Regulation Of Cardiac Function Research Articles

Biventricular function in exercise during autonomic (thoracic epidural) block

BackgroundBlockade of cardiac sympathetic fibers by thoracic epidural anesthesia (TEA) was previously shown to reduce right and left ventricular systolic function and effective pulmonary arterial elastance. At conditions of constant paced heart rate, cardiac output and systemic hemodynamics were unchanged. In this study, we further investigated the effect of cardiac sympathicolysis during physical stress and increased oxygen demand.MethodsIn a cross-over design, 12 patients scheduled to undergo thoracic surgery performed dynamic ergometric exercise tests with and without TEA. Hemodynamics were monitored and biventricular function was measured by transthoracic two-dimensional and M-mode echocardiography, pulsed wave Doppler and tissue Doppler imaging.ResultsTEA attenuated systolic RV function (TV Sʹ: − 21%, P < 0.001) and LV function (MV Sʹ: − 14%, P = 0.025), but biventricular diastolic function was not affected. HR (− 11%, P < 0.001), SVI (− 15%, P = 0.006), CI (− 21%, P < 0.001) and MAP (− 12%, P < 0.001) were decreased during TEA, but SVR was not affected. Exercise resulted in significant augmentation of systolic and diastolic biventricular function. During exercise HR, SVI, CI and MAP increased (respectively, + 86%, + 19%, + 124% and + 17%, all P < 0.001), whereas SVR decreased (− 49%, P < 0.001). No significant interactions between exercise and TEA were found, except for RPP (P = 0.024) and MV E DT (P = 0.035).ConclusionCardiac sympathetic blockade by TEA reduced LV and RV systolic function but did not significantly blunt exercise-induced increases in LV and RV function. These data indicate that additional mechanisms besides those controlled by the cardiac sympathetic nervous system are involved in the regulation of cardiac function during dynamic exercise.Trial registration Clinical trial registration: Nederlands Trial Register, NTR 4880 http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=4880.

Emergence of the N-Terminal Regulatory Domain of Cardiac Troponin I for Living on Land and the Function of Adult Heart of Higher Vertebrates

The troponin complex plays a central role in regulating the contraction and relaxation of striated muscles. Troponin-based thin filament regulation of muscle contraction emerged approximately 700 million years ago with largely conserved functions. Troponin I (TnI) is the inhibitory subunit of troponin and has evolved into three muscle type-specific isoforms in vertebrates. Cardiac TnI has an N-terminal extension that is specifically expressed in the adult heart, implicating a unique selection value. Cardiac TnI of higher vertebrate species contains beta-adrenergic regulated PKA phosphorylation sites in the N-terminal extension, which is a mechanism to enhance cardiac muscle relaxation and facilitate ventricular filling. Our data mining showed that the N-terminal extension of cardiac TnI first emerged in the genomes of early tetrapods as well as primordial lobe-finned fishes such as the coelacanth whereas it is absent in ray-finned fish. An intriguing finding is the lack of a transitional species that has an N-terminal extension in cardiac TnI without the PKA phosphorylation sites. This apparently rapid evolution of the beta-adrenergic regulation of cardiac function suggests a high selection value in the cardiac function of vertebrate animals on land. To understand the evolution and original function of the N-terminal extension in modulating cardiac muscle contractility, our study comparing the cardiac muscle of primitive lobe-finned fish with that of mammals and ray-finned fish investigates its role in cardiac adaptation to the increased energetic demands of life on land and significance in human health and the treatment of heart failure.

GRKs and Epac1 Interaction in Cardiac Remodeling and Heart Failure.

β-adrenergic receptors (β-ARs) play a major role in the physiological regulation of cardiac function through signaling routes tightly controlled by G protein-coupled receptor kinases (GRKs). Although the acute stimulation of β-ARs and the subsequent production of cyclic AMP (cAMP) have beneficial effects on cardiac function, chronic stimulation of β-ARs as observed under sympathetic overdrive promotes the development of pathological cardiac remodeling and heart failure (HF), a leading cause of mortality worldwide. This is accompanied by an alteration in cAMP compartmentalization and the activation of the exchange protein directly activated by cAMP 1 (Epac1) signaling. Among downstream signals of β-ARs, compelling evidence indicates that GRK2, GRK5, and Epac1 represent attractive therapeutic targets for cardiac disease. Here, we summarize the pathophysiological roles of GRK2, GRK5, and Epac1 in the heart. We focus on their signalosome and describe how under pathological settings, these proteins can cross-talk and are part of scaffolded nodal signaling systems that contribute to a decreased cardiac function and HF development.

Metabonomics Analysis of Myocardial Metabolic Dysfunction in Patients with Cardiac Natriuretic Peptide Resistance.

Brain natriuretic peptide (BNP) is an important biological marker and regulator of cardiac function. BNP resistance is characterized by high concentrations of less functionally effective BNP and common in heart failure (HF) patients. However, the roles and consequences of BNP resistance remain poorly understood. Investigate the effects of cardiac BNP resistance and identify potential metabolic biomarkers for screening and diagnosis. Thirty patients and thirty healthy subjects were enrolled in this study. Cardiac functions were evaluated by echocardiography. The plasma levels of cyclic guanosine monophosphate (cGMP) and BNP were measured by enzyme-linked immunosorbent assay (ELISA) and the cGMP/BNP ratio is calculated to determine cardiac natriuretic peptide resistance. Liquid chromatograph tandem mass spectrometry (LC-MS) based untargeted metabolomics analysis was applied to screen metabolic changes. The cGMP/BNP ratio was markedly lower in HF patients than controls. The cGMP/BNP ratio and ejection fraction (EF) were strongly correlated (R2 = 0.676, P < 0.05). Importantly, metabolic profiles were substantially different between HF patients and healthy controls. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis demonstrated that the differentially expressed metabolites are involved in signaling pathways that regulate cardiac functions. In HF patients, BNP resistance develops in association with a reduction in heart function and metabolic remodeling. It suggests possible functional roles of BNP resistance in the regulation of cardiac metabolism.

Cardiac‑specific deletion of natriuretic peptide receptor A induces differential myocardial expression of circular RNA and mRNA molecules involved in metabolism in mice.

Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are important biological markers and regulators of cardiac function. The natriuretic peptide receptor A (NPRA), also known as NPR1 or guanylyl cyclase A, binds ANP and BNP to initiate transmembrane signal transduction by elevating the intracellular levels of cyclic guanosine monophosphate. However, the effects and mechanisms downstream of NPRA are largely unknown. The aim of the present study was to evaluate the changes in the global pattern of mRNA and circular RNA (circRNA) expression in NPRA−/− and NPRA+/+ myocardium. Differentially expressed mRNA molecules were characterised using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis and were found to be primarily related to metabolic processes. Moreover, circRNA expression was also examined, and a possible competing endogenous RNA network consisting of circRNA, microRNA (miRNA), and mRNA molecules was constructed. The results of this study indicated that NPRA may play a role in cardiac metabolism, which could be mediated by circRNA through endogenous competition mechanisms. These findings may provide insight into future characterisation of various ceRNA network pathways.

β2-Adrenergic Receptors Increase Cardiac Fibroblast Proliferation Through the Gαs/ERK1/2-Dependent Secretion of Interleukin-6.

Fibroblasts are an important resident cell population in the heart involved in maintaining homeostasis and structure during normal conditions. They are also crucial in disease states for sensing signals and initiating the appropriate repair responses to maintain the structural integrity of the heart. This sentinel role of cardiac fibroblasts occurs, in part, through their ability to secrete cytokines. β-adrenergic receptors (βAR) are also critical regulators of cardiac function in the normal and diseased state and a major therapeutic target clinically. βAR are known to influence cytokine secretion in various cell types and they have been shown to be involved in cytokine production in the heart, but their role in regulating cytokine production in cardiac fibroblasts is not well understood. Thus, we hypothesized that βAR activation on cardiac fibroblasts modulates cytokine production to influence fibroblast function. Using primary fibroblast cultures from neonatal rats and adult mice, increased interleukin (IL)-6 expression and secretion occurred following β2AR activation. The use of pharmacological inhibitors and genetic manipulations showed that IL-6 elevations occurred through the Gαs-mediated activation of ERK1/2 and resulted in increased fibroblast proliferation. In vivo, a lack of β2AR resulted in increased infarct size following myocardial infarction and impaired wound closure in a murine dermal wound healing assay. These findings identify an important role for β2AR in regulating fibroblast proliferation through Gαs/ERK1/2-dependent alterations in IL-6 and may lead to the development of improved heart failure therapies through targeting fibrotic function of β2AR.

Use of thyroid hormones in the treatment of cardiovascular diseases: literature review

Cardiovascular diseases remain the leading cause of death all over the world. Thyroid hormones play a significant role in the regulation of cardiac function. According to a number of researches, patients with cardiovascular diseases usually have a decrease in the concentration of thyroid hormones in the blood serum, which may be associated with a poor prognosis. Today it still remains unclear whether the change in the bioavailability of thyroid hormones in the myocardium is a favorable physiological mechanism or a replication of an adaptation disorder. Experimental researches suggest that thyroid hormone therapy may be applied in clinical cardiology. This review describes the results of researches examining the use of thyroid hormones in patients with cardiovascular diseases, as well as experiment data on animal models. The available data on the use of thyroid hormones in patients with acute myocardial infarction and heart failure allow us to suggest that normalization of thyroid hormone levels is a safe and potentially effective treatment method in the group of patients with cardiovascular disease. At the same time, the data on the use of thyroid hormones in patients who have undergone an open-heart surgery or heart transplantation are limited. However, at present, it is difficult to draw unambiguous conclusions about the benefits, as well as about the possible risk of using thyroid hormones in the described conditions. Large-scale clinical researches are required to confirm the safety and evaluate the effectiveness of such therapy. Moreover, it is necessary to set parameters for evaluating the safety and effectiveness and understand which hormone (thyroxine or triiodothyronine), what dosage and at what stage of the disease should be applied. Until we do not have answers for these questions, thyroid hormone therapy in patients with cardiovascular diseases should remain within the research field.

Abstract MP133: Development of β-arrestin-biased Positive Allosteric Modulators for the β 1 Adrenergic Receptor

The β 1 adrenergic receptor (β 1 AR) is a central regulator of cardiac function and an important therapeutic target for cardiac diseases. Two emerging areas of receptor biology are biased agonism: ligand directed selective engagement of a receptor toward either a G protein or β-arrestin transducer; and allosteric modulation: ligands that bind to topographically distinct sites on the receptor to modulate its activity. Advances in these areas have the potential to yield new drugs that precisely enhance cardioprotective effects while limiting untoward detrimental actions. Compound 6 (Cmpd6) is a newly discovered positive allosteric modulator (PAM) for the β 2 AR. Interestingly, we now show that Cmpd6 has the unique property to enhance the binding affinity of the β-arrestin-biased agonist carvedilol to both the β 2 AR and the β 1 AR, while having minimal effect on the affinity of a panel of agonists and antagonists of the β 1 AR. We further tested the effect of Cmpd6 on β 1 AR signaling induced by a broad range of ligands. Cmpd6 selectively enhanced carvedilol-stimulated ERK activation in a β-arrestin-dependent signaling fashion, while having no effect on carvedilol-induced G protein-dependent cAMP production. To test the in vivo effect of Cmpd6 on cardiac injury, mice were pretreated with carvedilol with or without Cmpd6, then underwent ischemia/reperfusion through the left anterior descending artery ligation. Cell apoptosis was assessed by TUNEL. Carvedilol decreased the level of I/R-induced apoptosis compared to the vehicle-treated animals, and Cmpd6 significantly positively enhanced the anti-apoptotic effects of carvedilol. In conclusion, we identified Cmpd6 as a potential β-arrestin-biased PAM for the β 1 AR that enhances the cardioprotective effect of carvedilol. Ongoing studies will test Cmpd6 on heart failure post myocardial infarction.

Fetal Cardiac Cellular Damage Caused by Anemia in Utero in Hb Bart's Disease.

Severe fetal anemias can cause high output cardiac failure. Mitochondria are key regulators of cardiac function. However, the effects of an early phase of fetal anemia on the fetal heart and cardiac mitochondrial function are not known. The aim of this study is to compare mitochondrial function and cardiac biochemical alterations in the fetal cardiac tissue between anemic and non-anemic fetuses. A cross-sectional study was conducted in Fetuses affected by Hb Bart's disease (n=18) and non-anemic fetuses (n=10) at 17-20 weeks. Echocardiograms had been carried out in all cases to assess prenatal cardiac function. Cardiac tissues were collected after pregnancy termination for the determination of cardiac iron accumulation, mitochondrial function, including mitochondrial ROS production, mitochondrial depolarization and mitochondrial swelling, mitochondrial dynamics, inflammation, and apoptosis. Prenatal cardiac function evaluated by ultrasound was comparable between the Hb Bart's and non-anemic groups. In Bart's group, the levels of cardiac mitochondrial depolarization and swelling, and the TNF-α level were significantly higher, compared to the non-anemic group. On the contrary, anti-inflammatory (IL-10) levels were significantly lower in the Hb Bart's group. Additionally, active caspase-3 and Bcl-2 expression were also significantly higher (P= 0.001, P=0.035) in Bart's group. The mitochondrial fission protein expression, including p-DRP1/total DRP1, was significantly higher in Bart's group. However, there was no difference in cardiac iron accumulation levels between these two groups. Despite equivalent prenatal cardiac function and comparable cardiac iron accumulation in the Bart's and non-anemic groups, fetal anemia is significantly associated with cardiac mitochondrial dysfunction, increased mitochondrial fission, and increased inflammation and apoptosis. These findings indicate that an early phase of fetal anemia without cardiac iron overload can lead to cardiac mitochondrial dysfunction in fetuses with Hb Bart's.

Circular RNA in Diseased Heart.

Heart disease remains the leading cause of death globally and leads to tremendous socio-economic burden. Despite advances in the field of cardiovascular research, novel theranostics are still in urgent need. Remarkable progress has been made in understanding aberrant protein interactions and signaling pathways in the diseased heart, but less is known regarding epigenetic regulation. Non-coding RNAs have emerged as important regulators of cardiac function and have been implicated in disease. While significant progress has been made in understanding the roles of microRNAs and long non-coding RNAs, the functional roles of circular RNAs are less explored. Recent studies have provided ample evidence supporting their roles in multiple physiological processes including regulating the function of the heart. Compared with other RNAs, circular RNAs exhibit higher stability and more versatile functional modes: including sponging microRNAs, scaffolding proteins, regulating transcription, and even encoding small regulatory peptides. These characteristics make circular RNAs promising candidates for the development of diagnostic tools and therapies for heart disease. In this review, we will discuss the biogenesis of circular RNAs and provide an update of their functional implications in heart disease, with an emphasis on heart failure and arrhythmias.

Evaluation of cardiac dysfunction in adult zebrafish using high frequency echocardiography

AimsRecently, the zebrafish has gained attention as an innovative experimental model to decipher molecular and cellular mechanisms involved in cardiovascular development and diseases. Nevertheless, the use of zebrafish models has been challenged because the transparency of these fish, which allows for accurate cardiac evaluation, disappears in adulthood. In this study, the epicardial outline method was performed to investigate the feasibility of echocardiography in assessing cardiac function in pathological adult zebrafish. Materials and methodsWe attempted to estimate heart failure in adult zebrafish treated with three distinct regulators of cardiac function: phenylhydrazine hydrochloride (PHZ), doxorubicin (DOX), and ethanol. B-mode and Doppler images were evaluated at frequencies of up to 50 MHz and 40 MHz, respectively. The correlation between alterations in cardiac function, haemoglobin concentration, and myocardial histopathology were assessed. Key findingsCardiac output (CO) in PHZ-treated zebrafish was significantly higher than that in control zebrafish (151 ± 67 vs. 84 ± 37 μl/min, P = 0.004), whereas ejection fraction (EF) was lower (36.3 ± 10.9 vs. 50.9 ± 8.7%, P < 0.001), indicating typical high output heart failure derived from anaemia. Additionally, ventricular dysfunction in DOX-treated zebrafish was characterised by low CO (57 ± 38 μl/min) and EF (28.8 ± 10.4%), accompanied by an enlarged ventricle in diastole and systole, representing low output heart failure. For ethanol-treated zebrafish, EF was markedly reduced (39.6 ± 7.2%) indicating a dilated heart, while CO remained unchanged (90 ± 40 μl/min). SignificanceThe epicardial outline method is an effective way of using echocardiography to assess cardiac dysfunction in pathological adult zebrafish, unlocking a major bottleneck in this research field with limited cardiac functional assays.

Role of Transient Receptor Potential Canonical Channels in Heart Physiology and Pathophysiology.

Transient receptor potential canonical (TRPC) channels are involved in the regulation of cardiac function under (patho)physiological conditions and are closely associated with the pathogenesis of cardiac hypertrophy, arrhythmias, and myocardial infarction. Understanding the molecular mechanisms and the regulatory pathway/locus of TRPC channels in related heart diseases will provide potential new concepts for designing novel drugs targeting TRPC channels. We will present the properties and regulation of TRPC channels and their roles in the development of various forms of heart disease. This article provides a brief review on the role of TRPC channels in the regulation of myocardial function as well as how TRPC channels may serve as a therapeutic target in heart failure and cardiac arrhythmias including atrial fibrillation.

GPCR Stimulation Modulates Camkii Translocation and Targeting in Cardiomyocytes

Calcium/Calmodulin-dependent protein kinase II (CaMKIIδ) is a key regulator of cardiac function via its influence on ion channels, calcium handling, contraction, and transcription. Our group recently showed that pacing-induced activation of CaMKIIδ in cardiomyocytes enhances its mobility and rapid translocation to its extra-dyadic targets, providing a mechanism for broad myocyte target phosphorylation. It is not known whether GPCR-induced CaMKIIδ activation likewise stimulates CaMKII mobility. Here we used immunocytochemistry and protein expansion microscopy of endogenous CaMKII and fluorescence recovery after photobleach (FRAP) of GFP-tagged CaMKIIδ isoforms to measure CaMKIIδ mobility and intracellular targeting in intact adult cardiomyocytes. At low [Ca] (BAPTA-treated cells) and at rest, CaMKII was concentrated at the Z-lines but spread throughout the sarcomere with isoproterenol (ISO, 1 µM) or Angiotensin II (Ang II,100 nM) stimulation for 10 min. FRAP experiments likewise showed increased mobility for δC-GFP (τ for BAPTA ∼ 35s, ISO ∼ 16s and AngII ∼13s) and δB-GFP (τ for respectively BAPTA ∼ 21s, ISO ∼ 10s and AngII ∼10s). These effects were more pronounced upon chronic (20-24 hr) exposure to 0.5 Hz pacing with or without AngII or ISO. FRAP was significantly faster with pacing (τ ∼ 12s vs. rest ∼ 17s) and even more so with ISO or AngII exposure for δC-GFP (τ ISO ∼ 10s and AngII ∼10s) and δB-GFP (ISO ∼ 7s). The contribution of specific activating posttranslational modifications were also assessed using PTM-resistant CaMKIIδ constructs. In conclusion, acute and chronic activation of CaMKII via GPCR stimulation enhances its translocation which could explain CaMKII's regulation of pathological conditions, and widespread signaling within the myocyte.

MiR-29a activates expression of α-cardiac myosin heavy chain via β1 thyroid hormone receptor in neonatal rats.

MicroRNAs (miRs) are small noncoding RNAs which are regulators of gene expression and also regulate the genes in heart tissues. The aim of the study was to evaluate the effect of miRs on the expression level of myosin heavy chain (MHC), which is responsible for regulation of cardiac functions in neonatal rat ventricular myocytes and mice. The miRs were suppressed in neonatal rat ventricular myocytes using small interfering RNAs (siRNAs) against Dicer followed by evaluation of MHC levels. For in vivo study the C57 black/6 Jacksonian mice were subjected to the transverse aortic constriction (TAC) procedure. The Dicer siRNA suppressed the endogenous miRs and the α-MHC gene but failed to down-regulate the β-MHC. Among the 17 selected miRs, miR-29a was found to up-regulate the α-MHC gene significantly but not β-MHC. The expression of α-MHC was suppressed by silencing the expression of miR-29a. Bioinformatics study done by TargetScan suggested thyroid hormone receptor-β1 (TR-β1) as a potential target of miR-29a. Additionally, miR-29a was found to regulate the expression of α-MHC via TR-β1 signaling. The findings of the present study indicated that miR-29a modulates expression of α-the MHC gene by targeting TR-β1 in cardiac cells. The study may provide a new direction for treating cardiac failure and cardiac hypertrophy.

094 Characterisation of Novel Knockout Mouse Models to Investigate the Role of B55α in the Heart

Protein phosphatase 2A (PP2A) is a critical regulator of cardiac function. PP2A catalytic activity is targeted to specific protein substrates by regulatory B subunits, of which ≥13 are expressed in the mammalian heart. Of these, B55α has been identified in vitro as a potential regulator of cardiomyocyte hypertrophy and heart failure pathogenesis. However, the role of B55α in cardiac physiology and pathology remains unknown. To investigate the function of cardiac B55α in vivo. Male and female mice with global or cardiomyocyte-specific disruption of Ppp2r2a were characterised at 3 months of age. Left ventricular dimensions and function were assessed by echocardiography, and heart tissue collected for gravimetric, histological and molecular analyses. Global heterozygote mice displayed a ∼65% (female; p=0.002) or ∼40% (male; p=0.02) reduction in ventricular B55α expression (n=6-7/group). No overt cardiac pathology was observed in heterozygote mice (normal systolic function, no fibrosis or induction of the cardiac stress markers Nppa or Nppb, p>0.05). Global knockout embryos were smaller than wildtype littermates (∼10% reduction in crown-to-rump length) and died between embryonic day 13.5 and birth. Preliminary analyses of female cardiomyocyte-specific knockout mice revealed a ∼90% decrease in ventricular B55α expression (p=0.10, n=3/group), in the absence of overt hypertrophy, systolic dysfunction, fibrosis, atrial enlargement or lung congestion (p>0.05; n=4-6/group). B55α is essential for embryogenesis, but does not appear to be required for postnatal cardiac development. Ongoing analyses are investigating the impact of B55α deficiency in settings of cardiac stress/injury.

Association between Work-Related Stress and QT Prolongation in Male Workers.

Background: Work-related stress is a potential cardiovascular risk factor, but the underlying mechanism is not fully explained. The autonomic nervous system control of cardiac function might play a specific role; therefore, monitoring the QT interval in the electrocardiogram can highlight an autonomic imbalance induced by occupational stressors. The aim of our study was to explore the QT interval parameters as early indicators of imbalance of the autonomic cardiac function in relation to work-related stress. Methods: During 2015–2016 annual workplace health surveillance, we measured work-related stress in 484 workers of a logistic support company using the Health and Safety Executive (HSE) tool. We assessed the frequency-corrected QT (QTc) interval and the QT index (QTi) on the electrocardiogram of each participant, and collected demographic and clinical data. We compared the QTc values by the four Karasek’s categories (active/passive jobs, low/high strain job), and by job support (present/lacking), and conducted multivariate analysis to adjust for possible confounders. Results: The results of the multivariate regression analysis showed that QTc was prolonged among workers operating at a specific site where stress level was found to be elevated. Regular physical activity showed a beneficial effect against QTc prolongation. We did not observe an effect on QTc length by the cross-combined Karasek’s categories of job control, job demand, and job support. Conclusions: Our study suggests subclinical effects of conditions associated with work-related stress on the autonomic regulation of cardiac function. Further research is warranted to elucidate the combined effect of work organization and lifestyle factors on autonomic cardiac function.

G protein-coupled receptor kinase-2: A potential biomarker for early diabetic cardiomyopathy.

BackgroundG protein‐coupled receptor kinase‐2 (GRK2) has been shown as a key regulator of cardiac function, and the myocardial GRK2 levels are mirrored by the levels in peripheral blood mononuclear cells (PBMCs). In this study, we evaluated the myocardial and PBMCs GRK2 levels in early diabetic cardiomyopathy (DCM).MethodsC57BL/KS‐db/db male diabetic mice at 12 weeks of age, as the type 2 diabetes (T2DM) animal model of early DCM were evaluated. Forty‐four T2DM patients with left ventricular diastolic dysfunction (LVDD), without evidence of hypertension, coronary artery diseases, congestive heart failure, and diabetic complications and without evidence of ischemia in a maximal treadmill exercise test, were recruited as the DM + LVDD group; 30 age‐matched T2DM patients without LVDD were recruited as the DM control group. Left ventricular diastolic function was evaluated by cardiac tissue Doppler. The pseudonormal pattern of ventricular filling and E′/A′ < 1 were regarded as LVDD.ResultsCompared to 8‐week‐old diabetic mice and 12‐week‐old control mice, GRK2‐mRNA level and expression in myocardial tissues of 12‐week‐old diabetic mice were significantly increased, as well as the left ventricular wall thickness and systolic function. And the collagen volume fraction (CVF), collagen‐3 expression, P53 expression, and cell apoptotic rate in the myocardium of 12‐week‐old diabetic mice elevated as well. The GRK2‐mRNA level in PBMCs of DM with LVDD was significantly higher than in DM control without LVDD.ConclusionsGRK2 expression increased in the myocardial tissue and the PBMCs at the early stage of DCM. These data support further research on the role of GRK2 as the clinical biomarker for early DCM.

CHARACTERISTICS OF THE HEART RHYTHM VARIABILITY IN RESIDENTS OF MIDDLE OB REGION WITH DERMAL DISEASES

The aim of the study was to identify the characteristics of heart rate variability (HRV) in patients with chronic dermatoses, citizens of the Middle Ob Region. Methods. 74 patients with chronic dermal diseases (psoriasis and eczema), as well as 37 people who were included in the control group, were examined using the method of variational pulse oximetry using the Elox-01 hardware complex and the ELOGRAPH software product. The assessment of the constituent characteristics of HRV was carried out using different approaches: methods of mathematical statistics using non-parametric tests of Wilcoxon, Shapiro-Wilk and multivariate analysis of multidimensional phase spaces, which determined the evidential base for quantitative measures and diagnostic markers (criteria) in disorders of neuro-vegetative regulation of cardiac function in patients with dermatoses. Results. Peculiarities of the heart rhythm structure were found in patients with dermal diseases: a statistically significant decrease in the LF and HF components was revealed and an imbalance was found in the regulation of the autonomic nervous system with a predominance of sympathetic imbalance in patients with dermatoses living in the Middle Ob region in the Khanty-Mansi Autonomous Okrug - Ugra. Diagnostic indicators of the characteristics of HRV in patients with eczema and psoriasis were determined, which made it possible to distinguish a complex of signs in the differences in the autonomic regulation of heart rhythm - Total P (mc2), VLF (mc2), LF (mc2) and the integral characteristics of HRV - Baevsky stress index (INB (cu), indicators of the sympathetic and parasympathetic system (SIM, PAR, cu). Conclusions. Patients with chronic dermatoses (psoriasis, eczema) living in severe climatic conditions of the Middle Ob Region have a tendency to early development of complicated forms of the disease with detection of imbalance in the regulation of the autonomic nervous system with a predominance of parasympathetic tone. The data obtained are important diagnostic aspects of the diseases pathogenesis, contributing to the determination of the further prognosis and correction of medical treatment.

Angiotensin-(1–12)/chymase axis modulates cardiomyocyte L-type calcium currents in rats expressing human angiotensinogen

BackgroundActivation of the intracrine renin angiotensin systems (RAS) is increasingly recognized as contributing to human pathologies, yet non-canonical renin-independent mechanisms for angiotensin II (Ang II) biosynthesis remain controversial. Direct Ang II generation from angiotensin-(1–12) [Ang-(1–12)] by chymase is an essential intracrine source for regulation of cardiac function. Using a transgenic rat model that overexpresses the human angiotensinogen gene [TGR(hAGT)L1623] and displays increased cardiac Ang II levels, this study aimed to provide evidence for intracrine activation of L-type calcium currents (ICa-L) mediated by the Ang-(1–12)/chymase axis. Methods and resultsOn patch clamp, ICa-L density was significantly higher in TGR(hAGT)L1623 (−6.4 ± 0.3 pA/pF) compared to Sprague Dawley (SD) cardiomyocytes (−4.8, ± 0.5 pA/pF). Intracellular administration of Ang II and Ang-(1–12) elicited a ICa-L increase in both SD and TGR(hAGT)L1623 cardiomyocytes, albeit blunted in transgenic cells. ICa-L activation by intracellular Ang II and Ang-(1–12) was abolished by the specific Ang II type 1 receptor blocker E−3174. Co-administration of a chymase inhibitor prevented activation of ICa-L by Ang-(1–12). Confocal micrographs revealed abundant chymase (mast cell protease 5) immunoreactive protein in SD and TGR(hAGT)L1623 cardiomyocytes. ConclusionsOur data demonstrate the existence in cardiomyocytes of a calcium channel modulatory activity responsive to Ang II generated by the Ang-(1–12)/chymase axis that signals via intracellular receptors. Chronically elevated Ang II in TGR(hAGT)L1623 hearts leading to increased intracellular calcium through ICa-L suggests that activation of this Ang-(1–12)/chymase-governed cardiac intracrine RAS may contribute to the pathological phenotypes observed in the humanized model of chronic hypertension and cardiac hypertrophy.

Role of catecholamines in the pathogenesis of diabetic cardiomyopathy 1.

Although the sympathetic nervous system plays an important role in the regulation of cardiac function, the overactivation of the sympathetic nervous system under stressful conditions including diabetes has been shown to result in the excessive production of circulating catecholamines as well as an increase in the myocardial concentration of catecholamines. In this brief review, we provide some evidence to suggest that the oxidation products of catecholamines such as aminochrome and oxyradicals, lead to metabolic derangements, Ca2+-handling abnormalities, increase in the availability of intracellular free Ca2+, as well as activation of proteases and changes in myocardial gene expression. These alterations due to elevated levels of circulatory catecholamines are associated with oxidative stress, subcellular remodeling, and the development of cardiac dysfunction in chronic diabetes.