The regulatory light chain mediates inactivation of myosin motors during active shortening of cardiac muscle

The normal function of heart muscle depends on its ability to contract more strongly at longer length. Increased venous filling stretches relaxed heart muscle cells, triggering a stronger contraction in the next beat- the Frank-Starling relation. Conversely, heart muscle cells are inactivated when they shorten during ejection, accelerating relaxation to facilitate refilling before the next beat. Although both effects are essential for the efficient function of the heart, the underlying mechanisms were unknown. Using bifunctional fluorescent probes on the regulatory light chain of the myosin motor we show that its N-terminal domain may be captured in the folded OFF state of the myosin dimer at the end of the working-stroke of the actin-attached motor, whilst its C-terminal domain joins the OFF state only after motor detachment from actin. We propose that sequential folding of myosin motors onto the filament backbone may be responsible for shortening-induced de-activation in the heart.

Histopathological Profile of Therapeutic Doses of Mango Mistletoe Methanolic Extract (MMME) in Cardiac of Hypertensive Rats (DOCA-Salt)

This study determined the effect of Mango mistletoe Methanolic Extract (MMME) on the cardiac's histopathological profile of hypertensive rats (DOCA-Salt) treated. The MMME was treated on fifty rats for 14 days, divided into five treatments: negative control, positive control, doses 50, 100, and 200 mg/kg BW with five replications. One-way ANOVA analysis was used, namely JAMOVI with version 1.1.9.0, and for cell calculation, diameter using the IMAGE J application. Results showed that there were no significant differences in the histopathological profile of the cardiac in hypertensive rats (DOCA-Salt) treated with MMME for 14 days on the diameter of the heart muscle cells between the control (+) and control groups (-), treatments 1, 2, and 3. This is evidenced by the analysis of p-value> 0.05, namely 0.187 millimeters. Therefore, we concluded that MMME does not affect the diameter of heart/cardiac organ muscle cells. However, there was a significant difference in the amount of necrosis in the cardiac of hypertensive rats between control (+) and control (-) groups, treatments 1, 2, and 3. Based on the results, MMME reduces the number of necrosis in the heart/cardiac organ.

Heart regeneration: beyond new muscle and vessels

The most striking consequence of a heart attack is the loss of billions of heart muscle cells, alongside damage to the associated vasculature. The lost cardiovascular tissue is replaced by scar formation, which is non-functional and results in pathological remodelling of the heart and ultimately heart failure. It is, therefore, unsurprising that the heart regeneration field has centred efforts to generate new muscle and blood vessels through targeting cardiomyocyte proliferation and angiogenesis following injury. However, combined insights from embryological studies and regenerative models, alongside the adoption of -omics technology, highlight the extensive heterogeneity of cell types within the forming or re-forming heart and the significant crosstalk arising from non-muscle and non-vessel cells. In this review, we focus on the roles of fibroblasts, immune, conduction system, and nervous system cell populations during heart development and we consider the latest evidence supporting a function for these diverse lineages in contributing to regeneration following heart injury. We suggest that the emerging picture of neurologically, immunologically, and electrically coupled cell function calls for a wider-ranging combinatorial approach to heart regeneration.

Mitochondria at Work: New Insights into Regulation and Dysregulation of Cellular Energy Supply and Metabolism

Mitochondria are of great relevance to health, and their dysregulation is associated with major chronic diseases. Research on mitochondria—156 brand new publications from 2019 and 2020—have contributed to this review. Mitochondria have been fundamental for the evolution of complex organisms. As important and semi-autonomous organelles in cells, they can adapt their function to the needs of the respective organ. They can program their function to energy supply (e.g., to keep heart muscle cells going, life-long) or to metabolism (e.g., to support hepatocytes and liver function). The capacity of mitochondria to re-program between different options is important for all cell types that are capable of changing between a resting state and cell proliferation, such as stem cells and immune cells. Major chronic diseases are characterized by mitochondrial dysregulation. This will be exemplified by cardiovascular diseases, metabolic syndrome, neurodegenerative diseases, immune system disorders, and cancer. New strategies for intervention in chronic diseases will be presented. The tumor microenvironment can be considered a battlefield between cancer and immune defense, competing for energy supply and metabolism. Cancer cachexia is considered as a final stage of cancer progression. Nevertheless, the review will present an example of complete remission of cachexia via immune cell transfer. These findings should encourage studies along the lines of mitochondria, energy supply, and metabolism.

Somatic mutations in single human cardiomyocytes demonstrate accelerated age-related DNA damage and cell fusion

The accumulation of somatic DNA mutations is a hallmark of aging in many dividing cells and contributes to carcinogenesis. Here we survey the landscape of somatic single-nucleotide variants (sSNVs) in heart muscle cells (cardiomyocytes) which normally do not proliferate but often become polyploid with age. Using single-cell whole-genome sequencing we analyzed sSNVs from 48 single cardiomyocytes from 10 healthy individuals (ages 0.4 - 82 yrs.). Cardiomyocyte sSNVs increased strikingly with age, at rates faster than reported in many dividing cells, or in non-dividing neurons. Analysis of nucleotide substitution patterns revealed age-related “clock-like” mutational signatures resembling those previously described. However, cardiomyocytes showed distinct mutational signatures that are rare or absent in other cells, implicating failed nucleotide excision repair of oxidative damage and defective mismatch repair (MMR) during aging. A lineage tree of cardiomyocytes, constructed using clonal sSNVs, revealed that some tetraploid (10%) and most cardiomyocytes with higher ploidy (>60%) derive from distinct clonal origins, implicating cell fusion as a mechanism contributing to many polyploid cardiomyocytes. Since age-accumulated sSNVs create dozens of damaging exonic mutations, cell fusion to form multiploid cardiomyocytes may represent an evolutionary mechanism of cellular genetic compensation that minimizes complete knockout of essential genes during aging. The rates and patterns of accumulation of cardiac mutations provide a paradigm to understand the influence of genomic aging on age-related heart disease.

Effects of fibrillin mutations on the behavior of heart muscle cells in Marfan syndrome

Marfan syndrome (MFS) is a systemic disorder of connective tissue caused by pathogenic variants in the fibrillin-1 (FBN1) gene. Myocardial dysfunction has been demonstrated in MFS patients and mouse models, but little is known about the intrinsic effect on the cardiomyocytes (CMs). In this study, both induced pluripotent stem cells derived from a MFS-patient and the line with the corrected FBN1 mutation were differentiated to CMs. Several functional analyses are performed on this model to study MFS related cardiomyopathy. Atomic force microscopy revealed that MFS CMs are stiffer compared to corrected CMs. The contraction amplitude of MFS CMs is decreased compared to corrected CMs. Under normal culture conditions, MFS CMs show a lower beat-to-beat variability compared to corrected CMs using multi electrode array. Isoproterenol-induced stress or cyclic strain demonstrates lack of support from the matrix in MFS CMs. This study reports the first cardiac cell culture model for MFS, revealing abnormalities in the behavior of MFS CMs that are related to matrix defects. Based on these results, we postulate that impaired support from the extracellular environment plays a key role in the improper functioning of CMs in MFS.

Modelling and Simulation for Preclinical Cardiac Safety Assessment of Drugs with Human iPSC-Derived Cardiomyocytes

As a potentially life threatening side effect, pharmaceutical compounds may trigger cardiac arrhythmias by impeding the heart’s electrical and mechanical function. For this reason, any new compound needs to be tested since 2005 for its proarrhythmic risk both during the preclinical and the clinical phase of the drug development process. While intensive monitoring of cardiac activity during clinical tests with human volunteers constitutes a major cost factor, preclinical in vitro tests with non cardiac cells and in vivo tests with animals are currently under serious debate because of their poor extrapolation to drug cardiotoxicity in humans. For about five years now, regulatory agencies, industry and academia are working on an overhaul of the cardiac drug safety paradigm that is built a) on human heart muscle cells, that can be abundantly bioengineered from donor stem cells without ethical concerns (human induced pluripotent stem cell derived cardiomyocytes, hiPSC-CMs), and b) on computational models of human cardiac electrophysiology both at the cellular and the organ level. The combined use of such human in vitro and human in silico models during the preclinical phase is expected to improve proarrhythmia test specificity (i.e. to lower the false-positive rate), to better inform about the need of thorough heart monitoring in the clinic, and to reduce or even replace animal experiments. This review article starts by concisely informing about the electrical activity of the human heart, about its possible impairment due to drug side effects, and about hiPSC-CM assays for cardiac drug safety testing. It then summarizes the mathematical description of human cardiac electrophysiology in terms of mechanistic ODE and PDE models, and illustrates how their numerical analysis may provide insight into the genesis of drug induced arrhythmias. Finally, this paper surveys proarrhythmic risk estimation methods, that involve the simulation of human heart muscle cells, and addresses opportunities and challenges for future interdisciplinary research.

Self Affirmation Reduces the Anxiety, LDH and Troponin I in the Clients with Coronary Heart Disease (CHD)

Introduction: Positive self affirmation is one of the psychological interventions that can be applied to the treatment of coronary heart disease; its effect is currently unknown. The purpose of this study was to prove the effect of self affirmation on anxiety, troponin I and LDH in coronary heart disease patients.Methods: The type and design of the study was quasi-experimental with a non-randomized post-test control group design. Thirty patients with coronary heart disease who were treated in the Camelia room of Dr Soetomo Hospital who had been selected were divided into 2 groups. The first group was given self affirmation twice / day for 20 minutes and the second group had standard care as the control group. After the intervention, anxiety measurements were taken, in addition to the measurement of troponin I and LDH.Results: The results showed that self affirmation reduced anxiety (ρ = 0.03), decreased troponin I (ρ = 0.003) and decreased the lactate dehydrogenase (LDH) levels (ρ = 0.006).Conclusion: Self-affirmation improves the client’s emotions, preventing damage to the heart muscle cells. This is reflected by a decrease in the troponin I and LDH levels which are indicators of heart muscle damage.