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Myocardial infarction (MI) results in aberrant cardiac metabolism, but no therapeutics have been designed to target cardiac metabolism to enhance heart repair. We engineer a humanized monoclonal antibody against the ectonucleotidase ENPP1 (hENPP1mAb) that targets metabolic crosstalk in the infarcted heart. In mice expressing human ENPP1, systemic administration of hENPP1mAb metabolically reprograms myocytes and non-myocytes and leads to a significant rescue of post-MI heart dysfunction. Using metabolomics, single-nuclear transcriptomics, and cellular respiration studies, we show that the administration of the hENPP1mAb induces organ-wide metabolic and transcriptional reprogramming of the heart that enhances myocyte cellular respiration and decreases cell death and fibrosis in the infarcted heart. Biodistribution and safety studies showed specific organ-wide distribution with the antibody being well tolerated. In humanized animals, with drug clearance kinetics similar to humans, we demonstrate that a single "shot" of the hENPP1mAb after MI is sufficient to rescue cardiac dysfunction.

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.

Lipoprotein lipase (LPL) and multiple regulators of LPL activity (e.g., APOC2 and ANGPTL4) are present in all vertebrates, but GPIHBP1-the endothelial cell (EC) protein that captures LPL within the subendothelial spaces and transports it to its site of action in the capillary lumen-is present in mammals but in not chickens or other lower vertebrates. In mammals, GPIHBP1 deficiency causes severe hypertriglyceridemia, but chickens maintain low triglyceride levels despite the absence of GPIHBP1. To understand intravascular lipolysis in lower vertebrates, we examined LPL expression in mouse and chicken hearts. In both species, LPL was abundant on capillaries, but the distribution of Lpl transcripts was strikingly different. In mouse hearts, Lpl transcripts were extremely abundant in cardiomyocytes but were barely detectable in capillary ECs. In chicken hearts, Lpl transcripts were absent in cardiomyocytes but abundant in capillary ECs. In zebrafish hearts, lpl transcripts were also in capillary ECs but not cardiomyocytes. In both mouse and chicken hearts, LPL was present, as judged by immunogold electron microscopy, in the glycocalyx of capillary ECs. Thus, mammals produce LPL in cardiomyocytes and rely on GPIHBP1 to transport the LPL into capillaries, whereas lower vertebrates produce LPL directly in capillary ECs, rendering an LPL transporter unnecessary.

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

Acute myocarditis (AM) is an inflammatory disease of the heart muscle that can progress to fulminant myocarditis (FM), a severe and life-threatening condition. The cytokine profile of myocarditis in children, especially in relation to fulminant myocarditis, is not well understood. This study aims to evaluate the cytokine profiles of acute and fulminant myocarditis in children. Pediatric patients diagnosed with myocarditis were included in the study. Cytokine levels were measured using a multiplexed fluorescent bead-based immunoassay. Statistical analysis was performed to compare patient characteristics and cytokine levels between FM, AM, and healthy control (HC) groups. Principal component analysis (PCA) was applied to cytokine groups that were independent among the FM, AM, and HC groups. The study included 22 patients with FM and 14 with AM patients. We identified four cytokines that were significantly higher in the FM group compared to the AM group: IL1-RA (p = 0.002), IL-8 (p = 0.005), IL-10 (p = 0.011), and IL-15 (p = 0.005). IL-4 was significantly higher in the AM group compared to FM and HC groups (p = 0.006 and 0.0015). PDGF-AA, and VEGF-A were significantly lower in the FM group than in the AM group (p = 0.013 and <0.001). Similar results were obtained in PCA. Cytokine profiles might be used to differentiate pediatric FM from AM, stratify severity, and predict prognosis. The targeted therapy that works individual cytokines might provide a potential treatment for reducing the onset of the FM and calming the condition, and further studies are needed. [ABSTRACT FROM AUTHOR]

Background: Telocytes (TCs) are small interstitial cells that extend into multiple bead-like protrusions called telopodes (TPs). TCs are widely found in many tissues and organs, form connections with almost all types of cardiomyocytes, and participate in regulating cardiac microenvironment homeostasis. Methods: In this study, transmission electron microscopy combined with special staining techniques (Gomori's, Masson's trichrome, and toluidine blue staining) were used to analyse the ultrastructure, distribution, and cytochemical characteristics of TCs in yak hearts. Immunohistochemistry and immunofluorescence double staining techniques were combined to identify the immunophenotypic characteristics of TCs functional markers (CD34, CD117, PDGFR-α and α-SMA) and further reveal their potential functions. Results: The results showed that the TCs in the aortic bulb of yak hearts had prominent nuclei, and thin, long TPs with abundant secretory vesicles. TCs in the myocardial tissue exhibited irregularly shaped nuclei, shorter TPs, and connections with myocardial fibres and adjacent capillaries, forming a complex TC network. Immunohistochemical results demonstrated the positive expression of functional markers CD34, CD117, α-SMA and PDGFR-α in both the aortic bulb and myocardium. Immunofluorescence double staining results indicated co-expression of CD34/CD117, CD34/α-SMA, and CD117/PDGFR-α in TCs. Conclusion: This is the first study to report the presence of TCs in the aortic bulb and myocardium of yak hearts and that it may form TC networks that mainly participate in mechanical support and cell communication in the heart. The presence and distribution characteristics of TCs in the heart of yaks provide important clues for further research on the role of TC networks in the adaptability of plateau animals to the environment. [ABSTRACT FROM AUTHOR]

Cardiomyopathies are primary disorders of the heart muscle. Three key phenotypes have been defined, based on morphology and arrhythmia burden: hypertrophic cardiomyopathy (HCM), with thickened heart muscle and diastolic dysfunction; dilated cardiomyopathy (DCM), with left ventricular enlargement and systolic dysfunction; and arrhythmogenic cardiomyopathy (ACM), with right, left, or biventricular involvement and arrhythmias out of proportion to systolic dysfunction. Genetic discoveries of the molecular basis of disease are paving the way for greater precision in diagnosis and management and revealing mechanisms that account for distinguishing clinical features. This deeper understanding has propelled the development of new treatments for cardiomyopathies: disease-specific, mechanistically based medicines that counteract pathophysiology, and emergent gene therapies that aim to intercept disease progression and restore cardiac physiology. Together, these discoveries have advanced fundamental insights into cardiac biology and herald a new era for patients with cardiomyopathy. Research on the molecular genetic basis for cardiomyopathies, primary heart muscle disorders, has made significant progress in the past decades. This article reviews current understanding of the genetic underpinnings of inherited cardiomyopathies and discusses future therapeutic opportunities. [ABSTRACT FROM AUTHOR]

Background: The increased myocardial vulnerability that occurs in diabetic patients following an ischemia-reperfusion injury (I/RI) represents a significant perioperative safety risk. A comprehensive understanding of the intrinsic mechanisms underlying this phenomenon is therefore of paramount importance. Purposes: The objective of this study is to investigate the potential mechanism of action between impaired autophagic flux and increased vulnerability in diabetic myocardium. This will provide a foundation for the clinical search for effective preventive and curative measures. Methods: The transcriptomic alterations in autophagy-related genes following myocardial exposure to I/RI were analyzed by single-cell sequencing. This was followed by the validation of potential mechanisms of action between impaired autophagic flux and increased susceptibility at the cellular and animal levels, respectively. Results: After I/RI in diabetic myocardium, there was a significant increase in the number of CM1 subgroups and a specific downregulation of 239 autophagy-related genes led by RILP. HE staining revealed that myocardial injury was exacerbated in diabetic mice subjected to I/RI. Transmission electron microscopy revealed that the accumulation of autophagic vesicles in cardiomyocytes of diabetic mice resulted in impaired autophagic flux. qRT-PCR revealed that the expression of RILP was significantly reduced in diabetic mice subjected to I/RI. WB showed that P62 was significantly increased and RILP was significantly decreased in diabetic mice subjected to I/RI compared to healthy mice. Inhibition of mTOR during hypoxia/reoxygenation (H/R) injury restored RILP expression and attenuated cellular injury in cardiomyocytes cultured with high glucose. Conclusion: Following I/RI in diabetic myocardium, an increase in the CM1 subpopulation and a reduction in RILP expression result in impaired autophagic flux. Regulation of the mTOR/RILP pathway can restore impaired autophagic flux and improve myocardial vulnerability, thereby exerting cardioprotective effects. [ABSTRACT FROM AUTHOR]

Atrial fibrillation (AF) poses a serious health threat to human health and causes various adverse effects. It is currently the most common type of arrhythmia in adults. Long-term AF induces a series of heart-remodeling events, including mainly cardiac structural remodeling and electrical remodeling, which further exacerbates AF. The oxidative stress has been shown to play a role in inducing myocardial remodeling and the progression of AF. Recent studies have shown that ferroptosis occurs in the myocardium of patients with AF, which exacerbates oxidative stress and may constitute a new mechanism for the progression of AF. However, it is unknown to us how ferroptosis is involved in the initiation and maintenance of AF, so the purpose of this review is to elucidate the possible underlying mechanism of ferroptosis exacerbating AF. We reviewed the latest studies on myocardial ferroptosis and AF and speculate that the lipid peroxidation products isolevuglandins (IsoLGs), which are produced during myocardial ferroptosis, may be involved in the progression of AF through two pathways: (1) IsoLGs inhibit the degradation of myocardial collagen, worsening myocardial fibrosis; and (2) IsoLGs promote the occurrence of amyloidosis in the myocardium and increase the risk of AF. Consequently, we aim to prevent the progression of atrial fibrillation by either suppressing the production of IsoLGs or enhancing their clearance process to inhibit ferroptosis in the myocardium, improving the prognosis of patients with AF. [ABSTRACT FROM AUTHOR]

The study was conducted during July to October, 2020 at the Department of Veterinary Anatomy, College of Veterinary Science and Animal Husbandry, Nanaji Deshmukh Veterinary Science University, Jabalpur, Madhya Pradesh, India to investigate the histological and histochemical features of the hearts of 18 prenatal healthy goats (Capra hircus). The heart shape varied among the groups; groups I and II exhibited an ovoid shape, while group III had a flattened cone shape. Histological examinations revealed both superficial and deep cardiac muscle fibers in the atrial walls, forming muscular arches in the atrium. The ventricular myocardium was composed of three distinct layers of muscle fibers, with the middle layer being the thickest. The left ventricular wall was significantly thicker than the right. The cardiac valves were identified as endocardial flaps. Histochemical analysis showed that collagen and elastic fibers were more abundant in the atria than in the ventricles, with collagen primarily surrounding blood vessels. Reticular fibers formed networks in both the atria and ventricles. A weak to moderate periodic acid- Schiff (PAS) reaction was observed in the atria, ventricles, blood vessels, and atrioventricular cusps. Metachromasia was noted in both the atria and ventricles. Additionally, DNA content in atrial nuclei exhibited moderate staining across all age groups. These findings provide a detailed histological and histochemical description of prenatal goat heart development, contributing to the understanding of fetal cardiovascular maturation. [ABSTRACT FROM AUTHOR]

Adeno-associated viral (AAV) vectors are increasingly used for preclinical and clinical cardiac gene therapy approaches. However, gene transfer to cardiomyocytes poses a challenge due to differences between AAV serotypes in terms of expression efficiency in vitro and in vivo. For example, AAV9 vectors work well in rodent heart muscle cells in vivo but not in cultivated neonatal rat ventricular cardiomyocytes (NRVCMs), necessitating the use of AAV6 vectors for in vitro studies. Therefore, we aimed to develop an AAV that could efficiently express genes in NRVCMs, human engineered heart tissue (hEHT), and mammalian hearts. The production of AAV6 vectors results in lower yields compared with AAV9. Hence, we used random AAV9 peptide libraries and selected variants on NRVCMs at the vector genome and RNA levels in parallel. The enriched library variants were characterized using high-throughput analysis of barcoded variants, followed by individual validation of the most promising candidates. Interestingly, we found striking differences in NRVCM transduction and gene expression patterns of the AAV capsid variants depending on the selection strategy. AAV variants selected based on the vector genome level enabled the highest transduction but were outperformed by AAVs selected on the RNA level in terms of expression efficiency. In addition, we identified a new AAV9 capsid variant that not only allowed significantly higher gene expression in NRVCMs compared with AAV6 but also enabled similar gene expression in murine hearts as AAV9 wild-type vectors after being intravenously injected into mice. Moreover, the novel variant facilitated significantly higher gene expression in hEHT compared with AAV9. Therefore, this AAV variant could streamline preclinical gene therapy studies of myocardial diseases by eliminating the need for using different AAVs for NRVCMs, hEHT, and mice. [ABSTRACT FROM AUTHOR]

Both continuous aerobic training (CAT) and high-intensity interval training (HIIT) are recommended to promote health and prevent diseases. Exercise-induced circulating extracellular vesicles (EX-EVs) have been suggested to play essential roles in mediating organ crosstalk, but corresponding molecular mechanisms remain unclear. To assess and compare the systemic effects of CAT and HIIT, five healthy male volunteers were assigned to HIIT and CAT, with a 7-day interval between sessions. Plasma EVs were collected at rest or immediately after each training section, prior to proteomics and miRNA profile analysis. We found that the differentially expressed (DE) miRNAs in EX-EVs were largely involved in the regulation of transcriptional factors, while most of the DE proteins in EX-EVs were identified as non-secreted proteins. Both CAT and HIIT play common roles in neuronal signal transduction, autophagy, and cell fate regulation. Specifically, CAT showed distinct roles in cognitive function and substrate metabolism, while HIIT was more associated with organ growth, cardiac muscle function, and insulin signaling pathways. Interestingly, the miR-379 cluster within EX-EVs was specifically regulated by HIIT, involving several biological functions, including neuroactive ligand–receptor interaction. Furthermore, EX-EVs likely originate from various tissues, including metabolic tissues, the immune system, and the nervous system. Our study provides molecular insights into the effects of CAT and HIIT, shedding light on the roles of EX-EVs in mediating organ crosstalk and health promotion. [ABSTRACT FROM AUTHOR]

Left ventricular hypertrabeculation is one of the most debated conditions in modern cardiology. Many studies have tried to characterise this disease by addressing the various clinical risks and diagnostic tools, but its very nosological existence is currently being challenged. The latest ESC guidelines on cardiomyopathies state that it should be addressed as a morphologic trait rather than an intrinsic disease of the cardiac muscle. Despite the huge number of diagnostic criteria and possible phenocopies, no specific consensus identifies a specific flowchart regarding the management of patients with suspected hypertrabeculation. This review aims to provide a clinical approach for patients with a phenotypical appearance of excessive trabeculation. [ABSTRACT FROM AUTHOR]

We propose a coupled electrical and mechanical bidomain model for the myocardium tissue. The structure that we investigate possesses an elastic matrix with embedded cardiac myocytes. We are able to apply the asymptotic homogenization technique by exploiting the length scale separation that exists between the microscale where we see the individual myocytes and the overall size of the heart muscle. We derive the macroscale model which describes the electrical conductivity and elastic deformation of the myocardium driven by the existence of a Lorentz body force. The model comprises balance equations for the current densities and for the stresses, with the novel coefficients accounting for the difference in the electric potentials and elastic properties at different points in the microstructure. The novel coefficients of the model are to be computed by solving the periodic cell differential problems arising from application of the asymptotic homogenization technique. By combining both the mechanical and electrical behaviors, we obtain a macroscale model that highlights how the elastic deformation of the heart tissue is influenced and driven by the difference in the electric potentials at various points in the material. [ABSTRACT FROM AUTHOR]

Doxorubicin (Dox) is an effective and commonly used anticancer drug; however, it leads to several side effects including cardiotoxicity which contributes to poor quality of life for cancer patients. Creatine (Cr) is a promising intervention to alleviate Dox-induced cardiotoxicity. This study aimed to examine the effects of Cr beforeDox on cardiac mitochondrial creatine kinase (MtCK). Male rats were randomly assigned to one of two 4-week Cr feeding interventions (standard Cr diet or Cr loading diet) or a control diet (Con, n = 20). Rats in the standard Cr diet (Cr1, n = 20) were fed 2% Cr for 4-weeks. Rats in the Cr loading diet (Cr2, n = 20) were fed 4% Cr for 1-week followed by 2% Cr for 3-weeks. After 4-weeks, rats received either a bolus injection of 15 mg/kg Dox or a placebo saline injection (Sal). Five days post-injections left ventricle (LV) was excised and analyzed for MtCK expression using Western blot and ELISA. A significant drug effect was observed for LV mass (p < 0.05), post hoc testing revealed LV mass of Con + Dox and Cr2 + Dox was significantly lower than Con + Sal (p < 0.05). A significant drug effect was observed for MtCK (p = 0.03) through Western blot. A significant drug effect (p = 0.03) and interaction (p = 0.02) was observed for MtCK using ELISA. Post hoc testing revealed that Cr2 + Dox had significantly higher MtCK than Cr1 + Sal and Cr2 + Sal. Data suggest that a reduction in LV mass and MtCK may contribute to Dox-induced cardiotoxicity, and Cr supplementation may play a potential role in mitigating cardiotoxicity by preserving mitochondrial CK. [ABSTRACT FROM AUTHOR]

Background: Alpha-actinin-2, a protein with high expression in cardiac and skeletal muscle, is located in the Z-disc and plays a key role in sarcomere stability. Mutations in ACTN2 have been associated with both hypertrophic and dilated cardiomyopathy and, more recently, with skeletal myopathy. Methods: Genetic, clinical, and muscle imaging data were collected from 37 patients with an autosomal dominant ACTN2 myopathy belonging to 11 families from Spain and Belgium. Haplotypes were studied to confirm a common ancestry for the two most common recurrent variants identified in this study. A trained machine learning model was used to compare muscle MRI scans in ACTN2 myopathy with other neuromuscular diseases to identify a specific pattern of muscle involvement. Results: The clinical phenotype ranged from asymptomatic to limb-girdle weakness and facial involvement and was depending on genotype. Cardiac and respiratory involvement were not common. Belgian families carrying the p.Ile134Asn variant and Basque-Spanish families carrying the p.Cys487Arg variant each showed unique haplotypes supporting respective common ancestry. Available muscle biopsies showed non-specific changes. In muscle imaging, the most affected muscles were the glutei minor, glutei medius, hamstrings, tibialis anterior, and soleus. A machine learning model showed that the most differentiating features in dominant ACTN2 myopathy were the involvement of the tibialis anterior and gluteus medius muscles and preservation of the quadratus femoris, gastrocnemius lateralis, and tensor fasciae latae muscles. Conclusion: We provide new insights into genetic, clinical, and muscle imaging characteristics of non-congenital dominant ACTN2 myopathy, broadening the phenotypic spectrum of muscle disorders caused by ACTN2 variants. [ABSTRACT FROM AUTHOR]

Aims Quantification of cardiac [99mTc]-3,3-diphosphono-1,2-propanodicarboxylic acid (DPD) uptake enhances diagnostic capabilities and may facilitate prognostic stratification in patients with transthyretin cardiac amyloidosis (ATTR-CA). This study aimed to evaluate the association of quantitative left ventricular (LV) DPD uptake with myocardial structure and function, and their implications on outcome in ATTR-CA. Methods and results Consecutive ATTR-CA patients (n = 100) undergoing planar DPD scintigraphy with Perugini grade 2 or 3, alongside quantitative DPD single-photon emission computed tomography/computed tomography imaging and speckle-tracking echocardiography between 2019 and 2023, were included and divided into two cohorts based on median DPD retention index (low DPD uptake: ≤5.4, n = 50; high DPD uptake: >5.4, n = 50). The DPD retention index showed significant, albeit weak to modest, correlations with LV global longitudinal strain (LV-GLS: r = 0.366, P < 0.001), right ventricular free wall longitudinal strain (RV-FW-LS: r = 0.316, P = 0.002), LV diastolic function (E/e′ average: r = 0.304, P = 0.013), NT-proBNP (r = 0.332, P < 0.001), troponin T (r = 0.233, P = 0.022), 6 min walk distance (6MWD: r = −0.222, P = 0.033), and National Amyloidosis Centre (NAC) stage (r = 0.294, P = 0.003). ATTR-CA patients in the high DPD uptake cohort demonstrated more advanced disease severity regarding longitudinal cardiac function (LV-GLS: P = 0.012, RV-FW-LS: P = 0.036), LV diastolic function (E/e′ average: P = 0.035), cardiac biomarkers (NT-proBNP: P = 0.012, troponin T: P = 0.044), exercise capacity (6MWD: P = 0.035), and disease stage (NAC stage I: P = 0.045, III: P = 0.006), and experienced adverse outcomes compared with the low DPD uptake cohort [composite endpoint: all-cause death or heart failure hospitalization, HR: 2.873 (95% CI: 1.439–5.737), P = 0.003; DPD retention index: adjusted HR 1.221 (95% CI: 1.078–1.383), P = 0.002]. Conclusion In ATTR-CA, enhanced quantitative LV DPD uptake indicates advanced disease severity and is associated with adverse outcome. DPD quantification may facilitate prognostic stratification when diagnosing patients with ATTR-CA. [ABSTRACT FROM AUTHOR]

Aims Myocardial disarray, an early feature of hypertrophic cardiomyopathy (HCM) and a substrate for ventricular arrhythmia, is poorly characterized in pre-hypertrophic sarcomeric variant carriers (SARC+LVH−). Using diffusion tensor cardiac magnetic resonance (DT-CMR) we assessed myocardial disarray and fibrosis in both SARC+LVH− and HCM patients and evaluated the relationship between microstructural alterations and electrocardiographic (ECG) parameters associated with arrhythmic risk. Methods and results Sixty-two individuals (24 SARC+LVH−, 24 HCM, and 14 matched controls) were evaluated with multi-parametric CMR including stimulated echo acquisition mode DT-CMR, and blinded quantitative 12-lead ECG analysis. Mean diastolic fractional anisotropy (FA) was reduced in HCM compared with SARC+LVH− and controls (0.49 ± 0.05 vs. 0.52 ± 0.04 vs. 0.53 ± 0.04, P = 0.009), even after adjustment for differences in extracellular volume (ECV) (P = 0.038). Both HCM and SARC+LVH− had segments with significantly reduced diastolic FA relative to controls (54 vs. 25 vs. 0%, P = 0.002). Multiple repolarization parameters were prolonged in HCM and SARC+LVH−, with corrected JT interval (JTc) being most significant (354 ± 42 vs. 356 ± 26 vs. 314 ± 26 ms, P = 0.002). Among SARC+LVH−, JTc duration correlated negatively with mean diastolic FA (r = −0.6, P = 0.002). In HCM, the JTc interval showed a stronger association with ECV (r = 0.6 P = 0.019) than with mean diastolic FA (r = −0.1 P = 0.72). JTc discriminated SARC+LVH− from controls [area under the receiver operator curve 0.88, confidence interval 0.76–1.00, P < 0.001], and in HCM correlated with the European Society of Cardiology HCM sudden cardiac death risk score (r = 0.5, P = 0.014). Conclusion Low diastolic FA, suggestive of myocardial disarray, is present in both SARC+LVH− and HCM. Low FA and raised ECV were associated with repolarization prolongation. Myocardial disarray assessment using DT-CMR and repolarization parameters such as the JTc interval demonstrate significant potential as markers of disease activity in HCM. [ABSTRACT FROM AUTHOR]

Every heartbeat depends on cyclical contraction-relaxation produced by the interactions between myosin-containing thick and actin-based thin filaments (TFs) arranged into a crystalline-like lattice in the cardiac sarcomere. Therefore, the maintenance of thin filament length is crucial for myocardium function. The thin filament is comprised of an actin backbone, the regulatory troponin complex and tropomyosin that controls interactions between thick and thin filaments. Thin filament length is controlled by the tropomodulin family of proteins; tropomodulin caps pointed ends of thin filaments, and leiomodin (Lmod) promotes elongation of thin filaments by a "leaky-cap" mechanism. The broader distribution of Lmod on the thin filament implied to the possibility of its interaction with the sides of thin filaments. Here, we use biochemical and structural approaches to show that cardiac Lmod (Lmod2) binds to a specific region on the native cardiac thin filament in a Ca2+-dependent manner. We demonstrate that Lmod2's unique C-terminal extension is required for binding to the thin filament actin backbone and suggest that interactions with the troponin complex assist Lmod2's localization on the surface of thin filaments. We propose that Lmod2 regulates the length of cardiac thin filaments in a working myocardium by protecting newly formed thin filament units during systole and promoting actin polymerization at thin filament pointed ends during diastole. Maintenance of the length of actin-based thin filaments in the human heart is crucial for myocardium function, but the mechanisms underlying this process remain unclear. Here, the authors show that cardiac leiomodin regulates the length of thin filaments by protecting newly formed filament units during systole and promoting actin polymerisation during diastole. [ABSTRACT FROM AUTHOR]

AbstractCreatine has demosntrated protective effects against muscle dysfunction, but its potential protection against doxorubicin-induced cardio and skeletal muscle toxicity remains poorly understood. We aimed to investigate the protective effects of creatine supplementation against doxorubicin-induced cardio and skeletal muscle myotoxicity. This study analyzed twenty male C57BL/6J mice, divided into three groups: Control (C; n = 6), Dox (n = 7) which received weekly doxorubicin injections (16 mg/kg i.p. in 20 days) and DoxCr (n = 7) with both doxorubicin and creatine supplementation (4%). Doxorubicin administration induced skeletal muscle atrophy in extensor digitorum longus (EDL) (-28%) and soleus muscles (-17%), accompanied by a decline in muscle strength. This atrophic response was concomitant with increased oxidative stress and elevated levels of IL-6. Cardiotoxic effects of doxorubicin were marked by a 15% reduction in cardiac mass and a significant 21% decrease in cardiomyocyte diameter, alongside a substantial 58% rise in IL-6 levels. On the opposite creatine supplementation mitigated doxorubicin-induced oxidative stress (elevated MDA and IL-6, and reduced GSH/GSSG ratio) and prevented skeletal muscle atrophy in both the EDL and soleus muscles, while also enhancing muscle strength. However, protective effects were not observed in cardiac muscle. Creatine protects skeletal, but not cardiac muscle against doxorubicin-induced toxicity, atrophy and strength loss. [ABSTRACT FROM AUTHOR]

Background: Heart muscle damage from myocardial infarction (MI) is brought on by insufficient blood flow. The leading cause of death for middle-aged and older people worldwide is myocardial infarction (MI), which is difficult to diagnose because it has no symptoms. Clinicians must evaluate electrocardiography (ECG) signals to diagnose MI, which is difficult and prone to observer bias. To be effective in actual practice, an automated, and computerized detection system for Myocardial Infarction using ECG images, must meet a number of criteria. Objective: In an actual clinical situation, these requirements—such as dependability, simplicity, and superior decision-making abilities—remain crucial. In the current work, we have developed a model using a dataset that consists of a combination of 928 ECG images taken from publicly available Mendeley Data. It was converted into three classes Myocardial Infarction, Abnormal heartbeat, and Normal. Methods: The dataset is then imported, pre-processed, and split into a 70:20:10 ratio of training, validation, and testing. It is then trained using the Siamese Network Model. Results: The classification accuracy comes out to be 98%. The algorithm works excellently with datasets having class imbalance by taking pair of images as input. The validation and testing classification matrix is then generated and the evaluation metrics for both of them come out to be a near-perfect value. Conclusion: In this study, we developed the ECG signals based early detection of cardiovascular diseases with Siamese network model. [ABSTRACT FROM AUTHOR]

Primary mitochondrial disorders are most often caused by deleterious mutations in the mitochondrial DNA (mtDNA). Here, we used a mitochondrial DddA-derived cytosine base editor (DdCBE) to introduce a compensatory edit in a mouse model that carries the pathological mutation in the mitochondrial transfer RNA (tRNA) alanine (mt-tRNAAla) gene. Because the original m.5024C→T mutation (G→A in the mt-tRNAAla) destabilizes the mt-tRNAAla aminoacyl stem, we designed a compensatory m.5081G→A edit (C→T in the mt-tRNAAla) that could restore the secondary structure of the tRNAAla aminoacyl stem. For this, the DdCBE gene construct was initially tested in an m.5024C→T mutant cell line. The reduced mt-tRNAAla amounts in these cells were increased after editing up to 78% of the mtDNA. Then, DdCBE was packaged in recombinant adeno-associated virus 9 (AAV9) and intravenously administered by retro-orbital injections into mice. Expression of the transduced DdCBE was observed in the heart and skeletal muscle. Total mt-tRNAAla amounts were restored in heart and muscle by the m.5081G→A edit in a dose-dependent manner. Lactate amounts, which were increased in the heart, were also decreased in treated mice. However, the highest dose tested of AAV9-DdCBE also induced severe adverse effects in vivo because of the extensive mtDNA off-target editing that it generated. These results show that although DdCBE is a promising gene therapy tool for mitochondrial disorders, the doses of the therapeutic constructs must be carefully monitored to avoid deleterious off-target editing. Editor's summary: Mitochondrial disorders are inherited and often linked to mitochondrial DNA (mtDNA) mutations. Pathologically mutated mtDNA can cause diverse physiological dysfunction that is limited to palliative care. Barrera-Paez et al. used a mitochondrial DddA-derived cytosine base editor (DdCBE) to correct a mutation in the mtDNA encoding a mitochondrial transfer RNA (tRNA) alanine. The mutation disrupted the aminoacyl stem of the tRNA. Correction with DdCBE restored the structure and amounts of the tRNA in cell culture and in mouse heart and muscle tissue. Mice carrying the mtDNA mutation had low mitochondrial tRNA alanine and increased lactate in heart, and editing with DdCBE reversed these abnormalities. At the highest amounts of editing, DdCBE also induced off-target edits that resulted in severe adverse effects in mice. These data suggest that while DdCBE is a promising therapeutic avenue for mitochondrial gene editing, caution and further study are warranted to avoid damaging off-target effects. —Brandon Berry [ABSTRACT FROM AUTHOR]

Objective: miRNA, circRNA, and lncRNA play crucial roles in the pathogenesis and progression of myocardial ischemia-reperfusion injury (MI/RI). This study aims to provide valuable insights into miRNA, circRNA, lncRNA, and MI/RI from a bibliometric standpoint, with the goal of fostering further advancements in this area. Methods: The relevant literature in the field of miRNA, circRNA, lncRNA, and MI/RI was retrieved from the Science Citation Index Expanded (SCI-E) database within Web of Science. The "Analyze Results" and "Citation Report" functions in WOS were utilized to compile the annual publication and citation counts in this field. Microsoft Office Excel 2019 was used to organize and visualize the data. Furthermore, bibliometric and visualization analyses of countries/regions, institutions, authors, keywords, and references were conducted using the bibliometric visualization software CiteSpace. Results: A total of 858 publications were included for further analysis in this field. The literature was published across 297 journals, with Molecular Medicine Reports contributing the highest number of publications. Researchers from 45 countries participated in studies within this field, with those from China contributing the most publications. The research hotspots in this field primarily focus on three areas: the role of miRNA, circRNA, and lncRNA in the pathogenesis of MI/RI, their potential as therapeutic targets, and their role as biomarkers. Among these, circular RNA, therapy target, inflammatory response, and cardiomyocyte ferroptosis are likely to emerge as emerging trends in this field. Conclusion: The overall development of research in this field is on the rise. The compilation of research hotspots and emerging trends in this area may provide researchers with more references and assistance in selecting research directions, ultimately benefiting MI/RI patients. [ABSTRACT FROM AUTHOR]

In maximally Ca2+-activated demembranated fibres from the mammalian skeletal muscle, the depression of the force by lowering the temperature below the physiological level (~35 °C) is explained by the reduction of force in the myosin motor. Instead, cooling is reported to not affect the force per motor in Ca2+-activated cardiac trabeculae from the rat ventricle. Here, the mechanism of the cardiac performance depression by cooling is reinvestigated with fast sarcomere-level mechanics. We determine the changes in the half-sarcomere compliance of maximally Ca2+-activated demembranated rat trabeculae in the range of temperatures of 10–30 °C and analyse the data in terms of a simplified mechanical model of the half-sarcomere to extract the contribution of myofilaments and myosin motors. We find that the changes in the ensemble force are due to changes in the force per motor, while the fraction of actin-attached motors remains constant independent of temperature. The results demonstrate that in the cardiac myosin, as in the skeletal muscle myosin, the force-generating transition is endothermic. The underlying large heat absorption indicates the interaction of extended hydrophobic surfaces within the myosin motor, like those suggested by the crystallographic model of the working stroke. [ABSTRACT FROM AUTHOR]

Early events in the reprogramming of fibroblasts to cardiac muscle cells are unclear. While various histone undergo modification and re-positioning, and these correlate with the activity of certain genes, it is unknown if these events are causal or happen in response to reprogramming. Histone modification and re-positioning would be expected to open up chromatin on lineage-specific genes and this can be ascertained by studying nucleosome architecture. We have recently developed a set of tools to identify significant changes in nucleosome architecture which we used to study skeletal muscle differentiation. In this report, we have applied these tools to understand nucleosome architectural changes during fibroblast to cardiac muscle reprogramming. We found that nucleosomes surrounding the transcription start sites of cardiac muscle genes induced during reprogramming were insensitive to reprogramming factors as well as to agents which enhance reprogramming efficacy. In contrast, significant changes in nucleosome architecture were observed distal to the transcription start site. These regions were associated with nucleosome build-up. In summary, investigations into nucleosome structure do not support the notion that fibroblasts to cardiac muscle cell reprogramming involves chromatin opening and suggests instead long-range effects such as breaking closed-loop inhibition. [ABSTRACT FROM AUTHOR]

Cardiac wall motion abnormalities (WMA) are strong predictors of mortality, but current screening methods using Q waves from electrocardiograms (ECGs) have limited accuracy and vary across racial and ethnic groups. This study aimed to identify novel ECG features using deep learning to enhance WMA detection, referencing echocardiography as the gold standard. We collected ECG and echocardiogram data from 35,210 patients in California and labeled WMA using unstructured language parsing of echocardiographic reports. A deep neural network (ECG-WMA-Net) was trained and outperformed both expert ECG interpretation and Q-wave indices, achieving an AUROC of 0.781 (CI: 0.762–0.799). The model was externally validated in a diverse cohort from Georgia (n = 2338), with an AUC of 0.723 (CI: 0.685–0.757). Explainability analysis revealed significant contributions from QRS and T-wave regions. This deep learning approach improves WMA screening accuracy, potentially addressing physiological differences not captured by standard ECG-based methods. [ABSTRACT FROM AUTHOR]

Background: Cell membrane chromatography (CMC) is a biochromatography with a dual function of recognition and separation, offering a distinct advantage in screening bioactive compounds from Chinese medicines (CMs). Yindan Xinnaotong soft capsule (YD), a CM formulation, has been widely utilized in the treatment of cardiovascular disease. However, a comprehensive mapping of the myocardial protective active compounds remains elusive. Purpose: To establish a stable and efficient 2D H9c2/CMC-RPLC-MS system, and to utilize it for screening the active compounds of YD that are associated with myocardial protection. Methods: An imidazole-modified silica gel exhibiting high modification efficiency and protein binding capacity was synthesized to enhance the longevity and efficiency of H9c2/CMC. Subsequently, the potentially bioactive compounds of YD were screened by integrating the 2D H9c2/CMC-RPLC-MS system with a high-content component knockout strategy. Additionally, an RNA-seq approach was employed to predict the targets and mechanisms of YD and the active compounds for myocardial protection. Results: The developed imidazole-modified H9c2/CMC exhibits remarkable selectivity, specificity, stability, and reproducibility. Following three rounds of screening, a total of 24 potential myocardial protective compounds were identified, comprising 8 flavonoids, 8 phenolic acids, 4 saponins, and 4 tanshinones. Bioinformatic analysis utilizing RNA-seq indicated that the FOXO signaling pathway, with FOXO3 identified as a key target, plays a significant role in the cardioprotective effects of YD. Furthermore, all 24 screened compounds exhibit strong binding affinities with FOXO3 evaluated by molecular docking. Conclusion: A highly stable and efficient 2D imidazole-modified H9c2/CMC-RPLC-MS system was developed, allowing for the screening of potentially active compounds from YD. Through the integration of the bioinformatic analysis, the pharmacodynamic foundation of YD for myocardial protection has been comprehensively characterized. [ABSTRACT FROM AUTHOR]

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The second-generation myosin activator danicamtiv (DN) has shown improved function compared with the first-generation myosin activator omecamtiv mecarbil (OM) in nonfailing myocardium by enhancing cardiac force generation but attenuating slowed relaxation. However, whether the functional improvement with DN compared with OM persists in remodeled failing myocardium remains unknown. Therefore, this study aimed to investigate the differential contractile responses to myosin activators in nonfailing and failing myocardium. Mechanical measurements were performed in detergent-skinned myocardium isolated from donor and failing human hearts. Steady-state force, stretch activation responses and loaded shortening velocity were analyzed at submaximal [Ca2+] in the absence or presence of 0.5 µmol/L OM or 2 µmol/L DN. The effects of DN and OM on Ca2+ sensitivity of force generation were determined by incubating myocardial preparations at various [Ca2+]. The inherent impairment in force generation and cross-bridge behavior sensitized the failing myocardium to the effects of myosin activators. Specifically, increased Ca2+ sensitivity of force generation, slowed rates of cross-bridge recruitment and detachment following acute stretch, slowed loaded shortening velocity, and diminished power output were more prominent following treatment with OM or DN in failing myocardium compared with donor myocardium. Although these effects were less pronounced with DN compared with OM in failing myocardium, DN impaired contractile properties in failing myocardium that were not affected in donor myocardium. Our results indicate that similar to first-generation myosin activators, the DN-induced slowing of cross-bridge kinetics may result in a prolongation of systolic ejection and delayed diastolic relaxation in the heart failure setting. NEW & NOTEWORTHY: This is the first study to provide a detailed mechanistic comparison of omecamtiv mecarbil (OM) and danicamtiv (DN) in failing and nonfailing human myocardium. These findings have clinical implications and the potential to inform the clinical utility of myosin activators in the heart failure setting. [ABSTRACT FROM AUTHOR]

Introduction:The strength of inspiratory muscles is one of the essential factors in preventing postoperative pulmonary complications (POPC). One of the new tools to safely measure the strength of the inspiratory muscles in heart patients dynamically and without breath holding is the strength-index (S-index). This study aims to evaluate the immediate effects of a respiratory warm-up (RWU) session on the S-index and other lung parameters in cardiac surgery candidates, a subject with limited existing research. Materials and Methods: This study was conducted as a randomized controlled trial. Forty participants scheduled for heart surgeries were randomly assigned to either the study (RWU between two tests) or control (without RWU) groups. RWU consists of threshold loading inspiratory muscle training (TL-IMT) exercises at 30% of the S-index with 30 breathing cycles. Respiratory tests, including S-index, peak inspiratory flow (PIF) and vital capacity (VC), were assessed twice using an electronic respiratory device. Results: Covariance analysis showed no significant difference in the average and best values of the S-index, PIF or VC indices at the second tests, between two groups (P>0.05), or in the independent t test and Mann-Whitney U test for the "rate of changes," between two tests (P>0.05). Finally, intragroup changes, assessed with paired sample t test between two tests, were mostly non-significant for these indices (P>0.05), except for the best VC in the study group (P=0.03). Conclusion: The study results suggest that a RWU session does not significantly impact cardiac surgery candidates' S-index or other respiratory parameters. Thus, incorporating RWU before S-index testing may not be necessary. [ABSTRACT FROM AUTHOR]

The article discusses the importance of early genetic testing for cardiomyopathies, focusing on a case study of a premature infant with severe cardiac issues. Despite rapid clinical improvement, the patient eventually required a left ventricular assist device (LVAD) due to genetic mutations in the MYL2 gene. The study highlights the significance of comprehensive genetic testing in cases of unclear cardiomyopathy to guide treatment decisions effectively. [Extracted from the article]

In the conducted studies, the effect of vincanine and pyrazoline indole alkaloids on cardiac muscle cell sarcoplasmic reticulum (SR) Ca2+-transport systems (RyR2 and SERCA2a) was investigated under normal and hypoxic conditions. The effect of vincanine and pyrazoline on ryanodine receptor (RyR2) was evaluated in the presence of ruthenium red and it was found that the role of RyR2 in the positive inotropic effect of these alkaloids is small. Also, in the presence of cyclopiazonic acid (IC50 = 5.6 µM), an inhibitor of sarcoplasmic reticulum Ca2+-ATPase (SERCA2a), the positive inotropic effect of vincanine and pyrazoline alkaloids was reduced. In general, the positive inotropic effects and cardioprotective properties of vincanine and pyrazoline alkaloids are mediated by modulation of SERCA2a function. [ABSTRACT FROM AUTHOR]

Adequate assessment of the contribution of the different phases of atrial mechanical activity to the value of ejection volume and pressure developed by the ventricle is a complex and important experimental and clinical problem. A new method and an effective algorithm for controlling the interaction of isolated rat right atrial and right ventricular strips during the cardiac cycle were developed and tested in a physiological experiment. The presented functional model is flexible and has the ability to change many parameters (temperature, pacing rate, excitation delay, pre- and afterload levels, transfer length, and force scaling coefficients) to simulate different types of cardiac pathologies. For the first time, the contribution of the duration of the excitation delay of the right ventricular strips to the amount of work performed by the muscles during the cardiac cycle was evaluated. Changes in the onset of atrial systole and the delay in activation of ventricular contraction may lead to a reduction in cardiac stroke volume, which should be considered in the diagnosis and treatment of cardiovascular disease and in resynchronization therapy. [ABSTRACT FROM AUTHOR]

Dilated cardiomyopathy (DCM) is a highly prevalent and genetically heterogeneous condition that results in decreased contractility and impaired cardiac function. The FK506-binding protein FKBP12 has been implicated in regulating the ryanodine receptor in skeletal muscle, but its role in cardiac muscle remains unclear. To define the effect of FKBP12 in cardiac function, we generated conditional mouse models of FKBP12 deficiency. We used Cre recombinase driven by either the α-myosin heavy chain, (αMHC) or muscle creatine kinase (MCK) promoter, which are expressed at embryonic day 9 (E9) and E13, respectively. Both conditional models showed an almost total loss of FKBP12 in adult hearts compared with control animals. However, only the early embryonic deletion of FKBP12 (αMHC-Cre) resulted in an early-onset and progressive DCM, increased cardiac oxidative stress, altered expression of proteins associated with cardiac remodeling and disease, and sarcoplasmic reticulum Ca2+ leak. Our findings indicate that FKBP12 deficiency during early development results in cardiac remodeling and altered expression of DCM-associated proteins that lead to progressive DCM in adult hearts, thus suggesting a major role for FKBP12 in embryonic cardiac muscle. [ABSTRACT FROM AUTHOR]

Pregnancy-associated spontaneous coronary artery dissection (P-SCAD) poses a rare yet critical concern among postpartum individuals, increasingly recognized as a significant trigger for acute myocardial infarction. Timely identification, accurate diagnosis, and prompt treatment are paramount for clinicians confronted with this condition. Patients with P-SCAD commonly manifest signs and symptoms akin to acute coronary syndrome but have different etiology and treatment. SCAD is defined as a non-traumatic, non-iatrogenic separation of the coronary artery wall, not associated with atherosclerosis. The predominant mechanism of myocardial injury is coronary artery obstruction caused by an intramural hematoma or intimal disruption compromising the lumen at the site of dissection. Diagnosis is made with a comprehensive history and physical examination, cardiac biomarkers, a 12-lead ECG, transthoracic echocardiogram, and confirmed with coronary angiography. Stable patients are managed medically, while more severe cases may require additional intervention. [ABSTRACT FROM AUTHOR]

To observe the effect of sevoflurane(SEV) on the expression of myocardial biological clock gene aromatic hydrocarbon receptor nuclear transport-like protein 1(BMAL1) in diabetic rats and to explore its changes. Methods Sixty healthy male SD rats with a body mass of 200-250 g were divided into oxygen inhalation group (NC) and sevoflurane inhalation group (SEV). The diabetic model was routinely replicated, and the model was divided into oxygen group (DM) and sevoflurane group (DM+SEV) with an inhalation time of 5 h(n=15). Four groups of experimental animals were executed at 0, 12 and 24 h after the anesthesia was stopped and then myocardial tissue was isolated. Western blot was used to determine the expression level of biological clock gene BMAL1 protein and its activation enzyme USP9X; HE staining microspy to observe the pathological changes of myocardial tissue and immuno-fluorescence co-localization to observe the relationship between USP9X and BMAL1. Results At 0 and 12 h after stopping anesthesia, the expression of BMAL1 and USP9X in the DM+SEV group was significantly down-regulated as compared with the DM group, and the expression of BMAL1 and USP9X in the DM+SEV group was significantly down-regulated(P＜0.05) at 24 h after stopping anesthesia (P＞0.05). HE staining microscopy found changes of myocardial tissue structure in the DM+SEV group at 0 and 12 hrs after stopping anesthesia. This change was most significant at 0 h after stopping anesthesia, but the myocardial tissue structure was neatly arranged at 24 h. The results of immuno-fluorescence colocalization showed that USP9X and BMAL1 proteins were mainly distributed in the cytoplasm of cardio-myocardium with and overlapping parts between them. Under the influence of sevoflurane, there was less overlap between the two at 0 and 12 hrs after stopping anesthesia and more overlap between the two at 24 h, which was close to that of the DM group. Conclusions Sevoflurane reversibly changes the expression of myocardial circadian clock gene BMAL1 in diabetic rats and this change still existe for 12 h after stopping anesthesia, then significantly fade away 24 hrs after stopping anesthesia. [ABSTRACT FROM AUTHOR]

Background/Objectives: Abnormal development of the second heart field significantly contributes to congenital heart defects, often caused by disruptions in tightly regulated molecular pathways. Smyd1, a gene encoding a protein with SET and MYND domains, is essential for heart and skeletal muscle development. Mutations in SMYD1 result in severe cardiac malformations and misregulation of Hand2 expression in mammals. This study examines the role of Smyd1b in zebrafish cardiac morphogenesis to elucidate its function and the mechanisms underlying congenital heart defects. Methods: Smyd1b (still heart) mutant embryos were analyzed for cardiac defects, and changes in gene expression related to heart development using live imaging, in situ hybridization, quantitative PCR and immunofluorescent comparisons and analysis. Results: Smyd1b mutants displayed severe cardiac defects, including failure to loop, severe edema, and an expansion of cardiac jelly linked to increased has2 expression. Additionally, the expression of key cardiac transcription factors, such as gata4, gata5, and nkx2.5, was notably reduced, indicating disrupted transcriptional regulation. The migration of cardiac progenitors was impaired and the absence of Islet-1-positive cells in the mutant hearts suggests a failed contribution of SHF progenitor cells. Conclusions: These findings underscore the essential role of Smyd1b in regulating cardiac morphogenesis and the development of the second heart field. This study highlights the potential of Smyd1b as a key factor in understanding the genetic and molecular mechanisms underlying congenital heart defects and cardiac development. [ABSTRACT FROM AUTHOR]

Hypertension is a common condition in older cats, often secondary to chronic kidney disease (CKD). Although the heart is one of the organs damaged by hypertension, the pathology of the feline hypertensive (HT) heart has been poorly studied. The aim of this retrospective study was to describe the gross and microscopic pathology of hearts obtained from cats at post-mortem examination and to compare cats diagnosed with hypertension with cats of similar age and kidney function for which antihypertensive treatment was not deemed clinically necessary. Hearts from 32 cats were examined‒18 from HT and 14 from normotensive (NT) cats. The prevalence of CKD was 72.2% vs. 78.6% in the HT and NT groups, respectively. The time-averaged blood pressure over the longitudinal follow-up from diagnosis was significantly higher in the HT group compared with the NT group (153.4 ± 20.8 vs. 133.9 ± 19.3 mmHg; P = 0.0106), respectively. HT cats, when compared with NT cats, had a thicker left ventricular free wall (7.67 [5.45–9.29] vs. 5.07 [4.72–7.16] mm; P = 0.001) and interventricular septum (6.92 [6.26–7.56] vs. 4.96 [4.15–6.46] mm; P = 0.008) and higher ventricular weight as a percentage of body weight (0.34 [0.29–0.36] vs. 0.28 [0.21–0.31]%; P = 0.02), respectively. Myocardial fibrosis was present in 72% of cases with no significant difference in the prevalence (P = 0.45) or score (P = 0.81) between the HT (1 [0.75–2]; 77.8% scoring one or above) and NT cats (1 [0–2]; 64.3% scoring one or above). Similarly, the population prevalence of myocyte hypertrophy, myofibre disarray and microvascular change was 71.9%, 50% and 43.7%, respectively, and did not differ significantly between groups. These results suggest that age-related cardiac pathology, exacerbated by azotaemic CKD, in cats is very common. The role that hypertension plays in mediating these pathological changes is uncertain. [ABSTRACT FROM AUTHOR]