Myocardial Structure Research Articles

Inactivation of notch1-TGF-β-smads signaling pathway by atorvastatin improves cardiac function and hemodynamic performance in acute myocardial infarction rats.

To determine the effects of atorvastatin on cardiac function and hemodynamics and to investigate its functional mechanism on cardiac fibrosis in acute myocardial infarction (AMI) rats. Cardiac functions and hemodynamic changes were evaluated in each group on day 28. Quantitative reverse transcription-polymerase chain reaction, Western blot, and immunohistochemistry were performed to detect the expression of notch1, transforming growth factor-β (TGF-β), Smad2, Smad7, as well as myocardial fibrosis factors (i.e. collagen I, collagen III, and galectin-3) in the myocardial tissues of AMI rats. The changes of myocardial cell structure and myocardial collagen fibers of AMI rats were observed with hematoxylin and eosin staining and Masson staining. Atorvastatin improved the cardiac function and hemodynamic performance. Atorvastatin down-regulated the expression of notch1, smad2, collagen I, and collagen III in AMI rats. Atorvastatin treatment decreased the transcription of notch1, TGF-β, and smad2, while increased smad7 in AMI rats. Atorvastatin induced the down-regulation of collagen I, collagen III, and galectin-3. Myocardial immunohistochemical analysis showed atorvastatin inhibited the expression of notch1, TGF-β, and smad2 in myocardial tissues. Atorvastatin inhibited myocardial fibrosis by interfering with notch1-TGF-β-smads signal pathways. In addition, it could mitigate myocardial remodeling, and improve cardiac functions and hemodynamics.

Near-Field Clutter Mitigation in Speckle Tracking Echocardiography.

Near-field (NF) clutter filters are critical for unveiling true myocardial structure and dynamics. Randomized singular value decomposition (rSVD) stands out for its proven computational efficiency and robustness. This study investigates the effect of rSVD-based NF clutter filtering on myocardial motion estimation. In silico, material points and their displacements in a homogeneous medium under uniaxial compressions (0.5% - 9% axial strains at 0.5% increments) were simulated in finite-element models. They were exported to the k-Wave toolbox for simulations of pre- and post-deformed ultrasound images with/ without a realistic phase aberrating layer in a high-contrast diverging wave compounding scheme. In vivo, echocardiograms of 20 normal human hearts were acquired using a coded diverging wave compounding imaging method at 3200 frames/second in the transthoracic apical four-chamber view. Morphological component analysis (MCA), which is also a sparse representation method but computationally intensive, was used for comparison with rSVD. Both rSVD- and MCA-based filters were applied to beamformed ultrasound radio-frequency (RF) data before cross-correlation-based speckle tracking. Contrast-to-noise ratios (CNRs) and root-mean-square deviations (RMSDs) were computed from regions of interest to evaluate NF clutter filtering performance of rSVD and MCA. In silico, 2-D displacements estimated from rSVD-based clutter-reduced image data showed strong agreement with ground truth (R2 of 0.95). In vivo, CNR improvements ranged from 1.02 dB to 17.68 dB, consistently enhancing image quality across all subjects. An improvement of ∼4.9 dB in the apical segments was observed in 80% of cases. Mean RMSDs were below 5.0% for all rSVD-based NF clutter-reduced data. While both rSVD and MCA effectively filtered NF clutter, rSVD was significantly more practical. Our findings confirm the reliability, accuracy, and efficiency of rSVD-based clutter filtering in speckle tracking echocardiography. This underscores the feasibility of matrix decomposition-based methods, exemplified by rSVD, in NF clutter filtering for myocardial motion estimation.

Mangiferin Attenuates Myocardial Ischemia Reperfusion Injury by Regulating the GAS6/Axl Signaling Pathway.

Ischemia reperfusion-induced myocardial injury is a prominent pathological feature in patients with coronary artery disease, contributing to significant mortality and morbidity rates. Mangiferin (MGF), the main active ingredient extracted from Anemarrhena asphodeloides Bge, has anti-inflammatory, anti-oxidation, anti-diabetes, and anti-tumor effects. The present study confirmed that the GAS6/Axl pathway was identified as a promising novel target for the treatment of myocardial ischemia reperfusion (IR) injury. However, whether MGF exerts anti-myocardial ischemia reperfusion injury through GAS6/Axl is still unclear. In this study, BALB/c male mice and HL-1 cardiomyocytes were used to construct a model of IR and hypoxia-reoxygenation (HR) (or H2O2) injury invivo and invitro, respectively. MGF significantly improved cardiac function indicators, myocardial structure, myocardial enzymes, and mitochondrial function, together with reduced oxidative stress and apoptosis in IR-injured mice. Invitro, MGF significantly increased cell viability, inhibited the release of LDH, reduced oxidative stress and apoptosis, and improved mitochondrial function in both HR and H2O2-injured HL-1 cells. In particular, the GAS6/Axl signaling pathway plays an important role in this process. Additionally, we also demonstrated that GAS6 gene knockout reversed the protective effect of MGF against HR and H2O2-injured cardiomyocytes. The present study confirmed that MGF has protective effects against myocardial IR injury by activating the GAS6/Axl pathway, providing a theoretical basis for MGF as a potential cardioprotective drug in the clinical setting of myocardial IR injury.

Swimming induces physiological cardioprotection associated with pro-growth versus anti-inflammatory influences in extracardiac organs.

Physical activity improves myocardial structure, function, and resilience via complex, incompletely defined mechanisms. We explored the effects of 1- to 2-wk swim training on cardiac and systemic phenotype in young male C57Bl/6 mice. Two-week forced swimming (90 min twice daily) resulted in cardiac hypertrophy (22% increase in heart:body weight, P < 0.01), with improved inotropy (22% higher left ventricular +dP/dt, P < 0.01) and functional tolerance to ischemia-reperfusion (I-R) (40%-50% reductions in stunning and diastolic dysfunction, P < 0.01; without changes in cell death assessed from enzyme loss) in Langendorff perfused hearts. Initial Western immunoblot analysis indicated no shifts in cardiac expression of determinants of autophagy (LC3A/B), mitochondrial biogenesis/dynamics (PGC-1α, MFN-1, and OPA-1), or stress signaling (caveolin-3 and GSK-3β). Furthermore, no changes in cardiac cytokines (IL-1b, IL-6, IL-10, IL-12, GM-CSF, TNF-α, and IFN-γ) were detected in multiplex immunoassays. Exploratory profiling of RTK phosphorylation provided evidence for moderately increased activity of receptors involved in cardiac/coronary growth and protection (insulin, IGF-1, FGF R2, Tie-2, PDGFβ, and EphB4), together with a fall in M-CSF R and ephrin sub-type receptor phosphorylation. Swimming increased growth factor while reducing inflammatory mediators across extracardiac tissues [brain, pancreas, thymus, lymph nodes, and white adipose tissue (WAT)]. This included a pattern of increased LIF, VEGF, and pentraxin-2 versus reduced CXCL2/MIP-2a, chitinase 3-like 1, CCL6, MMP9, CD40/TNFRSF5, and IGFBP6 in multiple tissues, and a shift to a pro-browning profile in WAT. In summary, swimming produces integrated systemic benefits, improving cardiac growth, inotropy, and resilience in association with increased growth factor and reduced inflammatory and lipogenic mediators in multiple tissues.NEW & NOTEWORTHY Swimming may induce cardiac and systemic benefits distinct from other modes of physical activity. We show that 2-wk forced swim training increases cardiac growth, contractility, and functional resilience to ischemia in hearts of male mice. This is associated with increased growth factor levels and reduced inflammatory and lipogenic protein profiles in peripheral tissues.

Beyond convention: non-compacted myocardium, ventricular tachycardia, and systolic dysfunction in dextrocardia patients: a case series

Background: Noncompaction of the left ventricle (LVNC) is linked to a higher risk of sudden cardiac death and stroke. Its prevalence ranges from 0.014% to 1.3% in the general population, rising to 7.5% in patients with dextrocardia. Case summary: A male in his late 70s presented with worsening dyspnea and leg swelling, with dextrocardia and frequent extrasystoles. Imaging revealed right-sided pleural effusion, severely reduced ejection fraction, and ventricular and atrial dilatation. He developed sustained monomorphic VT, was treated with amiodarone, had successful coronary stenting, and received an ICD with no further hospital readmissions or ICD events. A second case involved a male in his late 50s who presented with dyspnea. He had dextrocardia with situs inversus, subsegmental pulmonary embolism, and LVNC. He was treated with enoxaparin, medical therapy, and Holter monitoring, which showed mild arrhythmias. He declined ICD placement but remained event-free during the first year of follow-up. Discussion: LVNC is a rare condition resulting from abnormal myocardial development during embryogenesis, leading to a two-layered myocardial structure. Diagnosis is based on imaging criteria. LVNC is linked to arrhythmias, heart failure, and conduction abnormalities, requiring interventions such as ICD placement, arrhythmia monitoring, and genetic testing. Further research is needed on genetic associations and long-term outcomes in dextrocardia patients.

Tongmai Hypoglycemic Capsule Attenuates Myocardial Oxidative Stress and Fibrosis in the Development of Diabetic Cardiomyopathy in Rats.

To investigate the effect of Tongmai Hypoglycemic Capsule (THC) on myocardium injury in diabetic cardiomyopathy (DCM) rats. A total of 24 Sprague Dawley rats were fed for 4 weeks with high-fat and high-sugar food and then injected with streptozotocin intraperitoneally for the establishment of the DCM model. In addition, 6 rats with normal diets were used as the control group. After modeling, 24 DCM rats were randomly divided into the model, L-THC, M-THC, and H-THC groups by computer generated random numbers, and 0, 0.16, 0.32, 0.64 g/kg of THC were adopted respectively by gavage, with 6 rats in each group. After 12 weeks of THC administration, echocardiography, histopathological staining, biochemical analysis, and Western blot were used to detect the changes in myocardial structure, oxidative stress (OS), biochemical indexes, protein expressions of myocardial fibrosis, and nuclear factor erythroid 2-related faactor 2 (Nrf2) element, respectively. Treatment with THC significantly decreased cardiac markers such as creatine kinase, lactate dehydrogenase, and creatine kinase-MB, etc., (P<0.01); enhanced cardiac function indicators including heart rate, ejection fraction, cardiac output, interventricular septal thickness at diastole, and others (P<0.05 or P<0.01); decreased levels of biochemical indicators such as fasting blood glucose, total cholesterol, triglycerides, low-density lipoprotein cholesterol, aspartate transaminase, (P<0.05 or P<0.01); and decreased the levels of myocardial fibrosis markers α-smooth muscle actin (α-SMA), and collagen I (Col-1) protein (P<0.01), improved myocardial morphology and the status of myocardial interstitial fibrosis. THC significantly reduced malondialdehyde levels in model rats (P<0.01), increased levels of catalase, superoxide dismutase, and glutathione (P<0.01), and significantly increased the expression of Nrf2, NAD(P)H:quinone oxidoreductase 1, heme oxygenase-1, and superoxide dismutase 2 proteins in the left ventricle of rats (P<0.01). THC activates the Nrf2 signaling pathway and plays a protective role in reducing OS injury and cardiac fibrosis in DCM rats.

Comprehensive assessment of subchronic low-dose exposure to doxorubicin in the Wistar rat model

Rationale. Doxorubicin is a chemotherapeutic antibiotic from the anthracycline class that has cumulative and dose-dependent cardiotoxic effects. The cardiotoxic properties of doxorubicin are manifested in characteristic pathologies of the heart and its microenvironment. Doxorubicin also exhibits genotoxic properties and is often used to model acute genotoxic effects in small laboratory animal models.Aim: To evaluate chronic low-dose exposure to doxorubicin in a Wistar rat model using cytogenetic methods and electron microscopy.Material and Methods. The study included two groups of 10 male Wistar rats: an experimental group (weekly doxorubicin in the tail vein 2 mg/kg for 4 weeks) and a control group (0.9% NaCl). A micronucleus test was used to evaluate genotoxic effects. Visualization of the myocardial structure was carried out using scanning electron microscopy in back-scattered electrons on an electron microscope.Results. The analysis showed a significant difference between the control (0.8%) and experimental groups (3.2%) in the level of polychrome erythrocytes with a micronucleus. It was found that rats from the experimental group were characterized by a significant decrease in the number of polychromatic red blood cells compared to the control group. In the experimental group, pronounced heterogeneity of the morphological structure of the myocardium was noted. Electron micrographs of hepatocytes from rats treated with doxorubicin showed degenerative changes in the structure of liver cells.Conclusion. The results of our study provide insight into the subacute effect of a small dose of doxorubicin on the heart, liver and hematopoietic system of normolipidemic Wistar rats. We have proposed mechanisms of interaction between important organs and systems of the body exposed to doxorubicin against the background of a general pathological condition. In the future, the nature of the toxic effects of lower and optimal doses of the mutagen in the context of subchronic cumulative exposure should be determined.

Diagnostic capabilities of cardiac computed tomography in the preoperative diagnosis of hypertrophic cardiomyopathy

BACKGROUND: A comprehensive approach to studying hypertrophic cardiomyopathy with diagnostic equipment and the latest scanning methods will ensure quality control and effective treatment of patients with this condition. The implementation of innovative technologies and computer calculation using next-generation scanners may become relevant and promising in studying various phenotypes of left ventricular remodeling in combination with abnormalities of the chordopapillary apparatus of the mitral valve and myocardial structure. AIM: To examine the diagnostic capabilities of computed tomography in the preoperative examination of various hypertrophic cardiomyopathy phenotypes. MATERIALS AND METHODS: The retrospective data analysis included 47 patients with hypertrophic cardiomyopathy (mean age, 52±7 full years) before surgical correction. computed tomography was performed using our protocol with automatic bolus tracking in the left atrium with a 90 HU threshold and biphasic contrast injection to assess the heart chambers and coronary arteries anatomy and mitral valve morphology. Moreover, to assess myocardial structure remodeling, iodine dual-energy computed tomography maps obtained with delayed contrast enhancement were analyzed. All patients with hypertrophic cardiomyopathy were classified by morphological types. The anatomy of chordopapillary apparatus was evaluated in each case. RESULTS: This study demonstrated variability in hypertrophic cardiomyopathy phenotypes, which were conventionally divided into five morphological categories, but not restricted by them. Among the patients, 26 (55%) had diffuse septum hypertrophic cardiomyopathy, 5 (11%) had midventricular hypertrophic cardiomyopathy, 2 (4%) had midventricular obstruction and apical aneurysm, 8 (18%) had focal basal septum hypertrophic cardiomyopathy, 4 (8%) had concentric hypertrophic cardiomyopathy, and the remaining 4 (8%) had apical hypertrophic cardiomyopathy. Most patients were diagnosed with chordopapillary abnormalities of the mitral valve, categorized by papillary muscle number and position, and the ratio of chords to muscles. In 10 (21%) patients, data on the myocardial bridge of a coronary artery were obtained, whereas 3 (14%) of them had dynamic stenosis. All patients had focal iodine uptake on dual-energy computed tomography maps. An extracellular volume increase was observed in 10 out of 13 (76%) patients. As shown by dual-energy computed tomography, the mean extracellular volume of the left ventricular myocardium was 30.58% (95% confidence interval, 27–34%). CONCLUSION: Our scanning protocols developed with computed tomography scanners of various generations enable to evaluate the specific morphological patterns of hypertrophic cardiomyopathy in a single study and provide a detailed interpretation of the geometry of cardiac valves and chambers, left ventricular function, state of the coronary bed, and structural changes of the left ventricular myocardium.

Acclimation of Hairless Spontaneously Hypertensive Rat to Ambient Temperature Attenuates Hypertension-Induced Pro-Arrhythmic Downregulation of Cx43 in the Left Heart Ventricle of Males.

Due to poor treatment adherence and lifestyle-based interventions, chronic hypertension is a dominant risk factor predisposing individuals to heart failure and malignant arrhythmias. We investigated the impact of the postnatal acclimation of hairless SHR to ambient temperature that is, for them, below thermoneutrality, on the electrical coupling protein connexin-43 (Cx43) and pro-fibrotic markers in both heart ventricles of male and female hairless SHR rats compared to the wild SHR. Some 6-month-acclimated male and female hairless SHR as well as age- and sex-matched wild SHR were included and compared with the non-hypertensive Wistar strain. The left and right heart ventricles were examined for Cx43 topology, myocardial structure, and the histochemistry of capillaries. The protein levels of Cx43, relevant protein kinases, and extracellular matrix proteins (ECMs) were determined by immunoblotting. MMP-2 activity was assessed via zymography, and susceptibility to malignant arrhythmias was tested ex vivo. Cx43 and its phosphorylated variant pCx43368 were significantly reduced in the left heart ventricles of wild SHR males, while to a lesser extent in the hairless SHR. In contrast, these proteins were not significantly altered in the right heart ventricles of males or in both heart ventricles in females, regardless of the rat strain. Pro-arrhythmic Cx43 topology was detected in the left heart ventricle of wild SHR and to a lesser extent in hairless SHR males. TGFβ protein was significantly increased only in the left ventricle of the wild SHR males. MMP-2 activity was increased in the right ventricle but not in the left ventricles of both males and females, regardless of the rat strain. The findings indicate that the postnatal acclimation of hairless SHR to ambient temperature hampers the downregulation of Cx43 in the left heart ventricle compared to wild SHR males. The decline of Cx43 was much less pronounced in females and not observed in the right heart ventricles, regardless of the rat strain. It may impact the susceptibility of the heart to malignant arrhythmias.

SIRT1-dependent regulation of mitochondrial metabolism participates in miR-30a-5p-mediated cardiac remodeling post-myocardial infarction

Myocardial infarction-triggered myocardial remodeling is fatal for therapies. The miR-30 family is an essential component of several physiological and pathological processes. Previous studies have proved that the miR-30 family may contribute to regulating myocardial infarction. This study aimed to demonstrate that the combination of miR-30a-5p and mitochondrial metabolism recapitulates the critical features for remodeling post-myocardial infarction. Using gain- and loss-of-function of miR-30a-5p in mice, we found miR-30a-5p is highly expressed in the heart and is reduced in infarcted hearts. Further evidence showed that miR-30a-5p acts as a protective molecule to maintain myocardial remodeling, fibrosis, and mitochondrial structure. Mitochondrial function, ATP production, and mitochondrial respiratory chain proteins were positively regulated by miR-30a-5p. Mechanistically, alterations in these properties depend on SIRT1, which modulates miR-30a-5p-regulated mitochondrial metabolism. Remarkably, reactivation of SIRT1 prevented miR-30a-5p deficiency-aggravated myocardial infarction-induced myocardial remodeling. These data identified miR-30a-5p as a critical modulator of mitochondrial function in cardiomyocytes and revealed that the miR-30a-5p-SIRT1-mitochondria network is essential for myocardial infarction-induced cardiac remodeling.

Prognostic implication of DPD quantification in transthyretin cardiac amyloidosis.

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. Consecutive ATTR-CA patients (n=100) undergoing planar DPD scintigraphy with Perugini grade 2 or 3, alongside quantitative DPD SPECT/CT 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-minute 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 to 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]. 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 4138701: Phenotypic clustering of HFpEF using cardiac magnetic resonance imaging

Background: Improved understanding of the high-risk features associated with HFpEF may facilitate risk stratification. Cardiac magnetic resonance (CMR)-based strain and structural data can define detailed myocardial structure, which can be leveraged to define heterogenous HFpEF phenotypes. This study used phenotypic clustering integrating CMR-based strain and structural data to identify a high-risk HFpEF phenotype. Methods: Retrospective analyses of 48 HFpEF participants, who underwent cardiac MRI and invasive cardiopulmonary exercise testing (median time between the two studies=40 days), was performed. We conducted unsupervised and unbiased K-means clustering analyses using CMR-based strain and myocardial structural variables. We associated two identified clusters with mortality using Cox proportional hazards modeling and constructed Kaplan-Meier survival curves. A p-value was considered significant if &lt; 0.05. Results: We identified a low (n=32) and high-risk (n=16) cluster. Patients in the identified clusters had similar ages and comorbidities. The high-risk cluster had more male participants and hemodynamically had a higher exercise mPAP/CO and PAWP/CO slope, which are metrics of pulmonary vascular disease. The high-risk cluster displayed greater LV mass, worse biventricular longitudinal strain, decreased right ventricular ejection fraction, and greater interventricular septal angle (all P&lt;0.05) as characterized by CMR as compared to the low-risk cluster (Table 1, Figure 1A). Mortality for the high-risk cluster was 5.43 times that for the low-risk cluster at 12 months (95% CI 1.69-17.42, Figure 1B). Conclusions: Using clustering analyses with CMR strain and structural variables, we identified a high-risk HFpEF phenotype with increased LV mass, reduced biventricular strain, and reduced RV ejection fraction.

Reducing the Сardiotoxicity of Daunorubicin by Conjugation with Natural Sesquiterpene Lactones

We present the results of a histological study into the cardiotoxicity of conjugates of daunorubicin with dehydrocostus lactone and epoxyisoalantolactone in mature male mice of the C57BL/6 line. The effect of conjugates on the morphology of cardiomyocytes and the structure of the left ventricular myocardium in mice was studied.

Multiphysics simulations reveal haemodynamic impacts of patient-derived fibrosis-related changes in left atrial tissue mechanics.

Stroke is a leading cause of death and disability worldwide. Atrial myopathy, including fibrosis, is associated with an increased risk of ischaemic stroke, but the mechanisms underlying this association are poorly understood. Fibrosis modifies myocardial structure, impairing electrical propagation and tissue biomechanics, and creating stagnant flow regions where clots could form. Fibrosis can be mapped non-invasively using late gadolinium enhancement magnetic resonance imaging (LGE-MRI). However, fibrosis maps are not currently incorporated into stroke risk calculations or computational electro-mechano-fluidic models. We present multiphysics simulations of left atrial (LA) myocardial motion and haemodynamics using patient-specific anatomies and fibrotic maps from LGE-MRI. We modify tissue stiffness and active tension generation in fibrotic regions and investigate how these changes affect LA flow for different fibrotic burdens. We find that fibrotic regions and, to a lesser extent, non-fibrotic regions experience reduced myocardial strain, resulting in decreased LA emptying fraction consistent with clinical observations. Both fibrotic tissue stiffening and hypocontractility independently reduce LA function, but, together, these two alterations cause more pronounced effects than either one alone. Fibrosis significantly alters flow patterns throughout the atrial chamber, and particularly, the filling and emptying jets of the left atrial appendage (LAA). The effects of fibrosis in LA flow are largely captured by the concomitant changes in LA emptying fraction except inside the LAA, where a multifactorial behaviour is observed. This work illustrates how high-fidelity, multiphysics models can be used to study thrombogenesis mechanisms in patient-specific anatomies, shedding light onto the links between atrial fibrosis and ischaemic stroke. KEY POINTS: Left atrial (LA) fibrosis is associated with arrhythmogenesis and increased risk of ischaemic stroke; its extent and pattern can be quantified on a patient-specific basis using late gadolinium enhancement magnetic resonance imaging. Current stroke risk prediction tools have limited personalization, and their accuracy could be improved by incorporating patient-specific information such as fibrotic maps and haemodynamic patterns. We present the first electro-mechano-fluidic multiphysics computational simulations of LA flow, including fibrosis and anatomies from medical imaging. Mechanical changes in fibrotic tissue impair global LA motion, decreasing LA and left atrial appendage (LAA) emptying fractions, especially in subjects with higher fibrosis burdens. Fibrotic-mediated LA motion impairment alters LA and LAA flow near the endocardium and the whole cavity, ultimately leading to more stagnant blood regions in the LAA.

Hydrogen Protects Mitochondrial Function by Increasing the Expression of PGC-1α and Ameliorating Myocardial Ischaemia-Reperfusion Injury.

To investigate the application of H2 to alleviate cardiac ischaemia-reperfusion (I/R) injury in a PGC-1α-dependent manner. Arat invitro myocardial I/R injury model was used, Western blot was used to detect the expression levels of apoptosis markers (Bax, cleaved caspase-3, Bcl2), inflammatory factors (IL-1β, TNF-α), mitochondrial fission (DRP1, MFF) and mitochondrial fusion (MFN1, MFN2, OPA1). HE staining was used to observe the effect of H2 on the myocardial tissue structure injured by I/R. Transmission electron microscopy (TEM) was used to observe the changes in the mitochondrial structure of myocardial tissue after I/R injury. Real-time quantitative PCR (qPCR) was used to detect the expression of PGC-1α in the myocardial tissue of rats after I/R injury and H2 treatment. H2 increases the expression level of PGC-1α, while the deletion of PGC-1α inhibited the therapeutic effect of H2. H2 can improve the changes of the myocardial tissue and mitochondrial structure caused by I/R injury. H2 treatment effectively inhibited the inflammatory response, and the loss of PGC-1α could inhibit the therapeutic effect of H2. The application of H2 can alleviate myocardial I/R injury, and the loss of PGC-1α weakens the protective effect of H2 on the I/R heart.

Kaempferol alleviates myocardial ischemia injury by reducing oxidative stress via the HDAC3-mediated Nrf2 signaling pathway

IntroductionKaempferol (KAE) is a flavonoid found in various plants. Recent studies showed that high dietary intake of KAE was associated with a lower risk of myocardial infarction; however, the cardioprotective mechanism of KAE remains unknown. ObjectivesTo determine the effect of KAE on cardiac injury in isoproterenol (ISO)-induced rats and cobalt chloride (CoCl2)-treated cardiomyocytes, and the underlying mechanisms. MethodsMale rats were pretreated with different doses of KAE for 14 days, and then injected with ISO to induce myocardial ischemia injury. We also established a model of myocardial cell injury using rat H9c2 cardiomyocytes stimulated with CoCl2. ResultsWe found that KAE pretreatment significantly alleviated myocardial injury and improved cardiac function in ISO-injected rats. In addition, KAE reduced oxidative stress in rats with myocardial ischemia by decreasing malondialdehyde concentration and increasing superoxide dismutase activity, and protection of the myocardial mitochondrial structure. KAE also attenuated CoCl2-induced injuryof H9c2 cardiomyocytes via suppression ofoxidative stress. With regard to the mechanism, we found that KAE down-regulated HDAC3 expression and up-regulated Nrf2 expression in ISO-induced rats and CoCl2-stimulated cardiomyocytes. Incubation of cardiomyocytes with HDAC3-selective inhibitor RGFP966 augmented the protective effect of KAE and reduced oxidative stress. By contrast, HDAC3 overexpression by adenovirus attenuated the effect of KAE on oxidative stress compared with KAE treatment group. HDAC3 also regulated Nrf2 expression in the cardiomyocytes with RGFP966 or an adenovirus overexpressing HDAC3; but Nrf2 inhibition reduced the effect of KAE on ROS generation in CoCl2-induced cardiomyocytes. Immunoprecipitation assay showed that HDAC3 interacted with Nrf2 in cardiomyocytes. Further studies found that KAE increased the acetylation level of Nrf2, while HDAC3 overexpression decreased the acetylation of Nrf2 compared with KAE treatment group. ConclusionOur data show that KAE ameliorates cardiac injury by reducing oxidative stress via the HDAC3-mediated Nrf2 signaling pathway in cardiomyocytes.

Fractional-order modeling of myocardium structure effects on atrial fibrillation electrograms

Atrial fibrillation (AF) is the most common cardiac arrhythmia with mechanisms of initiation and sustaining that are not fully understood. The clinical procedure for AF contemplates the analysis of the atrial electrograms, whose morphology has been correlated with the underlying structure of the atrial myocardium. This study employs a mathematical model incorporating fractional calculus to simulate cardiac electrical conduction, accounting for tissue structural inhomogeneities using complex-valued orders. Simulations of different wavefront propagation patterns were performed, and virtual electrograms were analyzed using an asymmetry factor. Our results evinced that the shapes of the action potential and the propagating wavefront can be modulated through the fractional order under both healthy and AF conditions. Moreover, the asymmetry factor changes with variations in the fractional order. For a given propagation pattern under AF conditions, variation intervals for the asymmetry factor can be generated by forming sets of simulations with different configurations for the fractional order, representing diverse samples of atrial tissue with varying degrees of structural heterogeneity. This approach successfully reproduces the electrogram negative deflection predominance seen in AF patients, which standard integer-order models cannot predict. Our fractional-order conduction model aligns with the effects of atrial structure on the electrical dynamics observed in clinical AF. Therefore, it offers a valuable tool for studying cardiac electrophysiology, encompassing both electrical and structural interactions of the tissue within a unified model.

Effect and mechanism of Adipokine Omentin-1 on cardiac hypertrophy in heart failure with preserved ejection fraction

Abstract Background Omentin-1 secreted by epicardial adipose tissue can inhibit ventricular remodeling and improve early cardiac function after myocardial infarction. Our previous studies have identified the omentin-1 receptor as integrin receptors αvβ3 and αvβ5. However, the effect of omentin-1 on heart failure with preserved ejection fraction (HFpEF) remains poorly understood. Purpose The present study aims to study the role and mechanism of omentin-1 in cardiac function and myocardial cell structure in HFpEF. Methods and Results The influences of omentin-1 were investigated in HFpEF mice (HFD (60% calories from lard) and L-NAME (0.5 g/L in drinking water)), which were treated in vivo. Echocardiography showed better diastolic function in HFpEF mice treated with omentin-1 (5 ug/kg/h) subcutaneously for 4 weeks, and tissue staining showed alleviated myocardial fibrosis and myocardial hypertrophy. The RNA sequencing analysis revealed variations in the gene expression related to ketone body metabolism in HFpEF mice after omentin-1 treatment (600 ng/ml). The supernatant was obtained from mouse bone marrow macrophages treated with ultrapure endotoxin and ATP and was utilized as the macrophage-conditioned medium for culturing primary cardiomyocytes, which were stimulated with isoproterenol for 48 hours to construct the HFpEF cardiomyocyte model. In the heart tissue of HFpEF mice and HFpEF cardiomyocytes treated with omentin-1, there was a notable increase in the expression of a pivotal enzyme of ketone body metabolism- succinyl-CoA transferase (SCOT), and a decrease in the expression of hypertrophy signal. The myocardial hypertrophy model was established by stimulating the myocardial cell line H9C2 with isoproterenol. Following the inhibition of the integrin receptor and PI3K-AKT pathway, the impacts of omentin-1 on SCOT and myocardial hypertrophy signal expression in hypertrophic cardiomyocytes were eliminated. Conclusion This study provides evidence for the effects of omentin-1 on cardiac function and myocardial structure in HFpEF and proposes that omentin-1 may stimulate the downstream PI3K/AKT pathway via integrin receptors on cardiomyocytes, leading to increased expression of SCOT and improvement of cardiomyocyte hypertrophy.

Mitochondrial Oxidative Stress and Cardiac Dysfunction in TERT Knockout Mice

Abstract Background Heart failure (HF) is a major cause of hospitalization in the elderly, with its incidence increasing due to aging and associated risk factors like hypertension, diabetes, and myocardial fibrosis. Aging-related myocardial fibrosis, characterized by alterations in the extracellular matrix and myocardial structure, impairs cardiac function. Mitochondrial oxidative stress plays a pivotal role in cardiac electrical and structural remodeling, necessitating a deeper understanding of its involvement in aging-related heart failure. Purpose The purpose of this study is to investigate the mechanisms of aging-related ventricular electrical and structural remodeling by constructing an aging mouse model. This research aims to provide potential therapeutic targets for heart failure associated with aging. Methods We developed a third-generation homozygous telomerase reverse transcriptase (TERT) knockout mouse model. Comparing third-generation homozygous TERT knockout mice (F3 group) with age-matched wild-type males (WT group). The study encompassed blood pressure measurement, electrocardiographic analysis, echocardiography, ELISA for cardiac biomarkers, ventricular tissue electrophysiology, fibrosis assessment through staining, transcriptomic profiling via RNA-seq, and electron microscopy of ventricular mitochondria. Results Compared to the WT group, the F3 group demonstrated increased P53 and P16 protein expression. Decreased LVEF and FS, along with increased interventricular septum thickness, left ventricular diameter, and left ventricular volume. Elevated serum NT-pro-BNP and troponin I (cTnI) levels, with prolonged QRS duration. Decreased left and right ventricular conduction velocity, accompanied by increased conduction dispersion. Notable elevation in COLI, TGFβ, and α-SMA gene transcription and protein expression in ventricular tissue. Significant differences in mitochondrial oxidative stress signal pathways via RNA-seq analysis. Elevated serum MDA levels and decreased SOD levels, with up-regulated Mn-SOD gene transcription and protein expression, and down-regulated MFN2 and Drp1 gene transcription and protein expression in ventricular tissue. Electron microscopy revealed mitochondrial abnormalities such as loose arrangement, decreased number, swelling, vacuolation, and myofilament disintegration or breakage in the F3 group. Conclusion Third-generation TERT-/- senescent mice exhibit notable cardiac impairments, including electrical remodeling, structural changes, and mitochondrial dysfunction. These findings suggest a potential link between mitochondrial oxidative stress and aging-related heart failure, indicating novel therapeutic opportunities targeting mitochondrial dysfunction for managing such conditions.

Type 2 diabetes individuals have a shorter QRS duration, prolonged QTc interval, flatter T wave, and reduced left ventricular cycle volumes compared to matched controls in the UK Biobank

Abstract Background Type 2 diabetes is associated with an increased risk of heart failure even in the absence of overt coronary artery disease, though underlying mechanisms are unclear. ECG and cardiac magnetic resonance (CMR) imaging provide windows into subclinical changes in myocardial structure and function and could be exploited to understand this. Purpose We investigate differences in ECG and CMR biomarkers in a large cohort of participants with type 2 diabetes, compared to a matched control cohort. We hypothesise that individuals with diabetes may exhibit concurrent differences in biomarkers, reflecting underlying cardiac remodelling. Methods We carried out a pair-matched cross-sectional study to examine the association between type 2 diabetes and multi-modal cardiac biomarkers. The exposure cohort consists of 1,781 UK Biobank participants with an imaging and ECG visit, prevalent type 2 diabetes and no known cardiovascular events at the time of visit. The control cohort is matched on age, sex and body mass index (BMI), and consists of 1,781 participants without diabetes. ECG and CMR biomarkers derived from UK Biobank data were used as outcome variables. We built four multiple multivariate linear regression models, incrementally adjusted for socio-demographic, lifestyle, and clinical covariates. Results Both cohorts were mostly male (63.6%), had a median age of 67 years [IQR: 72-85] and a median BMI of 27.8 kg/m2 [24.6-31.0]. Individuals with type 2 diabetes were more likely to be non-white (7.9% vs 2.7%, p&amp;lt;0.001), current or previous smokers (43.6% vs 40.6%, p=0.04), have lower diastolic blood pressure (79 [72-85] vs 81 [74-88] mmHg, p&amp;lt;0.001), and take cholesterol medication (72.3% vs 27.2%, p&amp;lt;0.001); anti-hypertensives (56.3% vs 27.3%, p&amp;lt;0.001); insulin (13.7% vs 0.1%, p&amp;lt;0.001); and metformin (53.1% vs 0.1%, p&amp;lt;0.001). They had a higher ventricular rate, shorter QRS duration, longer QTc interval, and flatter T wave amplitude, as well as lower left ventricular end-diastolic and end-systolic volumes, among other differences (Table 1). Covariates including cholesterol medication, metformin, and HbA1c were excluded as they were strongly correlated with diabetes, age and/or sex (Pearson correlation coefficient &amp;gt;0.3 or &amp;lt;-0.3). After full adjustment, we found that the exposure variable, diabetes, had a statistically significant association with ventricular rate, QRS duration, T wave offset, T wave amplitude in lead V3, left ventricular stroke volume and global average thickness (p&amp;lt;0.05) (Table 2). Conclusion Our results reveal that individuals with type 2 diabetes exhibit a shorter QRS, longer QTc, and lower end-diastolic and end-systolic volumes, compared to matched controls. This may be indicative of subclinical cardiac abnormalities, both electrophysiological and mechanical. Our association analysis suggests that other factors correlated with diabetes may be also responsible for certain biomarker differences and their underlying causes.