Impaired Cardiac Function Research Articles

Assessment of right ventricular sequelae by speckle tracking echocardiography in recovered COVID-19 patients

Background TTE is the main modality used to assess RV function, but conventional TTE parameters have limited diagnostic value because they may fail to detect early abnormalities in RV systolic function. Due to its ability to detect subclinical impairment of cardiac function, 2D STE has been widely used to investigate RV function. In this study, we aimed to investigate whether there are sequelae of RV function in recovered COVID-19 patients with pulmonary involvement. Methods This is a prospective observational cohort study of 57 healthy volunteers and 54 patients. Participants had no history of chronic illness and no evidence of respiratory or cardiac symptoms. The patients had been hospitalised with COVID-19 with pulmonary involvement but did not require intensive care unit follow-up or non-invasive mechanical ventilation support. TTE was performed. Demographic and clinical characteristics and laboratory test results were collected. Results LVEF, TAPSE, St and FAC were significantly lower in the patient group. LV-LS 3-chamber, LV-GLS, RV-FWS, RV-GLS were significantly lower in the patient group. Conclusions RV-LS and LV-GLS were shown to decrease in the patient group. Although no obvious pathological values were observed in RV parameters on conventional echocardiography, TAPSE, St and FAC values were lower in the patient group.

Skeletal muscle symptoms and quantitative MRI in females with dystrophinopathy.

The dystrophinopathies primarily affect males; however, female carriers of pathogenic dystrophin variants can develop skeletal muscle symptoms. This study aimed to evaluate muscle involvement and symptoms in females with dystrophinopathy using quantitative magnetic resonance imaging (MRI), functional assessments, and patient-reported outcomes. Controls and females with dystrophinopathy with muscle symptoms of pain, weakness, fatigue, or excessive tightness were enrolled in this cross-sectional study. Participants underwent lower extremity MRI to quantify muscle inflammation, replacement by fat, and disease asymmetry. Cardiac MRI, functional ability, muscle symptoms, and serum creatine kinase levels were also evaluated. Six pediatric females with dystrophinopathy (mean age: 11.7 years), 11 adult females with dystrophinopathy (mean age: 41.3 years), and seven controls enrolled. The mean fat fraction was increased in females with dystrophinopathy compared to controls in the soleus (0.11 vs. 0.03, p = .0272) and vastus lateralis (0.16 vs. 0.03, p = .004). Magnetic resonance spectroscopy water T2, indicative of muscle inflammation, was elevated in the soleus and/or vastus lateralis in 11 of 17 individuals. North Star Ambulatory Assessment score was lower in the dystrophinopathy group compared to controls (29 vs. 34 points, p = .0428). From cardiac MRI, left ventricle T1 relaxation times were elevated in females with dystrophinopathy compared to controls (1311 ± 55 vs. 1263 ± 25 ms, p < .05), but ejection fraction and circumferential strain did not differ. Symptomatic females with dystrophinopathy quantitatively demonstrate muscle replacement by fat and inflammation, along with impairments in functional ability and cardiac function. Additional research is needed to evaluate how symptoms and muscle involvement change longitudinally.

Lab-on-a-chip models of cardiac inflammation.

Cardiovascular diseases are the leading cause of morbidity and mortality worldwide with numerous inflammatory cell etiologies associated with impaired cardiac function and heart failure. Inflammatory cardiomyopathy, also known as myocarditis, is an acquired cardiomyopathy characterized by inflammatory cell infiltration into the myocardium with a high risk of progression to deteriorated cardiac function. Recently, amidst the ongoing COVID-19 pandemic, the emergence of acute myocarditis as a complication of SARS-CoV-2 has garnered significant concern. Given its mechanisms remain elusive in conjunction with the recent withdrawal of previously FDA-approved antiviral therapeutics and prophylactics due to unexpected cardiotoxicity, there is a pressing need for human-mimetic platforms to investigate disease pathogenesis, model dysfunctional features, and support pre-clinical drug screening. Traditional in vitro models for studying cardiovascular diseases have inherent limitations in recapitulating the complexity of the in vivo microenvironment. Heart-on-a-chip technologies, combining microfabrication, microfluidics, and tissue engineering techniques, have emerged as a promising approach for modeling inflammatory cardiac diseases like myocarditis. This review outlines the established and emerging conditions of inflamed myocardium, identifying key features essential for recapitulating inflamed myocardial structure and functions in heart-on-a-chip models, highlighting recent advancements, including the integration of anisotropic contractile geometry, cardiomyocyte maturity, electromechanical functions, vascularization, circulating immunity, and patient/sex specificity. Finally, we discuss the limitations and future perspectives necessary for the clinical translation of these advanced technologies.

Abstract 47: Deletion of PRR in AgRP Neurons of the Arcuate Nucleus Contributes to the Development of DOCA-Salt Hypertension

Agouti-related protein (AgRP) neurons, a key neuronal population within the arcuate nucleus (ARC), are known for their pivotal roles in regulating energy- and glucose homeostasis. However, their involvement in cardiovascular regulation remains poorly understood. Using RNAscope in situ hybridization, we found that 95.4% of the ARC AgRP neurons express the (pro)renin receptor (PRR), a component of the brain renin-angiotensin system that is crucial for blood pressure (BP) regulation. We therefore hypothesized that PRR signaling in the ARC AgRP neurons plays a regulatory role in the development of hypertension. To test this hypothesis, we selectively deleted PRR in ARC AgRP neurons by crossing AgRP-IRES-Cre mice with PRR fl/fl mice. Using RNAscope, as expected, AgRP Cre+ PRR fl/y mice displayed a significantly lower PRR mRNA in the ARC AgRP neurons than WT mice (76.3 ± 6.1 vs. 127.7 ± 2.9 AFU, p &lt; 0.05), indicating efficient ablation of PRR in ARC AgRP neurons. To examine the impact of PRR deletion in the ARC AgRP neurons on BP, the AgRP Cre+ PRR fl/y and control mice were implanted with telemetry probes to monitor BP continuously. After baseline recording, mice received DOCA-salt treatment (50 mg DOCA + saline as drinking water) for two weeks. BP variability and standard time domain heart rate variability (HRV) parameters, including overall HRV (SDNN) and short-term HRV (rMSSD), were analyzed from beat-to-beat intervals (n = 2-7 mice/group). At baseline, there was no difference between the two groups in BP, BP variability, and HRV. Two weeks of DOCA-salt induced a significantly higher BP in AgRP Cre+ PRR fl/y mice than the controls (156.2 ± 6 vs. 119.4 ± 3 mmHg, p &lt; 0.05), while BP variability did not differ between the two groups. Noteworthy, AgRP Cre+ PRR fl/y mice exhibited lower SDNN than the controls (13.3 ± 4 vs. 19.4 ± 4 ms), indicating increased sympathetic and/or reduced parasympathetic nervous activity. This lower SDNN suggests impaired cardiac autonomic function and adaptability to physiological demands in AgRP Cre+ PRR fl/y mice. Concurrently, AgRP Cre+ PRR fl/y mice showed a lower rMSSD (4.7 ± 0.5 vs. 10.8 ± 3.5 ms), implying reduced parasympathetic activity. In conclusion, deletion of PRR in the ARC AgRP neurons results in compromised cardiac autonomic function associated with the development of hypertension. Our findings underscore a novel protective role of PRR signaling in the ARC AgRP neurons in BP regulation.

Cardiac dysfunction in dialysing adults with end-stage kidney disease is associated with exercise intolerance: A pilot observational study.

People with end-stage kidney disease (ESKD) often exhibit impaired cardiac structure and function, which may contribute to poor exercise capacity. This study used multimodal exercise testing to investigate the central and peripheral mechanisms of exercise limitation in adults with ESKD, also comparing in-centre hemodialysis (ICHD) to home hemodialysis (HHD). Seventeen adults (55.5 ± 14.5 years; n = 14 male; n = 12 HHD) participated. Resting cardiac examinations, followed by submaximal cycling cardiopulmonary exercise testing (CPET) and functional exercise testing, revealed cardiac structural abnormalities (increased left ventricular mass) and cardiac injury. Aerobic fitness in adults with ESKD was low, with pulmonary oxygen uptake (V̇O2) at the gas exchange threshold (GET) occuring at 39 ± 8% predicted V̇O2peak. O2 pulse, an estimate of stroke volume (SV), was higher in HHD at rest (p = 0.05, ES = 0.58) and during unloaded cycling (p = 0.05, ES = 0.58) compared to ICHD. However, thoracic bioreactance derived SV at the GET was significantly higher in adults receiving ICHD versus HHD (p = 0.01, ES = 0.74). In adults with ESKD, cardiac output was positively associated with V̇O2 at the GET (r = 0.61, p = 0.04). This study highlights prevalent exercise dysfunction in adults with ESKD undergoing dialysis, with potential distinct differences between in-centre and home hemodialysis, mechanistically linked to underlying cardiac abnormalities.

High Uric Acid Orchestrates Ferroptosis to Promote Cardiomyopathy Via ROS-GPX4 Signaling.

Aims: High uric acid (HUA), as a pro-oxidant, plays a significant role in the pathophysiology of cardiovascular disease. Studies have indicated that elevated uric acid levels can adversely affect cardiovascular health. Nevertheless, the impact of hyperuricemia on cardiomyopathy remains uncertain. Further research is needed to elucidate the relationship between HUA and cardiomyopathy, shedding light on its potential implications for heart health. Results: We demonstrated that uricase knockout (Uox-KO) mice accelerated the development of cardiomyopathy, causing significantly impaired cardiac function and myocardial fibrosis. Meanwhile, the mitochondrial morphology was destroyed, the lipid peroxidation products increased in number and the antioxidant function was weakened. In addition, we evaluated the effects of ferrostatin-1 (Fer-1), the ferroptosis inhibitor. Myocardial damage can be reversed by the Fer-1 treatment caused by HUA combined with doxorubicin (DOX) treatment. Benzbromarone, a uric acid-lowering drug, decreases myocardial fibrosis, and ferroptosis by alleviating hyperuricemia in Uox-KO mice by DOX administration. In vitro, we observed that the activity of cardiomyocytes treated with HUA combined with DOX decreased significantly, and lipid reactive oxygen species (ROS) increased significantly. Afterward, we demonstrated that HUA can promote oxidative stress in DOX, characterized by increased mitochondrial ROS, and downregulate protein levels of glutathione peroxidase 4 (GPX4). N-acetyl-l-cysteine, an antioxidant, inhibits the process by which HUA promotes DOX-induced ferroptosis by increasing the GPX4 expression. Innovation: We verified that HUA can exacerbate myocardial damage. This has clinical implications for the treatment of cardiac damage in patients with hyperuricemia. Conclusions: Our data suggested that HUA promotes the cardiomyopathy. HUA promotes DOX-induced ferroptosis by increasing oxidative stress and downregulating GPX4. Antioxid. Redox Signal. 00, 00-00.

Preventing Cardiac Damage in Patients Treated for Breast Cancer and Lymphoma: The PROACT Clinical Trial

BackgroundCardiotoxicity is a concern for cancer survivors undergoing anthracycline chemotherapy. Enalapril has been explored for its potential to mitigate cardiotoxicity in cancer patients. The dose-dependent cardiotoxicity effects of anthracyclines can be detected early through the biomarker cardiac troponin. ObjectivesThe PROACT (Preventing Cardiac Damage in Patients Treated for Breast Cancer and Lymphoma) clinical trial assessed the effectiveness of enalapril in preventing cardiotoxicity, manifesting as myocardial injury and cardiac function impairment, in patients undergoing high-dose anthracycline-based chemotherapy for breast cancer or non-Hodgkin lymphoma. MethodsThis prospective, multicenter, open-label, randomized controlled trial employed a superiority design with observer-blinded endpoints. A total of 111 participants, scheduled for 6 cycles of chemotherapy with a planned dose of ≥300 mg/m2 doxorubicin equivalents, were randomized to receive either enalapril (titrated up to 20 mg daily) or standard care without enalapril. ResultsMyocardial injury, indicated by cardiac troponin T (≥14 ng/L), during and 1 month after chemotherapy, was observed in 42 (77.8%) of 54 patients in the enalapril group vs 45 (83.3%) of 54 patients in the standard care group (OR: 0.65; 95% CI: 0.23-1.78). Injury detected by cardiac troponin I (>26.2 ng/L) occurred in 25 (47.2%) of 53 patients on enalapril compared with 24 (45.3%) of 53 in standard care (OR: 1.10; 95% CI: 0.50-2.38). A relative decline of more than 15% from baseline in left ventricular global longitudinal strain was observed in 10 (21.3%) of 47 patients on enalapril and 9 (21.9%) of 41 in standard care (OR: 0.95; 95% CI: 0.33-2.74). An absolute decline of >10% to <50% in left ventricular ejection fraction was seen in 2 (4.1%) of 49 patients on enalapril vs none in patients in standard care. ConclusionsAdding enalapril to standard care during chemotherapy did not prevent cardiotoxicity in patients receiving high-dose anthracycline-based chemotherapy. (PROACT: Can we prevent Chemotherapy-related Heart Damage in Patients With Breast Cancer and Lymphoma?; NCT03265574)

Epicardial fat in heart failure-Friend, foe, or bystander.

Epicardial adipose tissue (EAT) is a fat depot covering the heart. No physical barrier separates EAT from the myocardium, so EAT can easily affect the underlying cardiac muscle. EAT can participate in the development and progression of heart failure with preserved (HFpEF) and reduced ejection fraction (HFrEF). In healthy humans, excess EAT is associated with impaired cardiac function and worse outcomes. In HFpEF, this trend continues: EAT amount is usually increased, and excess EAT correlates with worse function/outcomes. However, in HFrEF, the opposite is true: reduced EAT amount correlates with worse cardiac function/outcomes. Surprisingly, although EAT has beneficial effects on cardiac function, it aggravates ventricular arrhythmias. Here, we dissect these phenomena, trying to explain these paradoxical findings to find a target for novel heart failure therapies aimed at EAT rather than the myocardium itself. However, the success of this approach depends on a thorough understanding of interactions between EAT and the myocardium.

Comprehensive Clinical Characterization of Patients Diagnosed With Dilated Cardiomyopathy: A Cross-Sectional Study.

Background The term "cardiomyopathy" encompasses a wide range of diseases with various underlying causes. Dilated cardiomyopathy (DCM) is characterized by ventricular dilation and impaired cardiac function in the absence of congenital, valvular, hypertensive, or ischemic heart disease (IHD). This study was motivated by the high prevalence of underlying DCM and chronic heart failure, coupled with a lack of comprehensive information on DCM. The primary objective of this study was to identify the clinical characteristics and contributing factors associated with individuals diagnosed with DCM. Methods A total of 120 patients with DCM were enrolled in a two-year, hospital-based observational cross-sectional study conducted within the Medicine Department of a tertiary care center. The study assessed risk factors, including IHD, diabetes mellitus, alcohol consumption, and smoking. Results DCM was observed across all age groups, though it was notably more prevalent among middle-aged individuals (n = 50, or 41.7%) and the elderly (n = 35, or 37.5%). The condition was more commonly seen in men. IHD emerged as the predominant risk factor, affecting 75% of patients (n = 90), followed by diabetes mellitus (n = 85, or 70.8%), alcohol use (n = 75, or 62.5%), and smoking (n = 50, or 41.7%). Common symptoms included pedal edema, palpitations, easy fatigability, and exertional dyspnea. Conclusion In conclusion, DCM is a critical condition that necessitates vigilant monitoring. Consistent observation of symptoms, recognition of potential triggers, and prompt identification of adverse drug reactions, electrolyte disturbances, and echocardiographic changes are essential. This awareness and early detection were responsible for the lower mortality and early symptom improvement observed in the present study group.

Cannabinoid receptor-2 agonist AM1241 attenuates myocardial ischemia-reperfusion-induced oxidative stress in rats via Nrf2/HO-1 pathway.

The cannabinoid receptor-2 agonist AM1241 exhibits notable cardioprotective effects against myocardial infarction, positioning it as a promising therapeutic candidate for cardiovascular disease. This study explores AM1241's protective role in myocardial ischemia-reperfusion (IR) injury and its association with the Nrf2/HO-1 pathway. In an established SD rat IR model, AM1241's impact on cardiac injury was assessed through echocardiography, 2,3,5-triphenyl tetrazolium chloride staining, and histological analysis. H9c2 cells underwent hypoxia-reoxygenation, with AM1241's influence on cell viability determined by the CCK-8 assay. Reactive oxygen species (ROS) production was measured using the DCFH-DA assay, and Nrf2 and HO-1 protein expressions were evaluated through immunofluorescence and Western blot. Myocardial ischemia-reperfusion injury (MIRI) increased infarct size, inflammatory cell presence, oxidative and nitrosative stress, impaired cardiac function, and elevated apoptosis rates. AM1241 mitigated these effects, enhancing cell viability, reducing ROS production, and upregulating Nrf2 and HO-1 expression. The antioxidant effect of AM1241 was inhibited by ML385 intervention. AM1241 attenuates oxidative stress, alleviates MIRI, and activates the Nrf2/HO-1 signaling pathway, underscoring its potential as a therapeutic strategy for myocardial ischemia-reperfusion injury.

Compromised cardiac autonomic function in non-diabetic subjects with 1 h post-load hyperglycemia: a cross-sectional study

BackgroundA compromised cardiac autonomic function has been found in subjects with insulin resistance related disorders such as obesity, impaired glucose tolerance (IGT) and type 2 diabetes and confers an increased risk of adverse cardiovascular outcomes. Growing evidence indicate that 1 h plasma glucose levels (1hPG) during an oral glucose tolerance test (OGTT) ≥ 155 mg/dl identify amongst subjects with normal glucose tolerance (NGT) a new category of prediabetes (NGT 1 h-high), harboring an increased risk of cardiovascular organ damage. In this study we explored the relationship between 1 h post-load hyperglycemia and cardiac autonomic dysfunction.MethodsPresence of cardiac autonomic neuropathy (CAN) defined by cardiovascular autonomic reflex tests (CARTs) and heart rate variability (HRV), assessed by 24-h electrocardiography were evaluated in 88 non-diabetic subjects subdivided on the basis of OGTT data in: NGT with 1 h PG < 155 mg/dl (NGT 1 h-low), NGT 1 h-high and IGT.ResultsAs compared to subjects with NGT 1 h-low, those with NGT 1 h-high and IGT were more likely to have CARTs defined CAN and reduced values of the 24 h time domain HVR parameters including standard deviation of all normal heart cycles (SDNN), standard deviation of the average RR interval for each 5 min segment (SDANN), square root of the differences between adjacent RR intervals (RMSSD), percentage of beats with a consecutive RR interval difference > 50 ms (PNN50) and Triangular index. Univariate analyses showed that 1hPG, but not fasting and 2hPG, was inversely associated with all the explored HVR parameters and positively with CARTs determined presence of CAN. In multivariate regression analysis models including several confounders we found that 1hPG was an independent contributor of HRV and presence of CAN.ConclusionSubjects with 1hPG ≥ 155 mg/dl have an impaired cardiac autonomic function.

Cardiac biomarkers are associated with increased risks of adverse clinical outcomes after ischemic stroke.

Impaired cardiac function was suggested to be implicated in the functional recovery after ischemic stroke, but the prognostic value of cardiac biomarkers among ischemic stroke patients remains unclear. We aimed to prospectively explore the associations of serum lactate dehydrogenase (LDH), plasma N-terminal pro-brain natriuretic peptide (NT-proBNP), and plasma high-sensitivity cardiac troponin T (hs-cTnT) with adverse clinical outcomes after ischemic stroke in a large-scale cohort study. We measured serum LDH, plasma NT-proBNP, and plasma hs-cTnT levels at baseline among 5056 ischemic stroke patients from the Minhang Stroke Cohort study. All patients were followed up at 3months after ischemic stroke onset. The primary outcome was composite outcome of death and major disability (modified Rankin Scale [mRS] score ≥ 3) at 3months after stroke onset, and secondary outcomes included death and ordered 7-level categorical score of the mRS. During 3months of follow-up, 1584 patients developed the primary outcome. Baseline serum LDH, plasma NT-proBNP, and plasma hs-cTnT were positively associated with the risk of adverse outcomes after ischemic stroke. The multivariable-adjusted odds ratios of primary outcome for the highest versus lowest quartile of LDH, NT-proBNP, and hs-cTnT were 1.37 (95% CI 1.13-1.66; Ptrend = 0.001), 2.51 (95% CI, 2.00-3.16; Ptrend < 0.001), and 2.24 (95% CI 1.77-2.83; Ptrend < 0.001), respectively. Each SD increase of log-transformed cardiac biomarker score was associated with a 49% (95% CI 37-62%; P < 0.001) increased risk of primary outcome. Multivariable-adjusted spline regression analyses showed linear relationships between cardiac biomarkers and the risk of primary outcome (all P for linearity < 0.001). Moreover, adding LDH, NT-proBNP, hs-cTnT, or cardiac biomarker score to conventional risk factors significantly improved the risk reclassification of primary outcome after ischemic stroke (all P < 0.05). High LDH, NT-proBNP, hs-cTnT, and cardiac biomarker score were independently associated with increased risks of adverse clinical outcomes among ischemic stroke patients, suggesting that cardiac biomarkers might be potential prognostic biomarkers for ischemic stroke.

ZC3H13-Mediated m6A Modification Ameliorates Acute Myocardial Infarction through Preventing Inflammation, Oxidative Stress and Ferroptosis by Targeting lncRNA93358.

Acute myocardial infarction (AMI) is a life-threatening event that is associated with RNA modification and programmed cell death (PCD). This study attempted to investigate the impacts of zinc finger CCCH domain-containing protein 13 (ZC3H13)-mediated N6-methyladenosine (m6A) on ferroptosis in AMI. The infarcted areas and cardiac function were evaluated, and the expression level of ZC3H13 was measured in AMI rats that were induced by isoproterenol. Meanwhile, oxygen glucose deprivation (OGD) in vitro model was induced to investigate the alterations on inflammation, oxidative stress and ferroptosis. The m6A modification site of lncRNA93358 modified by ZC3H13 was predicted using bioinformatics, and the interaction between ZC3H13 and lncRNA93358 was verified using the dual-luciferase reporter assays. ZC3H13 was overexpressed and lncRNA93358 was silenced to study their regulatory role in cell death, inflammation, oxidative stress and ferroptosis in AMI. Significant decreased expression of ZC3H13 was observed in AMI rats, with impaired cardiac function, enhanced inflammation and oxidative stress. ZC3H13 targeted the modification site GGACC of lncRNA93358 and downregulated lncRNA93358. Silencing lncRNA93358 inhibited cell death, reduced the levels of inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-1β, suppressed oxidative stress-related indicators (lactate dehydrogenase (LDH), reactive oxygen species (ROS), glutathione (GSH) and malondialdehyde (MDA), as well as downregulated ferroptosis-related acyl-CoA synthetase long chain family member 4 (ACSL4), prostaglandin-endoperoxide synthase 2 (PTGS2) and glutathione peroxidase 4 (GPX4). The effect of silencing lncRNA93358 was further enhanced by overexpression of ZC3H13. This study reveals the ZC3H13-mediated epigenetic RNA modification targeting lncRNA93358 and suggests that ZC3H13 overexpression may be a promising approach for AMI treatment.

Novel Approach for Cardioprotection: In Situ Targeting of Metformin via Conductive Hydrogel System.

Ischemia/reperfusion (I/R) injury following myocardial infarction is a major cause of cardiomyocyte death and impaired cardiac function. Although clinical data show that metformin is effective in repairing cardiac I/R injury, its efficacy is hindered by non-specific targeting during administration, a short half-life, frequent dosing, and potential adverse effects on the liver and kidneys. In recent years, injectable hydrogels have shown substantial potential in overcoming drug delivery challenges and treating myocardial infarction. To this end, we developed a natural polymer hydrogel system comprising methacryloylated chitosan and methacryloylated gelatin modified with polyaniline conductive derivatives. In vitro studies demonstrated that the optimized hydrogel exhibited excellent injectability, biocompatibility, biodegradability, suitable mechanical properties, and electrical conductivity. Incorporating metformin into this hydrogel significantly extended the administration cycle, mitigated mitochondrial damage, decreased abnormal ROS production, and enhanced cardiomyocyte function. Animal experiments indicated that the metformin/hydrogel system reduced arrhythmia incidence, infarct size, and improved cardiac mitochondrial and overall cardiac function, promoting myocardial repair in I/R injury. Overall, the metformin-loaded conductive hydrogel system effectively mitigates mitochondrial oxidative damage and improves cardiomyocyte function, thereby offering a theoretical foundation for the potential application of metformin in cardioprotection.

The cGAS-STING Pathway: A New Therapeutic Target for Ischemia-Reperfusion Injury in Acute Myocardial Infarction?

The innate immune system is the body's natural defense system, which recognizes a wide range of microbial molecules (such as bacterial DNA and RNA) and abnormal molecules within cells (such as misplaced DNA, self-antigens) to play its role. DNA released into the cytoplasm activates the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway to initiate an immune response. Ischemia-reperfusion injury (IRI) after acute myocardial infarction refers to the phenomenon where myocardial tissue suffers further damage upon the restoration of blood flow. This issue is a significant clinical problem in the treatment of myocardial infarction, as it can diminish the effectiveness of reperfusion therapy and lead to further deterioration of cardiac function. Studies have found that the cGAS-STING signaling pathway is closely related to this phenomenon. Therefore, this review aims to describe the role of the cGAS-STING signaling pathway in ischemia-reperfusion injury after myocardial infarction and summarize the current development status of cGAS-STING pathway inhibitors and the application of nanomaterials to further elucidate the potential of this pathway as a therapeutic target.

Abstract Tu111: Effect Of Grandmaternal Diabetes and High Fat Diet on Cardiometabolic Dysfunction in the Second Generation (F2) Newborns

Infants exposed to diabetic pregnancy are at higher risk of cardiomyopathy at birth and early onset cardiovascular disease (CVD) as adults. We have previously used a rat model to demonstrate that a combination of high fat diet (HFD) and late gestational diabetes causes impaired cardiac function in first generation (F1) newborn and adult offspring via mitochondrial dysfunction and metabolic stress. The objective of this study was to determine whether grandmaternal HFD and diabetes can cause inheritable CVD in second generation offspring (F2), even if the first generation is cross fostered during lactation and fed a standard control diet throughout life. Myocardial function in the F2 newborns was assessed using echocardiography and mitochondrial function in the isolated neonatal cardiomyocytes (NRCM) was assessed using extracellular flux analyses. Exposed F2 newborns had a higher birthweight (p=0.03) and blood glucose (p&lt;0.0001) compared to control newborns and F1 generation parents (p=0.0002 and p&lt;0.0001). Of significant interest, exposed F2 newborns had higher heart rates (p&lt;0.0001), heart:body weight ratios (p&lt;0.0001) and systolic dysfunction which was evident from lower ejection fraction (p&lt;0.0001) and fractional shortening (p&lt;0.0001) compared to control F2 newborns. While control and combination exposed NRCM had similar basal respiration, exposed F2 NRCM had a higher proton leak (p=0.0004) which indicates damage to the inner mitochondrial membrane and/or electron transport chain complex. There was also shift to higher glycolysis at baseline (p=0.005), but blunted glucose-induced glycolytic rate (p=0.04) in F2 newborns compared to controls. Overall results suggest that maternal HFD and diabetes causes multigenerational programming of cardiometabolic dysfunction in F2 offspring despite the F1 parent having normal diet, weight, and euglycemia during the pregnancy.

Abstract We064: Investigating the Cardioprotective Role of Neutrophil-Specific STING in Myocardial Ischemia/Reperfusion Injury

Introduction: Inflammation following myocardial ischemia/reperfusion injury (MI/R) plays a significant role in damaging cardiomyocytes and influencing infarct size, with neutrophils being the most rapid and numerous cells recruited to the myocardium post reperfusion. Single-cell RNA sequencing data identified neutrophils with upregulated type I interferon (IFN) signaling in the hearts of mice 24 hours post-MI/R. Aim: This study aims to address how the type I IFN neutrophil phenotype identified affects inflammation in MI/R. We hypothesize that neutrophils with upregulated type I IFN signaling are cardioprotective in MI/R. Methods: Male neutrophil-specific STING knockout (KO) mice underwent 60 minutes of ischemia followed by reperfusion for 24 hours. Immune cells were isolated from the left ventricle for flow cytometry. Subsequently, mice underwent 60 minutes of ischemia followed by reperfusion, and cardiac function was assessed two weeks-post reperfusion. Results: Flow cytometry revealed a significant decrease in the number of neutrophils in the myocardium of neutrophil-specific STING KO mice compared to wildtype mice after 24 hours of reperfusion (5.7x10 4 ± 1.0x10 4 ; 8.7x10 4 ± 1.9x10 4 , Two-way ANOVA, N=5-6, p=0.0006). Neutrophil-specific STING KO mice showed significant reduction in ejection fraction (29.2% ± 6.4) compared to wildtype mice (38.3% ± 6.7; Two-way ANOVA, N=4-5, p=0.036), and significantly increased left ventricular end systolic volume (4.39mm ± 0.48) compared to wildtype mice (3.59 ± 0.62; Two-way ANOVA, N=4-5, p=0.017), indicating impaired cardiac function in knockout mice. Conclusion: These data suggest that neutrophil STING plays a cardioprotective role in MI/R. These studies provide the foundation to further investigate the cardioprotective mechanisms behind neutrophil-specific STING. Identifying a novel cardioprotective mechanism could be a clinically feasible point of intervention to improve recovery after MI/R.

Abstract Mo127: Nitrate Supplementation Plus Voluntary Activity in C57Bl/6 Mice Improves Fitness and Impairs Cardiac Calcium Handling In a Sex Specific Fashion

Nitrate supplements are commonly combined with aerobic exercise to potentially improve performance and cardiac function. Whether this combination benefits cardiac function at the organ and cellular levels is unclear. We will determine if nitrates affect fitness or cardiac function in both sexes. C57Bl/6 mice (9-mos) were given 1mM sodium nitrate (drinking water) and/or access to a running wheel for 3 mos. Cardiac function (echocardiography), blood pressure (tail cuff) and fitness (treadmill) were measured. Calcium transients (Fura-2) and contractions (2Hz) were measured in ventricular myocytes and calcium handling proteins were measured by qPCR. In both sexes, nitrates did not change blood pressure or voluntary wheel running although females ran more than males (3.7±0.3km vs 2.2±0.3km, p=0.002). In exercised female mice, nitrates increased fitness from baseline while control did not (top speed at exhaustion: 24.2±1.4 to 28.0±1.5 cm/s, p=0.07 vs 23.3±1.0 to 30.7±2.0 cm/s, p=0.002) but nitrate supplemented males showed no fitness benefit. However, while exercise improved cardiac function and contractility compared to sedentary mice, nitrates plus exercise impaired cardiac function in a sex-specific manner. Nitrate-treated males who exercised had lower E/A ratios (1.8±0.3 vs 1.3±0.1, p=0.01) and worse diastolic function than control exercised males. By contrast, nitrate-treated female mice who exercised had smaller global longitudinal strain (-19.5±1.5 vs -11.8±3.0%, p=0.01) than controls, indicative of worse systolic function. Corresponding changes were seen at the cellular level. Exercised males given nitrates had slower a calcium transient decay than controls (44.8±4 vs 73.8±6 ms, p=0.01), while females given nitrates had slower velocity to peak calcium (0.031±0.004 vs 0.018±0.003 µm/ms, p=0.005) and smaller cellular contractions (2.9±0.5 µm vs 1.4±0.5 µm: p=0.03). Cardiac calcium handling proteins were also modified in females. Exercise plus nitrates caused a decrease in SERCA2a and ryanodine receptor 2 expression (mRNA) compared to the control exercise group. Studies in males are ongoing. Exercise plus nitrates increased fitness levels in only females and reduced cardiac function in a sex specific way when compared to exercise alone. This suggests a potential balance between benefits to fitness and potential cardiac complications that could affect athletes taking nitrate supplementation.

Abstract We126: Myocarditis Following mRNA Vaccination for COVID-19 is Mediated by CXCL10 and IFN-γ

Introduction: mRNA vaccines have shown remarkable efficacy against symptomatic COVID-19, reshaping the pandemic's trajectory. Despite a robust safety profile, ongoing monitoring is crucial due to the rare but concerning myocarditis cases, predominantly affecting males under 30. Symptoms appear around 2.6 days post-vaccination, with chest pain, shortness of breath, and palpitations. Elevated cTnI and ST-segment changes are common, along with late gadolinium enhancement in cardiac MRI. Understanding these rare adverse effects is essential for the expanding scope of mRNA technology, spanning infectious disease vaccines and anti-cancer immunotherapies. Hypothesis: Myocarditis linked to COVID-19 mRNA vaccines involves cytokine production from myeloid cells, leading to impaired cardiac function. Methodology: a, Reanalysis of proteomics data of healthy and myocarditis individuals following COVID-19 vaccination; b, Macrophages (N = 7 lines) were exposed to BNT162b2 or mRNA-1273, and analyzed by cytokine array and RNA-seq; c, Cardiomyocytes (N = 4 lines) were treated with CXCL10 (1 and 10 ng/mL) and IFN-γ (0.5 and 5 ng/mL), with or without genistein (10 μM), followed by functional assessment, transcriptomic and proteomic profiling; d, Mice (6 per group) were administered with CXCL10 and IFN-γ, with or without genistein pretreatment (7 days). Myeloid cell infiltration in the heart, serum cTnI levels, RNA-seq, and immunoproteasome activity were analyzed. Results: Examination of post-vaccination plasma revealed a notable rise in CXCL10 and IFN-γ levels in patients. Similarly, macrophages exposed to mRNA vaccines displayed heightened production of these cytokines. When cardiomyocytes were exposed to these cytokines, they exhibited compromised contractility, increased arrhythmogenicity, and gene expression patterns reminiscent of myocarditis. Genistein, an anti-inflammatory phytoestrogen, demonstrated significant alleviation of these effects, preventing cytokine-induced proteasomal activation and preserving contractile function. Mouse model of cytokine-induced myocarditis showed that genistein substantially reduced cardiac injury markers and immune cell infiltration. Conclusion: These findings highlight CXCL10 and IFN-γ as pivotal contributors to myocarditis following mRNA vaccination and suggest genistein as a potential therapeutic intervention to mitigate associated cardiovascular risks.

Abstract We144: Fto Deficiency Causes Cardiac Dysfunction by Altering Expression of Serca2a mRNA

Introduction and Research Question: The impact of post-transcriptional regulation of gene expression, including N6-methyladenosine (m6A) messenger RNA methylation, on cardiac function has not yet been fully understood. Our study found that the absence of the m6A eraser, Fat mass and obesity-associated protein (Fto), in cardiomyocytes of adult mice led to cardiac dysfunction and cardiac hypertrophy. Methods and Results: To evaluate Fto physiological functions, we generated a tamoxifen-inducible cardiac-specific Fto knockout mouse model (Fto cKO). This resulted in a substantial reduction of Fto at both mRNA and protein levels in the whole heart, leading to an almost complete absence of Fto within cardiomyocytes. Echocardiography analyses showed that Fto cKO mice exhibit impaired cardiac functions, indicated by a 30% reduction in ejection fraction and 40% decrease in fractional shortening after one month of deletion of cardiac Fto ( p&lt;0.01 ). We found a significant increase in heart weight to body weight ratios in Fto cKO animals ( p&lt;0.05 ). This result corresponded with an increased expression of hypertrophic markers including Nppb and Myh7 mRNA in the absence of Fto ( p&lt;0.01 ). We noted an increase in the length of Fto cKO cardiomyocytes ( p&lt;0.05 ) in isolated cardiomyocytes, a characteristic feature of eccentric pathologic hypertrophy. Electron microscopy analysis of intact hearts showed ultrastructure abnormalities in cardiomyocytes from Fto cKO mice including Z-line density loss and disarray in cristae alignment of mitochondria. Moreover, cardiomyocytes from Fto cKO mice demonstrated defects in sarcomeric shortening including a prolongation of time to 90% peak, time to 90% rest, and decay time constant of relaxation for sarcomere shortening ( p&lt;0.001 ), compared to control mice. Mechanistically, we found down-regulation of Serca2a and Ryr2 mRNA in cardiomyocytes lacking Fto. We further demonstrated that Fto binds Serca2a mRNA and controls its cytoplasmic-nuclear shuttling. Fto deficiency led to accumulation of Serca2a mRNA in the nucleus. Conclusion: These findings suggest that Fto plays a pivotal role as a crucial regulator for cardiac function. Consequently, our results unveil a significant and novel mechanism through which Fto-dependent regulation contributes to the preservation of cardiac homeostasis.