Risultati per: Come stress e attacchi di cuore sono collegati

Circulation, Volume 150, Issue Suppl_1, Page A4147602-A4147602, November 12, 2024. Coronary microvascular dysfunction (CMD), which is associated with diabetic cardiomyopathy, Takotsubo cardiomyopathy, andheart failure with preserved ejection fraction (HFpEF), is understudied. CMD is characterized by impaired endothelial-dependent vasodilation, but detailed mechanisms have yet to be elucidated.Nuclear Sirtuin 6 (SIRT6) plays essential roles in gene transcriptional, stress tolerance, DNA repair, inflammation, and aging. SIRT6 is strongly associated with cardiovascular pathologies, but how SIRT6 regulates endothelial metabolisms and homeostasis under metabolic stress and the underlying mechanism remains poorly understood. It might be because global Sirt6 knockout mice are perinatally lethal caused by hypoglycemia, suggesting the essential role of SIRT6 in glucose metabolism.In our preliminary studies, we generated inducible global Sirt6 knockout mice by crossing with Sirt6 f/f mice with CAG-cre (Sirt6f/f, CAG), and mice were viable with normal glucose levels. However, they showed impaired endothelial-dependent dilation (EDD) and impaired coronary flow reserve (CFR), an index clinically used to diagnose CMD. It suggests that deletion of Sirt6 might cause EC dysfunction because Sirt6 is reported to protect EC from premature senescence and oxidative stress by sustaining high eNOS levels. Surprisingly, when we studied non-inducible Sirt6 endothelial-specific knockout (Sirt6f/f, tie-2 cre) and inducible Sirt6 endothelial-specific knockout (Sirt6 f/f,Cdh5-cre/ERT2) and wild-type (WT) mice, Sirt6f/f, Tie-2and Sirt6f/f, Cadh5mice do not phenocopy the inducible global SIRT6 knockout mice, they had normal EDD and CFR. When the mice were fed a high fat and high sugar (HFHS) diet, the Sirt6f/f, Tie-2and Sirt6f/f, Cadh5had impaired EDD, suggesting Sirt 6 functioned differently in the mice fed with chow diet or HFHS diet.We hypothesize Sirt 6 deficiency causes coronary endothelial dysfunction and contributes to CMD; activating Sirt6 will ameliorate CMD. EDD was assessed using myography (DMT). Myocardial blood flow (MBF) was measured by Doppler. Our preliminary data show that the mediator of coronary vasodilation switched from NO to H2O2in the Sirt6 knockout mice with impaired EDD. Interestingly, when the mice fed on HFHS were treated with Sirt 6 activator MDL-800, the coronary microvascular function was improved, and the blood glucose level was decreased. The underlying mechanism and the pathways involved will be elucidated.

Circulation, Volume 150, Issue Suppl_1, Page A4141446-A4141446, November 12, 2024. Emerging evidence suggests that vascular stress from cardiovascular-related co-morbidities promotes microvascular dysfunction, a key component in the development of heart failure with preserved ejection fraction. The sodium glucose co-transporter 2 (SGLT2) inhibitor empagliflozin has been shown to reduce both morbidity and mortality associated with heart failure with preserved ejection fraction, however the full scope of influence of this therapy on human microvascular function remains unknown. We hypothesized that pre-treatment of isolated human microvessels with empagliflozin will prevent stress-induced endothelial dysfunction as evidenced by preserving both the magnitude of flow-induced dilation (FID) as well as the ability to dilate to nitric oxide. Human resistance arterioles (80-250µm) from healthy adults (defined as patients with ≤1 risk factor for cardiovascular disease) were dissected from discarded surgical adipose tissue and treated with empagliflozin (1µM), or vehicle control (ethanol) for 16-20 hours prior to the flow experiment. Vessels were cannulated for videomicroscopy and subjected to high intraluminal pressure (150mmHg, 30 min), an acute stress known to induce endothelial dysfunction. Vessels were pre-constricted with endothelin-1 prior to initiation of flow. A nonlinear logistic regression was used to determine differences between curves. Compared to vehicle control, vessels pre-treated with empagliflozin (1µM ) exhibited nitric oxide-dependent FID as dilation was impaired in the presence of the nitric oxide synthase inhibitor L-NAME (EC50 Control: 10.7 vs L-NAME 83.45, p=0.0107). This data suggests that empagliflozin, an SGLT2 inhibitor, promotes microvascular resilience to stress via preservation of nitric oxide-mediated FID. The ability to elicit stress resilience may explain in part some of the cardiovascular benefits associated with SGLT2 inhibitors and may offer unique opportunities for early intervention or prevention of microvascular dysfunction associated with comorbidities that contribute to heart failure with preserved ejection fraction.

Circulation, Volume 150, Issue Suppl_1, Page A4147568-A4147568, November 12, 2024. Introduction:Cardiovascular disease (CVD) and cancer are among the leading causes of morbidity and mortality worldwide. Increasing evidence suggests that sociodemographic factors such as race, ethnicity, income, education, and stress levels significantly influence the prevalence and outcomes of these diseases. TheAll of UsResearch Program provides a unique opportunity to explore these disparities across a diverse U.S. population. This study aims to examine how sociodemographic disparities are associated with stress, CVD, and cancer outcomes. We hypothesize that higher perceived stress levels, lower income, lower education levels, and minority race/ethnicity groups are associated with higher incidences of CVD and cancer.Methods:Data from 55,505All of UsResearch program participants were analyzed. Key variables included age, race, ethnicity, education, household income, perceived stress level, and history of CVD and cancer. Descriptive statistics were used to summarize participant demographics. Multivariate logistic regression models were employed to examine the associations between sociodemographic factors and the outcomes of interest (CVD and cancer).Results:Older participants had a higher prevalence of both CVD (mean age: 60.8 vs. 50.5, p < 0.001) and cancer (mean age: 63.6 vs. 51.7, p < 0.001). Black/African Americans had a higher incidence of CVD (21.3% vs. 78.7%, p < 0.001), while Whites had a higher prevalence of cancer (5.3% vs. 94.7%, p < 0.001). Lower income and higher stress levels were also associated with higher CVD incidence (

Circulation, Volume 150, Issue Suppl_1, Page A4141350-A4141350, November 12, 2024. Background:Atrial fibrosis is crucial in developing atrial fibrillation (AF). Elevated atrial pressure may significantly mediate atrial fibrosis, yet its underlying mechanisms remain unclear.Methods:Patients with AF who underwent radiofrequency ablation were recruited. Clinical data, including high-density mapping and imaging information, was analyzed. Multivariate regression analysis was performed to identify risk factors for low-voltage areas in the atrium. The CS-CREM mouse model, an autonomic AF model, was previously developed by our research group. Millar pressure catheters were used to measure left ventricular, right ventricular, and right atrial pressures in CS-CREM mice. Single-nucleus sequencing was employed to map the single-cell transcriptomes of atrial samples in CS-CREM and wild-type mice at different disease stages. Human primary atrial endocardial endothelial cells (ACCE) and HUVEC cell lines were subjected to mechanical stretch using the Flexcell tension system, followed by in vitro validation experiments. Mg101, a calpain inhibitor, was administered to CS-CREM mice for in vivo validation experiments.Results:Elevated atrial pressure in AF patients was identified as a significant risk factor for atrial fibrosis. Atrial pressure-related indices were linearly correlated with atrial fibrosis. Compared to wild-type mice, CS-CREM heterozygous mice exhibited significantly higher atrial pressure and aggravated atrial fibrosis. Single-nucleus sequencing revealed that atrial endocardial endothelial cells in CS-CREM mice underwent endothelial-mesenchymal transition (EnMT) into fibroblasts, with mechanical stress protein Flna being a critical regulatory protein. In vitro experiments demonstrated mechanical stretch-induced EnMT in ACCE and HUVEC cell lines. Mechanical stretch-activated mechanosensitive receptors on ACCE cell membranes led to increased intracellular calcium levels and calpain activation, which cleaved Flna into Flna 90. Flna 90 facilitated the nuclear translocation of transcription factor Smad3/7 and TGF-β, promoting the expressions of EnMT genes. This EnMT process was reversible with Mg101. In vivo experiments showed that Mg101 reduced the incidence of AF and mitigated atrial fibrosis in CS-CREM mice.Conclusion:Mechanical stress induces cleaved Flna 90 from Flna in atrial endocardial endothelial cells, thus assisting transcription factors Smad3/7 and TGF-β in nuclear translocation, regulating EnMT and mediating atrial fibrosis.

Circulation, Volume 150, Issue Suppl_1, Page A4146434-A4146434, November 12, 2024. Background:PET/CT stress test may be performed to risk stratify patients including those without known coronary artery disease (CAD) who may be at risk for short-term adverse cardiac events. In patients with low- to moderate (LTM) risk for short-term MACE and without a known history of CAD, a small percentage of these patients will undergo a coronary angiogram within 90-days, of which some will be diagnosed with high-grade stenosis. The purpose of this study is to determine factors associated with this approach and findings.Methods:Patients without a history of known CAD (n=43,271) undergoing a PET/CT from 2018-2023 at Intermountain Health, with scan interpreted clinically as LTM short-term risk for adverse cardiac events, and ischemic burden 70% stenosis in any vessel), an a priori list of clinical data and PET/CT results were examined.Results:Within 90 days of the LTM risk PET/CT, 3,163 (8.2%) had a coronary angiogram. Of these, 806 (25.5% of angiograms and 2.1% of total LTM) had high-grade CAD. The PET/CT ancillary findings were associated with the largest odds of performing an angiogram and the presence of high-grade CAD (Tables). Factors most likely to be associated with performing an angiogram were an ischemic burden of 7.5-10% (adjusted-OR [adj. OR]=11.54), coronary artery calcification (CAC) score of >300 (adj.-OR =1.62), and myocardial blood flow (MBF) of MBF 2.3). Other clinical parameters associated, after adjustment, with an angiogram were age, male sex, hypertension, elevated troponin, and inpatient status. Many of the same factors were found to be associated with the identification of high-grade CAD. However, being an inpatient was associated with increased odds of angiogram but a decrease in odds of high-grade CAD.Conclusions:In patients without a known history of CAD who underwent PET/CT clinically adjudicated as LTM short-term risk and ischemic burden

Circulation, Volume 150, Issue Suppl_1, Page A4142869-A4142869, November 12, 2024. Introduction:Adverse childhood experiences, also known as early life stress (ELS), are associated with increased risk of cardiovascular disease in later life, yet the underlying mechanisms remain elusive. Recent evidence indicates that parental life experiences can be transmitted to the offspring.Aim:To investigate the effects of ELS on cardiac structure and function in exposed parents and in their offspring, across 3 generations.Methods:We used ELS mouse model based on unpredictable separation of mouse pups (F1) from their mother (F0) each day for 3 hours from postnatal day 1 (PND1) to PND14 combined with dams exposure to an additional unpredictable stressor (forced swim in 18°C water for 5 minutes or 20-minute physical restraint in a tube) during separation. Control litters were raised normally. Echocardiography was performed at 6, 12 and 18 months in exposed animals (F0), their unexposed offspring (F1) and grand-offspring (F2). Both male and female mice were studied. Heart weight/tibia length was used to assess cardiac mass while Masson’s Trichrome was employed to detect fibrosis. Lung congestion was assessed as lung wet/dry weight ratio. Single-cell RNA sequencing (scRNAseq) was performed in MSUS and control hearts. A 6-week environmental enrichment (EE) program (cages containing running wheels, maze) was employed to test the possible rescue of ELS effects in adult males and their offspring.Results:F1 MSUS mice displayed increased LV mass, impaired diastolic function (assessed by conventional and tissue Doppler analysis) myocardial fibrosis and lung congestion. Time-dependent worsening of cardiac performance was observed from 6 to 18 months, both in males and females. ScRNAseq unveiled dysregulation of transcriptional programs underlying inflammation and lipotoxicity in the cardiomyocyte and endothelial cell clusters. MSUS offsprings did not show changes of cardiac function at 6 months, however diastolic dysfunction and lung congestion were observed at 12 and 18 months. A similar impairment of cardiac function was observed in the MSUS grandoffspring (F3). Of interest, 6-week exposure to an environmental enrichment protocol was able to improve LV mass, diastolic function and lung congestion in 12 months-old MSUS mice.Conclusions:ELS induces a transgenerational transmission of cardiac phenotypic alterations which can be rescued by EE. Our results shed light on the potential role of ELS on heart failure development and potential mitigation strategies.

Circulation, Volume 150, Issue Suppl_1, Page A4143303-A4143303, November 12, 2024. Introduction:Preeclampsia is a hypertensive disorder of pregnancy associated with cardiovascular disease. Systemic peripartum microvascular alternations have been implicated in pregnancies complicated by preeclampsia. Whether coronary microvascular dysfunction is a potential mediator of preeclampsia-associated cardiovascular risk is unknown. We aimed to determine whether individuals with a history of preeclampsia have coronary microvascular dysfunction measured by cardiac magnetic resonance imaging (CMR) at least 5 years postpartum.Methods:Women with singleton pregnancies complicated by preeclampsia and a comparator group with uncomplicated, normotensive deliveries were identified and prospectively enrolled to undergo regadenoson stress perfusion CMR (1.5T Signa Artist GE HealthCare) at least 5 years postpartum. Using the dual sequence technique, fully quantitative perfusion values were determined using Fermi deconvolution. Myocardial perfusion reserve (MPR) was calculated as the ratio of stress to rest myocardial blood flow (MBF).Results:Twenty-three subjects (41.0 ± 6 years, 12.7 ± 5 years post-partum) were included. Women with a history of preeclampsia (n=11) were compared to a control group of women with prior normotensive pregnancy (n=12) (Figure 1A). Obesity and diabetes were more common with preeclampsia, but there was no significant difference in the presence of hypertension between the groups (Table 1A). There was no difference in stress MBF. However, preeclampsia was associated with higher rest MBF (1.47 ± 0.54 mL/g/min vs. 1.19 ± 0.29 mL/g/min; p=0.07) and MPR (1.96 ± 0.46 vs 2.66 ± 1.0; p=0.02) compared to normotensive pregnancy (Figure 1). Similarly, corrected MPR remained significantly lower with prior preeclampsia versus uncomplicated pregnancy (2.36 ± 1.0 vs 3.36 ± 1.46; p=0.03).Conclusions:In this study, we observed significantly reduced coronary microvascular function following a pregnancy complicated by preeclampsia at least 5 years postpartum. Heightened cardiovascular risk factors may attenuate this association; however, these observations indicate that systemic microvascular dysfunction in preeclampsia also involves the coronary microcirculation. Further research is needed to better understand the timing and association of these microvascular changes concerning preeclampsia and later heart disease.

Circulation, Volume 150, Issue Suppl_1, Page A4146754-A4146754, November 12, 2024. Background:Dobutamine stress echocardiography (DSE) is a frequently used tool in cardiovascular (CV) risk assessment of liver transplantation (LT) candidates. Its prognostic value compared to traditional cardiac risk stratification remains unclear.Research Question:How does the prognostic value of pre-transplant DSE in LT candidates compare to the revised cardiac risk index (RCRI)?Aim:Compare DSE’s prognostic value to RCRI in LT patients and analyze post-transplant CV outcomes.Methods:This single-center study included adult patients undergoing pre-transplant DSE as part of LT evaluation from 2008-2021. DSE were categorized as positive, negative, or inadequate. Primary outcomes were post-operative ischemic cardiac events and mortality, with secondary outcome of transplant delays from inadequate DSE. Mann-Whitney U and Fischer’s exact tests compared variables; logistic regression assessed RCRI and DSE for 30-day mortality and cardiac events.Results:Of 981 LT candidates, 644 (66%) had pre-transplant DSE with minimum 2-year follow-up. Average age was 57 ± 7 years, with 33% women. Four and eleven patients experienced cardiac events and mortality 1 (p-value 0.50), 0.51 for DSE (p-value 0.82), and 0.52 for RCRI >1 and DSE combined (p-value 0.80) in predicting 30-day mortality and cardiac events.Conclusion:Our study demonstrates limited prognostic value of DSE above RCRI score alone for predicting post-transplant mortality. Inadequate DSE was frequent and extended LT wait times. Further research is necessary to define clinically relevant subgroups and refine CV risk assessment in LT candidates.

Circulation, Volume 150, Issue Suppl_1, Page A4145408-A4145408, November 12, 2024. Background:Stress cardiomyopathy (SCM) is rarely triggered by ketamine and seldom leads to cardiogenic shock. Ketamine-induced catecholaminergic surge can lead to myocardial stunning with transient ischemia and subsequent reversible heart failure. Mechanical circulatory support can be successfully leveraged in SCM-associated cardiogenic shock while awaiting myocardial recovery.Case Presentation:A 28-year-old female with chronic pain was admitted for failure to thrive secondary to opioid-induced gastroparesis. The patient was weaned off opiates while on ketamine over 4 days. After halting ketamine, the patient had a cardiac arrest with eventual return of spontaneous circulation. After being extubated, she developed chest pain, hypotension, and ventricular tachycardia with anterolateral ST elevations, troponin leak, and lactic acidosis. TTE revealed an EF

Circulation, Volume 150, Issue Suppl_1, Page A4131424-A4131424, November 12, 2024. Introduction:Anomalous aortic origin of a coronary artery (AAOCA) can result in sudden cardiac death in the young and risk stratification is challenging. Though dobutamine stress cardiac MRI (DS-CMR) is feasible in pediatric patients, exercise stress CMR (ES-CMR) has lower rates of adverse events, higher diagnostic accuracy, and the ability to better reflect the physiologic changes occurring with exercise. No studies have evaluated ES-CMR in the pediatric population. We aim to describe our institution’s experience with ES-CMR using supine bicycle ergometry in patients with AAOCA.Methods:We retrospectively reviewed the medical records of AAOCA patients who underwent ES-CMR at our institution between 2011 and 2024 for demographic, clinical presentation, cardiopulmonary exercise test (CPET) and ES-CMR data. The exercise-based portion of the CMR consisted of supine cycle ergometry utilizing a ramp protocol, immediately after which perfusion imaging was performed. We used descriptive statistics for data analysis.Results:Of 38 patients who underwent ES-CMR, the median age was 16 years (range 13-24) and 68% were male. Diagnoses included anomalous right coronary artery (N=28), anomalous left coronary artery (N=8), and single coronary artery (N=1 single right, N=1 single left). Median maximal heart rate (HR) during ES-CMR was 160 bpm (range 130-190, median 80% predicted) with a median maximal HR during patients’ most recent CPET of 187 bpm (range 160-203, median 97% predicted). No patients had perfusion defects at rest or with exercise stress, or evidence of myocardial scarring. There were no adverse events.Discussion:We demonstrate for the first time the use of ES-CMR in a cohort of pediatric and young adult patients with AAOCA. ES-CMR can provide a unique modality to assess for ischemia at rest and stress as a means of risk stratification and simulate physiologic changes occurring with exercise stress in a single study. Although maximum heart rates during supine cycle ergometry are lower than those reached during CPET, they are similar to those reached during DS-CMR. ES-CMR can be a helpful and safe diagnostic tool in patients with AAOCA.

Circulation, Volume 150, Issue Suppl_1, Page A4147667-A4147667, November 12, 2024. The co-chaperone BAG3 is critical for protein quality control at the cardiac sarcomere. BAG3 binds to Hsp70 and coordinates the assembly of the CASA (chaperone-assisted selective autophagy) complex, thus supporting proteostasis and cardiomyocyte contractility. BAG3 mutations and/or decreased BAG3 levels are associated with cardiomyopathies, whereas BAG3 overexpression rescues ventricular function after myocardial infarction in mice. Despite BAG3’s promise as a therapeutic target, the mechanisms underlying BAG3 regulation are largely unresolved. Here, we investigate the mechanisms of BAG3 downregulation after stress. We found that BAG3 protein is reduced in human dilated cardiomyopathy hearts compared to non-failing hearts, yet there is an increase inbag3mRNA transcript, suggesting BAG3’s downregulation in heart disease may be controlled post-transcriptionally. To identify these post-transcriptional pathways, we subjected neonatal rat ventricular myocytes (NRVMs) to prolonged hypoxia-reoxygenation (H/R) stress, which recapitulated the decrease in BAG3 levels observed in human heart disease. Notably, disrupting Hsp70 binding to BAG3 in NRVMs via the drug JG-98 decreases BAG3’s half-life by ~90%, suggesting that Hsp70 protects BAG3 from degradation. Loss of Hsp70-mediated protection could contribute to declining BAG3 levels, so we quantified Hsp70 abundance after H/R stress in NRVMs, finding no significant change. We also found that overexpressing inducible Hsp70 did not rescue BAG3 levels. To examine BAG3 regulationin vivo,we subjected wildtype mice to ischemia-reperfusion injury. After 24 hours, male mice had no change in Hsp70 abundance in the left ventricle, whereas Hsp70 was significantly upregulated in female mice. Despite this difference in Hsp70, BAG3 levels were decreased by ~20% in both sexes. Thus, ourin vivoandin vitrodata both suggest that BAG3 downregulation is not caused by loss of Hsp70 binding/protection. Interestingly, the decline in full-length BAG3 (85 kDa) was accompanied by an increase in a BAG3 cleavage product at 74 kDa. We analyzed this product via mass spectrometry, discovering that it lacks a third of the WW domain, which is involved in autophagy. In future experiments, BAG3 cleavage will be explored as a potential mechanism of BAG3 loss. Such mechanisms will provide insight into how to maintain BAG3 levels, and thus cardiac function, during stress.

Circulation, Volume 150, Issue Suppl_1, Page A4145955-A4145955, November 12, 2024. Introduction:Cardiovascular problems are the primary cause of morbidity and death in people with diabetes mellitus.The whole nature of diabetic cardiomyopathy(DCM) is yet unknown.In order to investigate the pathogenesis of DCM and find possible treatment targets,animal models have proven invaluable.It has been common practice to create experimental models of type 2 diabetes(T2DM) using streptozotocin (STZ).Finerenone(F) is a selective mineralocorticoid receptor antagonist and reduces cardiovascular and adverse renal outcomes in diabetes.Exenatide(E) has been approved by the FDA to improve glycemic control in T2DM.Aim:The aim of this study is to investigate the possible cardiorenal protective effects of potential heart failure and chronic kidney injury associated with T2DM and to assess the potential therapeutic roles of Finerenone and Exenatide.To understand the interactions on cardiorenal outcomes of heart failure and diabetes and to effectively manage these two conditions.Methodology:Wistarmale rats with streptozotocin-induced T2DM were used.Five different groups were established as 1)Control,2)STZ,3)STZ+F,4)STZ+E,5)STZ+F+E groups.During the 21-day experiment, blood glucose concentrations were measured in all animal experimental groups.The kidney, heart tissues, and blood serum were collected. Serum urea and creatinine were exanimated.Total antioxidant status(TAS) and total oxidant status(TOS) were examined from blood serum,kidney,heart tissues by spectrophotometric assays. Kidney, heart tissues and blood IL-6, IL-1β, TNF-α gene expressions were examined by qPCR. Cardiac troponin T(cTnT) and troponin I(cTnI) gene expressions were examined by qPCR.p-STAT3 and p-NRF2 protein expressions in heart tissue were assessed by western blotting.Results:Serum urea and creatinine were significantly lower in STZ+E+F group than control group. TAS were significantly higher in STZ+E+F group than control group in serum,heart and kidney tissues.TOS, IL-1β, IL-6, and TNF-α gene expressions were lower in STZ+E+F groups than control group significantly in serum, heart and kidney tissues.cTnT and cTnI gene expressions and p-STAT3 and p-NRF2 protein expressions were lower in STZ+E+F groups than control group significantly in heart tissues.Conclusion:This study demonstrates the potential beneficial effects of Finerenone and Exenatide on cardiorenal complications in T2DM. Evaluation of these drugs in treatment strategies and further clinical trials are recommended.

Circulation, Volume 150, Issue Suppl_1, Page A4132820-A4132820, November 12, 2024. Connexin-43 (Cx43) plays a critical role in the propagation of action potentials among cardiomyocytes and proper cardiac contractility. In healthy cardiomyocytes, Cx43 is located at the intercalated disk; however, Cx43 remodeling is observed in cardiac pathologies and is linked with arrhythmogenesis and sudden cardiac death. Utilizing a mouse model of Duchenne muscular dystrophy (DMDmdx), we have previously demonstrated that cardiac Cx43 is laterally localized, forming undocked hemichannels that activate via S-nitrosylation in response to isoproterenol-evoked cardiac stress. This activation leads to the disruption of cardiac membrane permeability, triggered activity, and deadly arrhythmogenic behaviors. To establish the direct role of S-nitrosylated Cx43 in DMD cardiomyopathy, we developed a specific knock-in mouse line in which the single Cx43 site for S-nitrosylation, cysteine 271 (Cys271), was substituted with a serine (C271S+/-). Here, we developed a DMDmdx:C271S+/-line (4–6 months old), exhibiting reduced levels of S-nitrosylated Cx43 after crossing DMDmdx mice and C271S+/-mouse lines to assess the effect of β-adrenergic stimulation-induced cardiac stress and heart dysfunction. We show that cardiac Cx43 remodeling was not prevented in DMDmdx:C271S+/-, similar to what was shown in DMDmdxmice via immunofluorescence analysis. In addition, DMDmdxmice displayed an increased number of deadly arrhythmogenic events, increased Ca2+signaling, and prolonged action potentials in Langendorff-perfused whole hearts via optical mapping, compared to wild-type and DMDmdx:C271S+/-mice. Similarly, isoproterenol treatment evoked severe myocardial injury, increased levels of plasmatic cardiac troponin I (cTnI), and 40% mortality in DMDmdxmice. Notably, DMDmdx:C271S+/-mice, similar to DMDmdxmice treated with the Cx43 hemichannel blocker Gap19, exhibited cardioprotection compared to the cardiac dysfunction observed in DMDmdxmice. Therefore, these findings strongly suggest that S-nitrosylation of Cx43 proteins at site Cys271 represents a fundamental NO-mediated mechanism involved in the induction of arrhythmias and myocardial injury in DMDmdxafter β-adrenergic stress.

Circulation, Volume 150, Issue Suppl_1, Page A4141357-A4141357, November 12, 2024. Background:Cardiac allograft vasculopathy (CAV) is a rapidly progressive form of coronary atherosclerosis limiting long-term survival after heart transplantation.Objectives:We evaluated the diagnostic and prognostic yield of quantitative stress cardiovascular magnetic resonance (CMR) perfusion for CAV detection in heart transplant recipients.Methods:Patients who received orthotopic heart transplants and underwent stress CMR for CAV assessment were included in the study and followed up for almost 2 years (median 1.8; IQR 0.9,2.7). The diagnostic accuracy of qualitative and quantitative stress CMR was assessed by calculating sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), using invasive or CT coronary angiography as the reference for CAV detection. The area under the curve (AUC) was compared for qualitative and quantitative stress CMR. Adjusted hazard ratios for major adverse cardiac events (MACE), including death and unplanned cardiac hospitalizations were derived in all patients. The global myocardial perfusion reserve index (MPRi) was obtained by normalization to the rate-pressure product.Results:In a cohort of 60 patients, n=18 (30%) had significant CAV (grade 2 or 3), and n=11 (18.3%) experienced MACE. At the Youden index threshold of 2.1, the myocardial perfusion reserve index (MPRi) demonstrated a sensitivity of 85.7%, a specificity of 70.3%, a PPV of 52.2%, and an NPV of 92.9%. The MPRi was significantly more accurate than visual assessment (p < 0.001) in identifying underlying CAV (Figure 1) and it was an independent predictor of MACE (HR:0.26;95%CI:0.07,0.93; log-rank p=0.022; Figure 2), while the visual presence of inducible myocardial perfusion defect did not (HR:2.23;95%CI:0.57,8.66; p=0.2).Conclusions:In patients with previous heart transplantation, quantitative stress CMR perfusion has incremental diagnostic and prognostic value over qualitative stress CMR for the non-invasive detection of CAV.

Circulation, Volume 150, Issue Suppl_1, Page A4146347-A4146347, November 12, 2024. Background:Acute ischemic stroke (AIS) is a leading cause of mortality and disability globally, disproportionately affecting Black and Latinx populations who experience increased morbidity and mortality compared to their white counterparts. At one month, roughly 50% of AIS survivors experience mood disturbances (e.g., anger, irritability, and aggression) and exhibit a lower health-related quality of life (HRQOL) compared to pre-AIS levels. Downstream biomarkers of mitochondrial dysfunction such as oxidative stress may be important pathophysiological mechanisms underlying mood disturbance symptoms, stroke severity, and long-term functional recovery.Purpose:To examine associations among early and late peripheral plasma lipid levels, mood disturbance symptoms (e.g., anger, irritability), and HRQOL outcome over 3 months (baseline/study day 5, and months 1, 3) in persons following AIS.Methods:The pilot study is a non-probability, convenience sample of adult subjects ( > 18 years of age) with a diagnosis of AIS. Lipidomics analysis was performed using liquid chromatography-mass spectrometry (LC-MS) of untargeted lipids. The Agilent 6545 LC/Q-TOF platform was used to determine the absolute concentration of lipid species from peripheral plasma samples collected days 1, 3, 5 and months 1 and 3 post-AIS. General linear mixed models were used to test the predictive association of lipidomic biomarker mean value of peripheral plasma lipid levels and symptoms and outcomes over time (baseline and months 1 and 3).Results:We analyzed 82 subjects (age = 64 ± 12.1, 52% male, 78% Black, and 94% with hypertension). Elevated oxidative stress biomarkers (e.g., lipoxygenases, arachidonic acid, glycosylphosphatidylinositol) were associated with higher severity of anger and irritability symptoms, and a poorer HRQOL from baseline to 1- and 3-months post-AIS (p=0.04).Conclusion:An untargeted LC-MS lipidomics approach was used to identify lipids following AIS. Because oxidative stress plays a key regulatory role in complex downstream cellular function, these findings may be of great significance in understanding AIS pathophysiology that has the potential to inform personalized preventive strategies.

Circulation, Volume 150, Issue Suppl_1, Page A4145104-A4145104, November 12, 2024. Background:The optimal timing for intervention for pulmonary and right ventricular outflow tract stenosis in adult congenital heart disease (ACHD) remains uncertain. While stress echocardiography is an established modality to improve risk stratification in stenotic left-sided lesions, its utility in right-sided valve disease in the ACHD population has not been studied. We assessed if stress echocardiographic assessment of right ventricular (RV) function during cardiopulmonary exercise testing (CPET) can facilitate risk stratification in the ACHD population.Objectives:The purpose of this study was to determine the relationship between RV augmentation on stress echocardiogram during CPET and morbidity in ACHD patients with sub-pulmonary right ventricles and right-sided stenotic lesions.Methods:A retrospective cohort study of ACHD patients with sub-pulmonary right ventricles who underwent CPET with stress echocardiogram was performed. The primary outcome was defined as having at least one of the following: 1) cardiac related hospitalization, 2) new documented arrhythmia, or 3) new or worsening heart failure. RV augmentation on stress echo was verified by concordance with a second observer.Results:The study included 87 patients, 41 (47%) with repaired tetralogy of Fallot, 9 (10.3%) with RV-PA conduits, and 9 (10.3%) with pulmonary stenosis. On baseline transthoracic echocardiogram, median peak pulmonary valve gradient was 38.7 mmHg (Q1 17.9 , Q3 49.0) and 30% of patients had RV dysfunction. On stress imaging, 13 (14.9%) did not demonstrate RV augmentation. Those without RV augmentation had a lower percent predicted peak Vo2 (61.4% vs 75.4%, p=0.007). Eleven (12.6%) met the primary outcome. Lack of RV augmentation was strongly associated with the primary outcome (OR 4.25, CI 1.04 –17.46, p = 0.04). This association remained true in patients with baseline peak PV gradients less than 50mmHg (OR 8.7, CI 1.68 – 46.79, p = 0.009) and was more pronounced in patients with tetralogy of Fallot (OR 33.99, CI 3.29 – 829, p = 0.007).Conclusions:Lack of RV augmentation on stress echo during CPET is associated with increased morbidity in ACHD patients with right-sided stenotic lesions. These results suggest that stress echocardiography at the time of CPET should be considered in this population.