Myocardial Muscle Research Articles

Comparison of adenosine, dobutamine and bicycle exercise on intracoronary physiological indices in patients with myocardial bridges

Abstract Background We have recently demonstrated that patients with angina and nonobstructive coronary arteries (ANOCA) with myocardial bridges (MBs) exhibit maladaptive exercise physiology, due to abnormal wave energies arising at the tunnelled segment (1). Intracoronary pressure-derived indices in response to dobutamine and adenosine are used to identify an ischaemic substrate in these patients in clinical practice (2). However, it remains unknown if the changes induced by dobutamine and adenosine are comparable with physical exercise. Methods Patients with ANOCA and a MB in the left anterior descending artery underwent simultaneous acquisition of intracoronary pressure and flow sequentially during rest, supine bicycle exercise and intravenous adenosine and dobutamine infusion. We compared coronary perfusion efficiency (accelerating energy/total energy flux) and changes in specific wave energies in response to these three stressors. Results Twenty-five patients were enrolled (36% females, 59±9 years old). Patients had a high symptom burden (88% CCS II-IV) and myocardial bridge muscle index (79±30). Fractional flow reserve and coronary flow reserve were 0.86±0.05 and 2.5±0.5. Microvascular resistances during adenosine, dobutamine and exercise were 2.0±0.7, 3.4±1.4 and 4.3±1.3 mmHg.cm-1.s-1 respectively (p<0.001). There was a reduction in coronary perfusion efficiency in response to adenosine (64±8% to 51±12%), dobutamine (65±9% to 53±13%) and exercise (66±10% to 56±9%) (all p<0.001), with no between stressor differences in delta perfusion efficiency (ANOVA p=0.641). However, the impact of each stressor on the wave energy arising from the tunnelled segment was different whereas no such difference (between stressors) was observed in the wave energies arising from the microcirculation. There was no difference in tunnelled-segment derived delta wave energies between dobutamine and exercise (Figure 1). Conclusions Adenosine, dobutamine and exercise have different effects on coronary microvascular resistance and cardiac coronary coupling in patients with myocardial bridges. Our findings provide novel mechanistic insights into the pathophysiology of ANOCA in combination with MB, and suggest that dobutamine (but not adenosine) could be used as a surrogate for physical exercise during intracoronary physiological assessment.Figure 1.

Iron chelation therapy failed to improve cardiac dysfunction caused by mitochondrial injury in rats with iron overload cardiomyopathy a 7T Cardiac MR research in vivo

Abstract Purpose To assess the efficacy of iron chelation therapy in improving cardiac function in iron overload cardiomyopathy (IOC) rats by using Cardiac magnetic resonance feature-tracking (CMR-FT). Methods The IOC rat model was induced by intraperitoneal injection of iron dextran over 2 months. Subsequently, 7 rats with IOC were assigned as IOC group to receive continued intraperitoneal injections of saline for an additional 2 months, while another group of 5 rats received intraperitoneal injections of deferoxamine (DFO) for the same duration, forming the IOC+DFO group. Meanwhile, a control group consisting of 7 healthy rats received intraperitoneal injections of saline for the entire duration of 4 months. All rats underwent a 7T CMR scan to assess cardiac function, myocardial iron overload, and myocardial fibrosis via cine, T2 mapping, and late gadolinium enhancement (LGE) scanning, respectively. The cardiac function analysis included left ventricular ejection fraction (LVEF) and left ventricular global longitudinal strain (GLS) using cine images. Following CMR scans, all rats underwent open-chest blood collection to detect serum iron levels, and cardiac gross specimens were then subjected to pathological staining, including hematoxylin and eosin (HE) for cardiomyocytes injury, Prussian blue for iron deposition , and Masson staining for myocardial fibrosis. Furthermore, the ultrastructure of cardiomyocyte was examined using transmission electron microscopy (TEM). Results The T2 value, measured in the septum wall at the mid-layer of the LV, and LVEF, and GLS exhibited a significant decrease in the IOC or IOC+DFO group, compared to the control group, while there were no significant difference observed between the IOC and IOC+DFO group (Fig. 1A, B, C). Myocardial fibrosis was not detected in the LGE images in both IOC and IOC+DFO group. Compared to the control group (37.5±12.5μmol/L) , serum iron levels were significantly elevated in the IOC group (368.6±181.0μmol/L) and in chelation treatment group (106.1±32.2μmol/L). Histological examination with HE staining revealed a normal arrangement of myocardial cells in all rats, without cellular degeneration or necrosis. Prussian blue staining highlighted the presence of iron particles within the myocardial interstitium in the IOC and IOC+DFO groups. Masson staining demonstrated intact myocardial muscle bundles without any evidence of myocardial fibrosis. Transmission electron microscopy (TEM) revealed myocardial mitochondria injury, characterized by ruptured outer membranes, reduced cristae, and vacuolization. Conclusions Following iron chelation therapy, the excessive iron burden in the bloodstream was alleviated. However, myocardial iron overload persisted in IOC rats, with no significant improvement in cardiac function observed. This persistence may be attributed to mitochondrial injury. The findings underscore the importance of monitoring cardiac dysfunction in patients with iron overload.CMR parameters analysis in IOC rats

Optimization, characterization and biosafety of carotenoids produced from whey using Micrococcus luteus

This study aimed to optimize the production of carotenoid pigments from Micrococcus luteus (ATCC 9341) through the statistical screening of media components and the characterization of antimicrobial, antioxidant, cytogenetic and cytotoxic activities. A BOX-Behnken design was used to assess the effects of whey concentration, inoculum size, pH, temperature, and agitation speed on carotenoid yield. The optimum combination increased production to 2.19 g/L, with a productivity of 0.045 g L-1 h−1 and a productivity yield of 0.644 g/g, as confirmed by an observed carotene production of 2.19 g/L. The final response surface model fitting the data had an R2 of 0.9461. High-performance liquid chromatography (HPLC) analysis identified 12 carotenoid pigment compounds produced by M. luteus. The extracts displayed moderate antimicrobial efficacy against Gram-positive bacteria such as Bacillus cereus (ATCC 11778), Staphylococcus aureus (ATCC 6538), and E. faecalis (ATCC 19433), with inhibition zone diameters (IZD) of 29.0, 14.0, and 37.0 mm, respectively, at 1000 μg/mL. However, its effectiveness against Gram-negative bacteria is limited. In comparison, tetracycline exhibited greater antimicrobial potency. The IC50 value of carotenoids was used to indicate the antioxidant activity. IC50 value from the DPPH assay was 152.80 mg/100mL. An IC50 cytotoxicity value greater than 300 μg/mL was found against normal mouse liver cells, with over 68% cell viability even at 300 μg/mL, indicating low toxicity. Histological structure studies revealed normal myocardial muscle tissue, lung tissue, and kidney tissue sections, whereas liver tissue sections revealed ballooning degeneration of hepatocytes and disorganization of hepatic cords. Cytogenetic parameters revealed that the carotene treatment group had a mitotic index (70%) lower than that of the control but higher than that of the positive control, mitomycin, and did not substantially increase numerical (1.2%) or structural aberrations compared with those of the control, suggesting a lack of genotoxic effects under the experimental conditions. In conclusion, optimized culture conditions enhanced carotenoid yields from M. luteus, and the extracts displayed promising bioactivity as moderate antibiotics against certain gram-positive bacteria and as antioxidants. The high IC50 values demonstrate biosafety. Overall, this bioprocess for enhanced carotenoid production coupled with bioactivity profiling and low cytotoxicity support the application of M. luteus carotenoids.

The Possible Protective Role of Folic acid on the Myocardial and Gastrocnemius Muscles in cases of Rotenone-Induced Damage in Adult Male Albino Rat: Histological and Immunohistochemical Study

The Possible Protective Role of Folic acid on the Myocardial and Gastrocnemius Muscles in cases of Rotenone-Induced Damage in Adult Male Albino Rat: Histological and Immunohistochemical Study

Controlled Release Lercanidipine Tablets: A Study on Formulation and Evaluation by Wet Granulation

Lercanidipine blocks the entry of extracellular calcium into vascular and cardiac muscle cells, preventing myocardial smooth muscle contraction due to decreased intracellular calcium. This results in the dilation of coronary and systemic arteries, reducing blood pressure. This study aimed to develop and evaluate lercanidipine controlled-release tablets for oral administration using polymers like HPMC K 100M, sodium alginate, and guar gum. Lercanidipine, polymers, and diluents were sieved and mixed for 10 minutes. Granules were formed using isopropyl alcohol, dried at 60°C for one hour, and sieved. The granules were lubricated with colloidal silicon dioxide (Aerosil-200) and magnesium stearate, blended for 5 minutes, and compressed using a rotary machine (average weight: 500 mg; hardness: 5-6 kg/cm²). Bulk and tapped densities were nearly identical for all formulations. Compressibility index and Hausner ratio ranged from ?18 to 1.09-1.21, indicating good flow properties. Tablet thickness ranged from 5.82 to 5.91 mm, hardness from 5.9 to 6.3 kg/cm², and friability was less than 1.0 %W/W. Drug content was between 98-102%. The controlled-release order from dissolution data was F9 > F7 > F8, showing optimal release with a combination of HPMC and two natural polymers.

Relationship between N-terminal pro-brain natriuretic peptide concentration and heart-type fatty acid-binding protein in postmortem urine

The clinical use of N-terminal pro-brain natriuretic peptide (NT-proBNP) and blood concentrations of heart-type fatty acid-binding protein (HFABP) is well-established in diagnosing heart conditions. However, their applicability in forensics is controversial due to postmortem changes. NT-proBNP and HFABP are excreted in the urine due to their small molecular weights and may be found in postmortem urine samples; however, their correlation has not been evaluated. In this study, we compared the concentrations of urinary NT-proBNP and HFABP in 386 forensic autopsy cases. The urinary NT-proBNP levels were significantly higher in acute myocardial infarction (AMI), congestive heart failure (CHF), sepsis, and hyperthermia cases, with the highest levels in CHF cases. Similarly, HFABP concentration was significantly higher in CHF, sepsis, and hyperthermia cases, with the highest level observed in hyperthermia cases. However, the difference in urinary HFABP levels between the AMI and control cases was not significant. Our analysis revealed a correlation between postmortem urine NT-proBNP and HFABP levels, and the NT-proBNP/HFABP ratio was high in patients with CHF and sepsis cases and low in those with hyperthermia. The difference between the ratios was possibly due to the combined release of ventricular myocardial cells in response to ventricular wall stress and myocardial injury for NT-proBNP, as well as myocardial and skeletal muscle injuries for HFABP. This study, for the first time, demonstrates the utility of postmortem measurements of urinary NT-proBNP and HFABP levels, offering valuable insights for improving the accuracy of postmortem diagnosis in forensic medicine.

CHARACTERISTICS OF PATHOMORPHOLOGICAL CHANGES IN HYPERTROPHIC CARDIOMYOPATHY

In hypertrophic cardiomyopathy, the walls of the ventricles of the heart continue with symmetric or asymmetric myocardial hypertrophy. Morphologically, in hypertrophic cardiomyopathy, fibrotic foci are detected based on the incorrect arrangement of myocardial muscle fibers, small coronary vessel syndrome, and myocardial hypertrophy.

Clinical value of BRE-AS1 in myocardial infarction and its role in myocardial infarction-induced cardiac muscle cell apoptosis

Objectives. The aim of this study was to investigate the expression of long non-coding RNA (lncRNA) brain and reproductive organ-expressed protein (BRE) antisense RNA 1 (BRE-AS1) in patients with acute myocardial infarction (AMI) and its effect on ischemia/reperfusion (I/R)-induced oxidative stress and apoptosis of cardiomyocytes. Methods. Serum BRE-AS1 levels in patients with AMI was detected using quantitative real-time polymerase chain reaction (qRT-PCR). The diagnostic and prognostic values of BRE-AS1 were evaluated. H9c2 cells were treated with hypoxia/reoxygenation to establish an in vitro myocardial infarction cell model. The levels of inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6 were detected by enzyme-linked immunosorbent assay (ELISA). Levels of lactate dehydrogenase (LDH), malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) were determined by commercial kits. Cell counting kit-8 (CCK-8) and flow cytometry were used to evaluate the cell viability and cell apoptosis. Results. The expression of BRE-AS1 in serum of patients with AMI is upregulated, which shows the clinical diagnostic value for AMI. In the I/R injury cell model, the knockout of BRE-AS1 can significantly alleviate the increase in TNF-α, IL-1β, and IL-6 levels, inhibit the production of LDH and MDA, increase the activities of SOD and GSH-Px, promote the cell viability and suppress cell apoptosis. Conclusions. Abnormally elevated BRE-AS1 has a high diagnostic value for AMI as well as a prognostic value for major adverse cardiovascular events (MACEs). The elevation of BRE-AS1 promoted oxidative stress injury and cell apoptosis in vitro.

PROTEIN SOLUBLE SUPPRESSION OF TUMORIGENICITY 2 (sST2) SEBAGAI PENANDA KERUSAKAN KARDIOVASKULAR PADA PREEKLAMSIA

Preeclampsia as a pregnancy complication was still a direct cause of maternal death, especially in developing countries. The process of abnormal trophoblast invasion as a pathophysiology of preeclampsia would cause an ischemic environment in the placenta. This situation caused the placenta to release pro-inflammatory cytokines and anti-angiogenic factors into the maternal circulation, resulting in the vasocontriction of blood vessels, endothelial dysfunction in the vasculature of maternal organs, and the production of different clinical features depending on the organs affected. Vascular and myocardial muscle damage was a complication that causes cardiovascular disorders and could increase maternal morbidity and mortality in preeclampsia. sST2 as part of the interleukin (IL)-1 receptor, was a biomarker used to indicate myocardial muscle damage in cardiac disease. There had been a growing number of research investigating the use of sST2 as a marker of cardiac muscle damage in patients with heart failure. Some of them concluded that sST2 can be used as a predictor of acute cardiac muscle damage. Others stated that sST2 as a marker could accompany chronic cardiac defects. Preeclampsia, as a disease in pregnancy that showed damage to maternal organs, was starting to be studied using this biomarker as a marker for damages to the cardiac organ. There were studies that showed differences in sST2 levels in preeclampsia with and without complications. Preeclampsia with cardiac complications was characterized by damage to the myocardial muscle, especially to the left ventricular area. The sST2 protein was starting to be used as a marker for this damage. Further research was still being carried out to improve the use of this biomarker as a marker for other damage to the maternal cardiac organ.

RelA-mediated signaling connects adaptation to chronic cardiomyocyte stress with myocardial and systemic inflammation in the ADCY8 model of accelerated aging.

Mice with cardiac-specific overexpression of adenylyl cyclase (AC) type 8 (TGAC8) are under a constant state of severe myocardial stress. They have a remarkable ability to adapt to this stress, but they eventually develop accelerated cardiac aging and experience reduced longevity. We have previously demonstrated through bioinformatics that constitutive adenylyl cyclase activation in TGAC8 mice is associated with the activation of inflammation-related signaling pathways. However, the immune response associated with chronic myocardial stress in the TGAC8 mouse remains unexplored. Here we demonstrate that chronic activation of adenylyl cyclase in cardiomyocytes of TGAC8 mice results inactivation of cell-autonomous RelA-mediated NF-κB signaling. This is associated with non-cell-autonomous activation of proinflammatory and age-associated signaling in myocardial endothelial cells and myocardial smooth muscle cells, expansion of myocardial immune cells, increase in serum levels of inflammatory cytokines, and changes in the size or composition of lymphoid organs. All these changes precede the appearance of cardiac fibrosis. We provide evidence indicating that RelA activation in cardiomyocytes with chronic activation of adenylyl cyclase is mediated by calcium-protein Kinase A (PKA) signaling. Using a model of chronic cardiomyocyte stress and accelerated aging, we highlight a novel, calcium/PKA/RelA-dependent connection between cardiomyocyte stress, myocardial inflammation, and systemic inflammation. These findings suggest that RelA-mediated signaling in cardiomyocytes might be an adaptive response to stress that, when chronically activated, ultimately contributes to bothcardiac and systemic aging.

Control of Cardiac Biomarkers Concentrations, Central Hemodynamics and Their Correlation During Gastrointestinal Bleeding

We did not observe high values of cardiac markers and changes in central hemodynamic parameters in patients with acute gastrointestinal bleeding (AGIB) and a correlation between them, this led to the decision to conduct a study. Clinical materials of 457 patients diagnosed with GIB were analyzed. Cardiac pathology was detected in 150 patients. Dynamic changes in cardiac biomarkers and central hemodynamic indicators in patients were studied in 3 stages. Phase I, period included in ICU; Stage II - 24 hours after admission to the ICU; the third stage covers the next 48 hours. The concentration troponin, BNP, myoglobin and CK-Mb was studied in the patients and it was found that although the concentration of these biomarkers was high in the first stage, these concentrations decreased and reached normal levels in the later stages of the dynamics against the background of the treatment. Dynamic changes of central hemodynamic indicators (CHI): stroke volume, cardiac minute volume, peripheral vascular resistance and myocardial oxygen demand were studied in 3 stages. It was found that although SV was low, it dynamically increased in the later stages and did not reach the normal level. This is a clear example of continued hypovolemia. Peripheral vascular resistance (PVR) from blood loss from the gastrointestinal tract was greater than normal in all three phases. PVR remained high and was statistically honest because the volume of circulating blood was not fully corrected despite the treatments. Also, the correlation between central hemodynamic indicators and cardiac markers was studied, showing that in stage I, there is a strong contrast between CMV and CK-MB; Strong straight between PVR and BNP; In stage II, strong contrast between CMV and BNP; Strongly flat between PVR and CK-MB; In stage III, the average level is between CMV and myoglobin; We proved that there is a moderate inverse correlation between PVR and cTn and it is statistically honest. Thus, although CHI was slightly less than the norm in the initial period, it normalized in the later stages, but PVR remained high in all stages. This caused a sharp increase in PVR as a compensatory response to the decrease in circulating blood volume during acute GIB. Among the cardiac markers, we associate the rise of troponin during the bleeding period with damage to postanemic, hypoxic myocardial muscles. Among the cardiac markers, a sharp increase in BNP is an indicator of the development of left ventricular failure and is associated with a sharp increase in PVR, and we also proved that there is a strong direct relationship between them.

Physical Activity and Systemic Biomarkers in Persons With COPD: Insights from a Web-Based Pedometer-Mediated Intervention.

The relationships between physical activity (PA) and exercise performance and systemic biomarkers in persons with chronic obstructive pulmonary disease (COPD) have not been well characterized. The impact of PA promotion on biomarkers reflecting myocardial stress, systemic inflammation, and muscle injury is unclear. This secondary analysis used 3 previously published studies in persons with COPD (2 examined a PA intervention that promoted community-based walking for 3 months) to explore these relationships. PA (daily step counts) and exercise performance (6-minute walk test [6MWT]) were assessed. Serum N-terminal pro-β-type natriuretic peptide (NT-proBNP), the soluble receptor for advanced glycation end products (sRAGE), and muscle-type creatine kinase (CKMM) were assayed at baseline and 3 months. General linear models examined associations between PA/exercise performance and systemic biomarkers at baseline and the effect of the PA intervention on change in biomarkers. Participants included 366 U.S. Veterans: 98% male, mean age 70±8 years, and forced expiratory volume in 1 second percentage predicted 59±21%. Lower baseline NT-proBNP, but not sRAGE or CKMM, was associated with higher daily step count (-0.95pg/ml per 1000 steps/day, p=.060) and higher 6MWT distance (-0.80pg/ml per 100 meters, p=.001). Change in daily step count, but not 6MWT, was significantly greater in the intervention (789±1864) compared to the control group (-174±1448; p=.002). The PA intervention had no significant impact on change in the systemic biomarkers. Exercise performance is associated with NT-proBNP in persons with COPD. A 3-month community-based walking intervention is not associated with myocardial stress or muscle injury as assessed by NT-proBNP and CKMM, respectively. Clinical Trial Registration: NCT01772082 and NCT02099799.

A user-friendly machine learning approach for cardiac structures assessment.

Machine learning is increasingly being used to diagnose and treat various diseases, including cardiovascular diseases. Automatic image analysis can expedite tissue analysis and save time. However, using machine learning is limited among researchers due to the requirement of technical expertise. By offering extensible features through plugins and scripts, machine-learning platforms make these techniques more accessible to researchers with limited programming knowledge. The misuse of anabolic-androgenic steroids is prevalent, particularly among athletes and bodybuilders, and there is strong evidence of their detrimental effects on ventricular myocardial capillaries and muscle cells. However, most studies rely on qualitative data, which can lead to bias and limited reliability. We present a user-friendly approach using machine learning algorithms to measure the effects of exercise and anabolic-androgenic steroids on cardiac ventricular capillaries and myocytes in an experimental animal model. Male Wistar rats were divided into four groups (n = 28): control, exercise-only, anabolic-androgenic steroid-alone, and exercise with anabolic-androgenic steroid. Histopathological analysis of heart tissue was conducted, with images processed and analyzed using the Trainable Weka Segmentation plugin in Fiji software. Machine learning classifiers were trained to segment capillary and myocyte nuclei structures, enabling quantitative morphological measurements. Exercise significantly increased capillary density compared to other groups. However, in the exercise + anabolic-androgenic steroid group, steroid use counteracted this effect. Anabolic-androgenic steroid alone did not significantly impact capillary density compared to the control group. Additionally, the exercise group had a significantly shorter intercapillary distance than all other groups. Again, using steroids in the exercise + anabolic-androgenic steroid group diminished this positive effect. Despite limited programming skills, researchers can use artificial intelligence techniques to investigate the adverse effects of anabolic steroids on the heart's vascular network and muscle cells. By employing accessible tools like machine learning algorithms and image processing software, histopathological images of capillary and myocyte structures in heart tissues can be analyzed.

Study of Serum Magnesium, Potassium and Calcium in Acute Myocardial Infarction Patients

Introduction: A myocardial infarction happens when blood flow stops or decreases to the coronary arteries of the myocardial muscle, resulting in damage to the heart muscle. Magnesium is important electrolyte plays vital role in suppressing arrhythmias during myocardial ischemia and during reperfusion. Potassium is the most abundant cation of intracellular fluid. A significant correlation between hypokalemia and ventricular fibrillation is recorded. Calcium plays a vital role in myocardial muscle contraction. Aim: To study serum levels of magnesium, potassium and calcium in acute myocardial infarction patients. Material and methods: This was a prospective case control study conducted in Prathima Institute of medical sciences Nagunur, Karimnagar, Telangana state, India between January 2015 to December 2015. A total 50 acute myocardial infarction patients and 50 normal age and sex matched healthy controls selected for study. Serum magnesium estimated by colorimetric xylidyl blue complex method, serum potassium estimated by ion selective electrode method and serum calcium by OCPC method. Statistical analysis carried out using statistical software SPSS version 16 and p-value < 0.05 considered statistically significant. Results: Serum levels of magnesium, potassium and calcium were significantly decreased in acute myocardial infarction patients when compared healthy controls and is statistically significant (<0.05) Conclusion: The above study suggested decreased serum level of key elements such as magnesium, potassium and calcium in acute myocardial infarction patients when compared to healthy controls. Estimation and correction of these elements may play a pivotal role in management of patients with acute myocardial infarction

Mitral Annular Disjunction: Review of an Increasingly Recognized Mitral Valve Entity.

Mitral annular disjunction (MAD) refers to atrial displacement of the hinge point of the mitral valve annulus from the ventricular myocardium. MAD leads to paradoxical expansion of the annulus in systole and may often be associated with mitral valve prolapse (MVP), leaflet degeneration, myocardial and papillary muscle fibrosis, and, potentially, malignant cardiac arrhythmias. Patients with MAD and MVP may present similarly, and MAD is potentially the missing link in explaining why some patients with MVP experience adverse outcomes. Patients with a 5 mm or longer MAD distance have an elevated risk of malignant cardiac arrhythmia compared with those with a shorter MAD distance. Evaluation for MAD is an important component of cardiac imaging, especially in patients with MVP and unexplained cardiac arrhythmias. Cardiac MRI is an important diagnostic tool that aids in recognizing and quantifying MAD, MVP, and fibrosis in the papillary muscle and myocardium, which may predict and help improve outcomes following electrophysiology procedures and mitral valve surgery. This article reviews the history, pathophysiology, controversy, prevalence, clinical implications, and imaging considerations of MAD, focusing on cardiac MRI. Keywords: MR-Dynamic Contrast Enhanced, Cardiac, Mitral Valve, Mitral Annular Disjunction, Mitral Valve Prolapse, Floppy Mitral Valve, Cardiac MRI, Arrhythmia, Sudden Cardiac Death, Barlow Valve © RSNA, 2023.

Disturbance of iron metabolism related genes in advanced heart failure

Abstract Background/Introduction Heart failure (HF) is a clinical syndrome associated with poor quality of life, substantial health-care resource utilization, and premature mortality. Iron is a nutrient required in all organ systems for various metabolic processes, such as mitochondrial function, oxygen transport, myocardial and skeletal muscle metabolism, among others. Maintaining iron homeostasis is essential for proper cardiac function since both iron deficiency and iron overload are associated with HF through complex mechanisms, such as ferroptosis. Purpose The aim of this study was to analyse the status of iron metabolism in hearts from patients with dilated (DCM) and ischemic cardiomyopathy (ICM) and its implication with the pathophysiology of the disease. Methods Cardiac tissue samples were used to evaluated transcriptome differences in genes involved iron metabolism by mRNA-sequencing (mRNA-seq; ICM, n=13; DCM, n=13; CNT, n=10). Furthermore, the miRNA implicated in the mRNA posttrasciptional regulation was studied through non-coding RNA-seq (ICM, n=22; DCM, n=20; CNT, n=8). Results We observed a decrease in iron import with SNX4 underexpression in ICM (FC=-1.28) and DCM (FC=-1.27) patients, p<0.05. While the export is reduced only in patients with MCD: HAMP is underexpresed (FC=-2.41, p<0.01) and its miRNA, miR-184, overexpressed (FC=2.77, p<0.01). We also found alterations in molecules of iron homeostasis and transporters of both aetiologies: IREB2 (ICM, FC=-1.27, p<0.05; DCM, FC=-1.48, p<0.001), STEAP3 (ICM, FC=-1.63, p<0.05; DCM, FC=-2.24, p<0.001), NOX4 (DCM, FC=1.70, p<0.05), SLC39A14 (ICM, FC=-1.97, p<0.05) and SLC39A8(ICM, FC=-1.60, p<0.05; DCM, FC=-1.78, p<0.01). Myoglobin was increased (FC=1.18, p<0.05) and its miRNA, miR-133a-3p, decreased (FC=-1.39, p<0.05) in DCM patients. While other molecules implicated in iron metabolism such as NFE2L2 (ICM, FC=-1.52; DCM, FC=-1.30; p<0.05) and AGPAT5 (ICM, FC=-1.84, p<0.05) are decreased. It is worth noting the correlation with ventricular dysfunction shown by SLC39A8 (end systolic diameter, r=-0.674; end diastolic diameter, r=-0.648; p<0.05) in ICM patients and NFE2L2 (ejection fraction, r=0.609, p<0.05) in DCM patients. Conclusions Our results show an alteration in the iron metabolism specific of aetiology in HF, both in the genes involved in different functions of the pathway and in its post-translational regulation. These results offer new possible therapeutic targets and valuable information to elucidate the complex mechanisms that relate iron homeostasis to HF.

The RANK-RANK-L-OPG pathway: trait d’union between bone and muscle

From an operational point of view, the musculoskeletal system can be considered a single organ that, displaying great plastic capacity, continuously remodels itself in response to various functional demands, which change over the course of human life. Many factors, mechanical and biochemical, underlie the constant interaction between bone and muscle. Among the main biochemical signals mediating this crosstalk, the receptor activator of the nuclear factor kappa-Β (RANK)-RANK ligand (RANKL)-osteoprotegerin (OPG) system regulates not only bone remodeling but also muscle mass and performance, as well as its response to physiological or pathological stressing conditions. Administration of OPG or monoclonal antibodies (denosumab) against RANK-L improves skeletal mass and strength, and also plays an important role in reducing the risk of falls and improving the outcome of diseases involving skeletal and myocardial muscles. KEY WORDS: Bone, muscle, RANK, RANKL, OPG, denosumab.

Morphology, organo- and histometric features of the heart and lungs of a sexually mature domestic dog (Canis Lupus Familiaris L., 1758)

The cardiovascular system and respiratory organs in animals are interconnected, they perform extremely important functions for the vital activity of the organism, the main of which is gas exchange. Therefore, the study of the cardiovascular system and respiratory organs is an urgent issue of the present. The aim of the study was to morphologically evaluate the macro- and histological structures of the heart and lungs of the domestic dog. Comprehensive morphological methods of research were used: histological, anatomical, organ, histo-, cytometric, and statistical, which provided new data on the peculiarities of macro-, histo-, and cytomorphometric characteristics of the morphological structures of the heart and lungs. The dog heart has a rounded shape, its absolute weight is 167.58±9.46 g (without epicardial fat – 154.22±8.04 g), relative weight – 0.72±0.005%. It was found that cardiomyocytes of the left ventricle had the largest volume, the right ventricle – the smallest, and atrial cardiomyocytes – the smallest. At the same time, the nuclearcytoplasmic ratio of cardiomyocytes of the left ventricle is 0.0224±0.0076, the cardiomyocytes of the right ventricle have a greater value – 0.0275±0.0081 and the atrial cardiomyocytes have the highest value – 0.0367±0.0105. Such ambiguous cytometric parameters of cardiomyocytes are associated with the morphological and functional activity of the myocardial ventricular muscle tissue and its functional features inherent in spontaneous and rhythmic contractions, which result in blood flow through a closed system of vessels. The absolute weight of the domestic dog’s lungs is 201.3±18.4 g, the relative weight is 1.21±0.14%, the ratio of the absolute weight of the left to the right lung is 1:1.33. According to the asymmetry coefficient (1.37:1), the lungs of dogs are of the narrowed-elongated type. The connective tissue stroma of the lungs occupies 59.62±3.4%, the respiratory part – 40.38±2.6%. The data on the morphology of the heart and lungs of the domestic dog, including the results of the study of the macro- and microscopic structure of the organs under investigation, which are presented in the publication, are of great importance for histology and comparative anatomy, and also make a significant contribution to clinical veterinary medicine

Targeting Inflammation, Oxidative Stress, and Apoptosis by Indole-3-Carbinol to Ameliorate Doxorubicin- Induced Cardiotoxicity in Mice

Background: Doxorubicin (DOX) is an effective antineoplastic agent of the anthracycline group. However, as with most anticancer drugs, they cause some toxic effects, including major cardiotoxicity. Oxidative stress, inflammation and apoptosis contribute to the pathological basis of doxorubicin (DOX)-induced cardiotoxicity. Indole-3-carbinol is a cruciferous-derived phytochemical, with potential anti-inflammatory and antioxidant effects. Purpose: Our present study aimed to investigate the protective effects of I3C against DOX- induced cardiotoxicity in mice by Targeting Inflammation, Oxidative Stress, and Apoptosis. Methods: BALB/c mice were subjected to DOX (4 mg/kg/day, i.p.) once weekly on days 0, 7, 14, 21 (for 21 days) to generate DOX- induced cardiotoxicity. Indole-3-carbinol was administered daily orally in the diet at two dose levels; 1000 ppm and 2000 ppm for 7 days before and 42 days after first injection of DOX. Serum creatine kinase (CK-MB), lactate dehydrogenase (LDH) and troponin I (cTn-I) levels activities, which are cardiac function markers were determined. Also, the levels of malondialdehyde (MDA) was assessed and enzyme activities of superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR) and glutathione peroxidase (GPx) were assessed in the heart tissues to determine the protective effect of Indole-3-carbinol against oxidative stress. To determine the anti-inflammatory effect, the levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) were assessed in the heart tissues. Parts of the heart were subjected to histopathological and immunohistochemical examinations. Results: Indole-3-carbinol in a dose‐dependent manner was found to have the ability to mitigate the harmful effects of DOX on myocardial muscles with significant decrease in serum levels of CK-MB, LDH and cTn-I. In addition, Indole-3-carbinol significantly inhibited DOX-induced cardiac oxidative stress as seen in the reduced level of MDA and increased SOD, CAT, GR and GPx cardiac tissue levels; Indole-3-carbinol significantly reduced inflammatory mediators TNF-α and IL-6 levels and inhibited cardiac apoptosis by modulating Caspase 3 cardiac tissue levels. Moreover, Indole-3-carbinol, in a dose‐dependent manner, had the ability to combat the histopathological and immunohistochemical changes induced by doxorubicin in cardiomyocytes. Conclusion: These results demonstrate that administration of I3C in a dose dependent manner prevents heart injury induced by DOX via its antioxidant, anti-inflammatory, and antiapoptotic activities.

Ferroptosis: a new strategy for cardiovascular disease.

Cardiovascular disease (CVD) is currently one of the prevalent causes of human death. Iron is one of the essential trace elements in the human body and a vital component of living tissues. All organ systems require iron for various metabolic processes, including myocardial and skeletal muscle metabolism, erythropoiesis, mitochondrial function, and oxygen transport. Its deficiency or excess in the human body remains one of the nutritional problems worldwide. The total amount of iron in a normal human body is about 3-5 g. Iron deficiency may cause symptoms such as general fatigue, pica, and nerve deafness, while excessive iron plays a crucial role in the pathophysiological processes of the heart through ferroptosis triggered by the Fenton reaction. It differs from other cell death modes based on its dependence on the accumulation of lipid peroxides and REDOX imbalance, opening a new pathway underlying the pathogenesis and mechanism of CVDs. In this review, we describe the latest research progress on the mechanism of ferroptosis and report its crucial role and association with miRNA in various CVDs. Finally, we summarise the potential therapeutic value of ferroptosis-related drugs or ferroptosis inhibitors in CVDs.