Sudden Death Research Articles

Abstract 4136971: Prognostic Value of Late Gadolinium Enhancement to Predict Non-Sustained Ventricular Tachycardia in Patients with Hypertrophic Cardiomyopathy: A Systematic Review and Meta-Analysis

Background: Non-sustained ventricular tachycardia (NSVT) has been shown to be independently associated with sudden cardiac death (SCD) among patients with hypertrophic cardiomyopathy (HCM). There is limited evidence regarding the efficacy of late gadolinium enhancement (LGE) on cardiac magnetic resonance imaging to predict the incidence of NSVT. Aims: To address this gap in knowledge, our meta-analysis aims to comprehensively evaluate the prognostic value of LGE on cardiac magnetic resonance in predicting the incidence of NSVT in HCM. Methods: PubMed, Embase and Cochrane CENTRAL databses were queried from inception until May 2024 for all studies assessing the prognostic value of LGE on CMR in patients with HCM and reported the incidence of NSVT. Data were combined using a random-effects model meta-analysis to determine the pooled sensitivity, specificity and accuracy of LGE in predicting NSVT in patients with HCM. The association between the LGE extent on CMR and NSVT incidence was also assessed, and weighted mean differences (WMDs) were reported with 95% condidence intervals (CIs). Heterogeneity across the studies was evaluated using the Higgins I 2 statistic. Results: A total of twenty studies were included in our analysis. The pooled senstivity, specificity, and accuracy of LGE in predicting the incidence of NSVT among HCM patients was 91.33%, 37.45%, and 52.86%, respectively. Moreover, we saw a significantly greater extent of LGE (5.95%, CI: 3.08-8.81, P<0.0001) in patients who had NSVT, as compared to patients without NSVT ( Figure 1). Conclusion: Our meta-analysis underscores the significant prognostic value of LGE as a risk stratification tool on CMR imaging in predicting the incidence of NSVT in patients with HCM, by demonstrating a high sensitivity, and a notable association between the LGE extent and NSVT incidence. Nevertheless, the low to moderate Ispecificity and accuracy underscores the need for additional imaging biomarkers for risk stratification.

Abstract 4120929: Silent Myocardial Infarctions in Women with Ischemic Sudden Cardiac Death

Background: Sudden cardiac death (SCD) is a significant mode of death in both sexes, with most cases attributed to coronary artery disease (CAD). In women, ischemic SCD seems to occur more often without previously diagnosed CAD, but the prevalence and characteristics of silent myocardial infarctions (SMI) in women are not known. Aim: This study aimed to investigate the prevalence and characteristics of women with silent myocardial infarction (SMI) and ischemic SCD. Methods: The Fingesture study consists of 5,869 autopsy-verified SCD cases (21.1% women) in Northern Finland 1998-2017. In this study, we investigated women with ischemic SCD without previous CAD diagnosis (N=660). SMI was defined as a myocardial infarction (MI) scar at autopsy in the absence of CAD history in medical records. As a control group, we used women with ischemic SCD without MI scar and previous CAD diagnosis. Coronary artery stenosis, myocardial fibrosis, and MI scars were evaluated through macroscopic assessment during autopsy, with further histological verification for myocardial fibrosis and MI scars. Results: Among 660 ischemic SCD subjects without prior CAD diagnosis, 220 (33.3%) had SMI. Women with SMI were older compared to those without SMI (73.4 vs. 71.4 years in subjects without SMI, p=0.03), and SMIs became more prevalent with advancing age (+4.4% per decade, p<0.01). Women with SMI had higher heart weight (411 vs. 386 g in subjects without SMI, p<0.01) and a higher prevalence of left ventricular hypertrophy (LVH) (73.6% vs. 64.5% in subjects without SMI, p=0.02). The average body mass index was 27.1 kg/m 2 in subjects with SMI and 27.6 kg/m 2 in subjects without SMI (p=0.34). Subjects with SMI were more likely to have severe coronary artery stenosis with >90% occlusion (37.3% vs. 22.5% in subjects without SMI, p<0.01). Severe (15.0% vs. 3.0% in subjects without SMI, p<0.01) and moderate (69.1% vs. 39.4% in subjects without SMI, p<0.01) degrees of myocardial fibrosis were more prominent among subjects with SMI. Conclusions: One-third of ischemic SCD cases without prior CAD diagnosis in women had findings of SMI at autopsy. Women with SMI were slightly older and exhibited more severe coronary disease, LVH and myocardial fibrosis at autopsy. These findings underscore the importance of earlier diagnosis and treatment of CAD in SCD prevention in women.

Abstract 4141488: Initial Real-World Experience with a Novel Wearable Cardioverter Defibrillator

Background: The wearable cardioverter defibrillator (WCD) can reduce sudden cardiac death; effectiveness depends on adherence. A novel WCD designed for sex specific comfort and noise immunity has reported improved compliance. Hypothesis: Patient compliance with the WCD maximizes device utility in treating significant arrhythmia. Aims: Report WCD patient compliance and efficacy in a cohort with balanced gender representation. Evaluate WCD performance in minimizing noise artifact leading to false alarms and unnecessary shocks. Methods: Retrospective analysis of patients prescribed the ASSURE WCD at the Cleveland Clinic. Clinical data was collected via medical chart review. All device-detected arrhythmia episodes were manually adjudicated by a Board-certified Electrophysiologist. Detected rhythms that persist, result in an audible alarm notifying that a shock is imminent. A conscious patient can manually divert a shock. An alarm was deemed true and shock appropriate if the underlying rhythm was sustained VT/VF. Results: Fifty-five patients were fitted with a WCD. Median daily use 22 hr/day (IQR 13,24) and median duration of use 43 days (IQR 8,79). Female representation was 49%, significantly greater than prior reports of WCD experience. 4 episodes of sustained VT/VF were detected in 4 patients. A single shock terminated VT/VF in 2, while spontaneous termination of VT/VF occurred in the other 2 patients who diverted shocks. One shock for hemodynamically unstable atrial fibrillation with heart rate >200bpm was delivered and deemed necessary. No deaths occurred while wearing a WCD. Of 163 recorded episodes, 62 (38%) persisted and triggered an alarm (Figure 1). 10 patients experienced a median of 1 (IQR 1,9.5) alarm during the WCD wear period. The majority (97%) of alarms were associated with a significant tachyarrhythmia, with only 3% due to noise artifact. No inappropriate, unnecessary shocks were delivered. Discussion: Patient compliance with the ASSURE WCD was high in this real-world observational study with equal representation of both sexes. The WCD effectively terminated sustained hemodynamically significant tachyarrhythmias, emitted few false alarms due to noise and resulted in no unnecessary and inappropriate shocks.

Abstract 4138514: From Treatment to Trigger: A Case of Atomoxetine-Induced Brugada Pattern

Introduction: Brugada syndrome is an inherited cardiac disorder characterized by specific ECG patterns, notably the coved-type ST-segment elevation in the right precordial leads (V1-V3), leading to an increased risk of sudden cardiac death. This condition often stems from mutations in the SCN5A gene, which impair cardiac sodium channel function. The manifestation of Brugada Pattern, showing typical ECG findings without clinical criteria like sudden cardiac arrest or syncope, is significant. We highlight a case where atomoxetine, a selective norepinephrine reuptake inhibitor used for ADHD, unveiled a type 1 Brugada pattern. Case Presentation: A 26-year-old male with a history of ADHD on atomoxetine only presented to the emergency department with sudden substernal chest pain radiating to his left arm. His initial ECG showed right bundle branch block and type 1 Brugada pattern (Figure.1). Despite normal troponin levels and a negative coronary CT angiography, the patient's ECG abnormalities raised concerns. With no personal or familial history of arrhythmia or SCD and no other medications, atomoxetine was suspected as the trigger. Upon discontinuation, the patient's ECG type 1 Brugada pattern resolved (Figure. 2), and he remained asymptomatic with a normal Holter monitor at a 1-month follow-up. Discussion: Brugada syndrome is marked by dynamic ECG abnormalities, which can surface due to triggers like fever, certain medications, and electrolyte imbalances. Atomoxetine, an ADHD treatment and selective norepinephrine reuptake inhibitor, affects the human cardiac sodium channel (hNav1.5), encoded by the SCN5A gene. This interaction can disrupt heart action potentials, leading to conditions like long QT syndrome and Brugada pattern, by slowing cardiomyocyte depolarization and conduction. Its effect on hNav1.5 resembles that of antidepressants like Fluoxetine, increasing the risk of Brugada pattern. In our case, a patient's type 1 Brugada pattern, with no underlying heart disease or family history, pointed to atomoxetine as the cause. Discontinuing the drug resolved the ECG abnormalities. Conclusion: This case emphasizes the importance of assessing cardiovascular risk before prescribing atomoxetine, especially in individuals at risk for cardiac sodium channel dysfunctions. Immediate intervention and monitoring are critical to prevent severe arrhythmias.

Abstract 4138546: From Nature’s Remedy to Cardiac Emergency: A Case of Takotsubo Cardiomyopathy Induced by High-Dose Berberine Supplementation

Introduction: Takotsubo cardiomyopathy (TCM) is a reversible cardiac condition often precipitated by emotional or physical stress. Certain medications have also been implicated. While prognosis is generally favorable, associated QTc prolongation and ventricular arrhythmias can be life threatening, necessitating identification of potential triggers. This report highlights TCM in a patient using high-dose berberine, a plant alkaloid known for its hypoglycemic properties. Case description: A 69-year-old female with a history of type 2 diabetes mellitus, and hyperlipidemia presented after a syncopal event. It was preceded by sudden onset of dizziness, nausea, and vomiting. She had been using berberine for a year to lower her blood sugar and had recently switched to a higher dose of a more potent formulation. Vitals were unremarkable. Initial evaluation revealed a prolonged QTc interval of 659 ms (Figure 1A) and elevated troponin-I levels. She was treated with intravenous magnesium, which improved her QTc to 540 ms and revealed new T-wave inversions in the precordial leads. Echocardiogram showed an ejection fraction (EF) of 35%, with LV apical akinesia and hypercontractile basal segments. Cardiac catheterization ruled out significant coronary artery disease, leading to a diagnosis of TCM. Berberine was discontinued, and guideline-directed medical therapy was initiated. Given the presentation with syncope and high suspicion of aborted sudden cardiac death (SCD), she was discharged with a wearable cardioverter-defibrillator (WCD) as a precaution due to the risk of ventricular arrhythmias during recovery. At her 8-week follow-up, QTc and EF had normalized (Figure 1B), prompting WCD removal. Conclusion: The pathophysiology of berberine-induced cardiomyopathy remains uncertain and requires further research. This case underscores the importance of recognizing the potential cardiotoxic effects of berberine, particularly when used in high doses. A thorough medication and supplement history is crucial in patients presenting with unexplained cardiac symptoms. The reversible nature of TCM, when promptly recognized and treated, highlights the need for comprehensive follow-up to ensure recovery of cardiac function.

Abstract 4123956: Upgrade to Implantable Cardioverter-Defibrillator in Patients Diagnosed with Cardiac Sarcoidosis after Permanent Pacemaker Implantation for High-Grade Atrioventricular Block

Introduction: Unexplained high-grade AV block (AVB) in patients age <65 years is among the salient features of cardiac sarcoidosis (CS). Guidelines recommend that CS patients with high-grade AVB should receive an implantable cardioverter-defibrillator (ICD) or cardiac resynchronization therapy-defibrillator (CRT-D) rather than a permanent pacemaker (PPM). However, in clinical practice, CS may be recognized after PPM implantation for high-grade AVB. Aims: To evaluate the characteristics and outcomes of patients diagnosed with CS after PPM implantation for high-grade AVB and assess the decision-making and rationale for upgrade to ICD/CRT-D. Methods: Retrospective review of the Mayo Clinic Sarcoid Registry (n=848) was performed to identify all patients for which a PPM was implanted for high-grade AVB prior to the diagnosis of CS. Baseline clinical and imaging characteristics were collected during index evaluation at our institution. Decision-making for ICD upgrade, lead management strategy, immunosuppression initiation, and outcomes were assessed. Results: Overall, 29 of 848 (3.4%) of CS patients (62% probable/definite CS; 77% male; median (IQR) age 56 (48-61) years; and median (IQR) LVEF 58% (50-62) received a PPM for high-grade AVB prior to a CS diagnosis. Median (IQR) interval between PPM implant and index evaluation was 10 (3-23) months. Eight of 29 patients underwent upgrade to ICD (n=4) or CRT-D (n=4). Among them, the pacing lead was extracted in 4. All patients were upgraded for primary prevention of sudden cardiac death (SCD), with 3 of them also having LVEF<50% requiring upgrade to CRT-D. Twenty-two (79%) patients in the total cohort were treated with immunosuppression. During median (IQR) follow-up 37 months (11-74), 1 patient in the upgrade group had sustained VT appropriately treated with anti-tachycardia pacing. No events were documented among patients in the non-upgrade group. At last follow-up, 6 (75%) patients in the upgrade group and 12 (57%) in the non-upgrade group were pacemaker dependent. Median LVEF change was 0% in patients who underwent upgrade to CRT-D and –0.2% in those who underwent upgrade to ICD or no upgrade. Conclusions: In this cohort of patients diagnosed with CS several months after a PPM had been implanted for high-grade AVB, incident VT/VF was infrequent with contemporary CS management. In the absence of other SCD risk factors, CS patients who received a PPM for high-grade AVB prior to their CS diagnosis may not require ICD upgrade.

Morphology of Cortical Microglia in the Hyperacute Phase of Subarachnoid Hemorrhage

Hemorrhagic stroke is the deadliest type of stroke. Cellular and molecular biomarkers are important for understanding the pathophysiology of stroke. Microglia are among the most promising biological markers. However, the morphological and physiological characteristics of microglia, as well as the structural and functional aspects of their interactions with neurons and other cells, are largely unknown. Due to the large number of different morphological phenotypes and very limited information on microglial changes in subarachnoid hemorrhage (SAH), we performed this study aimed at identifying the features of the distribution of various microglial phenotypes in the layers of the cerebral cortex in the hyperacute phase of non-traumatic SAH. We studied the distribution of various microglial phenotypes in the layers of the cerebral cortex of SAH non-survivors with a control group (coronary heart disease and sudden cardiac death were the underlying causes of death). An immunohistochemical study using antibodies to iba-1 (a marker of microglia) revealed changes in the morphological phenotypes of microglia in the cerebral cortex after subarachnoid hemorrhage. Significant differences between the groups indicate a rapid microglial response to injury. The findings indicate that there are quantitative and phenotypic changes in microglia in the cerebral cortex during early SAH in the human cortex.

Abstract 4136788: Lipoprotein(a) Levels and the Risk of Ventricular Arrhythmia: Insights from a Comprehensive Retrospective Cohort Study

Background: Sustained ventricular arrhythmias (VAs) are associated with an elevated risk of sudden cardiac death (SCD). Lipoprotein(a) (Lp[a]) is a recognized risk factor for atherosclerotic cardiovascular disease (ASCVD), which in turn associated with increased risk of VAs. However, whether Lp(a) is linked with VAs independent of ASCVD remains unknown. Objective: To examine the association of Lp(a) with VAs in a population-based, retrospective cohort study utilizing data from the TriNetX Research Network. Methods: We conducted a retrospective analysis of the data from 89 healthcare organizations within the TriNetX Research Network. Patients over 18 years old with available serum Lp(a) measurement were included. Participants were divided into two cohorts based on their Lp(a) levels: cohort 1 (Lp(a) ≤75 nmol/L), and cohort 2 (Lp(a) ≥76 nmol/L). Follow-up time to VA occurrence was calculated from the time of Lp(a) level measurement within each cohort. The composite endpoint was the incidence of VAs to include ventricular tachycardia, ventricular fibrillation, ventricular flutter, or cardiac arrest due to underlying cardiac conditions. We compared the two cohorts using Kaplan-Meier survival analysis along with cox proportional hazard regression analysis after propensity score matching. Results: 50,752 patients were included in cohort 1 and 24,474 in cohort 2. After propensity score matching, both cohorts had 23,668 patients. In cohort 1, 307 patients experienced VAs, compared to 303 in cohort 2 (Table 1). The mean age was 53.3 ± 15.7 years, with 53.35% of participants being female, 10.75% being Black, and 69.89% being White. The Kaplan-Meier survival analysis showed a higher survival probability at the end of the study period for the Lp(a) ≤75 compared to the Lp(a) ≥76 cohort (95.11% vs 85.35%, p=0.002). The hazard ratio (HR) for VA was 0.768 (95% CI: 0.652-0.904, p = 0.002), indicating that lower Lp(a) levels are associated with reduced VA risk. Conclusion: This study shows that increased Lp(a) levels are independently associated with a higher incidence of VA. Future research should focus on the mechanisms underlying the relationship between Lp(a) levels and VA, and whether Lp(a) reduction can reduce the risk of VA and other cardiovascular outcomes.

Abstract 4134308: Re-evaluating the safety profile of Semaglutide: An updated meta-analysis

Background: Semaglutide is increasingly used in the management of type 2 diabetes mellitus and obesity. Ensuring safety of this medication is crucial for its clinical use. This meta-analysis evaluates the safety profile of semaglutide across patient populations and treatment durations. Methods: Randomized controlled trials assessing the safety of semaglutide versus placebo, with specified treatment durations were identified. The primary outcome was occurrence of any cardiovascular adverse events. Secondary outcomes included sudden cardiac death, adverse events leading to death, adverse events, gastrointestinal side effects, occurrence of hypoglycemia and new-onset neoplasm. Results: A total of 23 studies met the inclusion criteria with a combined sample size of 57,911 participants. The meta-analysis revealed that the adverse event associated with semaglutide is gastrointestinal in nature (nausea and vomiting). No significant differences were observed between semaglutide and comparator groups. (See Figure 1) Conclusion: Semaglutide appears to have a favorable safety profile across diverse patient populations and treatment durations, supporting its continued use in the management of type 2 diabetes mellitus and obesity. It is generally well-tolerated, with a low incidence of adverse events. Clinicians should be aware of these findings and monitor patients accordingly. Further long-term studies are warranted to assess the safety of semaglutide in clinical practice.

Abstract 4135215: Eosinophilic Coronary Periarteritis (ECPA): An Under-recognized Coronary Disease with Fatal Consequences

Clinical presentation: A 50-year-old male with a paraesophageal hernia and grade D esophagitis presented to the ER with complaints of heartburn. He subsequently went into cardiac arrest and was diagnosed with a hemopericardium with tamponade physiology from a ruptured right coronary artery (RCA). Imaging Findings: Initial CT of the chest found a 1.5x1.5 cm dilation of the proximal RCA (Fig1A). Post cardiac arrest, repeat CT of the chest revealed an interval increase of the proximal RCA measuring 3.5x3.5 cm and a moderate-to-large hemopericardium (Fig1B). An emergent limited TEE demonstrated a large circumferential hemopericardium and biventricular standstill. Decision-making: In the ER, the initial symptoms resolved and he remained under observation. Hours later, he became bradycardic with a heart in the 20s and was found unresponsive. ACLS was activated and the patient was emergently cannulated and ECMO was initiated due to refractory cardiac arrest. Despite efforts from a multidisciplinary team including cardiology, cardiothoracic surgery and cardiac critical care, ROSC could not be achieved thus portending a poor prognosis. The family decided to withdraw care and the patient expired. Autopsy revealed a 925 mL hemopericardium from a ruptured 3.5 cm severely aneurysmal RCA and other remarkable findings included a 2 cm proximal aneurysm of left anterior descending artery and a 1 cm proximal aneurysm of left circumflex artery (Fig2A,B). Genetic testing for connective tissue disease was negative. Histopathology showed an eosinophilic predominant inflammatory infiltrate of the adventitia suggesting periarteritis (Fig2C) without signs of vasculitis in other organs. Conclusion: ECPA (eosinophilic coronary periarteritis) is a fatal entity with reported cases of sudden cardiac death and findings of vessel medial degeneration and coronary dissection. This case raises awareness of an under-recognized condition with limited guidance in diagnostic and therapeutic interventions.

Abstract 4137895: Serum High-density Lipoprotein-Associated Paraoxonase-1 Levels Predict Recurrent Cardiovascular Events after Stent Implantation in Patients with Stable Angina Pectoris

Background: Poor clinical outcomes for patients undergoing hemodialysis (HD) after drug-eluting stent (DES) implantation have been reported. High-density lipoprotein (HDL) cholesterol is well-established as a negative risk factor for coronary artery disease, and its anti-oxidant property has been attributed mainly to the HDL-bound enzyme paraoxonase-1 (PON-1). Myeloperoxidase (MPO), a pro-oxidant enzyme released from activated neutrophils, has been shown to alter the atheroprotective function of HDL to a dysfunctional form. The aim of this study was to investigate the relationship between plasma MPO and serum PON-1 levels after implantation of DES in patients with stable angina pectoris (SAP) with and without HD. Methods: Serum PON-1 concentrations and PON-arylesterase activity were measured in 183 patients with SAP after DES implantation (HD group, n=37; non-HD group, n=146) with a sandwich ELISA method. Cardiovascular events were defined as sudden cardiac death, fatal or non-fatal myocardial infarction, cerebral infarction and other non-fatal events including unstable angina pectoris or coronary revascularization. Results: Serum PON-1 concentrations and PON-arylesterase activity were significantly lower in the HD group than in the non-HD group (PON-1 concentrations, P<0.0001; PON-arylesterase activity, P<0.0001). In addition, plasma MPO in patients undergoing HD were significantly higher than in patients not undergoing HD (P<0.0001). Moreover, plasma MPO showed a significant inverse correlation with serum PON-1 concentrations and PON-arylesterase activity (concentration: R= -0.24, P=0.0013; arylesterase-activity: R=-0.24, P=0.0014). Cardiovascular event rates were significantly higher in the HD group than in the non-HD group (67.6% vs. 43.8%, P<0.01). Kaplan-Meier survival analysis showed that the low-PON-1 group (<58.0 mg/mL, median) had a significantly worse outcome than the high-PON-1 group ( P =0.013). Multivariate analysis showed that a low serum PON-1 concentration was the only independent predictor of cardiovascular events (odds ratio, 1.93; 95% confidence interval, 1.10 to 3.40, P =0.024). Conclusions: These findings demonstrate that plasma MPO have a significant inverse correlation with PON-1 in patients undergoing HD and suggest that an imbalance between pro-oxidants and anti-oxidants may contribute to the progression and destabilization of human coronary atherosclerotic lesions in patients with SAP who undergo HD following DES implantation.

Abstract 4137975: 9-Year Longitudinal Assessment of the 12-lead Electrocardiogram of Volunteer Firefighters

Introduction: In the US, the most common cause of death among active-duty firefighters is sudden cardiac death (SCD). Underlying heart diseases are important propagator of ventricular tachyarrhythmias that cause SCD. The objective of this abstract is to assess the incidence of underlying heart disease, identified on 12-lead electrocardiograph (ECG), that may place firefighters at greater risk of SCD. Methods: We digitalized 12-lead ECGs recorded among firefighters who visited a firefighter health screening program at least 4 times from 2011-2019. We extracted the interval measurements (Heart Rate, T-axis, QRS-axis, QRS duration, QTc duration) and interpretation statements from each of the 12-lead ECGs and grouped potential propagators of ventricular tachyarrhythmias including left ventricular hypertrophy (LVH), coronary artery disease (CAD), and cardiac conduction disease. We used simple mean imputation to handle missing data. Descriptive statistics including means and frequencies were used to analyze the sample. Results: Among 465 firefighters (90.1% male) with a mean age of 47.1 (±13.6) whom 1,296 12-lead ECGs were analyzed, 21.5% (n=278) of Heart Rate, 0.39% (n=5) T-axis, 26.4% (n=342) QRS-axis, 40.0% (n=518) QRS duration, 5.40% (n=70) QTc duration were abnormal. In addition to intervals, the 12-lead ECGs generated 1,970 interpretation statements of which 28.2% (n=555) were deemed possible pathoanatomical substrates including 3.1% (n=34) LVH, 24.7% (n=137) CAD, and 69.2% (n=384) cardiac conduction diseases. Among cardiac conduction diseases, intraventricular conduction disease was the most prevalent (n=204, 36.8%), followed by vertical axis (n=70, 12.6%), right bundle branch block (n=59, 10.6%), left anterior fascicular block (n=34, 6.1%), and left bundle branch block (n=17, 3.1%). Interestingly, we did not observe a temporal relationship regarding the number of pathoanatomical substrates over the screening period. Conclusions: Nearly 30% of the interpretation statements generated from 12-lead ECGs were indicative of possible pathoanatomical substrates that cause SCD, which reflects the apparently negative effect of fire suppression activity on one’s cardiopulmonary health. Our result justifies the imperative need of effective prevention method for cardiac conduction diseases among firefighters. Further research is needed to collect 12-lead ECG systematically amongst other measures such as diet and BMI which reflect work culture and lifestyle of firefighters.

Abstract 4137913: Role of serial evaluation of myocardial inflammatory activity and oxidative stress in determining the therapeutic efficacy of immunosuppression and clinical outcome in patients with cardiac sarcoidosis

Background: Cardiac sarcoidosis (CS) was characterized by formation of granulomas in the heart. Enhancement in myocardial inflammatory activity and oxidative stress is a crucial cause of major cardiovascular adverse events (MACE). Although immunosuppressive therapy is recommended for active CS, there is no established markers for treatment and prognosis. Hypothesis: We hypothesized that the inflammation and oxidative stress in heart were associated with MACE after steroid therapy. Aims: We identified prognostic markers for MACE in patients with CS after steroid therapy. Methods: This study was a prospective observational cohort study. Patients with CS diagnosed according to Japanese criteria were enrolled in this study. Patients with abnormal accumulation of 18 F-FDG in heart were treated with steroids with standard guideline-recommended protocol. 18 F-FDG PET were performed after more than 6 months of induction. Urinary 8-hydroxy-2'-deoxyguanosine (U-8-OHdG), a marker of oxidative DNA damage, and indices of cardiac and renal function were measured. The major outcome was a composite of the first sustained ventricular tachycardia (sVT) /sudden cardiac death (SCD), hospitalization for heart failure, and radiological relapse with exacerbation of clinical manifestation. Results: Fifty consecutive patients with CS underwent steroid therapy and followed up (median follow-up period of 58 months). 39 of 50 patients underwent 18F-FDG PET/CT more than 6 months after steroid therapy. During the follow-up period, 17 of 39 patients showed MACE, consisting of sVT/SCD (N= 11), hospitalization (N= 2) and radiological relapse (N= 4). A Cox proportional-hazard model showed that the U-8-OHdG and SUV max value of FDG-PET were independent predictors of MACE. ROC analysis revealed that the cut-off values of U-8-OHdG and SUV max for predicting the MACE were 11.6 ng/mg Cr (AUC 0.913, sensitivity 86.7%, specificity 90.0%) and 4.64 (AUC 0.878, sensitivity 76.5%, specificity 91.0%), respectively (Fig.1). Patients with a U-8-OHdG ≧11.6 ng/mg Cr or SUV max ≧4.64 had a significantly higher MACE risk (P values for U-8-OHdG and SUV max were both 0.001 by Log Rank analysis) (Fig.2). It is noted that U-8-OHdG <11.6 ng/mg Cr and SUV max <4.64 after steroid therapy indicate the good responses to the immunosuppressive therapy and better prognosis (Fig.3). Conclusion: U-8-OHdG and SUV max may be useful markers in determining the therapeutic efficacy and clinical outcome in patients with CS.

Abstract 4148089: Comparative Efficacy of Carvedilol versus Metoprolol in Patients with Implantable Cardioverter Defibrillators and Ventricular Arrhythmias: A Systematic Review and Meta-Analysis

Background: Ventricular arrhythmias are major causes of morbidity and mortality in patients with cardiovascular disease. Implantable cardioverter-defibrillators (ICDs) are commonly used to prevent sudden cardiac death in these patients. However, patients with ICDs frequently experience recurrent arrhythmias and inappropriate shocks, which can impact their quality of life. Beta-blockers, specifically carvedilol and metoprolol, are commonly prescribed to manage these arrhythmias. This meta-analysis aims to compare the impact of both medications in this patient population. Methods: A comprehensive literature search was conducted to identify relevant studies comparing carvedilol to metoprolol in patients with ventricular arrhythmias or ICDs. Study outcomes included all-cause mortality, recurrent ventricular arrhythmia, and inappropriate ICD shocks. Effect estimates are presented as hazard ratios (HR) with 95% confidence intervals (CI). Results: 1,453 studies were identified through database search. After full-text screening, a total of 5 studies involving 9,292 patients were included. We found no significant difference in the incidence of recurrent ventricular arrhythmias between carvedilol and metoprolol (HR = 0.99, 95% CI [0.75, 1.32], P = 0.97). Additionally, Carvedilol showed a trend toward reduction of all-cause mortality (HR = 0.83, 95% CI [0.68, 1.03], P = 0.09). On the other hand, Carvedilol was associated with a statistically significant reduction of inappropriate ICD shocks (HR = 0.61, 95% CI [0.48, 0.78], P < 0.001). Conclusion: Carvedilol may offer additional benefits over metoprolol in managing patients with ventricular arrhythmias or ICDs, particularly in minimizing the incidence of inappropriate ICD shocks. However, no significant difference was found in terms of all-cause mortality and recurrent ventricular arrhythmia incidence. Further research is needed to confirm these findings and guide clinical decision-making.

Abstract 4136452: Acute Cardiac Function Change After Catheter Ablation of Ventricular Arrhythmias in Patients with Arrhythmogenic Right Ventricular Cardiomyopathy

Introduction: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetic disorder characterized by fibrofatty replacement of myocardial tissue, creating areas of electrical heterogeneity and increasing the risk of ventricular arrhythmias (VAs) and sudden cardiac death (SCD). Catheter ablation is commonly performed in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) for management of ventricular arrhythmias (VAs). Whether catheter ablation affects cardiac function post-procedurally is uncertain. Research Question: Does catheter ablation for ARVC result in acute change in cardiac function? Goals/Aims: To assess the impact of catheter ablation for VAs on cardiac function in the acute post-procedure setting. Methods: This retrospective study included patients with ARVC who underwent catheter ablation for VAs at Mayo Clinic. Cardiac function was assessed on pre- and post-procedure transthoracic echocardiograms (TTEs). Post-procedure TTEs were obtained within 4 weeks after the ablation procedure. Right ventricular (RV) enlargement and systolic dysfunction were evaluated as continuous variables (0=none, 1=mild, 2=mild-moderate, 3=moderate, 4=moderate-severe, 5=severe). Results: The study included 32 patients who underwent a total of 44 ablations. Mean age at the time of ablation was 49±16 years, and 24 (75%) were male. After a mean follow-up duration of 2.6±5.5 days, there was a significant worsening in mean RV dysfunction (1.6±1.5 to 2.0±1.4, P = 0.001). There were no significant changes in mean left ventricular ejection fraction (LVEF), left ventricular (LV) dimensions, and RV size. 6 (14%) patients had a >5% decline in LVEF, and 14 (32%) patients had worsening RV function. Transient inotropic support was required in 4 (9%) patients. Conclusion(s): This study is the first to assess the acute impact of catheter ablation for VAs on cardiac function in ARVC patients. These results underscore the importance of careful post-procedure monitoring and planning of the ablation target in these patients to avoid excessive ablation and therefore impairment in cardiac function.

Abstract 4138690: A Case of Hypertrophic Cardimyopathy: Digenic Variants of Uncertain Significance Mutations in MHY7 and RYR2 Genes

Introduction: Hypertrophic Cardiomyopathy (HCM) is primarily a disease caused by mutations in single genes, but around 5% of HCM patients, exhibit 2 (digenic) or more (oligogenic) causal mutations in the same gene or in different genes. We present a case of familial HCM with variants of uncertain significance (VUS) mutations in the MYH7 and RYR2 genes, highlighting the complexity of genetic inheritance and its implications on disease severity. Case presentation: A 40-year-old male presented with a history of hypertension, HCM, and two prior myocardial infarctions. He had syncope, non-sustained ventricular tachycardia, and a family history of sudden cardiac death (SCD) in his maternal grandfather. A dual-chamber ICD was placed for primary prevention of SCD because of his high-risk profile. Echocardiography demonstrated normal LV size and function with moderate asymmetric septal hypertrophy. Cardiac MRI indicated diffuse asymmetric hypertrophy and a 10.9% LV myocardial scar burden. Left heart catheterization revealed normal coronary arteries with LVOT gradient up to 60 mmHg, consistent with HCM. Genetic testing revealed VUS in the MYH7 (c.1305G>A, p.Met435Ile) and RYR2 (c.10528C>A, p.Arg3510Ser) genes (Figure 1). Further family genetic testing confirmed these VUS mutations in multiple relatives (Figure 2). Discussion: The identification of VUS mutations in MYH7 and RYR2 genes in multiple family members highlights the complexity of genetic inheritance in HCM. These findings underscore the challenges in clinical interpretation and risk stratification, as the co-occurrence of mutations in different genes may have synergistic effects on disease severity and phenotype expression. Comprehensive genetic evaluation, including family studies, is crucial for understanding the clinical significance of these mutations and guiding personalized management strategies. Further research is needed to elucidate the impact of VUS mutations on the clinical outcomes of HCM patients.

Abstract 4134426: Targeting the TRIM29-PERK signaling axis for treating viral myocarditis

Introduction: Viral myocarditis is an inflammatory disease of the myocardium that significantly contributes to sudden death in children and young adults. The COVID-19 pandemic underscores the critical need to understand the pathogenesis and develop effective treatment strategies for viral myocarditis. Methods: To investigate the role of the novel E3 ligase TRIM29 in viral myocarditis, we used wild-type and TRIM29 knockout mice infected with coxsackievirus B3 (CVB3) and encephalomyocarditis virus (EMCV), to induce the myocarditis. Additionally, wild-type mice infected with CVB3 were treated with the protein kinase RNA-like endoplasmic reticulum kinase (PERK) inhibitor GSK2656157 or a DMSO control to evaluate potential therapeutic interventions. Mice survival and heart function were monitored using transthoracic echocardiography, and hearts were harvested for histological and immunohistochemical analysis. Techniques including real-time PCR, western blotting, co-immunoprecipitation, enzyme-linked immunoassay, flow cytometry, over-expression, and knockdown were employed to elucidate the pathogenic mechanisms by which TRIM29 regulates the endoplasmic reticulum stress response after viral infection. Results: We found that TRIM29 was highly induced by cardiotropic viruses, including CVB3 and EMCV, and promoted PERK-mediated endoplasmic reticulum (ER) stress, apoptosis, and reactive oxygen species (ROS) responses, which restricted viral replication in cardiomyocytes in vitro . TRIM29 deficiency protected mice from viral myocarditis by enhancing cardiac antiviral functions and reducing PERK-mediated inflammation and immunosuppressive cells in vivo . Mechanistically, TRIM29 interacted with PERK to catalyze the SUMOylation of PERK, maintaining its stability and thereby promoting PERK-mediated signaling pathways. Furthermore, we demonstrated that the PERK inhibitor GSK2656157 mitigated viral myocarditis by disrupting the TRIM29-PERK interaction, which improved cardiac function, enhanced cardiac antiviral responses, and reduced inflammation and immunosuppressive cells in vivo . Conclusions: Our findings provide the first evidence that the TRIM29-PERK signaling axis can be targeted for the treatment of viral myocarditis. This suggests that targeting the TRIM29-PERK axis could effectively mitigate viral myocarditis and associated cardiovascular diseases.

Abstract 4138491: Association of histologic findings with long-term outcomes in symptomatic obstructive hypertrophic cardiomyopathy patients undergoing surgical myectomy

Background: In hypertrophic cardiomyopathy (HCM), histologic findings like myocyte hypertrophy&disarray, interstitial fibrosis (IF)&small intramural coronary arteriole dysplasia (SICAD) account for the left ventricular hypertrophy, diastolic dysfunction, arrhythmogenicity&microvascular ischemia. Objectives: To evaluate the association between histology&outcomes in obstructive HCM (oHCM) patients undergoing surgical myectomy (SM). Methods: This was an observational study of 1722 symptomatic oHCM patients (mean age 56±14 years, 948 [55%] men) who underwent SM at a tertiary care center between 2005-18. Baseline clinical data was collected. The SM specimen was analyzed for presence&severity of a) myocyte hypertrophy b) myocyte disarray c) IF&d) SICAD. Histologic findings were graded as 0-3 (none, mild, moderate,&severe)&a score from 0-12 was calculated. Primary endpoint was a composite of death, appropriate defibrillator discharge or cardiac transplantation during follow-up. Results: 896 (52%) were in New York Heart Association (NYHA) class III/IV, 457 (21%) had exertional syncope, 727 (42%) had ≥1 sudden death risk factor&409 (24%) had atrial fibrillation (AF). Moderate&severe histologic findings were distributed as follows: myocyte hypertrophy (1341 [78%]), disarray (237 [14%]), IF (448 [26%])&SICAD (258 [15%]). The mean total histologic score was 5.1±1.4. At 5.1±5.2 years, there were 352 (20%) primary events (317 [18%] deaths). On spline analysis (Figure 1A), a total histology score of ≥ 6 was associated with primary events. On Kaplan-Meier analysis (Figure 1B), patients with a histology score ≥ 6 had greater events vs. those with a score <6 (147/598 [25%] vs. 205/1124 [18%], log-rank p-value 0.002). On multivariable Cox analysis, age (for 10-year increase, Hazard ratio or HR 1.49 [95% confidence interval or CI 1.35-1.65], p<0.001), NYHA Class III/IV (HR 1.58 [95% CI -1.25-2.01], p<0.001), AF (HR 1.65 [95% CI 1.30-2.10], p<0.001)&histology score ≥6 (HR 1.24 [95% CI 1.03-1.54], p=0.03) were independently associated with higher primary events. Conclusions: In symptomatic oHCM patients undergoing SM, a higher histologic score was independently associated with long-term outcomes.

Abstract 4136033: High-Dose Folic acid Supplementation in Acute Myocardial Infarction - A systematic review

Background: Folic acid, a B vitamin, is essential for DNA synthesis and repair, and its role in reducing homocysteine levels has been linked to cardiovascular health. Elevated homocysteine is a risk factor for cardiovascular diseases, including acute myocardial infarction (MI) and coronary artery disease (CAD). Despite evidence suggesting that folic acid supplementation may lower homocysteine levels, its clinical benefits in reducing cardiovascular events remain unclear. Methods: A comprehensive literature search was conducted in PubMed/Medline, Google Scholar, and Cochrane Library databases for studies published from 2000 to 2024 using MeSH terms related to “folic acid,” “B vitamin,” “acute myocardial infarction,” “cardiac arrest,” “heart attack,” and “coronary heart disease.” Only randomized controlled trials (RCTs) and observational studies in English involving adult patients with acute MI or CAD were included. Exclusion criteria were applied to poor-quality studies, irrelevant outcomes, overlapping populations, and non-English texts. Data on study characteristics and patient demographics were extracted, and study quality was assessed using the RoB2 tool. Outcomes were pooled using RevMan 5.3.4 software. Results: Fourteen studies on all-cause mortality showed a risk ratio (RR) of 0.99 [95% CI: 0.94-1.04], indicating no significant difference between folic acid and control groups. Eight studies on cardiovascular mortality yielded a RR of 0.90 [95% CI: 0.82-0.99], suggesting a significant reduction in cardiovascular deaths with folic acid supplementation. Analyses of sudden death, coronary artery bypass graft (CABG) events, revascularization procedures, stroke, and recurrent MI found no significant associations with folic acid supplementation. Conclusions: High-dose folic acid supplementation appears to reduce cardiovascular mortality in post-MI patients but shows no significant impact on other clinical outcomes. This meta-analysis’s limitations include potential publication bias, heterogeneity among included studies, and variability in folic acid dosages and treatment durations. Furthermore, the lack of comprehensive homocysteine level data constrained the analysis. Future large-scale RCTs are needed to fully ascertain the therapeutic potential of folic acid supplementation in secondary prevention of cardiovascular events.

Mortality in older adults with epilepsy: An understudied entity.

Despite the recognition of Sudden Unexpected Death in Epilepsy (SUDEP) and other risks of premature mortality in people with epilepsy (PWE), mortality in older PWE remains an understudied entity. This review provides a comprehensive overview of the multifaceted causes of premature mortality in older adults with epilepsy and emphasizes the need for targeted interventions to reduce mortality and enhance the quality of life in this vulnerable population. It underscores the heightened prevalence of epilepsy among older adults and the interplay of intrinsic and extrinsic factors contributing to their mortality. Further, this paper delves into the nuances of diagnosing SUDEP in older adults and the underestimation of its incidence due to misclassification and lack of standardized protocols. Factors such as frailty, comorbidities, and the bidirectional relationship between epilepsy and conditions such as dementia and stroke further compound the mortality risks. Key factors, including status epilepticus, comorbid conditions (such as cardiovascular diseases, cerebrovascular events, and neurodegenerative disorders), and external causes like accidents, falls, and suicide, are discussed. It also examines the implications of anti-seizure medications, particularly polypharmacy, and their adverse effects on this population. Future directions include implementing enhanced diagnostic protocols, developing treatment plans, and integrating real-time monitoring technologies to reduce the risk of sudden death and multifaceted premature mortality in this patient population. Increasing awareness among healthcare providers and families about the risks and management of epilepsy in older adults, along with fostering collaborative research efforts, is essential to improve mortality outcomes. PLAIN LANGUAGE SUMMARY: There is a heightened risk of mortality in older people with epilepsy due to many causes unique to their population. Despite the risk, Sudden Unexpected Death in Epilepsy and early mortality in older adults with epilepsy are underestimated. Unique contributing factors include comorbid conditions like dementia, stroke, and frailty, adverse effects from polypharmacy, and increased risks of cardiovascular complications and external injuries such as falls and suicide. A careful consideration of all these factors can help mitigate the mortality in older adults with epilepsy.