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This article focuses on screening the major secreted proteins by the ischemia-challenged cardiac stromal fibroblasts (CF), the assessment of their expression status and functional role in the post-ischemic left ventricle (LV) and in the ischemia-challenged CF culture and to phenotype CF at single cell resolution based on the positivity of the identified mediators. The expression level of CRSP2, HSP27, IL-8, Cofilin-1, and HSP90 in the LV tissues following coronary artery bypass graft (CABG) and myocardial infarction (MI) and CF cells followed the screening profile derived from the MS/MS findings. The histology data unveiled ECM disorganization, inflammation and fibrosis reflecting the ischemic pathology. CRSP2, HSP27, and HSP90 were significantly upregulated in the LV-CABG tissues with a concomitant reduction ion LV-MI whereas Cofilin-1, IL8, Nrf2, and Troponin I were downregulated in LV-CABG and increased in LV-MI. Similar trends were exhibited by ischemic CF. Single cell transcriptomics revealed multiple sub-phenotypes of CF based on their respective upregulation of CRSP2, HSP27, IL-8, Cofilin-1, HSP90, Troponin I and Nrf2 unveiling pathological and pro-healing phenotypes. Further investigations regarding the underlying signaling mechanisms and validation of sub-populations would offer novel translational avenues for the management of cardiac diseases.

The objective of this preclinical study was to evaluate the feasibility and safety of transcatheter endocardial alginate hydrogel injection (TEAi) in a large animal model, utilizing the high-stiffness XDROP® alginate hydrogel in combination with the dedicated EndoWings® catheter-based system. All swine (n = 9) successfully underwent TEAi without complications. Acute results from a subset of animals (n = 5) demonstrated the ability of the catheter to access a wide range of endomyocardial areas and achieve consecutive circumferential hydrogel distribution patterns within the mid-left ventricular wall. Histological examinations at 6 months (n = 4) demonstrated that the XDROP® remained localized within the cardiac tissue. In addition, serial echocardiographic imaging showed that XDROP® had no adverse impacts on LV systolic and diastolic functions. In conclusion, this innovative combination technology has the potential to overcome the translational barriers related to alginate hydrogel delivery to the myocardium.

BACKGROUND: Aging-associated left ventricular dysfunction promotes cardiopulmonary fibrogenic remodeling, Group 2 pulmonary hypertension (PH), and right ventricular failure. At the time of diagnosis, cardiac function has declined, and cardiopulmonary fibrosis has often developed. Here, we sought to develop a molecular positron emission tomography (PET)-magnetic resonance imaging (MRI) protocol to detect both cardiopulmonary fibrosis and fibrotic disease activity in a left ventricular dysfunction model. METHODS AND RESULTS: Left ventricular dysfunction was induced by transverse aortic constriction (TAC) in 6-month-old senescence-accelerated prone mice, a subset of mice that received sham surgery. Three weeks after surgery, mice underwent simultaneous PET-MRI at 4.7 T. Collagen-targeted PET and fibrogenesis magnetic resonance (MR) probes were intravenously administered. PET signal was computed as myocardium- or lung-to-muscle ratio. Percent signal intensity increase and Δ lung-to-muscle ratio were computed from the pre-/postinjection magnetic resonance images. Elevated allysine in the heart (P=0.02) and lungs (P=0.17) of TAC mice corresponded to an increase in myocardial magnetic resonance imaging percent signal intensity increase (P

The polymerization of myosin molecules into thick filaments in muscle sarcomeres is essential for cardiac contractility, with the attenuation of interactions between the heads of myosin molecules within the filaments being proposed to result in hypercontractility, as observed in hypertrophic cardiomyopathy (HCM). However, experimental evidence demonstrates that the structure of these giant macromolecular complexes is highly dynamic, with molecules exchanging between the filaments and a pool of soluble molecules on the minute timescale. Therefore, we sought to test the hypothesis that the enhancement of interactions between the heads of myosin molecules within thick filaments limits the mobility of myosin by taking advantage of mavacamten, a small molecule approved for the treatment of HCM. Myosin molecules were labeled in vivo with a green fluorescent protein (GFP) and imaged in intact hearts using multiphoton microscopy. Treatment of the intact hearts with mavacamten resulted in an unexpected > 5-fold enhancement in GFP-myosin mobility within the sarcomere. In vitro biochemical assays suggested that mavacamten enhanced the mobility of GFP-myosin by increasing the solubility of myosin molecules, through the stabilization of a compact/folded conformation of the molecules, once disassociated from the thick filaments. These findings provide alternative insight into the mechanisms by which molecules exchange into and out of thick filaments and have implications for how mavacamten may affect cardiac contractility.

The heart, which is the first organ to develop, is highly dependent on its form to function1,2. However, how diverse cardiac cell types spatially coordinate to create the complex morphological structures that are crucial for heart function remains unclear. Here we integrated single-cell RNA-sequencing with high-resolution multiplexed error-robust fluorescence in situ hybridization to resolve the identity of the cardiac cell types that develop the human heart. This approach also provided a spatial mapping of individual cells that enables illumination of their organization into cellular communities that form distinct cardiac structures. We discovered that many of these cardiac cell types further specified into subpopulations exclusive to specific communities, which support their specialization according to the cellular ecosystem and anatomical region. In particular, ventricular cardiomyocyte subpopulations displayed an unexpected complex laminar organization across the ventricular wall and formed, with other cell subpopulations, several cellular communities. Interrogating cell-cell interactions within these communities using in vivo conditional genetic mouse models and in vitro human pluripotent stem cell systems revealed multicellular signalling pathways that orchestrate the spatial organization of cardiac cell subpopulations during ventricular wall morphogenesis. These detailed findings into the cellular social interactions and specialization of cardiac cell types constructing and remodelling the human heart offer new insights into structural heart diseases and the engineering of complex multicellular tissues for human heart repair.

Calmodulin transduces [Ca2+] information regulating the rhythmic Ca2+ cycling between the sarcoplasmic reticulum and cytoplasm during contraction and relaxation in cardiac and skeletal muscle. However, the structural dynamics by which calmodulin modulates the sarcoplasmic reticulum Ca2+ release channel, the ryanodine receptor, at physiologically relevant [Ca2+] is unknown. Using fluorescence lifetime FRET, we resolve different structural states of calmodulin and Ca2+-driven shifts in the conformation of calmodulin bound to ryanodine receptor. Skeletal and cardiac ryanodine receptor isoforms show different calmodulin-ryanodine receptor conformations, as well as binding and structural kinetics with 0.2-ms resolution, which reflect different functional roles of calmodulin. These FRET methods provide insight into the physiological calmodulin-ryanodine receptor structural states, revealing additional distinct structural states that complement cryo-EM models that are based on less physiological conditions. This technology will drive future studies on pathological calmodulin-ryanodine receptor interactions and dynamics with other important ryanodine receptor bound modulators.

Cardiac dysfunction is a hallmark of aging in humans and mice. Here we report that a two-week treatment to restore youthful Bridging Integrator 1 (BIN1) levels in the hearts of 24-month-old mice rejuvenates cardiac function and substantially reverses the aging phenotype. Our data indicate that age-associated overexpression of BIN1 occurs alongside dysregulated endosomal recycling and disrupted trafficking of cardiac CaV1.2 and type 2 ryanodine receptors. These deficiencies affect channel function at rest and their upregulation during acute stress. In vivo echocardiography reveals reduced systolic function in old mice. BIN1 knockdown using an adeno-associated virus serotype 9 packaged shRNA-mBIN1 restores the nanoscale distribution and clustering plasticity of ryanodine receptors and recovers Ca2+ transient amplitudes and cardiac systolic function toward youthful levels. Enhanced systolic function correlates with increased phosphorylation of the myofilament protein cardiac myosin binding protein-C. These results reveal BIN1 knockdown as a novel therapeutic strategy to rejuvenate the aging myocardium.

This comprehensive review explores the critical role of fatty acid (FA) metabolism in cardiac diseases, particularly heart failure (HF), and the implications for therapeutic strategies. The heart's reliance on ATP, primarily sourced from mitochondrial oxidative metabolism, underscores the significance of metabolic flexibility, with fatty acid oxidation (FAO) being a dominant source. In HF, metabolic shifts occur with an altered FA uptake and FAO, impacting mitochondrial function and contributing to disease progression. Conditions like obesity and diabetes also lead to metabolic disturbances, resulting in cardiomyopathy marked by an over-reliance on FAO, mitochondrial dysfunction, and lipotoxicity. Therapeutic approaches targeting FA metabolism in cardiac diseases have evolved, focusing on inhibiting or stimulating FAO to optimize cardiac energetics. Strategies include using CPT1A inhibitors, using PPARα agonists, and enhancing mitochondrial biogenesis and function. However, the effectiveness varies, reflecting the complexity of metabolic remodeling in HF. Hence, treatment strategies should be individualized, considering that cardiac energy metabolism is intricate and tightly regulated. The therapeutic aim is to optimize overall metabolic function, recognizing the pivotal role of FAs and the need for further research to develop effective therapies, with promising new approaches targeting mitochondrial oxidative metabolism and FAO that improve cardiac function.

BACKGROUND: Becker muscular dystrophy is an X-linked, genetic disorder causing progressive degeneration of skeletal and cardiac muscle, with a widely variable phenotype. OBJECTIVE: A 3-year, longitudinal, prospective dataset contributed by patients with confirmed Becker muscular dystrophy was analyzed to characterize the natural history of this disorder. A better understanding of the natural history is crucial to rigorous therapeutic trials. METHODS: A cohort of 83 patients with Becker muscular dystrophy (5-75 years at baseline) were followed for up to 3 years with annual assessments. Muscle and pulmonary function outcomes were analyzed herein. Age-stratified statistical analysis and modeling were conducted to analyze cross-sectional data, time-to-event data, and longitudinal data to characterize these clinical outcomes. RESULTS: Deletion mutations of dystrophin exons 45-47 or 45-48 were most common. Subgroup analysis showed greater pairwise association between motor outcomes at baseline than association between these outcomes and age. Stronger correlations between outcomes for adults than for those under 18 years were also observed. Using cross-sectional binning analysis, a ceiling effect was seen for North Star Ambulatory Assessment but not for other functional outcomes. Longitudinal analysis showed a decline in percentage predicted forced vital capacity over the life span. There was relative stability or improved median function for motor functional outcomes through childhood and adolescence and decreasing function with age thereafter. CONCLUSIONS: There is variable progression of outcomes resulting in significant heterogeneity of the clinical phenotype of Becker muscular dystrophy. Disease progression is largely manifest in adulthood. There are implications for clinical trial design revealed by this longitudinal analysis of a Becker natural history dataset.

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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]

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]

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]

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]

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]

We examine stochastic phase models for the community effect of cardiac muscle cells. Our model extends the stochastic integrate-and-fire model by incorporating irreversibility after beating, induced beating, and refractoriness. We focus on investigating the expectation and variance in the synchronized beating interval. Specifically, for a single isolated cell, we obtain the closed-form expectation and variance in the beating interval, discovering that the coefficient of variation has an upper limit of 2 / 3 . For two coupled cells, we derive the partial differential equations for the expected synchronized beating intervals and the distribution density of phases. Furthermore, we consider the conventional Kuramoto model for both two- and N-cell models. We establish a new analysis using stochastic calculus to obtain the coefficient of variation in the synchronized beating interval, thereby improving upon existing literature. [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]

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]

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]

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]

Cardiac lymphatic vessels (LyVs) are suggested to be important players in cardiovascular disease-associated myocardial remodeling. However, there is a gap in the knowledge of whether LyV remodeling is an integral component of cardiac remodeling, especially in obesity associated with other comorbidities, including increased levels of circulating angiotensin II (Ang II). We studied the structural alterations in the myocardium and LyVs in Ang II-treated db/db mice compared with db/db mice and Ang II-treated wild-type mice with histopathological imaging methods, confocal microscopy, ultrastructural morphology, and morphometric analysis. We demonstrated that Ang II-treated db/db mice exhibited significantly increased fibrosis, cardiomyocyte hypertrophy, and local edema compared with untreated db/db mice; however, the cardiomyocyte hypertrophy was similar to that in Ang II-treated control mice. The decreased density of the LyVs and their wall shape alterations, with disorganized anchoring filaments, widened junctional gaps, decreased numbers of cytoplasmic vesicles indicative of a leaky phenotype, and increased basement membrane (BM) thickness, were observed in Ang II-treated db/db mice compared with Ang II-treated controls. Our findings revealed a structural basis for intensive LyV remodeling in association with cardiac remodeling in obesity. [ABSTRACT FROM AUTHOR]

Introduction and purpose: Ethanol is still one of the most frequently consumed drugs worldwide and is a strong risk factor for more than 60 illnesses including alcoholic cardiomyopathy which is a specific heart muscle disease caused by long-term excessive alcohol consumption. The review aims to gather available data and summarize it to give better understanding of the disease, to help select patients with the condition to implement proper treatment, and to present possible future directions as the incidence of the disease is projected to persist in the future. Brief description of the state of knowledge: Alcoholic cardiomyopathy (ACM) is characterized by dilation, increased mass of the left ventricle, and reduced ejection fraction leading to end-stage heart failure. It is caused by ethanol's direct toxicity on myocytes disturbing many different metabolic pathways. The result is a decrease in both systolic and diastolic function of the heart. The ACM development depends on factors such as genetics, gender, dietary factors and the dosage of ethanol consumption. The goal of the treatment is total alcohol abstinence, but the reduction of ethanol intake may also be beneficial. Patients should obtain a complete pharmacological treatment for heart failure. Summary: Ethanol overconsumption remains an unresolved problem, with the incidence of ACM projected to persist in the future, especially among patients with alcohol use disorder (AUD). Efforts for prevention, early detection, and effective treatment of ACM need to be established. A primary focus should be on treating AUD because it is the most effective way to halt the progression of the disease. Further research should focus on both asymptomatic and symptomatic patients with AUD to better define clinical manifestations, diagnostic approaches, and the most effective treatments for ACM. [ABSTRACT FROM AUTHOR]

Background and purpose Methods Results Conclusions Sparse information is available on the correct interpretation of elevated high‐sensitivity cardiac troponin (hs‐cTn) in confirmed muscular dystrophies.Serum concentrations of hs‐cTn T (hs‐cTnT) and hs‐cTn I (hs‐cTnI) were determined in 35 stable outpatients with confirmed skeletal muscle dystrophies. We calculated sensitivities, specificities, and positive and negative predictive values of hs‐cTnT and hs‐cTnI for identification of cardiac involvement using a comprehensive definition that included diastolic left ventricular and right ventricular function, strain analysis using two‐dimensional transthoracic echocardiogram and magnetic resonance imaging, myocardial biopsies, and consideration of a variety of triggers for cardiac injury, including arrhythmias, conduction disorders, and hypoxemia due to respiratory failure.Cardiac involvement was diagnosed in 34 of 35 cases. Specificities of hs‐cTnT increased from 12.5% to 100% (p = 0.0006) applying the comprehensive definition compared to a definition based on electrocardiography and echocardiography alone. At the recommended 99th percentile upper limit of normal, sensitivities were significantly lower for hs‐cTnI than for hs‐cTnT (29.4% vs. 100%, p = 0.0164). Conversely, the specificities of hs‐cTnT and hs‐cTnI increased to 100% when using the comprehensive definition criteria for diagnosing cardiac involvement.Elevated hs‐cTnT but not hs‐cTnI discriminates cardiac involvement in cases with confirmed skeletal muscle dystrophies with very high sensitivity and 100% specificity. Prior reports on worse performance may be explained by the use of less sensitive imaging methods or incomplete assessment of cardiac involvement. [ABSTRACT FROM AUTHOR]

Background: The recently introduced super-resolution (SR) deep learning image reconstruction (DLR) is potentially effective in reducing noise level and enhancing the spatial resolution. We aimed to investigate whether SR-DLR has advantages in the overall image quality and intensity homogeneity on coronary computed tomography (CT) angiography with four different approaches: filtered-back projection (FBP), hybrid iterative reconstruction (IR), DLR, and SR-DLR. Methods: Sixty-three patients (mean age, 61 ± 11 years; range, 18–81 years; 40 men) who had undergone coronary CT angiography between June and October 2022 were retrospectively included. Image noise, signal to noise ratio, and contrast to noise ratio were quantified in both proximal and distal segments of the major coronary arteries. The left ventricle myocardium contrast homogeneity was analyzed. Two independent reviewers scored overall image quality, image noise, image sharpness, and myocardial homogeneity. Results: Image noise in Hounsfield units (HU) was significantly lower (P < 0.001) for the SR-DLR (11.2 ± 2.0 HU) compared to those associated with other image reconstruction methods including FBP (30.5 ± 10.5 HU), hybrid IR (20.0 ± 5.4 HU), and DLR (14.2 ± 2.5 HU) in both proximal and distal segments. SR-DLR significantly improved signal to noise ratio and contrast to noise ratio in both the proximal and distal segments of the major coronary arteries. No significant difference was observed in the myocardial CT attenuation with SR-DLR among different segments of the left ventricle myocardium (P = 0.345). Conversely, FBP and hybrid IR resulted in inhomogeneous myocardial CT attenuation (P < 0.001). Two reviewers graded subjective image quality with SR-DLR higher than other image reconstruction techniques (P < 0.001). Conclusions: SR-DLR improved image quality, demonstrated clearer delineation of distal segments of coronary arteries, and was seemingly accurate for quantifying CT attenuation in the myocardium. [ABSTRACT FROM AUTHOR]

Computational simulations of cardiac electrophysiology provide detailed information on the depolarization phenomena at different spatial and temporal scales. With the development of new hardware and software, in silico experiments have gained more importance in cardiac electrophysiology research. For plane waves in healthy tissue, in vivo and in silico electrograms at the surface of the tissue demonstrate symmetric morphology and high peak-to-peak amplitude. Simulations provided insight into the factors that alter the morphology and amplitude of the electrograms. The situation is more complex in remodeled tissue with fibrotic infiltrations. Clinically, different changes including fractionation of the signal, extended duration and reduced amplitude have been described. In silico, numerous approaches have been proposed to represent the pathological changes on different spatial and functional scales. Different modeling approaches can reproduce distinct subsets of the clinically observed electrogram phenomena. This review provides an overview of how different modeling approaches to incorporate fibrotic and structural remodeling affect the electrogram and highlights open challenges to be addressed in future research. [ABSTRACT FROM AUTHOR]

Background: Diabetic cardiac muscle disease or diabetic cardiomyopathy (DbCM) comprises a set of myocardial lesions that are not associated with coronary atherosclerosis or high blood pressure. It is characterized by fibrosis and hypertrophy, which ultimately results in heart failure. Diastolic dysfunction (DD) has been shown to be the first manifestation of diabetic cardiomyopathy. Currently, there are few studies on the prevalence of diabetic cardiomyopathy in adult patients diagnosed with type 1 diabetes mellitus (T1D). Methods: The study included 75 adult participants who underwent an echocardiogram. Data on their comorbidities were collected from their medical records and biochemical parameters were analyzed in blood and urine samples. Results: We found that the prevalence of DbCM in our T1D population was more than one-third (34%), which exceeded the prevalence reported in studies with adolescents and that reported in the population without diabetes. Also, we found that the probability of developing DD after 20 years of T1D diagnosis was 78%. Conclusions: Recommendations need to be issued in relation to diabetic cardiomyopathy to carry out secondary prevention in adult patients with T1D. More multicenter studies, which include a larger population, from different regions of the world need to be performed. [ABSTRACT FROM AUTHOR]

Simple Summary: Contrast-enhanced computed tomography (CT) is the standard radiologic examination for evaluating mediastinal tumors. In equivocal cases, cine magnetic resonance imaging (cine-MRI) and magnetic resonance imaging (MRI)/T1-weighted spin echo sequences (T1TSE) may be additionally performed. We retrospectively analyzed patients undergoing surgical resection of mediastinal tumors (benign and malignant) with prior CT, cine-MRI, and T1TSE for (re-)evaluation and comparison to the intraoperative findings and postoperative histology reports, which were defined as a gold standard. Unclear CT cases were further investigated. A total of 47 patients were included in the study. Cine-MRI is of crucial benefit in unclear CT findings compared with T1TSE, especially when infiltration into the large central vessels and atria is suspected. Background/Objectives: Contrast-enhanced computed tomography (CT) is the standard radiologic examination for evaluating the extent of mediastinal tumors. If tumor infiltration into the large central thoracic vessels, the pericardium, or the myocardium is suspected, cine magnetic resonance imaging (cine-MRI) can provide additional valuable information. Methods: We conducted a retrospective study of patients with mediastinal tumors who were staged with CT, cine-MRI, and a T1-weighted turbo spin echo (T1TSE) prior to surgical resection. Imaging was re-evaluated regarding tumor infiltration into the pericardium, myocardium, superior vena cava, aorta, pulmonary arteries, and atria and compared with intraoperative findings and postoperative histopathological reports (gold standard). Unclear CT findings were further investigated. Results: Forty-seven patients (29 female and 18 male patients; median age: 58 years) met the inclusion criteria. Cine-MRI was able to predict infiltration of the aorta in 86%, pulmonary arteries in 85%, and atria in 80% of unclear CT cases. Aortic tumor infiltration in unclear CT cases was significantly more often correctly diagnosed with cine-MRI than with T1TSE sequence. Conclusions: Additional cine-MRI is of crucial benefit in unclear CT cases. We recommend performing cine-MRI if infiltration into the large central vessels and atria is suspected. T1TSE sequence is of very limited additional value. [ABSTRACT FROM AUTHOR]

Cancer cachexia manifests as whole body wasting, however, the precise mechanisms governing the alterations in skeletal muscle and cardiac anabolism have yet to be fully elucidated. In this study, we explored changes in anabolic processes in both skeletal and cardiac muscles in the Yoshida AH‐130 ascites hepatoma model of cancer cachexia. AH‐130 tumor‐bearing rats experienced significant losses in body weight, skeletal muscle, and heart mass. Skeletal and cardiac muscle loss was associated with decreased ribosomal (r)RNA, and hypophosphorylation of the eukaryotic factor 4E binding protein 1. Endoplasmic reticulum stress was evident by higher activating transcription factor mRNA in skeletal muscle and growth arrest and DNA damage‐inducible protein (GADD)34 mRNA in both skeletal and cardiac muscles. Tumors provoked an increase in tissue expression of interferon‐γ in the heart, while an increase in interleukin‐1β mRNA was apparent in both skeletal and cardiac muscles. We conclude that compromised skeletal muscle and heart mass in the Yoshida AH‐130 ascites hepatoma model involves a marked reduction translational capacity and efficiency. Furthermore, our observations suggest that endoplasmic reticulum stress and tissue production of pro‐inflammatory factors may play a role in the development of skeletal and cardiac muscle wasting. [ABSTRACT FROM AUTHOR]

Omecamtiv mecarbil (OM) is a small molecule that has been shown to improve the function of the slow human ventricular myosin (MyHC) motor through a complex perturbation of the thin/thick filament regulatory state of the sarcomere mediated by binding to myosin allosteric sites coupled to inorganic phosphate (Pi) release. Here, myofibrils from samples of human left ventricle (β-slow MyHC-7) and left atrium (α-fast MyHC-6) from healthy donors were used to study the differential effects of μmolar [OM] on isometric force in relaxing conditions (pCa 9.0) and at maximal (pCa 4.5) or half-maximal (pCa 5.75) calcium activation, both under control conditions (15 °C; equimolar DMSO; contaminant inorganic phosphate [Pi] ~170 μM) and in the presence of 5 mM [Pi]. The activation state and OM concentration within the contractile lattice were rapidly altered by fast solution switching, demonstrating that the effect of OM was rapid and fully reversible with dose-dependent and myosin isoform-dependent features. In MyHC-7 ventricular myofibrils, OM increased submaximal and maximal Ca2+-activated isometric force with a complex dose-dependent effect peaking (40% increase) at 0.5 μM, whereas in MyHC-6 atrial myofibrils, it had no effect or—at concentrations above 5 µM—decreased the maximum Ca2+-activated force. In both ventricular and atrial myofibrils, OM strongly depressed the kinetics of force development and relaxation up to 90% at 10 μM [OM] and reduced the inhibition of force by inorganic phosphate. Interestingly, in the ventricle, but not in the atrium, OM induced a large dose-dependent Ca2+-independent force development and an increase in basal ATPase that were abolished by the presence of millimolar inorganic phosphate, consistent with the hypothesis that the widely reported Ca2+-sensitising effect of OM may be coupled to a change in the state of the thick filaments that resembles the on–off regulation of thin filaments by Ca2+. The complexity of this scenario may help to understand the disappointing results of clinical trials testing OM as inotropic support in systolic heart failure compared with currently available inotropic drugs that alter the calcium signalling cascade. [ABSTRACT FROM AUTHOR]

Introduction: Duchenne muscular dystrophy is a genetic X-linked recessive disorder. This condition is characterized by progressive loss of muscle tissue. Thus, it results in deterioration and inability to perform basic motor skills such as independent movement or breathing. Due to progressive muscle weakness, patients with advanced stages of DMD require mechanical ventilation, feeding, and rehabilitation. Furthermore, alterations in cardiac muscle lead to cardiomyopathy. Despite advanced supportive treatment, DMD is a fatal disease. Purpose: The aim of the paper is to present, using a case study description, the current standards of treatment for patients with Duchenne muscular dystrophy as well as the current state of knowledge and new discoveries regarding this medical condition. Material and methods The patient's medical records were analyzed and available literature in PubMed was reviewed to write this article using the keywords: „Duchenne muscular dystrophy"; „cardiomyopathy"; „mechanical ventilation"; „gene therapy"; Conclusions Early detection of respiratory and circulatory insufficiency improves the patient's quality of life. Many patients with an advanced stage of Duchenne muscular dystrophy need specialized treatment, for example, in the intensive care unit. Therefore there is an urgent need for new treatment methods, such as gene therapies, which can slow down or break the course of the disease. New discoveries and the implementation of new treatment standards can enhance the quality of life for patients and extend their lifespans. [ABSTRACT FROM AUTHOR]

Heart failure, the leading cause of mortality and morbidity in the developed world, is characterized by cardiac ryanodine receptor 2 channels that are hyperphosphorylated, oxidized, and depleted of the stabilizing subunit calstabin-2. This results in a diastolic sarcoplasmic reticulum Ca2+ leak that impairs cardiac contractility and triggers arrhythmias. Genetic mutations in ryanodine receptor 2 can also cause Ca2+ leak, leading to arrhythmias and sudden cardiac death. Here, we solved the cryogenic electron microscopy structures of ryanodine receptor 2 variants linked either to heart failure or inherited sudden cardiac death. All are in the primed state, part way between closed and open. Binding of Rycal drugs to ryanodine receptor 2 channels reverts the primed state back towards the closed state, decreasing Ca2+ leak, improving cardiac function, and preventing arrhythmias. We propose a structural-physiological mechanism whereby the ryanodine receptor 2 channel primed state underlies the arrhythmias in heart failure and arrhythmogenic disorders. Ryanodine receptors type 2 (RyR2) are essential for cardiac muscle excitation-contraction coupling. Here, authors show that preferred conformations of RyR2 variants linked either to heart failure or inherited sudden cardiac death are similar, suggesting a common cause and potential treatment. [ABSTRACT FROM AUTHOR]

Neonatal dilated cardiomyopathy (DCM) is a poorly understood muscular disease of the heart. Several homozygous biallelic variants in LMOD2, the gene encoding the actin-binding protein Leiomodin 2, have been identified to result in severe DCM. Collectively, LMOD2-related cardiomyopathies present with cardiac dilation and decreased heart contractility, often resulting in neonatal death. Thus, it is evident that Lmod2 is essential to normal human cardiac muscle function. This study aimed to understand the underlying pathophysiology and signaling pathways related to the first reported LMOD2 variant (c.1193 G > A, p.Trp398*). Using patient-specific human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and a mouse model harboring the homologous mutation to the patient, we discovered dysregulated actin-thin filament lengths, altered contractility and calcium handling properties, as well as alterations in the serum response factor (SRF)-dependent signaling pathway. These findings reveal that LMOD2 may be regulating SRF activity in an actin-dependent manner and provide a potential new strategy for the development of biologically active molecules to target LMOD2-related cardiomyopathies. [ABSTRACT FROM AUTHOR]

Dilated cardiomyopathy (DCM) is an inherited disorder often leading to severe heart failure. Linkage studies in affected families have revealed hundreds of different mutations that can cause DCM, with most occurring in genes associated with the cardiac sarcomere. We have developed an investigational pipeline for discovering mechanistic genotype-phenotype relationships in DCM and here apply it to the DCM-linked tropomyosin mutation TPM1 M8R. Atomistic simulations predict that M8R increases flexibility of the tropomyosin chain and enhances affinity for the blocked or inactive state of tropomyosin on actin. Applying these molecular effects to a Markov model of the cardiac thin filament reproduced the shifts in Ca2+sensitivity, maximum force, and a qualitative drop in cooperativity that were observed in an in vitro system containing TPM1 M8R. The model was then used to simulate the impact of M8R expression on twitch contractions of intact cardiac muscle, predicting that M8R would reduce peak force and duration of contraction in a dose-dependent manner. To evaluate this prediction, TPM1 M8R was expressed via adenovirus in human engineered heart tissues and isometric twitch force was observed. The mutant tissues manifested depressed contractility and twitch duration that agreed in detail with model predictions. Additional exploratory simulations suggest that M8R-mediated alterations in tropomyosin-actin interactions contribute more potently than tropomyosin chain stiffness to cardiac twitch dysfunction, and presumably to the ultimate manifestation of DCM. This study is an example of the growing potential for successful in silico prediction of mutation pathogenicity for inherited cardiac muscle disorders. [ABSTRACT FROM AUTHOR]

Background: Due to the lack of oestrogen, premature ovarian insufficiency (POI) is an independent risk factor for ischaemic heart disease and overall cardiovascular disease. This study aimed to apply layer-specific myocardial strain for early quantitative evaluation of subclinical left ventricular myocardial systolic function changes in patients with POI. Methods: Forty-eight newly diagnosed, untreated patients with POI (POI group) and fifty healthy female subjects matched for age, height and weight (control group) were enrolled. Standard transthoracic echocardiography was used to measure conventional parameters and layer-specific strain parameters.The layer-specific strain parameters included subendomyocardial global longitudinal strain (GLSendo), mid-layer myocardial global longitudinal strain (GLSmid), subepimyocardial global longitudinal strain (GLSepi), subendomyocardial global circumferential strain (GCSendo), mid-layer myocardial global circumferential strain (GCSmid), and subepimyocardial global circumferential strain (GCSepi). Results: There were no significant differences in age, body mass index (BMI), blood pressure, or left ventricular ejection fraction (LVEF) between the two groups. The end-diastolic interventricular septal thickness (IVST) was greater in the POI group (8.29 ± 1.32 vs. 7.66 ± 0.82, P = 0.008), and the POI group had lower E, E/A, and lateral e′ (all P < 0.05). As for systolic functions,the POI group had lower GLSendo, GLSmid, GLSepi, GCSendo, GCSmid, and GCSepi (all P < 0.05).The intraobserver and interobserver coefficients of GLSendo, GLSmid, GLSepi, GCSendo, GCSmid, and GCSepi were greater than 0.900. Conclusions: POI patients with normal LVEF may suffer from subclinical left ventricular myocardial systolic dysfunction. Echocardiography of layer-specific myocardial strain could more sensitively detect subclinical impairment of left ventricular systolic function in POI patients. [ABSTRACT FROM AUTHOR]

The electrocardiogram (ECG) is a fundamental and widely used tool for diagnosing cardiovascular diseases. It involves recording cardiac electrical signals using electrodes, which illustrate the functioning of cardiac muscles during contraction and relaxation phases. ECG is instrumental in identifying abnormal cardiac activity, heart attacks, and various cardiac conditions. Arrhythmia detection, a critical aspect of ECG analysis, entails accurately classifying heartbeats. However, ECG signal analysis demands a high level of expertise, introducing the possibility of human errors in interpretation. Hence, there is a clear need for robust automated detection techniques. Recently, numerous methods have emerged for arrhythmia detection from ECG signals. In our research, we developed a novel one‐dimensional deep neural network technique called linear deep convolutional neural network (LDCNN) to identify arrhythmias from ECG signals. We compare our suggested method with several state‐of‐the‐art algorithms for arrhythmia detection. We evaluate our methodology using benchmark datasets, including the PTB Diagnostic ECG and MIT‐BIH Arrhythmia databases. Our proposed method achieves high accuracy rates of 99.24% on the PTB Diagnostic ECG dataset and 99.38% on the MIT‐BIH Arrhythmia dataset. [ABSTRACT FROM AUTHOR]

Myocarditis is an inflammatory disease that may lead to dilated cardiomyopathy. Viral infection of the myocardium triggers immune responses, which involve, among others, macrophage infiltration, oxidative stress, expression of pro-inflammatory cytokines, and microRNAs (miRNAs). The cardioprotective role of estrogen in myocarditis is well documented; however, sex differences in the miRNA expression in chronic myocarditis are still poorly understood, and studying them further was the aim of the present study. Male and female ABY/SnJ mice were infected with CVB3. Twenty-eight days later, cardiac tissue from both infected and control mice was used for real-time PCR and Western blot analysis. NFκB, IL-6, iNOS, TNF-α, IL-1β, MCP-1, c-fos, and osteopontin (OPN) were used to examine the inflammatory state in the heart. Furthermore, the expression of several inflammation- and remodeling-related miRNAs was analyzed. NFκB, IL-6, TNF-α, IL-1β, iNOS, and MCP-1 were significantly upregulated in male mice with CVB3-induced chronic myocarditis, whereas OPN mRNA expression was increased only in females. Further analysis revealed downregulation of some anti-inflammatory miRNA in male hearts (let7a), with upregulation in female hearts (let7b). In addition, dysregulation of remodeling-related miRNAs (miR27b and mir199a) in a sex-dependent manner was observed. Taken together, the results of the present study suggest a sex-specific expression of pro-inflammatory markers as well as inflammation- and remodeling-related miRNAs, with a higher pro-inflammatory response in male CVB3 myocarditis mice. [ABSTRACT FROM AUTHOR]

Over 50% of patients who take statins are still at risk of developing atherosclerotic cardiovascular disease (ASCVD) and do not achieve their goal LDL-C levels. This residual risk is largely dependent on triglyceride-rich lipoproteins (TRL) and their remnants. In essence, remnant cholesterol-rich chylomicron (CM) and very-low-density lipoprotein (VLDL) particles play a role in atherogenesis. These remnants increase when lipoprotein lipase (LPL) activity is inhibited. ApoCIII has been thoroughly studied as a chief inhibitor and therapeutic options to curb its effect are available. On top of apoCIII regulation of LPL activity, there is a more precise control of LPL in various tissues, which makes it easier to physiologically divide the TRL burden according to the body's requirements. In general, oxidative tissues such as skeletal and cardiac muscle preferentially take up lipids during fasting. Conversely, LPL activity in adipocytes increases significantly after feeding, while its activity in oxidative tissues decreases concurrently. This perspective addresses the recent improvements in our understanding of circadian LPL regulations and their therapeutic implications. Three major tissue-specific lipolysis regulators have been identified: ANGPTL3, ANGPTL4, and ANGPTL8. Briefly, during the postprandial phase, liver ANGPTL8 acts on ANGPTL3 (which is released continuously from the liver) to inhibit LPL in the heart and muscle through an endocrine mechanism. On the other hand, when fasting, ANGPTL4, which is released by adipocytes, inhibits lipoprotein lipase in adipose tissue in a paracrine manner. ANGPTL3 inhibitors may play a therapeutic role in the treatment of hypertriglyceridemia. Several approaches are under development. We look forward to future studies to clarify (a) the nature of hormonal and nutritional factors that determine ANGPTL3, 4, and 8 activities, along with what long-term impacts may be expected if their regulation is impaired pharmacologically; (b) the understanding of the quantitative hierarchy and interaction of the regulatory actions of apoCIII, apoAV, and ANGPTL on LPL activity; (c) strategies for the safe and proper treatment of postprandial lipemia; and (d) the effect of fructose restriction on ANGPTL3, ANGPTL4, and ANGPTL8. [ABSTRACT FROM AUTHOR]

The number of structural aortic valve procedures has increased significantly in recent years. Pre-procedural planning and follow-up with noninvasive testing are essential. Although cardiac magnetic resonance (CMR) is the gold standard for assessing left ventricular mass, volume, and function, it is not performed routinely in patients undergoing structural interventions. CMR can provide useful information for pre- and post-procedural assessment, including quantification of cardiac function, myocardial assessment, grading of the severity of valvular heart disease, and evaluation of extracardiac anatomy while avoiding the limitations of other non-invasive modalities. Here, we review the use cases, future perspectives, and limitations of CMR for patients undergoing structural aortic valve procedures. [ABSTRACT FROM AUTHOR]

Introduction: The term "acute myocardial infarction" (AMI) describes the destruction of heart muscle tissue brought on by ischemia, or the lack of oxygen to the heart's tissue. Aim: To investigate the correlation between serum levels of homocysteine, uric acid, and C-reactive protein in patients diagnosed with acute myocardial infarction (AMI). Methods: A total of 60 patients with AMI were enrolled in this study. After recruitment, detailed history was recorded and physical examination of subjects was carried out. A serum sample, used to determine the homocysteine, uric acid concentrations and other general biochemical assays, was obtained with one anticoagulant-free 7.5 mL test tube. Other biochemical assays were performed and CRP (mg/L) was measured. Subjects were grouped according to Killip classification. Results: In present study, mean Homocysteine (umol/l) in Killip class I was 4.86±2.01, in class II was 5.97±2.30, in class III was 8.44±4.73 and in class IV was 13.47±6.12 (p <0.01). Mean uric acid (mg/dl) in Killip class I was 2.13±1.81, in class II was 2.54±1.74, in class III was 3.65±1.11 and in class IV was 4.51±1.07 (p <0.01). Mean C-Reactive Protein (mg/l) in Killip class I was 0.72±0.57, in class II was 1.61±0.88, in class III was 5.96±3.03 and in class IV was 8.75±4.84, (p value <0.01). A statistically significant correlation was found between Homocysteine & Uric acid level with Coefficient of correlation being 0.58 ( p value <0.01) ; between Homocysteine & C-Reactive Protein level with Coefficient of correlation being 0.43 (p=0.002) ; between Uric acid & C-Reactive Protein level with Coefficient of correlation being 0.41 (p value=0.005). Conclusion: The study found a significant correlation between blood levels of C-Reactive Protein (CRP), Uric acid, and Homocysteine with Killip classification in patients with Acute Myocardial Infarction. As the Killip classification stages progressed, the levels of these biomarkers also increased. There was a positive and statistically significant correlation between Homocysteine and Uric acid levels, Homocysteine and CRP levels, as well as Uric acid and CRP levels. These findings suggest that since these biomarkers are involved in Myocardial Infarction, monitoring their serum levels together could be beneficial for evaluating and managing these patients. [ABSTRACT FROM AUTHOR]

BACKGROUND: Ischemia/reperfusion injury is one of the most challenging postoperative situations in vascular surgery, both in elective procedures with prolonged clamping time and in delayed emergency cases with vascular occlusion. The inflammatory response that develops during ischemia and the oxygen-free radicals that proliferate during reperfusion have detrimental effects on the brain, heart, and kidneys. In this study, we aimed to compare the effects of vanillic and rosmarinic acid in preventing ischemia/reperfusion injury in a lower limb ischemia-reperfusion model in rats. METHODS: Thirty-two female Sprague-Dawley rats weighing 185-240 g were randomly divided into four groups of eight animals each. Group 1 was designated as the control, Group 2 as ischemia/reperfusion (I/R), Group 3 as ischemia/reperfusion + vanillic acid (I/R + VA), and Group 4 as ischemia/reperfusion + rosmarinic acid (I/R + RA). In all groups except the control, the infrarenal abdominal aorta was clamped, and 60 minutes of ischemia followed by 120 minutes of reperfusion was performed. Vanillic acid was administered intra-abdominally 15 minutes before the start of reperfusion in Group 3, and rosmarinic acid in Group 4. At the end of the reperfusion phase, blood samples and hearts were collected, and the rats were euthanized. Histopathologically, myofibrillar edema, myocytolysis, focal hemorrhages, and infiltration of polymorphonuclear leukocytes (PMNL) in cardiac tissue were examined. Total antioxidant capacity (TAC), total oxidative status (TOS), oxidative stress index (OSI), 8-OH-deoxyguanosine, lactonase, and arylesterase activity were measured in blood samples. RESULTS: Myofibrillar edema was most pronounced in the I/R group and less pronounced in the I/R + VA and I/R + RA groups (p=0.005 and p=0.066, respectively). There was no difference between the ischemia/reperfusion groups regarding myocytolysis, focal hemorrhage, and PMNL infiltration (p>0.99). Among all groups, TOS and OSI were lowest in the control group, while TAC was highest. TAC was similar in the I/R + VA and I/R + RA groups but was significantly higher in these two groups than in the I/R group. The lactonase activity in the I/R + VA group was similar to that in the control group but was significantly higher compared to the I/R and I/R + RA groups. CONCLUSION: Our study shows that vanillic and rosmarinic acids reduce myofibrillar edema in the heart after lower limb ischemia and increase TAC. However, vanillic acid increases the activity of lactonase, an enzyme known for its antioxidant effect, more than rosmarinic acid. [ABSTRACT FROM AUTHOR]

Despite scientific efforts, there is no cure for Duchenne muscular dystrophy (DMD), a lethal, progressive, X-linked genetic disorder caused by mutations in the dystrophin gene. DMD leads to cardiac and skeletal muscle weakness, resulting in premature death due to cardio-pulmonary complications. We have developed Dystrophin Expressing Chimeric (DEC) cell therapy, DT-DEC01, by fusing human myoblasts from healthy donors and from DMD patients. Preclinical studies on human DEC cells showed increased dystrophin expression and improved cardiac, pulmonary, and skeletal muscle function after intraosseous administration. Our clinical study confirmed the safety and efficacy of DT-DEC01 therapy up to 24 months post-administration. In this study, we conducted in vitro assays to test the composition and potency of DT-DEC01, assessing chimerism level and the presence of dystrophin, desmin, and myosin heavy chain. Myoblast fusion resulted in the transfer of healthy donor mitochondria and the creation of chimeric mitochondria within DT-DEC01. The Pappenheim assay confirmed myotube formation in the final product. This study highlights the unique properties of DT-DEC01 therapy and their relevance to DMD treatment mechanisms. [ABSTRACT FROM AUTHOR]

Myocardial perfusion imaging (MPI) with single photon emission computed tomography is an established non-invasive technique for assessing myocardial ischemia. This method involves the intravenous administration of a radiopharmaceutical that accumulates in the heart muscle proportional to regional blood flow. However, image quality and diagnostic accuracy can be compromised by various technical and patient-related factors, including high non-specific radiopharmaceutical uptake in abdominal organs such as the stomach, intestines, liver, and gall-bladder, leading to subdiaphragmatic artifacts. These artifacts are particularly problematic for evaluating inferior wall perfusion and often necessitate repeated imaging, which decreases gamma camera availability and prolongs imaging times. Despite numerous investigated techniques to reduce interfering gastrointestinal activity, results have been inconsistent, and current MPI guidelines provide scant information on effective procedures to mitigate this issue. Based on our experience, some possible approaches to reducing artifacts include choosing stress testing with an exercise stress test, when possible, late imaging, fluid intake, and consuming carbonated water immediately before imaging. [ABSTRACT FROM AUTHOR]

The vulnerability of cownose rays (Rhinoptera bonasus) to anthropogenic pressures, such as overfishing and habitat degradation, necessitates urgent and comprehensive conservation efforts to ensure the species' survival and maintain the marine ecosystem balance. In this study, six cownose rays, acquired post-mortem from a public aquarium, were meticulously examined under controlled laboratory conditions. Through the PCR targeting of the housekeeping genes and subsequent sequencing, gene fragments were concatenated into a 2022-bp sequence deposited in the PubMLST database. PCR and sequence analyses identified two distinct Vibrio isolates, labeled as gv9 and gv10, which by MLSA analysis were shown to be closely related to Vibrio atlanticus and Vibrio rotiferianus. A novel sequence type, ST 247, was identified, suggesting allelic differences compared to 60 closely related Vibrio species. Despite the absence of external lesions, internal examination revealed muscular, uterine, cardiac and endometrial hemorrhage, valvular intestinal dilatation, uterine pus accumulation, and pyometra. Histopathological examination demonstrated hemorrhage in the heart muscle, an increased number of microglial cells in the brain and severe vacuolar degeneration in the liver. This study provides insight into the intricate association between cownose rays and Vibrio bacteria, as well as the potential role of these bacteria in the pathologies observed. [ABSTRACT FROM AUTHOR]

Mammals have limited capacity for heart regeneration, whereas zebrafish have extraordinary regeneration abilities. During zebrafish heart regeneration, endothelial cells promote cardiomyocyte cell cycle reentry and myocardial repair, but the mechanisms responsible for promoting an injury microenvironment conducive to regeneration remain incompletely defined. Here, we identify the matrix metalloproteinase Mmp14b as an essential regulator of heart regeneration. We identify a TEAD-dependent mmp14b endothelial enhancer induced by heart injury in zebrafish and mice, and we show that the enhancer is required for regeneration, supporting a role for Hippo signaling upstream of mmp14b. Last, we show that MMP-14 function in mice is important for the accumulation of Agrin, an essential regulator of neonatal mouse heart regeneration. These findings reveal mechanisms for extracellular matrix remodeling that promote heart regeneration.

Abstract 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 (

AIMS: Acute myocardial infarction (MI) causes inflammation, collagen deposition, and reparative fibrosis in response to myocyte death and, subsequently, a pathological myocardial remodelling process characterized by excessive interstitial fibrosis, driving heart failure (HF). Nonetheless, how or when to limit excessive fibrosis for therapeutic purposes remains uncertain. Galectin-3, a major mediator of organ fibrosis, promotes cardiac fibrosis and remodelling. We performed a preclinical assessment of a protein inhibitor of galectin-3 (its C-terminal domain, Gal-3C) to limit excessive fibrosis resulting from MI and prevent ventricular enlargement and HF. METHODS AND RESULTS: Gal-3C was produced by enzymatic cleavage of full-length galectin-3 or by direct expression of the truncated form in Escherichia coli. Gal-3C was intravenously administered for 7 days in acute MI models of young and aged rats, starting either pre-MI or 4 days post-MI. Echocardiography, haemodynamics, histology, and molecular and cellular analyses were performed to assess post-MI cardiac functionality and pathological fibrotic progression. Gal-3C profoundly benefitted left ventricular ejection fraction, end-systolic and end-diastolic volumes, haemodynamic parameters, infarct scar size, and interstitial fibrosis, with better therapeutic efficacy than losartan and spironolactone monotherapies over the 56-day study. Gal-3C therapy in post-MI aged rats substantially improved pump function and attenuated ventricular dilation, preventing progressive HF. Gal-3C in vitro treatment of M2-polarized macrophage-like cells reduced their M2-phenotypic expression of arginase-1 and interleukin-10. Gal-3C inhibited M2 polarization of cardiac macrophages during reparative response post-MI. Gal-3C impeded progressive fibrosis post-MI by down-regulating galectin-3-mediated profibrotic signalling cascades including a reduction in endogenous arginase-1 and inducible nitric oxide synthase (iNOS). CONCLUSION: Gal-3C treatment improved long-term cardiac function post-MI by reduction in the wound-healing response, and inhibition of inflammatory fibrogenic signalling to avert an augmentation of fibrosis in the periinfarct region. Thus, Gal-3C treatment prevented the infarcted heart from extensive fibrosis that accelerates the development of HF, providing a potential targeted therapy.

ObjectiveFeline hypertrophic cardiomyopathy (HCM) remains a disease with little therapeutic advancement. Rapamycin modulates the mTOR pathway, preventing and reversing cardiac hypertrophy in rodent disease models. Its use in human renal allograft patients is associated with reduced cardiac wall thickness. We sought to evaluate the effects of once-weekly delayed-release (DR) rapamycin over 6 months on echocardiographic, biochemical, and biomarker responses in cats with subclinical, nonobstructive HCM.Animals43 client-owned cats with subclinical HCM.MethodsCats enrolled in this double-blinded, multicentered, randomized, and placebo-controlled clinical trial were allocated to low- or high-dose DR rapamycin or placebo. Cats underwent physical examination, quality-of-life assessment, blood pressure, hematology, biochemistry, total T4, urinalysis, N-terminal pro-B-type natriuretic peptide, and cardiac troponin I at baseline and days 60, 120, and 180. Fructosamine was analyzed at screening and day 180. Echocardiograms were performed at all time points excluding day 120. Outcome variables were compared using a repeated measures ANCOVA.ResultsNo demographic, echocardiographic, or clinicopathologic values were significantly different between study groups at baseline, confirming successful randomization. At day 180, the primary study outcome variable, maximum LV myocardial wall thickness at any location, was significantly lower in the low-dose DR rapamycin group compared to placebo (P = .01). Oral DR rapamycin was well tolerated with no significant differences in adverse events between groups.Clinical relevanceResults demonstrate that DR rapamycin was well tolerated and may prevent or delay progressive LV hypertrophy in cats with subclinical HCM. Additional studies are warranted to confirm and further characterize these results.