Advances in Hypertrophic Cardiomyopathy Disease Modelling Using hiPSC-Derived Cardiomyocytes.

The advent of human induced pluripotent stem cells (hiPSCs) and their capacity to be differentiated into beating human cardiomyocytes (CMs) in vitro has revolutionized human disease modelling, genotype-phenotype predictions, and therapeutic testing. Hypertrophic cardiomyopathy (HCM) is a common inherited cardiomyopathy and the leading known cause of sudden cardiac arrest in young adults and athletes. On a molecular level, HCM is often driven by single pathogenic genetic variants, usually in sarcomeric proteins, that can alter the mechanical, electrical, signalling, and transcriptional properties of the cell. A deeper knowledge of these alterations is critical to better understanding HCM manifestation, progression, and treatment. Leveraging hiPSC-CMs to investigate the molecular mechanisms driving HCM presents a unique opportunity to dissect the consequences of genetic variants in a sophisticated and controlled manner. In this review, we summarize the molecular underpinnings of HCM and the role of hiPSC-CM studies in advancing our understanding, and we highlight the advances in hiPSC-CM-based modelling of HCM, including maturation, contractility, multiomics, and genome editing, with the notable exception of electrophysiology, which has been previously covered.

Mechanisms of Pathogenicity of Hypertrophic Cardiomyopathy-Associated Troponin T (TNNT2) Variant R278C+/- During Development.

Hypertrophic cardiomyopathy (HCM) is one of the most common heritable cardiovascular diseases and variants of TNNT2 (cardiac troponin T) are linked to increased risk of sudden cardiac arrest despite causing limited hypertrophy. In this study, a TNNT2 variant, R278C+/-, was generated in both human cardiac recombinant/reconstituted thin filaments (hcRTF) and human- induced pluripotent stem cells (hiPSCs) to investigate the mechanisms by which the R278C+/- variant affects cardiomyocytes at the proteomic and functional levels. The results of proteomics analysis showed a significant upregulation of markers of cardiac hypertrophy and remodeling in R278C+/- vs. the isogenic control. Functional measurements showed that R278C+/- variant enhances the myofilament sensitivity to Ca2+, increases the kinetics of contraction, and causes arrhythmia at frequencies >75 bpm. This study uniquely shows the profound impact of the TNNT2 R278C+/- variant on the cardiomyocyte proteomic profile, cardiac electrical and contractile function in the early stages of cardiac development.

Using human induced pluripotent stem cell-derived cardiomyocytes to understand the mechanisms driving cardiomyocyte maturation.

Cardiovascular diseases are the leading cause of mortality and reduced quality of life globally. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) provide a personalized platform to study inherited heart diseases, drug-induced cardiac toxicity, and cardiac regenerative therapy. However, the immaturity of CMs obtained by current strategies is a major hurdle in utilizing hiPSC-CMs at their fullest potential. Here, the major findings and limitations of current maturation methodologies to enhance the utility of hiPSC-CMs in the battle against a major source of morbidity and mortality are reviewed. The most recent knowledge of the potential signaling pathways involved in the transition of fetal to adult CMs are assimilated. In particular, we take a deeper look on role of nutrient sensing signaling pathways and the potential role of cap-independent translation mediated by the modulation of mTOR pathway in the regulation of cardiac gap junctions and other yet to be identified aspects of CM maturation. Moreover, a relatively unexplored perspective on how our knowledge on the effects of preterm birth on cardiovascular development can be actually utilized to enhance the current understanding of CM maturation is examined. Furthermore, the interaction between the evolving neonatal human heart and brown adipose tissue as the major source of neonatal thermogenesis and its endocrine function on CM development is another discussed topic which is worthy of future investigation. Finally, the current knowledge regarding transcriptional mediators of CM maturation is still limited. The recent studies have produced the groundwork to better understand CM maturation in terms of providing some of the key factors involved in maturation and development of metrics for assessment of maturation which proves essential for future studies on in vitro PSC-CMs maturation.

Effects of selenium intake on the expression of prostaglandin-endoperoxide synthase 2 (cyclooxygenase-2) and matrix metallopeptidase-9 genes in the coronary artery disease: Selenegene study, a double-blind randomized controlled trial.

BACKGROUND: The oxidative stress is regarded as one of the main contributors to the health problem. Cyclooxygenase-2 (COX-2) and matrix metallopeptidase-9 (MMP-9) are two of the important genes that are reported to be involved in the cardiovascular disease (CVD) development in the molecular and genetic association studies. The aim of this study was to evaluate the level of expression of COX-2 and MMP-9 after selenium supplementation in patients with coronary artery disease (CAD). METHODS: In this sub-study of Selenegene study, subjects were randomly divided into groups, 19 subjects who received selenium and 22 patients with CAD who received placebo. Patients received either 200-mg selenium yeast tablets or placebo tablets after a meal, once daily for 60 days. The messenger ribonucleic acid (mRNA) levels of the selenium and prostaglandin-endoperoxide synthase 2 (PTGS2) (COX-2) and MMP-9 genes products were determined before and after the study. RESULTS: In this sub-study, 41 Iranian patients with CVD were enrolled (placebo group: n = 22, selenium intervention: n = 19). Fasting blood sugar (FBS) was higher among placebo group than selenium group (93.4 ± 12.7 vs. 124.4 ± 40.6 mg/dl, P = 0.03). Triglyceride (TG) level was higher among selenium group versus placebo group (123.3 ± 34.0 vs. 184.8 ± 69.4 mg/dl, P = 0.006). The data analysis demonstrated that the expression of MMP-9 and COX-2 genes did not change significantly in both selenium and placebo groups. CONCLUSION: This study showed a positive association between the expression of MMP-9 and COX-2 in the patients with CAD who received selenium but not the placebo groups. Yet, these findings need to be confirmed in further details and expanded sample size.

ASGR1 but not FOXM1 expression decreases in the peripheral blood mononuclear cells of diabetic atherosclerotic patients.

BACKGROUND: The ASGR1 was recently shown to play a key role in the development of coronary artery disease (CAD), but its exact mechanism of action in the CAD pathogenesis is not yet known. This study evaluates the possible association between the expression level of ASGR1 and its downstream transcription factor FOXM1 in the inflammatory cells of peripheral blood (PBMC) and the pathogenesis of CAD in the Diabetic condition. METHODS: Blood samples were taken from the candidates who had visited the Tehran Heart Center and had underwent diagnostic tests with respect to diabetes and CAD. The peripheral blood cells were harvested, RNA was extracted, and cDNA was synthesized. The qRT-PCR was performed on 79 cDNA samples taken from 49 CAD+ patients and 30 CAD- patients. RESULTS: In this study, we observed a significant decrease of ASGR1 expression in the PBMC of CAD+ patients compared to the CAD- patients. We did not identify any considerable differences in the expression of FOXM1 in patients' subgroups with respect to the diabetes and CAD. CONCLUSION: The results of our study determine the association of ASGR1 expression and CAD pathogenesis. However, we do not know whether this result is the cause or the effect of CAD.