), Cardiac myosin binding protein-C (MYBPC3), Oxidative stress ![]()
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