Nanoscale Organization, Regulation, and Dynamic Reorganization of Cardiac Calcium Channels

The architectural specializations and targeted delivery pathways of cardiomyocytes ensure that L-type Ca2+ channels (CaV1.2) are concentrated on the t-tubule sarcolemma within nanometers of their intracellular partners the type 2 ryanodine receptors (RyR2) which cluster on the junctional sarcoplasmic reticulum (jSR). The organization and distribution of these two groups of cardiac calcium channel clusters critically underlies the uniform contraction of the myocardium. Ca2+ signaling between these two sets of adjacent clusters produces Ca2+ sparks that in health, cannot escalate into Ca2+ waves because there is sufficient separation of adjacent clusters so that the release of Ca2+ from one RyR2 cluster or supercluster, cannot activate and sustain the release of Ca2+ from neighboring clusters. Instead, thousands of these Ca2+ release units (CRUs) generate near simultaneous Ca2+ sparks across every cardiomyocyte during the action potential when calcium induced calcium release from RyR2 is stimulated by depolarization induced Ca2+ influx through voltage dependent CaV1.2 channel clusters. These sparks summate to generate a global Ca2+ transient that activates the myofilaments and thus the electrical signal of the action potential is transduced into a functional output, myocardial contraction. To generate more, or less contractile force to match the hemodynamic and metabolic demands of the body, the heart responds to β-adrenergic signaling by altering activity of calcium channels to tune excitation-contraction coupling accordingly. Recent accumulating evidence suggests that this tuning process also involves altered expression, and dynamic reorganization of CaV1.2 and RyR2 channels on their respective membranes to control the amplitude of Ca2+ entry, SR Ca2+ release and myocardial function. In heart failure and aging, altered distribution and reorganization of these key Ca2+ signaling proteins occurs alongside architectural remodeling and is thought to contribute to impaired contractile function. In the present review we discuss these latest developments, their implications, and future questions to be addressed.

Integrative Bioinformatics Analysis Reveals That Infarct-Mediated Overexpression of Potential miR-662/CREB1 Pathway-Induced Neuropeptide VIP Is Associated with the Risk of Atrial Fibrillation: A Correlation Analysis between Myocardial Electrophysiology and Neuroendocrine

Background. Neuropeptide levels are closely associated with the development and maintenance of atrial fibrillation (AF) after myocardial infarction (MI). This study was aimed at investigating the regulatory network that affects neuropeptide expression through transcription factor modulation. Methods. We downloaded three datasets from the GEO database, and after performing differential and crosstabulation analyses, we screened out differentially expressed (DE) miRNAs and DEmRNAs coexpressed in AF and MI and performed DEmiRNA–DEmRNA pairing prediction; from which, we constructed a regulatory network. Subsequently, the hsa-miR-662-CREB1-VIP axis was obtained, and the role of CREB1 and VIP in the development of AF after MI was further revealed by single-cell analysis and prediction model construction. Results. In this study, eight DEmRNAs and four miRNAs were screened. hsa-miR-662 was identified by database integration analysis to regulate the transcription factor CREB1, a potential transcriptional regulator in VIP. CREB1 and VIP are mainly enriched in pathways of energy metabolism, ion channels, and myocardial contraction. CREB1 and VIP were identified as biomarkers of the onset and prognosis of MI and AF. Conclusions. In this study, the miR-662/CREB1/VIP regulatory pathway was constructed through integrated analysis of datasets, thus providing new ideas to study the mechanisms of AF development.

Monitoring of Physiological Sounds with Wearable Device based on Piezoelectric MEMS Acoustic Sensor

Physiological mechano-acoustic signals play a pivotal role in medical diagnosis and fitness monitoring. Mechanical waves generated by natural physiological activities such as myocardial contraction, and vocal fold vibration, propagate through the tissues and fluids of the body and reveal characteristic signals of these events. Conventional methods such as stethoscope and electrocardiography (ECG) are not suitable for wearable mode and continuous monitoring. In this paper, we propose a wearable physiological sounds sensing device to monitor heart sound and detect speech and voice with high accuracy. The device consists of a MEMS (microelectromechanical systems) acoustic sensor and a low-noise amplification circuit, and both of them are packaged by silicone polymers with an air cavity to achieve conformal contact with human skin. The proposed device has advantages of light weight, sweatproof capability, resistant to noise and good stability. The wearable device has great potential in clinical diagnosis, healthcare, human-machine interaction and many other applications.

Cardiomyocyte Dysfunction in Inherited Cardiomyopathies

Inherited cardiomyopathies form a heterogenous group of disorders that affect the structure and function of the heart. Defects in the genes encoding sarcomeric proteins are associated with various perturbations that induce contractile dysfunction and promote disease development. In this review we aimed to outline the functional consequences of the major inherited cardiomyopathies in terms of myocardial contraction and kinetics, and to highlight the structural and functional alterations in some sarcomeric variants that have been demonstrated to be involved in the pathogenesis of the inherited cardiomyopathies. A particular focus was made on mutation-induced alterations in cardiomyocyte mechanics. Since no disease-specific treatments for familial cardiomyopathies exist, several novel agents have been developed to modulate sarcomere contractility. Understanding the molecular basis of the disease opens new avenues for the development of new therapies. Furthermore, the earlier the awareness of the genetic defect, the better the clinical prognostication would be for patients and the better the prevention of development of the disease.

Deciphering the Protein, Modular Connections and Precision Medicine for Heart Failure With Preserved Ejection Fraction and Hypertension Based on TMT Quantitative Proteomics and Molecular Docking

Background: Exploring the potential biological relationships between heart failure with preserved ejection fraction (HFpEF) and concomitant diseases has been the focus of many studies for the establishment of personalized therapies. Hypertension (HTN) is the most common concomitant disease in HFpEF patients, but the functional connections between HFpEF and HTN are still not fully understood and effective treatment strategies are still lacking.Methods: In this study, tandem mass tag (TMT) quantitative proteomics was used to identify disease-related proteins and construct disease-related networks. Furthermore, functional enrichment analysis of overlapping network modules was used to determine the functional similarities between HFpEF and HTN. Molecular docking and module analyses were combined to identify therapeutic targets for HFpEF and HTN.Results: Seven common differentially expressed proteins (co-DEPs) and eight overlapping modules were identified in HFpEF and HTN. The common biological processes between HFpEF and HTN were mainly related to energy metabolism. Myocardial contraction, energy metabolism, apoptosis, oxidative stress, immune response, and cardiac hypertrophy were all closely associated with HFpEF and HTN. Epinephrine, sulfadimethoxine, chloroform, and prednisolone acetate were best matched with the co-DEPs by molecular docking analyses.Conclusion: Myocardial contraction, energy metabolism, apoptosis, oxidative stress, immune response, and cardiac hypertrophy were the main functional connections between HFpEF and HTN. Epinephrine, sulfadimethoxine, chloroform, and prednisolone acetate could potentially be effective for the treatment of HTN and HFpEF.

Stop the beat to see the rhythm: excitation-contraction uncoupling in cardiac research

Optical mapping is an imaging technique that is extensively used in cardiovascular research, wherein parameter-sensitive fluorescent indicators are used to study the electrophysiology and excitation-contraction coupling of cardiac tissues. Despite the many benefits of optical mapping, eliminating motion artifacts within the optical signals is a major challenge, as myocardial contraction interferes with the faithful acquisition of action potentials and intracellular calcium transients. As such, excitation-contraction uncoupling agents are frequently used to reduce signal distortion by suppressing contraction. Compared to other uncoupling agents, blebbistatin is the most frequently used as it offers increased potency with minimal direct effects on cardiac electrophysiology. Nevertheless, blebbistatin may exert secondary effects on electrical activity, metabolism, and coronary flow, and the incorrect administration of blebbistatin to cardiac tissue can prove detrimental, resulting in erroneous interpretation of optical mapping results. In this "Getting It Right" perspective, we briefly review the literature regarding the use of blebbistatin in cardiac optical mapping experiments, highlight potential secondary effects of blebbistatin on cardiac electrical activity and metabolic demand, and conclude with the consensus of the authors on best practices for effectively using blebbistatin in optical mapping studies of cardiac tissue.

Passive myocardial mechanical properties: meaning, measurement, models

Passive mechanical tissue properties are major determinants of myocardial contraction and relaxation and, thus, shape cardiac function. Tightly regulated, dynamically adapting throughout life, and affecting a host of cellular functions, passive tissue mechanics also contribute to cardiac dysfunction. Development of treatments and early identification of diseases requires better spatio-temporal characterisation of tissue mechanical properties and their underlying mechanisms. With this understanding, key regulators may be identified, providing pathways with potential to control and limit pathological development. Methodologies and models used to assess and mimic tissue mechanical properties are diverse, and available data are in part mutually contradictory. In this review, we define important concepts useful for characterising passive mechanical tissue properties, and compare a variety of in vitro and in vivo techniques that allow one to assess tissue mechanics. We give definitions of key terms, and summarise insight into determinants of myocardial stiffness in situ. We then provide an overview of common experimental models utilised to assess the role of environmental stiffness and composition, and its effects on cardiac cell and tissue function. Finally, promising future directions are outlined.

Evaluation of the anti-atherosclerosis effect of Shanhuaxiaozhi Formulation by combination of GC–MS-based metabolomics and TMT-based proteomics technology

Objective Shanhuaxiaozhi formulation (SHXZF) is a traditional Chinese medicine preparation composed of Saffron, Crataegi Fructus, Chrysanthemi Flos, Tangerine Peel and Fructus Lycii. It is used in clinics for treating atherosclerosis with promising evidence of efficacy. Although some of the drugs in SHXZF have been reported to have significant therapeutic effects on atherosclerosis, the metabolic regulation and underlying mechanism of SHXZF during the remission of atherosclerosis are still unclear. This study aimed to integrate proteome and metabolome data sets for a holistic view of the molecular mechanisms of SHXZF in treating atherosclerosis. Methods Serum samples and aortic arch tissue from male ApoE−/− mice and C57BL/6L mice were analyzed respectively using gas chromatography–mass spectrometry (GC–MS) based metabolomics technology and Tandem Mass Tags (TMT) based quantitative proteomics technology. Metabonomics and proteomics data were integrated to analyze the mechanism of SHXZF in the treatment of atherosclerosis. Results A total of 24 potential biomarkers and 70 differential proteins were identified. These substances were mainly involved in three biological pathways: the cAMP signaling pathway, the lipid metabolism pathway, and the myocardial contraction pathway. Conclusions The results suggested that SHXZF could effectively treat atherosclerosis, partially by regulating the above three metabolic pathways. The combination of proteomics and metabolomics provided a feasible method to uncover the underlying interventional effect and therapeutic mechanism of SHXZF on atherosclerosis.