Adverse Cardiac Outcomes Research Articles

Association between anti-seizure medications and cardiac arrhythmias in patients undergoing ambulatory electroencephalographic and electrocardiographic monitoring.

Background Anti-seizure medications (ASMs) are commonly prescribed in epilepsy. However some have been associated with adverse cardiac outcomes including cardiac arrhythmias. Methods We conducted an observational study evaluating patients aged ≥16 years undergoing ambulatory video - electroencephalographic (EEG) - electrocardiographic (ECG) monitoring (AVEEM) between 2020 and 2023 in Australia. Data collected included baseline demographics, type, number and dose of ASMs and cardiac arrhythmias during monitoring. ASMs were not withdrawn while monitored. Average QT interval was calculated and corrected for heart rate (QTc). Logistic regression was used to evaluate association between demographic variables, ASMs and cardiac arrhythmias. Results 3695 patients underwent AVEEM (median age 40 years [interquartile range 26-57], female 64 %). Median AVEEM duration was 6.8 days. 51 % of patients were taking ≥1 ASMs. About 28 % (1029/3695) patients had a cardiac arrhythmia; the most frequent was non-sustained SVT (19 %; 695/3695). On multivariable analysis, carbamazepine (OR 0.72, 95 %CI 0.53-0.98, p = 0.03), lamotrigine (OR 0.57, 95 %CI 0.44-0.73, p<0.001) and lacosamide (OR 0.63, 95 %CI 0.43-0.92, p = 0.02) were associated with fewer cardiac arrhythmias. Their association with cardiac arrhythmias was not dose-dependent. No commonly-prescribed ASMs were associated with increased risk of cardiac arrhythmias. There was no significant association between use of ASMs and dynamic QTc interval change. Conclusions Certain ASMs, namely carbamazepine, lamotrigine and lacosamide, were associated with fewer cardiac arrhythmias and this association was not dose-dependent. No other ASM was associated with cardiac arrhythmias. Further large clinical prospective studies are needed to confirm these findings and to clarify the mechanism for any potential antiarrhythmic properties of ASMs.

The effect of first intervention on cardiac parameters in patients with acromegaly: a systematic review.

Cardiovascular disease in acromegaly patients remains a major cause of morbidity and all-cause mortality. This systematic review investigates the effect of the first growth hormone lowering intervention on cardiac parameters. Systematic review. Studies evaluating cardiac parameters following first intervention in acromegaly published up to February 25 2022 were included in this systematic review. Risk of bias was assessed using a modified Newcastle-Ottawa Scale and Joanna Briggs Institute Critical Appraisal Checklist. Primary treatment modalities included (transsphenoidal) surgery and medical treatment with first-generation somatostatin receptor ligands. Cardiac outcome measures were divided into cardiac structure [left ventricular hypertrophy (LVH), (indexed) left ventricular mass (LVM/LVMi)] and cardiac function [left ventricular ejection fraction (LVEF) and E/A ratio]. Twenty-six studies (17 cohort studies and 9 case reports) were included out of 2541 potential studies. The risk of bias analysis categorized, 24 studies as low risk and 2 studies as intermediate risk. Disease-associated changes in cardiac structure and function generally improved in most studies following primary treatment. LVM/LVMi significantly decreased in 9/15 studies and the prevalence of LVH in 3/13 studies. LVEF significantly increased in 9/14 studies and E/A ratio in 6/7 studies. Despite the limited number of studies, cardiac structure improved more in patients achieving biochemical remission than in those failing to achieve biochemical remission. Acromegaly-associated structural and functional myocardial changes improve with both medical and surgical treatment. Normalizing or even reducing GH/IGF-I levels may be key in prevention of further progression of cardiac involvement in acromegaly and adverse cardiac outcomes.

Impact of Acute Myocardial Injury on Short- and Long-Term Outcomes in Patients With Primary Intracerebral Hemorrhage.

Myocardial injury is common after brain injury; however, few studies have reported serial cardiac troponin (cTn) measurements to distinguish whether the myocardial injury is acute or chronic. The fourth Universal Definition of Myocardial Infarction introduced for the first time the criteria for acute myocardial injury (AMI). We aimed to investigate the prevalence and prognostic implications of AMI in primary intracerebral hemorrhage. We retrospectively analyzed patients with primary intracerebral hemorrhage within 48 hours after symptom onset. All patients included had at least 2 cTn measurements: 1 obtained at the time of emergency admission and at least 1 more within the first 2 days of hospitalization. AMI was defined as an elevated cTn above the upper-reference limit (14 ng/L) along with a rise/fall >20%. Patients were followed for up to 5 years. Outcomes included major adverse cardiac events (MACEs; a composite of vascular death, nonfatal coronary events, and nonfatal stroke) and 90-day unfavorable outcomes (modified Rankin scale score ≥4). Cox proportional hazards models, multivariable logistic regression models, and Kaplan-Meier analyses were used to evaluate the association between AMI and outcomes. Of 600 patients included, 115 had AMI (19.2%). AMI independently conferred an increased risk for major adverse cardiac events (adjusted hazard ratio, 1.69 [95% CI, 1.12-2.53]) and 90-day unfavorable outcomes (adjusted odds ratio, 2.15 [95% CI, 1.26-3.67]) compared with patients without AMI. AMI is relatively common in patients with intracerebral hemorrhage and is associated with both long-term major adverse cardiac events and 90-day unfavorable outcomes.

Cardiac complications of arteriovenous access: a narrative review from a multidisciplinary team perspective

Although cardiovascular disease is common among hemodialysis patients, arteriovenous access creation has been invariably implicated in the evolution of adverse cardiac outcomes or deterioration of pre-existing cardiovascular disease. In most cases, these effects are subclinical but with potential underlying echocardiographic findings. Compared with grafts, arteriovenous fistulas are implicated more often, due to the progressively increased flow from the continuous dilatation of the venous outflow tract in the long term. The increasing flow is in the majority of patients well tolerated by cardiac adaptive alterations. However, the clinical impact is based on the balance between the amount of flow volume and the patient’s cardiac reserves. Having extensively reviewed the existing English literature, we present the pathophysiology and the different types of cardiovascular complications, the indications, types, and efficacy of flow-restrictive procedures in the context of a high-flow AVF, as well as some precautions and considerations for AVF creation in high-risk patients.

Left ventricular hypertrophy in young hypertensives: the possible crosstalk of mTOR and angiotensin-II -a case-control study

BackgroundHypertension is a major cause of cardiac dysfunction. The earliest manifestation is left ventricular remodeling/hypertrophy. The occurrence of adverse cardiac remodeling and outcomes occurs irrespective of age in blacks. This necessitated an estimate of the prevalence of left ventricular hypertrophy (LVH) and an assessment of the roles of the mammalian target organ of rapamycin (mTOR) and angiotensin-II (Ang II) as possible pathogenic markers of LVH among young hypertensives.MethodsThis prospective case-control study involved 110 hypertensive and 60 normotensive (control) participants aged 18–45 across tertiary hospitals in Ekiti state. Ethical approval was obtained from all the various institutions. Participants were recruited consecutively after giving informed consent. Sociodemographic/clinical information, resting electrocardiogram and echocardiography were obtained. Venous blood was obtained to estimate mTOR, Ang II, Chemerin, lipids – triglyceride (TG), high-density lipoprotein (HDL), total cholesterol (TC), troponin-T, NF-Kβ, and Galectin-3 using enzyme-linked immunosorbent assay.ResultsThe prevalence of LVH among the hypertensive group was 20.9%, 39%, 11.01%, and 15.74% using 2D-transthoracic echocardiography, Sokolow-Lyon, Cornell’s and Cornell product ECG criteria. Also, hypertensives with LVH had a significantly increased blood pressure, body mass index, serum level of TG, TG/HDL, TC/HDL, chemerin, troponin T, Galectin-3 and total mTOR compared to normotensive and hypertensives without LVH. At the same time, serum NF-kβ and Ang II were only significant when compared with normotensive but not hypertensives without LVH. The total mTOR moderately correlated positively with ANG-II.ConclusionsThe results suggest an interaction between mTOR and Ang II in the development of LVH. In addition, it shows that LVH is associated with dyslipidemia, inflammation, and fibrosis.

A retrospective analysis of cardiovascular outcomes of clozapine treated individuals within Hunter New England.

Clozapine has demonstrated superiority in improving both positive and negative symptoms of treatment-resistant schizophrenia; however, there are associated treatment-limiting side effects, including myocarditis, cardiomyopathy and agranulocytosis. This retrospective cohort study describes the prevalence of myocarditis, left ventricular (LV) dysfunction, cardiovascular risk factors and outcomes in a cohort of patients maintained on clozapine therapy. Data were retrospectively collated from patients who had a diagnosis of schizophrenia, had been managed with clozapine at any stage during their care and undergone at least one echocardiogram. Between March 2020 and September 2021 674 patients were identified, 71% were male, with a mean age of 47 years old (interquartile range (IQR) 40-57). The mean duration of clozapine use was 7 years (IQR 4-13). The overall mortality was 5.54% during the follow-up period. Myocarditis was identified in one patient (0.15%) within the first 30 days, and an additional five cases were identified over the follow-up period (0.89%). The combined incidence of heart failure (HF) and myocarditis was 1.6% during the follow-up period. There was no association between LV size and function at baseline or during follow-up and adverse cardiac outcomes (comprising death, myocarditis, HF). Older age at initiation of therapy and baseline E/e' ratio were associated with risk of HF and myocarditis. The overall incidence of myocarditis and HF during follow-up was low, with surveillance echocardiography offering limited predictive value. Patients maintained on clozapine are at risk of significant cardiovascular sequelae, likely reflecting an adverse risk factor profile.

Serum and Plasma Sphingolipids as Biomarkers of Anthracycline-Induced Cardiotoxicity.

Although effective as a chemotherapy, the utility of Doxorubicin (Dox) is hampered by cardiotoxicity. Despite this, the ability to predict and guide monitoring of patients receiving Dox or other anthracyclines is hampered by a lack of effective biomarkers to identify susceptible patients, and to detect early signs of subclinical cardiotoxicity. Based on their well-established roles in the response to Dox and other chemotherapies, we performed a retrospective analysis of serum and plasma sphingolipids (SLs) from patients undergoing anthracycline-containing therapy, correlating with cardiac parameters assessed by echocardiography. Results showed there were substantial changes in both plasma and serum SL species during therapy including ceramide (Cer), deoxydihydroCer, and dihydrosphingosine with reversion towards baseline following treatment. Linear mixed-effects model analysis revealed that at baseline, a number of SLs correlated with adverse cardiac outcomes with serum sphingosine-1-phosphate (S1P) and dihydroS1P, and plasma Cer performing comparably to the prognostic value of pro-NT-BNP, an established biomarker of cardiotoxicity. Intriguingly, while pro-NT-BNP had no predictive value at mid- and post-therapy timepoints, serum S1P and dhS1P and plasma Cer levels showed correlation with adverse outcomes, particularly at the post-therapy timepoint. Finally, analysis of plasma and serum C16:C24- Cer ratios - previously reported as predictive of adverse cardiac outcomes - showed no correlation in the context of anthracycline treatment. Taken together, this pilot study provides supporting evidence that plasma and serum SLs may have benefit as both prognostic and diagnostic biomarkers for patients undergoing anthracycline-containing therapy. This suggests that diagnostic SL measurements - recently implemented for metabolic-associated cardiac disorders - could have wider utility.

Finerenone: a breakthrough mineralocorticoid receptor antagonist for heart failure, diabetes and chronic kidney disease.

Aldosterone is categorized as a mineralocorticoid hormone produced in the zona glomerulosa of the adrenal cortex. Aldosterone has considerable action in sodium and water retention along with cardiac remodeling, promoting fibrosis and these detrimental effects have been counteracted by mineralocorticoid receptors antagonists over time. Spironolactone, a non-selective steroidal MRA used extensively is potent but has serious adverse effects like gynecomastia and hyperkalemia. Eplerenone another second generation MRA, though non-steroidal and selective causes hyperkalemia and adversely effecting renal functions. Recently Finerenone- a novel MRA has been introduced which is as potent like spironolactone with less adverse effects and improved cardiovascular outcomes particularly in chronic kidney failure with diabetes. The article reviews the physical and chemical properties of Finerenone and compares it with MRAs already in use, and thenabout the patient specific uses of Finerenone and future avenues of it. Finerenone is non-steroidal selective MRA, with promising results in improving the deterioration of renal functions in CKD with DM, reducing albuminuria with less hyperkalemia along with improvement in cardiovascular outcomes by reducing heart failure events. Mineralocorticoid receptor antagonists have a proven role in preventing the adverse effects of RAAS pathway on heart, kidneys and blood vessels. Non-selective steroidal MRAs have potent action but by virtue of their non-selectivity associated with adverse effects like gynecomastia, hirsutism along with hyperkalemia Finerenone is novel non-steroidal & highly selective MRA, with promising results in halting the deterioration of renal functions in CKD with DM, reducing albuminuria, improvement in cardiovascular outcomes by reducing heart failure events albeit with less hyperkalemia. More randomized studies in dedicated HF patients are ongoing with Finerenone to prove it is worth in this sector with huge unmet need despite GDMT. Finerenone alleviates the risk of adverse renal and cardiac outcomes in patients with diabetes and CKD despite baseline medical therapy.

A US payer budget impact analysis of Flurpiridaz-PET-MPI compared to SPECT-MPI in the diagnosis of coronary artery disease

Aims This economic model was developed to assess the budget impact of a novel radiotracer, Flurpiridaz (F18-PET-MPI), compared to SPECT-MPI from a US payer perspective. Materials and Methods The model was developed comparing F18-PET-MPI and SPECT-MPI, with F18-PET-MPI modality share increasing from 0.5% to 2.5% of the total MPI modality share, over a 5-year time horizon. The model estimates the impact of diagnostic performance on downstream healthcare resource utilization (HCRU) including invasive coronary angiography (ICA), revascularization, pharmacological treatment, and cardiac outcomes (CO) such as cardiac mortality (CM) and myocardial infarction (MI). Four suspected CAD populations, including general and difficult-to-image subgroups, were analyzed. Clinical inputs used to support the parameterization of the model were sourced from a systematic literature search and included claims-based real-world evidence, observational, and multicenter registry studies to inform the rates of HCRU and CO, and head-to-head comparative clinical trial data advised diagnostic performance inputs. Reimbursement codes informed MPI modality costs. Results are reported as per-member per-month (PMPM) based on a hypothetical health plan. Results In all suspected CAD populations analyzed, there was a nominal cost increase in the world with F18-PET-MPI. The 5-year average PMPM incremental budget impact ranged from $0.02 to $0.05 across all suspected CAD subgroups. Cost-savings were associated with decreased downstream CO such as CM, MI, and ICA. Limitations and Conclusion The available literature to source all parameters in the model was limited; therefore, assumptions and additional calculations were made based on published evidence to inform the model. A one-way sensitivity analysis was performed to confirm and address uncertainty in key parameters. This comprehensive analysis illustrates that the superior diagnostic performance of F18-PET-MPI may result in reduced adverse CO events and associated costs, increased appropriate identification and treatment of CAD, and a minimal increase in overall costs among general and difficult-to-image patient subgroups.

Abstract 4138303: Stress Hyperglycemia Ratio Predicts MACE and All-cause Mortality in Acute Coronary Syndrome Patients: A Meta-Analysis Comparing Patient with Diabetes Mellitus and Non-Diabetes Mellitus

Background: A higher stress hyperglycemic ratio (SHR) has been reported to be associated with adverse cardiac outcomes. However, the role of SHR in predicting clinical outcomes by comparing patients with and without diabetes mellitus is yet to be explored. Objective: To evaluate the prognostic value of the SHR for predicting major adverse cardiovascular (MACE) and all-cause mortality in ACS patients with and without diabetes mellitus. Methods: Per PRISMA guidelines, we comprehensively reviewed PubMed, Google Scholar, and SCOPUS for eligible studies reporting on SHR and its association with MACE (8 studies) and all-cause mortality (7 studies) in ACS patients. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a binary random-effects model, with results displayed as forest plots. Heterogeneity was assessed using I2 statistics, and a leave-one-out sensitivity analysis was performed. P&lt;0.05 was considered significant. Results: A total of 15 studies with 45,774 patients with ACS were included in the analysis. The majority of patients were males (72.6%) with a mean age of 62.8 years. High SHR was associated with higher odds of MACE (1.93 [1.54–2.42]) and all-cause mortality (1.91 [1.58–2.31]) (Fig. 1). Subgroup analysis revealed increased odds of all-cause mortality (1.69 [1.34–2.11] for patients with diabetes vs 2.12 [1.65–2.71] for patients without diabetes) and MACE (1.60 [1.30–1.97] for patients with diabetes vs 1.44 [1.28–1.62] for patients without diabetes), all p&lt;0.01. (Fig. 2). Additionally, the leave-one-out sensitivity analysis demonstrated that excluding any particular study did not significantly affect outcomes (p&lt;0.05). Conclusions: In patients with ACS, SHR is an independent predictor of MACE and all-cause mortality, irrespective of diabetes status. Strict glycemic control strategies may improve outcomes in this high-risk population. These findings underscore the importance of early recognition and management of stress hyperglycemia in ACS patients.

Abstract 4135861: Lipoprotein(a) and Its Impact on Left Ventricular Remodeling Over a Decade: The Multi-Ethnic Study of Atherosclerosis

Background: Lipoprotein (a) (Lp[a]) is associated with an increased risk of cardiovascular disease and mortality, as well as heart failure and myocardial fibrosis. However, the link between Lp(a) and cardiac remodeling as a pathway to adverse cardiac outcomes remains unknown. Objectives: This study investigated the relationship between Lp(a) levels and longitudinal changes in the left ventricular (LV) remodeling over a decade among individuals without a previous history of cardiovascular disease. Methods: 2,366 Multi-Ethnic Study of Atherosclerosis (MESA) participants who underwent cardiac MRI at Visit 1 (2000-02) and Visit 5 (2010-12) and had available Lp(a) at baseline were examined. Lp(a) was analyzed as a continuous and a categorical variable based on quartiles (Q1[&lt;7.6 mg/dL], Q2[7.6-16.7 mg/dL], Q3[16.8-38.8 mg/dL], Q4[&gt;38.8 mg/dL]). Multivariable linear regression analysis was used to examine the association of Lp(a) with changes in cardiac MRI measures of LV remodeling ( Table ). Results: Participants had a mean age 60±9 years and 53% were women. Over 10-year follow-up, LV indexed volumes decreased, while LV indexed mass and mass to volume ratio increased across all the Lp(a) quartiles. However, LV ejection fraction only decreased in the third and fourth Lp(a) quartiles. Lp(a) examined as a continuous variable was associated with an increase in LV end-systolic indexed volume (per log-unit Lp[a]; β 0.32 mL/m 2 ; P = 0.01), LV indexed mass (per log-unit Lp[a]; β 0.38 g/m 2 ; P = 0.02), and a decrease in LV ejection fraction (per log-unit Lp[a]; β -0.29 %; P = 0.02) over 10 years after adjusting for sociodemographic and traditional cardiovascular risk factors ( Table ). Similarly, the fourth Lp(a) quartile was associated with an increase in LV end-systolic indexed volume (β 1.07 mL/m 2 ; P = 0.01), LV indexed mass (β 1.17 g/m 2 ; P = 0.02) and a decrease in LV ejection fraction (β -1.01 %; P = 0.01) compared to the first Lp(a) quartile after controlling for risk factors. The observed associations remained significant after further adjusting for aortic valve calcium score at Visit 1 ( Table - Model 3), and baseline coronary artery calcium score and interim myocardial infarction ( Table - Model 4). Conclusions: In a multi-ethnic cohort of participants free of cardiovascular disease at baseline, higher Lp(a) levels were independently associated with an increase in LV end-systolic volume and LV mass as well as a decrease in LV ejection fraction over the span of a decade.

IGF-1 levels in the general population, heart failure patients, and individuals with acromegaly: differences and projections from meta-analyses-a dual perspective.

The complex relationship between insulin-like growth factor 1 (IGF-1) levels and heart failure (HF) is not fully understood, particularly across different populations and conditions. This meta-analysis aims to elucidate the dual perspectives of IGF-1 levels in the general population, HF patients, and individuals with treatment-naïve acromegaly, highlighting IGF-1 as a biomarker and potential therapeutic target in HF management. Studies were searched across multiple electronic databases up to January 2024 and independently identified by reviewers. The outcomes were analyzed using RevMan 5.4 and STATA 15. A total of 25 articles were ultimately included in the analysis. Six studies compared IGF-1 levels between HF patients and non-HF controls, revealing significantly lower IGF-1 levels in HF patients (mean difference -20.93; 95% CI -37.88 to -3.97; p = 0.02). This reduction was consistent across various HF subtypes and severities. In addition, individuals with intermediate IGF-1 levels had a lower risk of developing HF [risk ratio (RR) 0.78; 95% CI 0.74-0.83; p < 0.01] and HF-related mortality (RR 0.98; 95% CI 0.97, 0.99; p < 0.01) compared to those with low IGF-1 levels, suggesting a protective role for maintaining adequate IGF-1 levels. Conversely, treatment-naïve acromegaly patients, characterized by excessively high IGF-1 levels, showed a significantly higher incidence of both diastolic HF [odds ratio (OR) 9.08; 95% CI 6.20-13.29; p < 0.01] and systolic HF (OR 13.1; 95% CI 6.64-25.84; p < 0.01), implicating supraphysiological IGF-1 levels in adverse cardiac outcomes. Our meta-analysis highlights the complex interplay between IGF-1 levels and HF. We found that reduced IGF-1 levels are commonly observed in HF patients and are associated with an increased risk of HF and higher HF-related mortality. Conversely, excessively high levels, as observed in acromegaly, are linked to a higher incidence of HF. Based on these results, it is recommended that cardiac function be closely monitored in patients with reduced IGF-1 levels and in those with acromegaly. These findings suggest that IGF-1 could hold potential prognostic value for risk stratification in HF.

Risk assessment using DEVI and CARPREG -1 score to predict maternal adverse cardiac cvents in pregnancies with valvular heart disease: external validation study from MPAC registry

Abstract Background Even though many risk assessment tools in pregnant women with valvular heart disease (VHD) are available, validation studies are few that assess their performance in diverse settings, which is needed prior to the application of routine clinical practice. Objectives To validate and establish the clinical utility of two risk stratification tools – DEVI (VHD-specific tool) and CARPREG-I in predicting adverse cardiac events in pregnant patients with VHD. Methods This cohort study involved consecutive pregnancies complicated with VHD enrolled in the prospective MPAC registry from July 2016 to December 2019(1). The ability to discriminate those with and without adverse cardiac outcomes was assessed using the area under the curve for both the DEVI and CARPREG-1 scores. Performance was assessed through discrimination and calibration characteristics. Clinical utility was evaluated with Decision Curve Analysis. Results Among 1029 pregnancies complicated with heart disease in the MPAC registry cohort, 604(52.3%) with valvular heart disease were included in this analysis. One or more composite adverse cardiac events occurred in 70 (11.6%) pregnancies during antenatal or the early postpartum period. Mitral regurgitation was the most common lesion (67.7%). In assessing the pregnancy outcomes, those who continued past 20 weeks were included, with the majority (92.0%) delivered at term, and the cesarean rates were 33.6% (n=203). The most common adverse event was heart failure (n=32, 5.3%), most of which (68.6%) occurred in the postnatal period. There were 11 maternal deaths (1.8%) during the study period, six among those with mechanical heart valves (four prosthetic valve thrombosis), two among those with severe mitral stenosis and pulmonary hypertension and two with severe mitral regurgitation and infective endocarditis. The area under the receiver operating characteristic curve (AUC) was 0.766, with 95% confidence intervals (CI) 0.703- 0.828 for DEVI and 0.703 (95%CI 0.644- 0.763) for CARPREG-I models. Calibration plots suggested that the DEVI score overestimates risk at higher probabilities, whereas the CARPREG-I score underestimates the risk at most probabilities. Decision curve analysis demonstrated that both models were useful across predicted probability thresholds between 10% and 60%. Conclusion In this external validation study in pregnant women with primary rheumatic VHD, DEVI and CARPREG-I scores showed good discrimination ability and clinical utility across various probabilities. Both can be used to classify those who develop adverse cardiac outcomes during pregnancy and childbirth. However, both models need recalibration to improve the agreement between the predicted and observed events prior to routine application in diverse clinical settings.Figure 1.a and b ROC and Decision Curves

Association between GDF-15 levels and cardiac morphology and function in cardiac magnetic resonance imaging: insights from UK Biobank data analysis

Abstract Background/Introduction Growth Differentiation Factor-15 (GDF-15) has emerged as a biomarker associated with cardiovascular disease and adverse cardiac outcomes. Cardiac morphology and function, assessed through cardiac magnetic resonance imaging (CMR), are critical indicators of cardiovascular pathology. Understanding the relationship between GDF-15 levels and LV characteristics could provide valuable insights into cardiac pathophysiology and disease progression. Purpose This study aims to investigate the association between GDF-15 levels and cardiac morphology and function, utilizing data from the UK Biobank and CMR. By analyzing various CMR-derived parameters, including LV strain, myocardial mass, LV mass-to-volume ratio, ventricular and atrial volumes, we seek to elucidate the impact of GDF-15 on cardiac structure and function. Methods Data from the UK Biobank, including 2,264 participants, were analyzed. The median age of the analyzed participants was 55 years, with a median BMI of 26.0. Among the participants, 53% were females and 47% were males. CMR-derived variables related to cardiac morphology and function, along with GDF-15 levels, were examined. Multiple linear regression models were constructed to assess the association between GDF-15 levels and cardiac parameters, adjusting for age, sex, and other relevant covariates. Confidence intervals (CI) and p-values were calculated to determine the significance of observed associations. Results Analysis of the UK Biobank data revealed significant associations between GDF-15 levels and specific cardiac parameters (table1). Notably, GDF-15 levels were negatively associated with LV myocardial mass (LVM)(coefficient = -1.146, p = 0.0071), LV end-diastolic volume LVEDV)(coefficient = -3.321, p &amp;lt; 0.0001), LV end-systolic volume (coefficient = -1.876, p &amp;lt; 0.0001), as well as right atrial maximum volume (coefficient = -3.025, p &amp;lt; 0.0001) and minimum volume (coefficient = -1.858, p = 0.0003). In addition, LVM/LVEDV was positively associated with GDF-15 level (p&amp;lt;0.03). However, no significant associations were observed between GDF-15 levels and LV strain parameters, ejection fraction, or left atrial volumes. Conclusion This study provides evidence of a significant association between GDF-15 levels and selected parameters of cardiac morphology and function, as assessed by CMR in the UK Biobank population. These findings suggest a potential role of GDF-15 in modulating specific aspects of cardiac structure, function and left ventricle concentric remodeling warranting further investigation.GDF 15

1-year outcomes of patients presenting with acute coronary syndromes in Western Cape, South Africa: findings from the PERFUSION ACS registry

Abstract Background Cardiovascular disease(CVD), particularly acute myocardial infarction(MI), has emerged as a public health challenge in South Africa(SA), however, there is a paucity of data regarding long-term clinical outcomes such as CVD mortality, heart failure, stroke and recurrence of MI in this region. Purpose To determine 1-year major adverse cardiac outcomes among individuals discharged alive following admission for troponin-positive Acute Coronary Syndromes(ACS) in Western Cape, SA. Methods Between February 2021 and May 2022, 838 adults(≥18 years) with a diagnosis of ACS were prospectively enrolled into the investigator-initiated, multi-center PrEsentation, Rationale, and impact of reperFUSION for Acute Coronary Syndromes (PERFUSION ACS) registry. Participants were enrolled at a tertiary-care referral center and four secondary-level healthcare facilities. Key data elements were measured at index admission, including baseline demographics, risk factors, clinical presentation, complications, laboratory tests, revascularization strategies, and discharge medication. Survivors at discharge provided consent for 30-day and 12-month telephonic evaluations for major adverse cardiovascular events(MACE), which were captured on a web-based system that was centrally managed and analyzed. Results Of 838 participants, 39% were female, one-third were &amp;lt;55 years of age, 76% had a history of smoking, 74% had hypertension, 58% had dyslipidemia, and 56% were obese. STEMI accounted for 51% of cases, with NSTEMI in 49%. Baseline data for the cohort, stratified into two categories of MI, are provided in Table 1. Median duration from symptom onset to hospital presentation was 10.42 (±15.26) hours, with a majority(80%) presenting first to a non-PCI-capable facility. Among STEMI cases, two-thirds received thrombolysis(65%), primarily with Streptokinase; 49% underwent angiography via a pharmacoinvasive strategy, and 3% received primary percutaneous coronary intervention(PCI). Overall, 57% of patients with NSTEMI were treated with an invasive approach. The one-year all-cause mortality was 21%, with 88% attributable to cardiovascular disease-related death. Cumulative MACE rate at one year was 57%. Event rates for the individual MACE components were 32% for heart failure, 19% for non-fatal MI, and 6% for non-fatal stroke. 6% of participants died in-hospital, while 30-day mortality was 9%. There were no significant differences in all-cause mortality between STEMI and NSTEMI at 1 year. Conclusion Troponin-positive ACS are associated with a high rate of 12-month mortality and non-fatal major adverse cardiac events in Western Cape, SA. The concerning registry findings emphasize the need to prioritize ischemic heart disease prevention and management, and highlight important gaps in care which can serve as targets for improvement throughout the country.PERFUSION: Table 1PERFUSION: All-cause mortality and MACE

Decreased ability to manage increases in reactive oxygen species may underlie susceptibility to arrhythmias in mice lacking Scn1b.

Scn1b plays essential roles in the heart, where it encodes β1-subunits that serve as modifiers of gene expression, cell surface channel activity, and cardiac conductivity. Reduced β1 function is linked to electrical instability in various diseases with cardiac manifestations and increased susceptibility to arrhythmias. Recently, we demonstrated that loss of Scn1b in mice leads to compromised mitochondria energetics and reactive oxygen species (ROS) production. In this study, we examined the link between increased ROS and arrhythmia susceptibility in Scn1b-/- mice. In addition, ROS-scavenging capacity can be overwhelmed during prolonged oxidative stress, increasing arrhythmia susceptibility. Therefore, we isolated whole hearts and cardiomyocytes from Scn1b-/- and Scn1b+/+ mice and subjected them to an oxidative challenge with diamide, a glutathione oxidant. Next, we analyzed gene expression and activity of antioxidant enzymes in Scn1b-/- hearts. Cells isolated from Scn1b-/- hearts died faster and displayed higher rates of ROS accumulation preceding cell death compared with those from Scn1b+/+. Furthermore, Scn1b-/- hearts showed higher arrhythmia scores and spent less time free of arrhythmia. Lastly, we found that protein expression and enzymatic activity of glutathione peroxidase is increased in Scn1b-/- hearts compared with wild type. Our results indicate that Scn1b-/- mice have decreased capability to manage ROS during prolonged oxidative stress. ROS accumulation is elevated and appears to overwhelm ROS scavenging through the glutathione system. This imbalance creates the potential for altered cell energetics that may underlie increased susceptibility to arrhythmias or other adverse cardiac outcomes.NEW & NOTEWORTHY Using an oxidative challenge, we demonstrated that isolated cells from Scn1b-/- mice are more susceptible to cell death and surges in reactive oxygen species accumulation. At the whole organ level, they were also more susceptible to the formation of cardiac arrhythmias. This may in part be due to changes to the glutathione antioxidant system.

0JAK Inhibitor Withdrawal Causes a Transient Proinflammatory Cascade: A Potential Mechanism for Major Adverse Cardiac Events.

Our objective was to define the effect of JAK1/2 inhibitor (JAKinib) withdrawal on JAK/STAT biochemical response in the context of systemic rheumatic diseases. We tested Type I (bind kinase active conformation) and Type II (bind kinase inactive conformation) JAKinibs in vitro using mesenchymal stromal cells and endothelial cells. We translated our findings in vivo studying NK cells from rheumatoid arthritis (RA) patients treated with Type I JAKinibs or methotrexate. Type I JAKinibs (ruxolitinib and baricitinib) increased phosphoJAK1 (pJAK1) and pJAK2 of IFNγ-stimulated MSCs and HUVECs in a time- and dose- dependent manner, with effect peaking after 24 hours. As expected, pSTAT1 was completely suppressed by JAKinibs. We found a marked and rapid increase of pSTATs upon discontinuation of Type I JAKinibs, that occurred to a lesser extent after Type II JAKinib withdrawal. Type I JAKinib withdrawal increased interferon and urokinase expression when compared to Type II JAKinib withdrawal. We found NK cells from RA patients taking Type I JAKinibs had a pro-inflammatory profile after JAKinib withdrawal compared to patients on methotrexate. Type I JAKinibs paradoxically accumulate functionally defective pJAK. Upon withdrawal, the primed pJAKs are de-repressed and initiate a pSTAT signaling cascade, resulting in high interferon and urokinase. Type II JAKinibs do not cause pJAK accumulation, pSTAT cascade, and subsequent pro-inflammatory transcripts. The resultant cytokines and proteins produced from this cascade might be associated with adverse cardiac outcomes. Thus, JAKinib withdrawal is a possible mechanism contributing to the major adverse cardiac events described with JAKinib therapy.

Abstract P122: Aberrant MicroRNA Expression May Underlie Cardiac Dysfunction in a rat model of Preeclampsia

Introduction: Preeclampsia (PE) patients exhibit left ventricular (LV) hypertrophy and dysfunction during pregnancy. While these clinical findings have been recapitulated in a PE animal model (reduced uterine perfusion pressure; RUPP), mechanisms underlying such adverse cardiac outcomes have not yet been explored. A few recent studies involving models of heart failure have shown that pathogenic effects of microRNAs (miRNAs) are attributed to their regulatory actions on cardiac mitochondria. Hypothesis: Inspired by this literature, we set out to test the hypothesis that cardiac dysfunction in PE is mediated by abnormal miRNA expression, and the resulting mitochondrial dysfunction within the myocardium. Methods: PE was induced in pregnant Sprague Dawley (SD) on gestational day(GD)14. After blood pressure measurements (carotid catheterization) on GD19, whole hearts were excised, weighed, and ventricular tissue was used for miRNA (Qiagen’s miRNeasy Micro Kit) and mitochondria (differential centrifugation) isolations. Small RNA sequencing(s-RNA seq) and mitochondrial experiments were performed by Illumina sequencer (NEXTFLEX Kit) and Oxygraph-2K, respectively. Differentially expression (diff-exp) analysis was conducted using DESeq2 in R (fold change=2, adj p=0.05). Results: PE phenotype in RUPP rats was confirmed by elevated MAP (116.1±1.83 vs.101.3±2.93 mmHg, p=0.0008,n=8) on GD19. Normalized heart weight was higher in RUPPs (0.0033 ±9.98e-005 vs. 0.0029±0.00014, p=0.05, n=7-8) suggesting a hypertrophied heart. S-RNA seq revealed a total of 53 (21 up and 32 down) diff-exp miRNAs in RUPP vs. control rats. The top 5 up (miR-741-5p, miR-1-5p, miR-1b, miR-30b-5p, let-7d-3p) and down (miR-871-5p, miR-2985, miR-185-3p, miR-494-3p, miR-1839-3p) regulated miRNAs included transcripts (miR-1 and miR-494-3p) shown to be implicated in cardiac remodeling. Further, complex III activity was reduced (1785±186.1 vs.2468±223.8nmol e - /min/mg, p=0.03, n=8) in RUPPs with accompanying increased trend in ROS levels (1.34±0.22 vs. 0.84±0.13nmol e - /min/mg, n=8, p=0.07) although activities of other complexes or oxygen consumption rates were unchanged. Conclusions: To the best of our knowledge, this is the first study to demonstrate abnormal expression of cardiac miRNAs in association with reduced cardiac mitochondrial function in the RUPP rat model of PE. Our ongoing work will determine whether these dysregulated miRNAs contribute to cardiac dysfunction via mitochondrial perturbations.

Prognostic Significance of Hemodynamics in Patients With Transposition of the Great Arteries and Systemic Right Ventricle.

Patients with transposition of the great arteries (TGA) and systemic right ventricle often confront significant adverse cardiac events. The prognostic significance of invasive hemodynamic parameters in this context remains uncertain. Our hypothesis is that the aortic pulsatility index and hemodynamic profiling utilizing invasive measures provide prognostic insights for patients with TGA and a systemic right ventricle. This retrospective multicenter cohort study encompasses adults with TGA and a systemic right ventricle who underwent cardiac catheterization. Data collection, spanning from 1994 to 2020, encompasses clinical and hemodynamic parameters, including measured and calculated values such as pulmonary capillary wedge pressure, aortic pulsatility index, and cardiac index. Pulmonary capillary wedge pressure and cardiac index values were used to establish 4 distinct hemodynamic profiles. A pulmonary capillary wedge pressure of ≥15 mm Hg indicated congestion, termed wet, while a cardiac index <2.2 L/min per m2 signified inadequate perfusion, labeled cold. The primary outcome comprised a composite of all-cause death, heart transplantation, or the requirement for mechanical circulatory support. Of 1721 patients with TGA, 242 individuals with available invasive hemodynamic data were included. The median follow-up duration after cardiac catheterization was 11.4 (interquartile range, 7.5-15.9) years, with a mean age of 38.5±10.8 years at the time of cardiac catheterization. Among hemodynamic parameters, an aortic pulsatility index <1.5 emerged as a robust predictor of the primary outcome, with adjusted hazard ratios of 5.90 (95% CI, 3.01-11.62; P<0.001). Among the identified 4 hemodynamic profiles, the cold/wet profile was associated with the highest risk for the primary outcome, with an adjusted hazard ratio of 3.83 (95% CI, 1.63-9.02; P<0.001). A low aortic pulsatility index (<1.5) and the cold/wet hemodynamic profile are linked with an elevated risk of adverse long-term cardiac outcomes in patients with TGA and systemic right ventricle.

Cardiac Electrical and Structural Changes after Iodinated Contrast Media Administration: A Longitudinal Cohort Analysis.

Background: Iodinated contrast is commonly used for radiological procedures, with one dose delivering several hundred-fold the daily requirements needed for normal thyroid hormone production. Risks of excess iodine include incident thyroid dysfunction, which is associated with adverse cardiac outcomes, yet there are no prospective studies investigating the changes in cardiac physiology following iodine contrast administration. This study was conducted to investigate the longitudinal relationships between the amount of iodinated contrast administration and changes in cardiac electrophysiology and structure. Methods: A longitudinal cohort study was conducted with prospectively enrolled participants who received iodine contrast for elective computed tomography or coronary angiography. Serum thyroid function tests, electrocardiograms (EKG), and transthoracic echocardiograms were obtained serially until 36 months. Trends of electrical and structural cardiac changes following iodine contrast administration were assessed using mixed effect models. Results: The cohort was composed of 129 patients (median age, 70 [interquartile range: 63, 75] years; 98% male). Larger amounts of iodine exposure were associated with increases in QRS and QTc durations and decreased ejection fraction (EF), and these associations were still observed for follow-up EF after additionally adjusting for baseline values (the high-iodine contrast group vs. the low-iodine contrast group, -4.23% [confidence interval, -7.66% to -0.79%]). Dose-response analyses also showed lower EF with larger amounts of iodine received; these trends were not significant for the EKG parameters studied. Conclusions: Over a period of up to 36 months, a larger amount of administered iodine contrast was associated with lower EF among participants. Further investigation is needed to elucidate the long-term trends of electrical and structural cardiac function after iodine contrast administration.