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Sarcomere activation in striated muscle requires both thin filament-based and thick filament-based activation mechanisms. Recent studies have shown that myosin heads on the thick filaments undergo OFF to ON structural transitions in response to calcium (Ca2+) in permeabilized porcine myocardium in the presence of a small molecule inhibitor that eliminated active force. The changes in X-ray diffraction signatures of OFF to ON transitions were interpreted as Ca2+ acting to activate the thick filaments. Alternatively, Ca2+ binding to troponin could initiate a Ca2+-dependent crosstalk from the thin filament to the thick filament via interfilament connections such as the myosin binding protein-C. Here, we exchanged native troponin in permeabilized porcine myocardium for troponin containing the cTnC D65A mutation, which disallows the activation of troponin through Ca2+ binding to determine if Ca2+-dependent thick filament activation persists in the absence of thin filament activation. After the exchange protocol, over 95% of the Ca2+-activated force was eliminated. Equatorial intensity ratio increased significantly in both WT and D65A exchanged myocardium with increasing Ca2+ concentration. The degree of helical ordering of the myosin heads decreased by the same amount in WT and D65A myocardium when Ca2+ concentration increased. These results are consistent with a direct effect of Ca2+ in activating the thick filament rather than an indirect effect due to Ca2+-mediated crosstalk between the thick and thin filaments. [ABSTRACT FROM AUTHOR]

Objectives: Engineered Heart Tissue (EHT) is a promising tool to repair heart muscle defects and can additionally be used for drug testing. Due to the absence of an in vitro vascularization, EHT geometry crucially impacts nutrient and oxygen supply by diffusion capacity. We analyzed cardiomyocyte survival in different EHT geometries. Methods: Different geometries with varying surface‐area‐to‐volume‐ratios were calculated (structure A (Ring) AS/V = 58.47 mm2/440 μL3, structure B (Infinity) 25.86 mm2/440 μL3). EHTs were generated from hiPSC‐derived cardiomyocytes (4 × 106) and a fibrin/thrombin hydrogel. Cell viability was evaluated by RT‐PCR, cytometric studies, and Bioluminescence imaging. Results: Using 3D‐printed casting molds, spontaneously beating EHTs can be generated in various geometric forms. At day 7, the RT‐PCR analyses showed a significantly higher Troponin‐T value in ring EHTs, compared to infinity EHTs. In cytometric studies, we evaluated 15% more Troponin‐T positive cells in ring (73% ± 12%), compared to infinity EHTs (58% ± 11%, p = 0.04). BLI visualized significantly higher cell survival in ring EHTs (ROI = A: 1.14 × 106 p/s and B: 8.47 × 105 p/s, p < 0.001) compared to infinity EHTs during longitudinal cultivation process. Conclusion: Use of 3D‐printing allows the creation of EHTs in all desired geometric shapes. The geometry with an optimized surface‐area‐to‐volume‐ratio (ring EHT) demonstrated a significantly higher cell survival measured by RT‐PCR, Bioluminescence imaging, and cytometric studies using FACS analysis. [ABSTRACT FROM AUTHOR]

Background/Objectives: Myocarditis is an inflammatory disease of the myocardium and remains to this day a challenging diagnosis. A promising novel imaging method uses the expression of somatostatin receptors (SSTRs) on inflammatory cells to visualize myocardial inflammation. However, little is known about the histopathological correlate of SSTR imaging in different forms of myocarditis. Methods: In the present retrospective histopathological study, we systematically analysed the expression of SSTR subtype 2 (SSTR2) on inflammatory cells of 33 patients with biopsy- or explant-proven myocarditis (lymphocytic myocarditis (n = 5), giant-cell myocarditis (n = 11), and cardiac sarcoidosis (n = 17)), and in eight controls (multi-organ donors) without signs of myocardial inflammation and/or scars. Results: In all patients, immunohistochemical staining for SSTR2 was positive in areas with CD68-positive macrophages and multinucleated giant cells. Staining for SSTR2 was most prominent in the presence of multinucleated giant cells. The colocalization of both SSTR2 and CD68 on the same cell could be confirmed using immunofluorescence microscopy. Western blotting confirmed the upregulated expression of SSTR2 in cases of granulomatous inflammation (sarcoidosis) of the skeletal and heart muscle, in comparison with controls. Conclusions: In conclusion, our findings demonstrate the expression of SSTR2 on the protein level on CD68-positive macrophages and multinucleated giant cells in various forms of myocarditis, which provides a clear rationale for the diagnostic use of SSTR imaging in this patient group. [ABSTRACT FROM AUTHOR]

The functioning of the ventricular myocardium in hypertrophic cardiomyopathy (HCM) under high hemodynamic load leads to depletion of its resources and is associated with the risk of developing a dilated stage. In patients with HCM, the cardiomyocytes of the interventricular septum are hypertrophied, the proportion of cardiomyocytes in which myofibrils constitute less than 50% of the sarcoplasm volume increases with increasing the cardiomyocyte length and correlates with echocardiographic signs of left ventricular obstruction. These cardiomyocytes are characterized by ultrastructural signs of synthetic activity. In the myocardium of patients with HCM, single cardiomyocytes with "critical" loss of myofibrils and nonspecific degenerative changes corresponding to the picture of irreversible changes in the cardiomyocyte ultrastructure were revealed. The presence of cardiomyocytes with this ultrastructural phenotype is an early marker of exhaustion of the compensatory capabilities of the myocardium in HCM. [ABSTRACT FROM AUTHOR]

In the recent years, electroconductive scaffolds have shown promising capabilities in guided regeneration of electroactive tissues including nerve, heart muscle, bone, cartilage, and skin. Herein, the fabrication of a novel electroconductive poly (L‐lactic acid) (PLLA)/polyamidoamine (PAMAM) dendrimer nanofibrous scaffold containing graphene oxide (GO) nanosheets is described. The presence of PAMAM with amine terminal groups successfully aminolyzed PLLA. Interestingly, both PAMAM (5% w/w) and GO (0.5, 1, 2% w/w) not only contributed to reducing the fiber diameter, increasing the hydrophilicity and degradation rate, but also provided a nanocomposite scaffold with enhancement in electrical conductivity. By incorporating 1% w/w of GO, the nanocomposite scaffold exhibited optimized properties, including electrical conductivity (≈3.09 × 10−5 S m−1), crystallinity (≈ 47%), Young's modulus (≈16.95 MPa), as well as strength (≈1.58 MPa). This nanocomposite also demonstrated significant antibacterial activity of ≥ 90% against both gram‐positive and gram‐negative bacteria. Cellular assays confirmed acceptable cytocompatibility of the nanocomposite scaffolds containing GO and PAMAM, which can support the viability and proliferation of PC‐12 cells. In conclusion, the presence of GO nanosheets alongside PAMAM dendrimers can synergically promote the properties of the prepared nanofibrous mats which can be used as potential electroconductive scaffolds for guided tissue regeneration. [ABSTRACT FROM AUTHOR]

Background: Hyperglycemia is a condition in which blood sugar levels increase excessively due to a variety of factors, one of which is the body's inability to regulate insulin properly. Diabetes closely relates to this condition, which significantly contributes to premature death and disability. Long-term diabetes treatment accompanied by a strict diet provides real results in controlling blood glucose levels but can cause side effects. Therefore, it is necessary to conduct research on the potential for new drug sources with minimal side effects. Traditional medicine empirically uses the plant Petiveria alliacea. Aim: This study was conducted to determine the effect of P. alliacea on hyperglycemic model rat and to further determine the mechanism of its active compounds in silico. Methods: The experimental animals were divided into 5 groups: 1 normal group, 1 group induced with Streptozotocin (STZ) 50 mg/kgBW to treat hyperglycemia, and 3 other groups induced with STZ 50 mg/kgBW and given 70% ethanol extract of P. alliacea leaves (EEPa) in different doses. Each group was measured for B-cell lymphoma 2 (Bcl2) expression and apoptosis. We also carried out in silico identification of the isoarborinol acetate and myricitrin compounds contained in EEPa against alpha-glucosidase and caspase-3. Results: It was found that giving STZ to rat can cause hyperglycemia. This was shown by measuring fasting blood glucose in rat and then measuring Bcl2 as an antiapoptotic agent. Bcl2 levels rose compared to the hyperglycemic control group and can lower apoptosis expression in heart cells of hyperglycemic model rat with an optimal dose of 90 mg/kgBW. In addition, the results showed that isoarborinol acetate and myricitrin compounds have inhibition of alpha-glucosidase and caspase-3. Conclusion: It can be concluded that EEPa is one of the alternative choices to overcome hyperglycemia. [ABSTRACT FROM AUTHOR]

Introduction: del Nido cardioplegia was developed for immature myocardium to prevent myocardial damage by Ca+2 in traditional blood cardioplegia. But due to increased hemodilution and decreased colloid oncotic pressure it may cause myocardial edema and increased cardiac morbidity. Microplegia may have better cardioprotection in comparison to del Nido as there is less hemodilution. Material and methods: 60 patients from the age group of 1 to 14 years were divided into two groups i.e. del Nido based microplegia group and conventional del Nido group for studying two different cardioplegia technique. Data were collected and compared for intraoperative Hb, CPK-MB and Trop-I levels changes and requirement for defibrillation in intraoperative period. Demographic data, CPB time and ACC time were also collected. Results: Marked elevation in CPK-MB and Trop-I levels were seen in both groups. Statistically significant difference was seen in CPK-MB levels after 6 h of surgery where del Nido group has higher value in comparison to microplegia group. No statistical difference was seen in Trop-I levels in both groups. Strength of correlation (r) was also stronger for CPK-MB rise in association with CPB time and ACC time, in del Nido group but not for Trop-I. Significantly higher hemodilution was also seen in del Nido group after delivering cardioplegia. None of the patients required defibrillation in any group. Conclusion: Lesser hemodilution was seen in microplegia group. Significant cardioprotection is associated with use of microplegia solution in pediatric age group. [ABSTRACT FROM AUTHOR]

Myocarditis, marked by heart muscle inflammation, poses significant clinical challenges. This study, guided by PRISMA guidelines, explores the expanding role of artificial intelligence (AI) in myocarditis, aiming to consolidate current knowledge and guide future research. Following PRISMA guidelines, a systematic review was conducted across PubMed, Cochrane Reviews, Scopus, Embase, and Web of Science databases. MeSH terms including artificial intelligence, deep learning, machine learning, myocarditis, and inflammatory cardiomyopathy were used. Inclusion criteria involved original articles utilizing AI for myocarditis, while exclusion criteria eliminated reviews, editorials, and non-AI-focused studies. The search yielded 616 articles, with 42 meeting inclusion criteria after screening. The identified articles, spanning diagnostic, survival prediction, and molecular analysis aspects, were analyzed in each subsection. Diagnostic studies showcased the versatility of AI algorithms, achieving high accuracies in myocarditis detection. Survival prediction models exhibited robust discriminatory power, particularly in emergency settings and pediatric populations. Molecular analyses demonstrated AI's potential in deciphering complex immune interactions. This systematic review provides a comprehensive overview of AI applications in myocarditis, highlighting transformative potential in diagnostics, survival prediction, and molecular understanding. Collaborative efforts are crucial for overcoming limitations and realizing AI's full potential in improving myocarditis care. [ABSTRACT FROM AUTHOR]

Copyright of Journal of China Medical University is the property of Journal of China Medical University Editorial Office and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background Human interleukin (IL)-37 is a constituent of the IL-1 family with potent anti-inflammatory and immunosuppressive attributes. It has been demonstrated extensive beneficial effects on various diseases; however, its role in the pathogenesis of diabetic cardiomyopathy (DCM) remains unclear. Methods In vivo, DCM mouse model was established with streptozotocin injection and a high-fat diet in WT and cardiac fibroblasts (CFs) specific hIL-37b overexpression mice (IL-37-Tg). In vitro, primary mouse CFs were isolated from the hearts of adult mice and cultured with high levels of glucose and palmitic acid. Cardiac function of the mice was assessed using echocardiography. Masson staining, immunofluorescence, western blot and RT-PCR assays were employed to evaluate the expression of cardiac fibrosis and SOCS3-JAK2-STAT3 signaling pathway-related proteins. Results In this study, we found that CFs specific IL-37-Tg significantly ameliorated cardiac dysfunction and reduced collagen production by inhibiting the JAK2-STAT3 axis, as evidenced by the decreased levels of p-JAK2 and p-STAT3 in the heart of CFs specific IL-37-Tg DCM mice. The beneficial effects of IL-37 were consistently observed in CFs treated with high glucose (HG) and palmitic acid (PA). Moreover, we also discovered that the presence of IL-37 increased the expression of SOCS3, a crucial regulator of JAK/STAT signaling, in DCM mice and HG and PA-treated CFs. Finally, the anti-fibrotic action of IL-37 in HG and PAtreated CFs was abolished when either SOCS3 was genetically knocked down or JAK2/STAT3 was pharmacologically activated. Conclusions Our findings indicate that IL-37 exerts its antifibrotic effect by promoting SOCS3-mediated JAK2-STAT3 inactivation and may be considered as a potential therapeutic agent for DCM. [ABSTRACT FROM AUTHOR]

Despite remarkable progress in therapeutic drugs, morbidity, and mortality for heart failure (HF) remains high in developed countries. HF with preserved ejection fraction (HFpEF) now accounts for around half of all HF cases. It is a heterogeneous disease, with multiple aetiologies, and as such poses a significant diagnostic challenge. Cardiac magnetic resonance (CMR) has become a valuable non-invasive modality to assess cardiac morphology and function, but beyond that, the multi-parametric nature of CMR allows novel approaches to characterize haemodynamics and with magnetic resonance spectroscopy (MRS), the study of metabolism. Furthermore, exercise CMR, when combined with lung water imaging provides an in-depth understanding of the underlying pathophysiological and mechanistic processes in HFpEF. Thus, CMR provides a comprehensive phenotyping tool for HFpEF, which points towards a targeted and personalized therapy with improved diagnostics and prevention. [ABSTRACT FROM AUTHOR]

Copyright of Retos: Nuevas Perspectivas de Educación Física, Deporte y Recreación is the property of Federacion Espanola de Asociaciones de Docentes de Educacion Fisica and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background. The Percutaneous Transluminal Coronary Angioplasty (PTCA) is an interventional cardiology procedure that allows revascularisation of ischemic myocardial areas both in acute and chronic settings. Over the years, this technique has improved in terms of efficacy, changing the therapeutic approach of myocardial ischemic pathology, with a significant reduction in the mortality rate of myocardial infarction. However, it does not appear free from complications, one of which, although very rare, is radiodermatitis, that is frequently correlated to acute or/and low dose ionizing radiation exposure and oxidative stress. Material and Methods. In this regard, the Authors proceeded to a review of the literature concerning the harmful effects of radiation during fluoroscope-guided procedures, underlining in particular the difficulties of univocally determining a "threshold dose" beyond which to define the onset of radiodermitic phenomena. Results. It has been highlighted how the onset of radiodermitic manifestations following PTCA is of primary medical-legal interest, since it is possible to recognise the existence of responsibility profiles in the hands of the healthcare professionals, and therefore the occurrence of compensation claims by patients. Conclusion. No specific contribution emerged from the literature consulted, so authors put forward the essential elements for a correct classification of healthcare responsibility and the evaluation of any consequent damage to the person concerned. [ABSTRACT FROM AUTHOR]

Background. Goals of this study include observing the origin, course, termination, dominance and branching outline of the coronary arteries with emphasis on Brocq and Mouchet's triangle. The objectives were to determine the prevalence of Kugel's artery, third coronary artery and myocardial bridges in formalin fixed cadavers of Indian population. Methods This cross-sectional anatomical study utilized 30 formalin fixed cadaveric hearts. The length of the trunk is measured for both the right and left coronary arteries with the help of measuring tape and width was determined by using the digital vernier calliper (Mitutoyo Corporation, Kawasaki, Japan). Results. The 25 hearts (83%) were right dominant, 4 heart specimens (14%) were left dominant and 1 heart specimen (3%) was co-dominant. Kugel's artery was observed in 12 hearts (30%), in this study. The third coronary artery was observed in 4 hearts (14%) of this study. The myocardial bridges were observed in only 4 hearts (7%) of this study. The presence of median artery (one artery) as Brocq and Mouchet's triangle content was observed in 16 specimens (53%), while the 11 specimens (37%) had presence of two arteries (median and diagonal) as its contents, 2 specimens (7%) showed 3 arteries (median, diagonal and one extra artery) as its contents and 1 specimen (3%) didn't have any artery as its content. In the present study, LCA exhibited more variations as in 12 specimens (40%), there was bifurcation, 9 specimens (30%), there was trifurcation and in 7 specimens (23%), there was tetrafurcation (Fig. 7) and in only 2 specimens (7%), there was pentafurcation of the LCA. Conclusions. We believe that the present research has provided detailed morphology of the coronary arteries with emphasis on myocardial bridges and Brocq and Mouchet's triangle. However, the data can be still better interpreted with a larger sample size. [ABSTRACT FROM AUTHOR]

Background & objective. Association of multiple coronary arterial microfistulae and myocardial bridge together with concentric diffuse hypertrophic obstructive cardiomyopathy is considerably rare and we aim to highlight a similar unusual but clinically significant association in a young adult female patient with hypertrophic cardiomyopathy, presenting with progressively worsening angina on exertion. Case findings. A young 38-year-old female presented to the cardiology clinic of our institute with complaints of angina on exertion New York Heart Association (NYHA) class III for 2 years. An electrocardiogram showed left ventricular enlargement and echocardiography showed diffuse hypertrophic obstructive cardiomyopathy with the systolic anterior motion of the mitral valve and left ventricular outflow tract gradient of 40 mm Hg on Valsalva. CT coronary angiography revealed a diffuse concentric hypertrophic left ventricular myocardium with no regional wall motion abnormality, a mid-left anterior descending artery myocardial bridge, multiple coronary arterial microfistulae from distal left anterior descending (LAD) and right coronary artery (RCA) emptying to the right ventricle and dilated pulmonary artery trunk. Conclusion. In patients with hypertrophic obstructive cardiomyopathy, angina can be rarely due to coronary artery fistula and or myocardial bridge in addition to myocardial perfusion mismatch owing to hypertrophy or a combination of all. CT coronary angiography seems to be the ideal first noninvasive modality for screening and pre-intervention planning. [ABSTRACT FROM AUTHOR]

Myocardial fibrosis is a common endpoint of many cardiac diseases and increasingly recognized as a predictor of heart failure, arrhythmia, and death. Recent studies have utilised cardiac computed tomography (CT) scans with delayed phase imaging to quantify diffuse fibrosis of the myocardium. CT extracellular volume (CT-ECV) measurement correlates well with CMR and histological myocardial fibrosis. Furthermore, CT-ECV predicts outcomes such as death, heart failure and arrhythmia in various disease states. This review summarizes the rationale and methodology behind CT-ECV measurement and provides a detailed summary of the current clinical evidence for the use of CT-ECV. [ABSTRACT FROM AUTHOR]

In this study, by pooling the clinical data of patients who died with a history of long-term clozapine use and by examining their hearts, it was found that long-term clozapine use can lead to cardiomyopathy and that its presentation resembles arrhythmogenic cardiomyopathy (ACM), i.e., it exhibits a predominantly right ventricular fatty infiltration with mild left ventricular damage. The transcriptomic data of rat cardiomyocytes after clozapine intervention were analyzed by transcriptomic approach to explore the causes of clozapine cardiomyopathy. The cause of clozapine cardiomyopathy was then explored by a transcriptomic approach, which revealed that its clozapine action on cardiomyocytes enriched cardiomyocyte-related differential genes in biological processes such as muscle development and response to hypoxia, as well as pathways such as fatty acid metabolism and cellular autophagy. Transcriptomic analysis showed that Egr1, Egr2, ler2, Jun, Mapk9, Nr1d2, Atf3, Bhlhe40, Crem, Cry1, Cry2, Dbp were hub genes for clozapine injury to the myocardium, and that these genes may play an important role in the myocardial ACM-like changes caused by clozapine. Combined with the results of pathological examination and transcriptomic analysis, it can be concluded that the long-term action of clozapine on cardiomyocytes leads to cellular autophagy and subsequent structural remodeling of the heart, and in the remodeling affects fatty acid metabolism, which eventually leads to ACM-like changes. [ABSTRACT FROM AUTHOR]

Camels possess exceptional adaptability, allowing them to withstand extreme temperatures in desert environments. They conserve water by reducing their metabolic rate and regulating body temperature. The heart of the camel plays a crucial role in this adaptation, with specific genes expressed in cardiac tissue that are essential for mammalian adaptation, regulating cardiac function and responding to environmental stressors. One such gene, nebulin‐related‐anchoring protein (NRAP), is involved in the assembly of myofibrils and the transmission of force within the heart. In our study of the NRAP gene across various livestock species, including three camel species, we identified a camel‐specific exon region in the NRAP transcripts. This additional exon (exon 4) contains an open reading frame predicted in camels. To investigate its function, we generated knock‐in mice expressing camel NRAP exon 4. These ‘camelized mice’ exhibited normal phenotypic characteristics compared with wild‐type mice but showed elevated body temperatures under cold stress. Transcriptome analyses of the hearts from camelized mice under cold stress revealed differentially expressed inflammatory cytokine genes, known to influence cardiac function by modulating the contractility of cardiac muscle cells. We propose further investigations utilizing these camelized mice to explore these findings in greater depth. [ABSTRACT FROM AUTHOR]

Background: Rheumatoid arthritis (RA) is a chronic inflammatory disease that affects not only the joints but also has significant cardiovascular (CV) manifestations. The mechanistic interplay between RA and cardiovascular complications is not yet well understood due to the lack of relevant in vitro models. In this study, we established RA cardiac microtisses (cMTs) from iPSC-derived cardiomyocytes (CMs), endothelial cells (ECs) and cardiac fibroblasts (CFs) to investigate whether this fully human 3D multicellular system could serve as a platform to elucidate the connection between RA and CV disorders. Methods: PBMC and FLS from healthy and RA donors were reprogrammed to hiPSCs with Sendai vectors. hiPSCs pluripotency was assessed by IF, FACS, spontaneous embryoid bodies formation and teratoma assay. hiPSCs were differentiated to cardiac derivatives such as CMs, ECs and CFs, followed by cell markers characterizations (IF, FACS, qRT-PCR) and functional assessments. 3D cMTs were generated by aggregation of 70% CMs, 15% ECs and 15% CFs. After 21 days in culture, structural and metabolic properties of 3D cMTs were examined by IF, qRT-PCR and Seahorse bioanalyzer. Results: hiPSCs demonstrated typical colony-like morphology, normal karyotype, presence of pluripotency markers, and ability to differentiate into cells originating from all three germ layers. hiPSC-CMs showed spontaneous beating and expression of cardiac markers (cTnT, MYL7, NKX2.5, MYH7). hiPSC-ECs formed sprouting spheres and tubes and expressed CD31 and CD144. hiPSC-CFs presented spindle-shaped morphology and expression of vimentin, collagen 1 and DDR2. Self-aggregation of CMs/ECs/CFs allowed development of contracting 3D cMTs, demonstrating spherical organization of the cells, which partially resembled the cardiac muscle, both in structure and function. IF analysis confirmed the expression of cTnT, CD31, CD144 and DDR2 in generated 3D cMTs. RA cMTs exhibited significantly greater formation of capillary-like structures, mimicking enhanced vascularization—key RA feature—compared to control cMTs. Seahorse examination of cMTs revealed changes in mitochondrial and glycolytic rates in the presence of metabolic substrates and inhibitors. Conclusions: The cMTs model may represent an advanced human stem cell-based platform for modeling CV complications in RA. The highly developed capillary-like structures observed within RA cMTs highlight a critical feature of inflammation-induced CV dysfunction in chronic inflammatory diseases. [ABSTRACT FROM AUTHOR]

We study the high-frequency, micro-mechanical response of suspensions composed of cardiac and skeletal muscle myosin by optical trapping interferometry. We observe that in low ionic strength solutions, upon the addition of magnesium adenosine triphosphate (MgATP2−), myosin suspensions radically change their micro-mechanics properties, generating a viscoelastic fluid characterized by a complex modulus similar to a suspension of worm-like micelles. This transduction of energy, from chemical to mechanical, may be related to the relaxed states of myosin, which regulate muscle contractility and can be involved in the etiology of many myopathies. Within an analogous generic mechanical response, cardiac and skeletal myosin suspensions provide different stress relaxation times, elastic modulus values, and characteristic lengths. These discrepancies probably rely on the dissimilar physiological functions of cardiac and skeletal muscle, on the different MgATPase hydrolysis rates of cardiac and skeletal myosins, and on the observed distinct cooperative behavior of their myosin heads in the super-relaxed state. In vitro studies like these allow us to understand the foundations of muscle cell mechanics on the micro-scale, and may contribute to the engineering of biological materials whose micro-mechanics can be activated by energy regulators. [ABSTRACT FROM AUTHOR]

Introduction: In multiplexed positron emission tomography (mPET) imaging, physiological and pathological information from different radiotracers can be observed simultaneously in a single dynamic PET scan. The separation of mPET signals within a single PET scan is challenging due to the fact that the PET scanner measures the sum of the PET signals of all the tracers. The conventional multitracer compartment modeling (MTCM) method requires staggered injections and assumes that the arterial input functions (AIFs) of each tracer are known. Methods: In this work, we propose a deep learning-based method to separate triple-tracer PET images without explicitly knowing the AIFs. A dynamic tripletracer noisy MLEM reconstruction was used as the network input, and dynamic single-tracer noisy MLEM reconstructions were used as training labels. Results: A simulation study was performed to evaluate the performance of the proposed framework on triple-tracer ([18F]FDG+82Rb+[94mTc]sestamibi) PET myocardial imaging. The results show that the proposed methodology substantially reduced the noise level compared to the results obtained from single-tracer imaging. Additionally, it achieved lower bias and standard deviation in the separated single-tracer images compared to the MTCM-based method at both the voxel and region of interest (ROI) levels. Discussion: As compared to MTCM separation, the proposed method uses spatiotemporal information for separation, which improves the separation performance at both the voxel and ROI levels. The simulation study also demonstrates the feasibility and potential of the proposed DL-based method for the application to pre-clinical and clinical studies. [ABSTRACT FROM AUTHOR]

It is important to consider the full spectrum of complex interactions between mineral elements and biologically active substances to evaluate the development of cardiovascular disease (CVD) in animals, in addition to the classical physiological approach. This study aimed to assess changes in mineral element levels in wild and exotic animals in relation to their cardiovascular diseases. A total of 171 animals, including 128 healthy and 43 sick animals from three Russian zoos, were sampled and analyzed. For the first time, species from the canine (nine) and feline (seven) families from Moscow, Ivanovo, and Yaroslavl zoos in the Central Federal District of Russia were selected. A total of 108 samples from canines and 63 samples from feline animals were collected. Mineral element measurements were conducted on 1026 samples via a "Kvant-2A" atomic absorption spectrometer from Russia. Correlation and regression analyses were performed. CVDs were found in 10.1% of the studied animals, with a high percentage of heart muscle pathologies noted (25.8% of all CVDs). Iron (Fe) accumulated in canine and feline fur at approximately 208 and 203 mg/kg, with variations of 72.8% and 80.9%, respectively. A significant decrease in Fe and an increase in cadmium (Cd) during CVD were observed (correlations r = 0.25 and r = 0.16, respectively). The dysregulation of Fe homeostasis, increased absorption, and accumulation of Fe in the reticuloendothelial system are discussed. Finally, the mineral elements absorbed by canine and feline fur can be ranked in descending order: Fe > Zn > Cu > Pb > Cd > As. [ABSTRACT FROM AUTHOR]

Muscle wasting is a serious complication in heart failure patients. Oxidative stress and inflammation are implicated in the pathogenesis of muscle wasting. Oxidative stress leads to the formation of toxic lipid peroxidation products, such as 4-hydroxy-2-nonenal (HNE), which covalently bind with proteins and DNA and activate atrophic pathways. Whether the formation of lipid peroxidation products and metabolic pathways that remove these toxic products are affected during heart failure-associated skeletal muscle wasting has never been studied. Male C57BL/6J mice were subjected to sham and transverse aortic constriction (TAC) surgeries for 4, 8 or 14 weeks. Different skeletal muscle beds were weighed, and the total cross-sectional area of the gastrocnemius muscle was measured via immunohistochemistry. Muscle function and muscle stiffness were measured by a grip strength meter and atomic force microscope, respectively. Atrophic and inflammatory marker levels were measured via qRT‒PCR. The levels of acrolein and HNE-protein adducts, aldehyde-removing enzymes, the histidyl dipeptide-synthesizing enzyme carnosine synthase (CARNS), and amino acid transporters in the gastrocnemius muscle were measured via Western blotting and qRT‒PCR. Histidyl dipeptides and histidyl dipeptide aldehyde conjugates in the Gastrocnemius and soleus muscles were analyzed by LC/MS–MS. Body weight, gastrocnemius muscle and soleus muscle weights and the total cross-sectional area of the gastrocnemius muscle were decreased after 14 weeks of TAC. Heart weight, cardiac function, grip strength and muscle stiffness were decreased in the TAC-operated mice. Expression of the atrophic and inflammatory markers Atrogin1 and TNF-α, respectively, was increased ~ 1.5–2fold in the gastrocnemius muscle after 14 weeks of TAC (p < 0.05 and p = 0.004 vs sham). The formation of HNE and acrolein protein adducts was increased, and the expression of the aldehyde-removing enzyme aldehyde dehydrogenase (ALDH2) was decreased in the gastrocnemius muscle of TAC mice. Carnosine (sham: 5.76 ± 1.3 vs TAC: 4.72 ± 0.7 nmol/mg tissue, p = 0.04) and total histidyl dipeptide levels (carnosine and anserine; sham: 11.97 ± 1.5 vs TAC: 10.13 ± 1.4 nmol/mg tissue, p < 0.05) were decreased in the gastrocnemius muscle of TAC mice. Depletion of histidyl dipeptides diminished the aldehyde removal capacity of the atrophic gastrocnemius muscle. Furthermore, CARNS and TAUT protein expression were decreased in the atrophic gastrocnemius muscle. Our data reveals that reduced expression of ALDH2 and depletion of histidyl dipeptides in the gastrocnemius muscle during heart failure leads to the accumulation of toxic aldehydes and might contribute to muscle wasting. [ABSTRACT FROM AUTHOR]

Cellular heterogeneity is a well-accepted feature of tissues, and both transcriptional and metabolic diversity have been revealed by numerous approaches, including optical imaging. However, the high magnification objective lenses needed for high-resolution imaging provides information from only small layers of tissue, which can result in poor cell statistics. There is therefore an unmet need for an imaging modality that can provide detailed molecular and cellular insight within intact tissue samples in 3D. Using GFP-tagged GLUT4 as proof of concept, we present here a novel optical mesoscopy approach that allows precise measurement of the spatial location of GLUT4 within specific anatomical structures across the myocardium in ultrathick sections (5 mm x 5 mm x 3 mm) of intactmouse heart.We reveal distinct GLUT4 distribution patterns across cardiac walls and highlight specific changes in GLUT4 expression levels in response to high fat dietfeeding, and we identify sex-dependent differences in expression patterns. This method is applicable to any target that can be labelled for light microscopy, and to other complex tissues when organ structure needs to be considered simultaneously with cellular detail. [ABSTRACT FROM AUTHOR]

Background: The role of epigenetics in cardiovascular diseases has paved the way for innovative therapeutic approaches. Investigating epigenetic changes using cell-free DNA (cfDNA) holds substantial promise beyond mere diagnostics, especially for heart-related conditions like acute myocardial infarction (AMI), where obtaining tissue samples is a challenge. This study explores the methylation patterns of cfDNA in AMI patients and compares them with genomic DNA (gDNA) from the same individuals, aiming to evaluate the effectiveness of cfDNA as a valuable resource for studying heart-related diseases. Methodology: We generated global methylome profiles of cfDNA and gDNA from 25 AMI patients using EM-Seq. Tissue deconvolution analysis was performed to estimate tissue specificity based on the methylation patterns. Differentially methylated loci were identified and explored to understand AMI pathophysiology. Results: Comparative analysis of cfDNA and gDNA methylation patterns in AMI patients reveals cfDNA holds more significance than gDNA. Principal component analysis revealed distinct clusters for cfDNA and gDNA, indicating distinct methylome profiles. cfDNA originated from multiple sources, predominantly from neutrophils (~ 75%) and about 10% from the left atrium, highlighting cardiac-specific changes. In contrast, immune cells are the major source of gDNA, indicative of inflammatory responses. Gene set enrichment analysis (GSEA) associates cfDNA methylation patterns with pathways related to cardiac muscle contraction, inflammation, hypoxia, and lipid metabolism. The affected genes include G protein-coupled receptors (GHSR, FFAR2, HTR1A, and VIPR2) that are part of the cAMP signaling pathway. Conclusion: Epigenetic changes in cfDNA are more specific to cardiac tissue compared to those in gDNA, providing better insights into the molecular mechanisms involved in AMI. Genes that are differentially methylated in cfDNA and regulate core pathways, such as cAMP signaling, could be targeted for clinical applications, including the development of effective biomarkers and therapeutic targets. [ABSTRACT FROM AUTHOR]

Introduction: Skeletal muscle (SkM) abnormalities are well-recognised in heart failure (HF). We aimed to systematically review studies of SkM energetics in patients with HF at rest and post-exercise using 31phosphorus magnetic resonance spectroscopy (31P MRS). Methods: A systematic search of cross-sectional studies used predefined search terms related to HF, SkM energetics, and 31P MRS (PROSPERO ID: CRD42023434698). Inclusion criteria for studies are as follows: 1. HF participants versus controls; and 2. SkM energetics assessed using 31P MRS reporting BOTH (i) PCr recovery time and (ii) PCr ratios (PCr/Pi and/or PCr/ATP). The primary outcome was SkM PCr recovery time following exercise, comparing patients with diagnosed HF and healthy controls and reported as standardised mean difference (SMD). Results: Of 465 identified studies, 6 met the inclusion criteria and were conducted from 1987 to 2021, comprising 162 participants (N = 86 HF, N = 76 healthy controls). HF patients (mean age 55.1 ± 4.16 years, 49 (56.9%) male) were reasonably matched to healthy controls (mean age 50 ± 8.9 years, 54 (71%) males). Two studies did not report patients' ejection fractions (EF); the mean EF among patients from the remaining six studies was 24.8%. No studies specifically included participants with HFpEF and none characterised sarcopenia. HF patients exhibited impaired SkM energetics compared to healthy controls, which were characterised by a significantly increased PCr recovery time (SMD: −1.35, CI: −2.11, −0.59). Conclusions: PCr recovery is significantly impaired in patients with HFrEF. Females were under-represented, no HFpEF studies were identified, and no studies linking abnormal SkM energetics directly to sarcopenia were identified. [ABSTRACT FROM AUTHOR]

Background: Cardiovascular diseases are prevalent worldwide with any age, and it is characterized by sudden blockage of blood flow to heart and permanent damage to the heart muscle, whose cause and underlying molecular mechanisms are not fully understood. This investigation aimed to explore and identify essential genes and signaling pathways that contribute to the progression of MI. Methods: The aim of this investigation was to use bioinformatics and next-generation sequencing (NGS) data analysis to identify differentially expressed genes (DEGs) with diagnostic and therapeutic potential in MI. NGS dataset (GSE132143) was downloaded from the Gene Expression Omnibus (GEO) database. DEGs between MI and normal control samples were identified using the DESeq2 R bioconductor tool. The gene ontology (GO) and REACTOME pathway enrichment analyses of the DEGs were performed using g:Profiler. Next, four kinds of algorithms in the protein–protein interaction (PPI) were performed to identify potential novel biomarkers. Next, miRNA-hub gene regulatory network analysis and TF-hub gene regulatory network were constructed by miRNet and NetworkAnalyst database, and Cytoscape software. Finally, the diagnostic effectiveness of hub genes was predicted by receiver operator characteristic curve (ROC) analysis and AUC more than 0.800 was considered as having the capability to diagnose MI with excellent specificity and sensitivity. Results: A total of 958 DEGs were identified, consisting of 480 up-regulated genes and 478 down-regulated genes. The enriched GO terms and pathways of the DEGs include immune system, neuronal system, response to stimulus and multicellular organismal process. Ten hub genes (namely cftr, cdk1, rps13, rps15a, rps27, notch1, mrpl12, nos2, ccdc85b and atn1) were obtained via protein–protein interaction analysis results. MiRNA-hub gene regulatory network and TF-hub gene regulatory network showed that hsa-mir-409-3p, hsa-mir-3200-3p, creb1 and tp63 might play an important role in the MI. Conclusions: Analysis of next-generation sequencing dataset combined with global network information and validation presents a successful approach to uncover the risk hub genes and prognostic markers of MI. Our investigation identified four risk- and prognostic-related gene signatures, including cftr, cdk1, rps13, rps15a, rps27, notch1, mrpl12, nos2, ccdc85b and atn1. This gene sets contribute a new perspective to improve the diagnostic, prognostic, and therapeutic outcomes of MI. [ABSTRACT FROM AUTHOR]

Background: Cachexia a multifactorial syndrome is a common sequala in patients with cancer. It varies from 42 to 80% depending upon the oncological stage and is directly responsible for 30% of deaths in these patients. Previous research from our laboratory demonstrated that peritoneal ovarian cancer generated in NSG mice resulted in skeletal and cardiac muscle atrophy - leading to loss of skeletal muscle mass and strength, and cardiac dysfunction (cachexia). Treatment of mice bearing i.p. tumors with withaferin A (WFA) showed reversal of skeletal muscle and cardiac cachexia. The present study is focused on determining effects of peritoneal ovarian tumors on kidney damage and effects of WFA treatment on ameliorating kidney damage. Methods: We generated intraperitoneal ovarian cancer by injecting female NSG mice with ovarian cancer cell line (A2780). After one week of injecting cancer cells, mice were treated with WFA (4 mg/kg) every third day, for three weeks. After 4 weeks of injection of cancer cells, the mice were sacrificed and various tissues including kidney and blood were collected, snap-frozen in liquid nitrogen, and stored at -800C. The presence of kidney biomarker creatinine, was measured in the plasma by an ELISA. The mRNA was isolated from mouse kidneys and was used to examine the expression levels of signaling proteins, inflammatory cytokines, and genes responsible for inducing cachexia (IL-1β, IL-6, TNF-α, TGF-β, GDF-15, and MYD88). Results: Our results showed a significant increase in levels of expression of inflammatory cytokine IL-1 β (p < 0.01), IL-6 (p < 0.001), TNF-α (p < 0.001), and other related genes including TRAF6 (p < 0.01), MYD88 (p < 0.01), and GDF-15 (p = 0.005) in tumor-bearing mice compared to controls. Treatment of mice bearing tumors with WFA attenuated the increase in expression of each gene. In addition, our results showed a significant increase in creatinine levels in circulation in tumor-bearing mice compared to control mice. Treatment of tumor-bearing mice with WFA resulted in a significant decrease in plasma creatinine levels compared to tumor-bearing mice. Conclusions: Our results conclude that ovarian tumors in NSG mice caused kidney damage and renal dysfunction, which was effectively ameliorated by WFA treatment, suggesting a protective effect of WFA on kidney injury induced by ovarian cancer. [ABSTRACT FROM AUTHOR]

Background: Inadequate myocardial glucose metabolism suppression (GMS) can hamper interpretation of cardiac [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET/CT). Use of β-hydroxybutyrate (BHB) measurement before [18F]FDG injection has been proposed for predicting adequate GMS. However, limited information is available on BHB measurement in guiding preparations for [18F]FDG-PET/CT. The purpose of this study was to evaluate if point-of-care measured BHB is useful in guiding heparin premedication for cardiac [18F]FDG-PET/CT. Results: 155 patients (82 male) had followed a high-fat, low-carbohydrate diet and fasted for at least twelve hours. For the first 63 patients, BHB was measured, but it was not used to guide premedication. For the subsequent 92 patients, heparin 50 IU/kg was injected intravenously 15–20 min before [18F]FDG injection if the BHB level was low (< 0.35 mmol/l). Cardiac [18F]FDG uptake pattern was evaluated visually and [18F]FDG uptake in the myocardium and blood pool were measured. Median BHB level was 0.4 (range 0.1–5.8) mmol/l. Eighty-eight patients (57%) reached a BHB level higher than 0.35 mmol/l. 112 patients (72%) had adequate GMS. In the high BHB group, 74 patients (84%) had adequate GMS, whereas of those with low BHB, only 38 (57%) had adequate GMS (p < 0.001). In the low BHB group, the prevalence of inadequate GMS was comparable in patients with and without heparin (44% vs. 42%, p = 0.875). Conclusions: While high BHB predicts adequate GMS, unfractionated heparin does not improve GMS in patients with low BHB. [ABSTRACT FROM AUTHOR]

Radiofrequency ablation is a promising technique for arrhythmia treatment in horses. Due to the thicker myocardial wall and higher blood flow in horses, it is unknown if conventional radiofrequency settings used in human medicine can be extrapolated to horses. The study aim is to describe the effect of ablation settings on lesion dimensions in equine myocardium. To study species dependent effects, results were compared to swine myocardium. Right ventricular and right and left atrial equine myocardium and right ventricular swine myocardium were suspended in a bath with circulating isotonic saline at 37 °C. The ablation catheter delivered radiofrequency energy at different-power-duration combinations with a contact force of 20 g. Lesion depth and width were measured and lesion volume was calculated. Higher power or longer duration of radiofrequency energy delivery increased lesion size significantly in the equine atrial myocardium and in equine and swine ventricular myocardium (P < 0.001). Mean lesion depth in equine atrial myocardium ranged from 2.9 to 5.5 mm with a diameter ranging from 6.9 to 10.1 mm. Lesion diameter was significantly larger in equine tissue compared to swine tissue (P = 0.020). Obtained data in combination with estimated wall thickness can improve lesion transmurality which might reduce arrhythmia recurrence. Optimal ablation settings may differ between species. [ABSTRACT FROM AUTHOR]

Introduction: The anterior and lateral position of the anterolateral papillary muscle (ALPM) has found to be reached with better catheter stability and less mechanical bumping via the transseptal (TS) compared to the retrograde aortic (RA) approach. The aim of this study is to compare the TS and RA approaches on mapping and ablation of ventricular arrhythmias (VAs) arising from ALPMs. Methods: Thirty‐two patients with ALPM‐VAs undergoing mapping and ablation via the TS approach were included and compared with 31 patients via the RA approach within the same period. Acute success was compared, as well as other outcomes including misinterpreted mapping results due to bumping, radiofrequency (RF) attempts, procedural time and success rate at 12‐month follow‐up. Results: Acute success was achieved in more cases in the TS group (96.4% vs. 72.0%, p =.020). During activation mapping, bump‐provoked premature ventricular complexes (PVCs) misinterpreted as clinical PVCs were more common in the RA group (30.0% vs. 58.3%, p =.036), leading to more RF attempts (3.5 ± 2.7 vs. 7.2 ± 6.8, p =.006). Suppression of VAs were finally achieved in the unsuccessful cases by changing to the alternative approach, but the procedural time was significantly less in the TS group (90.0 ± 33.0 vs. 113.7 ± 41.1 min, p =.027) with less need to change the approach, although follow‐up success rates were similar (75.0% vs. 71.0%, p =.718). Conclusion: A TS rather than RA approach as the initial approach appears to facilitate mapping and ablation of ALPM‐VAs, specifically by decreasing the possibility of misleading mapping results caused by bump‐provoked PVC, and increase the acute success rate thereby. [ABSTRACT FROM AUTHOR]

It is still debated whether changes in metabolic flux are cause or consequence of contractile dysfunction in non-ischemic heart disease. We have previously proposed a model of cardiac metabolism grounded in a series of six moiety-conserved, interconnected cycles. In view of a recent interest to augment oxygen availability in heart failure through iron supplementation, we integrated this intervention in terms of moiety conservation. Examining published work from both human and murine models, we argue this strategy restores a mitochondrial cycle of energy transfer by enhancing mitochondrial pyruvate carrier (MPC) expression and providing pyruvate as a substrate for carboxylation and anaplerosis. Metabolomic data from failing heart muscle reveal elevated pyruvate levels with a concomitant decrease in the levels of Krebs cycle intermediates. Additionally, MPC is downregulated in the same failing hearts, as well as under hypoxic conditions. MPC expression increases upon mechanical unloading in the failing human heart, as does contractile function. We note that MPC deficiency also alters expression of enzymes involved in pyruvate carboxylation and decarboxylation, increases intermediates of biosynthetic pathways, and eventually leads to cardiac hypertrophy and dilated cardiomyopathy. Collectively, we propose that an unbroken chain of moiety-conserved cycles facilitates energy transfer in the heart. We refer to the transport and subsequent carboxylation of pyruvate in the mitochondrial matrix as an example and a proposed target for metabolic support to reverse impaired contractile function. [Display omitted] • Metabolic cycles in the heart optimize transfer of available energy • Energy transfer is impaired in heart failure • Moiety-conserved cycles are a potential target in the treatment of heart failure [ABSTRACT FROM AUTHOR]

Cadherins are calcium dependent adhesion proteins that establish and maintain the intercellular mechanical contact by bridging the gap between adjacent cells. Desmoglein-2 (Dsg2) and desmocollin-2 (Dsc2) are tissue specific cadherin isoforms of the cell-cell contact in cardiac desmosomes. Mutations in the DSG2 -gene and in the DSC2 -gene are related to arrhythmogenic right ventricular cardiomyopathy (ARVC) a rare but severe heart muscle disease. Here, several possible homophilic and heterophilic binding interactions of wild-type Dsg2, wild-type Dsc2, as well as one Dsg2- and two Dsc2-variants, each associated with ARVC, are investigated. Using single molecule force spectroscopy (SMFS) with atomic force microscopy (AFM) and applying Jarzynski's equality the kinetics and thermodynamics of Dsg2/Dsc2 interaction can be determined. The free energy landscape of Dsg2/Dsc2 dimerization exposes a high activation energy barrier, which is in line with the proposed strand-swapping binding motif. Although the binding motif is not affected by any of the mutations, the binding kinetics of the interactions differ significantly from the wild-type. While wild-type cadherins exhibit an average complex lifetime of approx. 0.3 s interactions involving a variant consistently show - lifetimes that are substantially larger. The lifetimes of the wild-type interactions give rise to the picture of a dynamic adhesion interface consisting of continuously dissociating and (re)associating molecular bonds, while the delayed binding kinetics of interactions involving an ARVC-associated variant might be part of the pathogenesis. Our data provide a comprehensive and consistent thermodynamic and kinetic description of cardiac cadherin binding, allowing detailed insight into the molecular mechanisms of cell adhesion. [Display omitted] • Integrity of heart muscle tissue relies on weak molecular bonds between cadherins. • Single molecule force spectroscopy reveals cadherin binding kinetics. • Wild-type cadherin bonds exhibit characteristic fast (re-) binding kinetics. • Specific cardiomyopathy associated cadherin variants slow binding kinetics. • Impaired molecular dynamics could be a cardiomyopathy-specific pathomechanism. [ABSTRACT FROM AUTHOR]

Striated muscle cells, encompassing cardiac myocytes and skeletal muscle fibers, are fundamental to athletic performance, facilitating blood circulation and coordinated movement through contraction. Despite their distinct functional roles, these muscle types exhibit similarities in cytoarchitecture, protein expression, and excitation-contraction coupling. Both muscle types also undergo molecular remodeling in energy metabolism and cell size in response to acute and repeated exercise stimuli to enhance exercise performance. Reactive oxygen species (ROS) produced by NADPH oxidase (NOX) isoforms 2 and 4 have emerged as signaling molecules that regulate exercise adaptations. This review systematically compares NOX2 and NOX4 expression, regulation, and roles in cardiac and skeletal muscle responses across exercise modalities. We highlight the many gaps in our knowledge and opportunities to let future skeletal muscle research into NOX-dependent mechanisms be inspired by cardiac muscle studies and vice versa. Understanding these processes could enhance the development of exercise routines to optimize human performance and health strategies that capitalize on the advantages of physical activity. [Display omitted] • Striated muscle cells exhibit many redox-regulated similarities, including the expression of NOX2 and NOX4. • NOX2 and NOX4 are linked to responses to exercise in skeletal and cardiac muscles, influencing glucose metabolism and cell growth. • Further studies on NOX-dependent redox regulation of striated skeletal muscle may improve our understanding of the factors that limit human performance. [ABSTRACT FROM AUTHOR]

Mitoxantrone (MTX) is a therapeutic agent used in the treatment of solid tumors and multiple sclerosis, recognized for its cardiotoxicity, with underlying molecular mechanisms not fully disclosed. The cardiotoxicity is influenced by risk factors, including age. Our study intended to assess the molecular effect of MTX on the cardiac muscle of old male CD-1 mice. Mice aged 19 months received a total cumulative dose of 4.5 mg/kg of MTX (MTX group) or saline solution (CTRL group). Two months post treatment, blood was collected, animals sacrificed, and the heart removed. MTX caused structural cardiac changes, which were accompanied by extracellular matrix remodeling, as indicated by the increased ratio between matrix metallopeptidase 2 and metalloproteinase inhibitor 2. At the metabolic level, decreased glycerol levels were found, together with a trend towards increased content of the electron transfer flavoprotein dehydrogenase. In contrast, lower glycolysis, given by the decreased content of glucose transporter GLUT4 and phosphofructokinase, seemed to occur. The findings suggest higher reliance on fatty acids oxidation, despite no major remodeling occurring at the mitochondrial level. Furthermore, the levels of glutamine and other amino acids (although to a lesser extent) were decreased, which aligns with decreased content of the E3 ubiquitin-protein ligase Atrogin-1, suggesting a decrease in proteolysis. As far as we know, this was the first study made in old mice with a clinically relevant dose of MTX, evaluating its long-term cardiac effects. Even two months after MTX exposure, changes in metabolic fingerprint occurred, highlighting enduring cardiac effects that may require clinical vigilance. [Display omitted] • First study regarding late-onset chronic cardiotoxicity in aged MTX-treated mice. • Cardiac metabolic remodeling remained in aged heart two months post-MTX treatment. • Molecular outcomes include increased FAO and oxidation of amino acids after MTX. • Decreased glycolysis and UPP-mediated proteolysis were also seen in these aged mice. [ABSTRACT FROM AUTHOR]

Objectives Measures of right heart size and function are prognostic in systemic sclerosis-associated pulmonary hypertension (SSc-PH), but the importance of myocardial tissue characterisation remains unclear. We aimed to investigate the predictive potential and interaction of cardiovascular magnetic resonance (CMR) myocardial tissue characterisation and right heart size and function in SSc-PH. Methods A retrospective, single-centre, observational study of 148 SSc-PH patients confirmed by right heart catheterization who underwent clinically indicated CMR including native myocardial T1 and T2 mapping from 2016 to 2023 was performed. Results Sixty-six (45%) patients died during follow-up (median 3.5 years, range 0.1–7.3). Patients who died were older (65 vs 60 years, P  = 0.035) with more dilated (P  < 0.001), hypertrophied (P  = 0.013) and impaired (P  < 0.001) right ventricles, more dilated right atria (P  = 0.043) and higher native myocardial T1 (P  < 0.001). After adjustment for age, indexed right ventricular end-systolic volume (RVESVi, P  = 0.0023) and native T1 (P  = 0.0024) were independent predictors of all-cause mortality. Both RVESVi and native T1 remained independently predictive after adjusting for age and PH subtype (RVESVi P  < 0.001, T1 P  = 0.0056). Optimal prognostic thresholds for RVESVi and native T1 were ≤38 mL/m2 and ≤1119 ms, respectively (P  < 0.001). Patients with RVESVi ≤ 38 mL/m2 and native T1 ≤ 1119 ms had significantly better outcomes than all other combinations (P  < 0.001). Furthermore, patients with RVESVi > 38mL/m2 and native T1 ≤ 1119 ms had significantly better survival than patients with RVESVi > 38mL/m2 and native T1 > 1119ms (P  = 0.017). Conclusion We identified prognostically relevant CMR metrics and thresholds for patients with SSc-PH. Assessing myocardial tissue characterisation alongside right ventricular function confers added value in SSc-PH and may represent an additional treatment target. [ABSTRACT FROM AUTHOR]

Background: Delayed contrast enhancement in cardiac magnetic resonance (CMR) imaging plays a pivotal role in assessing myocardial tissue characteristics in non-ischemic cardiomyopathy (NICM). This study aims to explore the various patterns of late gadolinium enhancement (LGE) observed in NICM patients and their correlation with clinical outcomes. The study identifies distinct morphological and distributional variations, including diffuse, patchy, subepicardial, mid-wall, and subendocardial enhancement. Recognizing these patterns enhances diagnostic accuracy and improves prognostic evaluations in NICM, ultimately guiding therapeutic strategies for better patient management. Objective: The primary aim of this prospective study is to evaluate the patterns of delayed contrast enhancement in NICM patients using CMR imaging. Material & Methods: A total of 40 NICM cases were included in this study, conducted in the Department of Radiodiagnosis at G.S.V.M. Medical College, Kanpur, from September 2022 to July 2024. Patients were selected in collaboration with LPS Institute of Cardiology based on clinical and echocardiographic criteria. Cardiac MRI was performed on a 3T machine and the images were qualitatively analyzed for abnormal myocardium. Results: The mean age of patients in this study was 58 years. Of the total, 30 (75%) had dilated cardiomyopathy (DCM), 5 (12.5%) had myocarditis, 3 (7.5%) had restrictive cardiomyopathy (RCM), and 2 (5%) had sarcoidosis. Among the DCM patients, mid-wall enhancement was seen in 10 (33.33%). In the myocarditis group, 2 (40%) patients showed a subepicardial pattern of enhancement. Both sarcoidosis patients exhibited involvement of the subendocardium, mid-wall, and subepicardium. Additionally, one (33.3%) patient with RCM demonstrated subendocardial enhancement. A significant association was found between enhancement patterns and the underlying pathologies (p=0.0001). Conclusions: LGE CMR is becoming an indispensable tool for detecting, characterizing, and differentiating various cardiomyopathies. By classifying delayed myocardial enhancement based on its precise anatomical location, it is possible to distinguish between non-ischemic and ischemic (infarct-related) cardiomyopathies. When clinical suspicion is high, delayed-enhanced cardiac MRI can facilitate early detection and prompt management of cardiomyopathies, improving patient outcomes. [ABSTRACT FROM AUTHOR]

Background/Objectives: Hypertrophic cardiomyopathy (HCM) is a common heart disorder characterized by the thickening of the heart muscle, particularly in the left ventricle, which increases the risk of cardiac complications. This study aims to analyze the expression of apoptosis-regulating genes (CASP8, CASP9, CASP3, BAX, and BCL2) in blood samples from HCM patients, to better understand their potential as biomarkers for disease progression. Methods: Quantitative real-time PCR (qPCR) was used to evaluate gene expression in blood samples from 93 HCM patients. The correlation between apoptosis-regulating genes was conducted and clinical parameters were integrated for feature importance and clustering analysis. Results: Most patients exhibited significant downregulation of CASP8, CASP9, and CASP3. In contrast, BAX expression was elevated in 71 out of 93 patients, while BCL2 was increased in 55 out of 93 patients. Correlation analysis revealed weak negative correlations between the BAX/BCL2 ratio and CASP gene expression. Conclusions: These findings suggest that reduced expression of apoptotic genes may indicate a protective cellular mechanism, which could serve as a biomarker for disease progression. Further studies are needed to investigate the potential for therapeutic modulation of these pathways to improve patient outcomes. [ABSTRACT FROM AUTHOR]

Heart failure, a major public health issue, often stems from prolonged stress or damage to the heart muscle, leading to cardiac hypertrophy. This can progress to heart failure and other cardiovascular problems. Doxorubicin (DOX), a common chemotherapy drug, and isoproterenol (ISO), a β-adrenergic agonist, both induce cardiac hypertrophy through different mechanisms. This study investigates TongGuanWan (TGW,), a traditional herbal remedy, for its effects on cardiac hypertrophy and fibrosis in DOX-induced H9c2 cells and ISO-induced mouse models. TGW was found to counteract DOX-induced increases in H9c2 cell surface area (n = 8, p < 0.01) and improve biomarkers like ANP (n = 3, p < 0.01)) and BNP (n = 3, p < 0.01). It inhibited the MAPK pathway (n = 4, p < 0.01) and GATA-4/calcineurin/NFAT-3 signaling, reduced inflammation by decreasing NF-κB p65 translocation, and enhanced apoptosis-related factors such as caspase-3 (n = 3, p < 0.01), caspase-9 (n = 3, p < 0.01), Bax (n = 3, p < 0.01), and Bcl-2 (n = 3, p < 0.01). Flow cytometry showed TGW reduced apoptotic cell populations. In vivo, TGW reduced heart (n = 8~10, p < 0.01), and left ventricle weights (n = 6~7), cardiac hypertrophy markers (n = 3, p < 0.01), and perivascular fibrosis in ISO-induced mice, with Western blot analysis confirming decreased levels of fibrosis-related factors like fibronectin, α-SMA (n = 3, p < 0.05), and collagen type I (n = 3, p < 0.05). These findings suggest TGW has potential as a therapeutic option for cardiac hypertrophy and fibrosis. [ABSTRACT FROM AUTHOR]

Objective To investigate the efiect and mechanism of Jiawei Ditan Decoction on cardiomyocyte ierroptosis in rats with chronic intermittent hypoxia based on the phosphoinositide 3-kinase (PI3K) /protein kinase B ( Akt) signaling pathway. Methods Thirty 8-week-old male Sprague-Dawley rats were randomly divided into normal control, low-oxygen intervention, and Jiawei Ditan Decoction intervention groups using the random number table method, with 10 rats per group. The low-oxygen and Jiawei Ditan Decoction intervention groups were treated with intermittent hypoxia chamber for modeling, with 8 h of intervention daily. Gavage administration was performed before and after daily intervention. The intervention group received a dosage of 16. 38 g/kg Jiawei Ditan Decoction, whereas the other two groups received normal saline. The experimental intervention period was 12 weeks. Hematoxylin and eosin staining was used to observe the morphology of myocardial tissue. Transmission electron microscope was used to observe the mitochondrial ultrastructure in cardiomyocytes. Biochemical detection was used to measure the Fe2+ and malondialdehyde ( MDA ) content in myocardial tissue. Phosphorylated-phosphoinositide 3-kinase ( p-PI3K), PI3K, phosphorylated-protein kinase B ( p-Akt), Akt, solute carrier family 7 member 11 (SLC7A11), glutathione peroxidase 4 ( GPX4), nuclear factor erythroid 2-related factor 2 ( Nrf2), and acyl-coenzyme A synthetase long-chain family member 4 ( ACSL4) protein expression in myocardial tissue were measured using western blotting. The rat cardiomyocyte cell line, H9c2, was cultured in high glucose Dulbecco's Modified Eagle Medium, and the ultra-high-performance liquid chromatography was used to detect drug components in Jiawei Ditan Decoction. The CCK-8 assay was used to detect the cell survival rate of cells treated with different concentrations of Jiawei Ditan Decoction. The cells were divided into the normoxic, erastin, and erastin + Jiawei Ditan Decoction intervention groups, and p-Akt and GPX4 protein expression was measured using western blotting. p-PI3K and GPX4 protein expression were detected in the normoxic, low-oxygen intervention 12 h, and low-oxygen intervention 12 h + 740Y-P groups. The p-PI3K, PI3K, p-Akt, Akt, and GPX4 protein expression was detected in the normoxic, low-oxygen intervention 6 h, low-oxygen intervention 12 h, low-oxygen intervention 12 h + Jiawei Ditan Decoction low-dose, low-oxygen intervention 12 h + Jiawei Ditan Decoction medium-dose, and low-oxygen intervention 12 h + Jiawei Ditan Decoction high-dose groups (drug concentrations of 5, 10, and 20 g/L, respectively). Results The myocardial cells in the low-oxygen intervention group were disordered and swollen and the mitochondrial arrangement of myocardial cells was disordered, with increased mitochondrial membrane density, ruptured cristae, and vacudar degeneration compared with those in the normal control group. The myocardial cells in the Jiawei Ditan Decoction intervention group were arranged neater, and the morphology of mitochondria was relatively regular than those in the low-oxygen intervention group, and no apparent swelling was observed. Compared with the normal control group, the low-oxygen intervention group showed an increase in the MDA and Fe2+ content, a decrease in the p-PI3K/PI3K and p-Akt/Akt values, decreased SLC7A11, GPX4, and Nrf2 expression, and increased ACSL4 expression ( P <0.05). Compared with the low-oxygen intervention group, the Jiawei Ditan Decoction intervention group showed a decrease in MDA and Fe2+ content, an increase in the p-PI3K/PI3K and p-Akt/Akt values, increased SLC7A11, GPX4, and Nrf2 expression, and decreased ACSL4 expression ( P <0.05). Jiawei Ditan Decoction contained DL-stachydrine, D-( +) -malicacid, adenosine, etc. The cell survival rate of the 10. 00 g/L group increased (P<0.05) compared to that of the Jiawei Ditan Decoction 0, 1.25, 2.50, 5. 00, and 20. 00 g/L groups. Compared with the normoxic group, p-Akt and GPX4 expression decreased in the erastin group (P<0.05) ； compared with the erastin group, the erastin + Jiawei Ditan Decoction intervention group showed increased p-Akt and GPX4 expression ( P<0. 05). Compared with the normoxic group, p-PI3K and GPX4 expression decreased in the low-oxygen intervention 12 h group ( P<0. 01) ； compared with the low-oxygen intervention 12 h group, the low-oxygen intervention 12 h + 740Y-P group showed increased p-PI3K and GPX4 expression ( P<0. 05). Compared with the normoxic group, GPX4 expression and the p-Akt/Akt and p-PI3K/PI3K were reduced in the low-oxygen intervention 6 and 12 h groups ( P < 0. 05) ; compared with the low-oxygen intervention 6 h and 12 h groups, the p-PI3K/PI3K and p-Akt/Akt values increased in the low-oxygen intervention 12 h + Jiawei Ditan Decoction low, medium, and high-dose groups ( P<0. 05). GPX4 expression was also increased ( P<0. 05). Conclusion Jiawei Ditan Decoction may improve cardiomyocyte ierroptosis in rats by regulating the PI3K/Akt signaling pathway, thereby playing a protective role against chronic intermittent hypoxia-induced cardiac injury in rats. [ABSTRACT FROM AUTHOR]

Objective: Biallelic titin truncating variants (TTNtv) have been associated with a wide phenotypic spectrum, ranging from complex prenatal muscle diseases with dysmorphic features to adult‐onset limb‐girdle muscular dystrophy, with or without cardiac involvement. Given the size and complexity of TTN, reaching an unequivocal molecular diagnosis and precise disease prognosis remains challenging. Methods: In this case series, 12 unpublished cases and one already published case with biallelic TTNtv were collected from multiple international medical centers between November 2022 and September 2023. TTN mutations were detected through exome or genome sequencing. Information about familial and personal clinical history was collected in a standardized form. RNA‐sequencing and analysis of TTN exon usage were performed on an internal sample cohort including postnatal skeletal muscles, fetal skeletal muscles, postnatal heart muscles, and fetal heart muscles. In addition, publicly available RNA‐sequencing data was retrieved from ENCODE. Results: We generated new RNA‐seq data on TTN exons and identified genotype–phenotype correlations with prognostic implications for each titinopathy patient (whether worsening or improving in prenatal and postnatal life) using percentage spliced in (PSI) data for the involved exons. Interestingly, thanks to exon usage, we were also able to rule out a titinopathy diagnosis in one prenatal case. Interpretation: This study demonstrates that exon usage provides valuable insights for a more exhaustive clinical interpretation of TTNtv; additionally, it may serve as a model for implementing personalized medicine in many other genetic diseases, since most genes undergo alternative splicing. [ABSTRACT FROM AUTHOR]

Hutchinson‐Gilford progeria syndrome (HGPS) is a rare premature aging disorder resulting from de novo mutations in the lamin A gene. Children with HGPS typically pass away in their teenage years due to cardiovascular diseases such as atherosclerosis, myocardial infarction, heart failure, and stroke. In this study, we characterized the G608G HGPS mouse model and explored cardiac and skeletal muscle function, along with senescence‐associated phenotypes in fibroblasts. Homozygous G608G HGPS mice exhibited cardiac dysfunction, including decreased cardiac output and stroke volume, and impaired left ventricle relaxation. Additionally, skeletal muscle exhibited decreased isometric tetanic torque, muscle atrophy, and increased fibrosis. HGPS fibroblasts showed nuclear abnormalities, decreased proliferation, and increased expression of senescence markers. These findings provide insights into the pathophysiology of the G608G HGPS mouse model and inform potential therapeutic strategies for HGPS. [ABSTRACT FROM AUTHOR]

Left ventricular non-compaction (LVNC) is a rare heart muscle disease defined by the presence of prominent left ventricular trabeculation, deep intertrabecular recesses, and a thin compact layer. Several hypotheses have been proposed regarding its pathogenesis, with the most recently accepted one being that compact layer and trabeculated layers develop independently according to an "allometric growth". The current gold-standard diagnostic criteria (in particular, the Petersen index non-compaction/compaction ratio > 2.3) reflect an excess of myocardial trabeculation, which is not a specific morpho-functional feature of LVNC cardiomyopathy but merely a "phenotypic trait", even described in association with other myocardial disease and over-loading conditions. Accordingly, the European Society of Cardiology (ESC) guidelines have definitively abolished the term 'LVNC cardiomyopathy'. Recently, evolving perspectives led to the restoration of LVNC cardiomyopathy by distinguishing "hypertrabeculation phenotype" and "non-compaction phenotype". It has been proposed that the disease-specific pathophysiologic mechanism is a congenitally underdevelopment of the compact layer accounting for an impairment of the left ventricular systolic function. Future prospective research should focus on the clinical and prognostic relevance of compact layer thinning rather than excessive trabeculation, which could significantly influence the management of patients with LVNC. The review aims to update current knowledge on the pathogenesis, genetics, and diagnostic criteria of LVNC, offering modern insights for future perspectives. [ABSTRACT FROM AUTHOR]

The article claims that widely held views concerning interpretations of experimental observations on calcium handling in the heart are over simplified and may cause to miss opportunities for developing new therapeutic agents for heart failure and arrhythmias. It stresses the importance of additional experiments to clarify understanding of the mechanisms. It also discusses the actions of caffeine on cardiac myocytes.

Ca2+ release from the sarcoplasmic reticulum (SR) plays a central role in excitation-contraction coupling (ECC) in skeletal muscles. However, the mechanism by which activation of the voltage-sensors/dihydropyridine receptors (DHPRs) in the membrane of the transverse tubular system leads to activation of the Ca2+-release channels/ryanodine receptors (RyRs) in the SR is not fully understood. Recent observations showing that a very small Ca2+ leak through RyR1s in mammalian skeletal muscle can markedly raise the background [Ca2+] in the junctional space (JS) above the Ca2+ level in the bulk of the cytosol indicate that there is a diffusional barrier between the JS and the cytosol at large. Here, I use a mathematical model to explore the hypothesis that a sudden rise in Ca2+ leak through DHPR-coupled RyR1s, caused by reduced inhibition at the RyR1 Ca2+/Mg2+ inhibitory I1-sites when the associated DHPRs are activated, is sufficient to enable synchronized responses that trigger a regenerative rise of Ca2+ release that remains under voltage control. In this way, the characteristic response to Ca2+ of RyR channels is key not only for the Ca2+ release mechanism in cardiac muscle and other tissues, but also for the DHPRdependent Ca2+ release in skeletal muscle. [ABSTRACT FROM AUTHOR]

Myocarditis is a condition marked by inflammation of the heart muscle, which can lead to serious outcomes such as sudden cardiac death (SCD) and life-threatening arrhythmias. While myocarditis can affect any population, athletes, especially those engaged in high-intensity training, are at increased risk due to factors such as reduced immunity and increased exposure to pathogens. This review examines the clinical presentation, current guidelines, diagnostic challenges, and the significance of cardiac magnetic resonance imaging (CMR) in detecting myocardial inflammation and scarring. Current guidelines recommend a period of exercise restriction followed by thorough reassessment before athletes can return-to-play (RTP). However, there are several knowledge gaps, including the implications of persistent late gadolinium enhancement (LGE) on CMR and the optimal duration of exercise restriction. Additionally, the psychological impact of myocarditis on athletes highlights the importance of incorporating mental health support in the recovery process. A shared decision-making approach should be encouraged in RTP, considering the athlete's overall health, personal preferences, and the potential risks of resuming competitive sports. We have proposed an algorithm for RTP in athletes following myocarditis, incorporating CMR. Future research is warranted to refine RTP protocols and improve risk stratification, particularly through longitudinal studies that examine recovery and outcomes in athletes. [ABSTRACT FROM AUTHOR]

1. This study investigates the molecular mechanisms affecting brooding in Zhedong white geese by examining differences in reproductive endocrine levels, ovarian histology and transcriptomics. 2. Twenty 18-month-old Zhedong white geese were selected to examine their ovaries using histological, biochemical, molecular biological, and high-throughput sequencing techniques during the laying and brooding periods. 3. The results showed that the number of atretic follicles and apoptotic cells in the ovaries increased significantly (p < 0.05), the levels of follicle-stimulating hormone, luteinising hormone, gonadotropin-releasing hormone and oestradiol decreased significantly (p < 0.05), and the level of prolactin increased significantly (p < 0.01) during the brooding stage. 4. In broody geese, the expression of CASP3, CASP9, P53, BAX, and Cyt-c were considerably higher (p < 0.05), but BCL2 expression was significantly lower (p < 0.05). 5. In ovarian tissues, 260 differentially expressed lncRNAs, 13 differentially expressed miRNA and 60 differentially expressed mRNA were all discovered using transcriptome sequencing analysis. Functional enrichment analysis revealed that the differentially expressed mRNA and non-coding RNA target genes were primarily involved in ECM-receptor interaction, cell adhesion, cardiac muscle contraction, mTOR signalling, and the calcium signalling pathway. 6. In conclusion, follicular atrophy and apoptosis occurred in the ovaries and serum reproductive hormone levels were significantly changed during the brooding period of Zhedong white geese. COL3A1, COL1A2, GRIA1, RNF152, miR-192, and miR-194 may be important candidates for the regulation of brooding behaviour, with the mTOR signalling pathway playing a key role. [ABSTRACT FROM AUTHOR]

An additively stacked quasi-self-similarity Sierpinski Carpet-based fractal antenna embedded over a photonic band gap substrate is proposed in this paper. The proposed structure is designed for continuous in-vivo monitoring of cardiac Troponin I (cTnI) levels in the blood released from the heart muscles even with a trivial malfunction. The total size of the antenna biosensor is 0.4 λ0 × 0.33 λ0 × 0.025 λ0 and is assumed to be implanted over a leadless pacemaker. The substrate material used is Teflon (εr = 2.1) with gold as patch material to accomplish as bio-receptor. The frequency band of 0.1–3 Terahertz is considered for the design as per IEEE standard. Result validation without bio-model is performed through High Frequency Structural Simulator, Computer Simulation Technology, Advanced Design System, and COMSOL simulation software. The dielectric constant values of blood, myocardium, and other biological parameters are calculated based on the Cole–Cole model using Matrix Laboratory for further analysis. Those values are incorporated in the design to imitate a bio-model, to check the variation in frequency with regard to permittivity, in turn corresponding to troponin level change. [ABSTRACT FROM AUTHOR]

Using produced polyclonal antibodies specific to the N-terminal sequence (residues 61-298) of rat obscurin, we investigated the isoform composition of this protein in 4 striated muscles: myocardium of the left ventricle, diaphragm, skeletal m. gastrocnemius (containing mainly fast fibers), and m. soleus (containing mainly slow fibers). The m. gastrocnemius, m. soleus, and diaphragm were found to have 2 giant isoforms of obscurin: a smaller A-isoform and a larger B-isoform. Their molecular weights were ~870 and ~1150 kDa in the diaphragm and m. gastrocnemius and ~880 and ~1130 kDa in m. soleus, respectively. The B-isoform to A-isoform ratio was 1:3 in the diaphragm and m. soleus and 1:4 in the m. gastrocnemius. In the left-ventricular myocardium, A-isoform of obscurin with a molecular weight of ~880 kDa was found. No other obscurin isoforms or their fragments within the molecular weight range of 10 up to ~800 kDa were revealed in the investigated rat striated muscles. The antibodies produced are recommended for research into qualitative and quantitative changes of giant obscurin isoforms in rat striated muscles in the norm and during the development of pathological processes. [ABSTRACT FROM AUTHOR]

STEMI is a heart disease that completely blocks the coronary arteries so that oxygen does not enter the heart muscle. The aim of this research is to determine the description of nursing care in the implementation of Benson relaxation therapy to reduce pain intensity in STEMI patients. This research design uses a case study method. The sampling method used is purposive sampling. The samples taken were 2 respondents from STEMI patients. The instruments used were emergency assessment format, Benson relaxation therapy SOP, evaluation sheet, pain observation sheet. The results obtained from this research were found to reduce pain intensity in client I, namely from a pain scale of 7 to 6 and in client II from a pain scale of 6 to 1. Benson relaxation therapy is effective for STEMI sufferers to reduce pain intensity. [ABSTRACT FROM AUTHOR]