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Abstract Background Atrial fibrillation (AF) occurs more frequently in men, but women suffer more AF recurrence; mechanisms are not completely understood. Purpose To explore whether sex related differences in LA stiffness (LAstiffn) in patients with AF ablation could potentially explain differences in AF recurrence. Methods We screened patients with catheter ablation for AF, in sinus rhythm at 3 months post-ablation, with no significant mitral valve disease (< moderate), and with prospectively measured LA volumes [maximum (LAVI) and minimum volume index] by echocardiography. LAStiffn index was estimated as (E/e’)/LA emptying fraction. Outcome endpoint was AF recurrence up to 14 years post ablation. Results A total of 591 patients with AF ablation were studied (mean age 60±10 years; 25% women; Table1). At 3 months post-ablation, LAVI was 36±10 mL/m2 and LAstiffn was 0.31±0.21 1/%. Compared to males, female patients were slightly older, had more frequently hypertension, congestive heart failure, prior stroke/TIA, higher CHA2DS2-VASc score; they less often had persistent AF, coronary artery disease, or dilated cardiomyopathy. Women also had higher LAstiffn (0.37±0.24 vs. 0.29±0.19, P <.0001, Figure 1), despite similar indexed LA volumes (Table1). Rates of AF recurrence at follow-up (median 7.5 years; 347 patients with events) were higher in women vs. men (Figure 2, left; log-rank P<.001) and persisted after adjustment for age, type and duration of AF, body mass index, cardiovascular risk factors and comorbidities, CHA2DS2-VASc score ≥2, LV ejection fraction, and LAVI (adjusted HR 1.58 [1.20-2.08], P=.001). Overall, LA volumes and LAstiffn were higher in patients with older age and more comorbidities (hypertension, congestive heart failure, coronary artery disease, persistent AF, CHA2DS2-VASc score ≥2, etc; P<.01 for all). At multivariable regression analysis, LAVI and LAstiffn correlated with E/e’, LV size and mass, degree of mitral/tricuspid regurgitation, and LV stroke volume index (only LAVI). In addition, LAstiffn was higher in patients with elevated right ventricular systolic pressure (RVSP) >35 mmHg and increase in RVSP more than 10 mmHg from pre-ablation (P<.0001) (correlation R=0.44, P<.0001). At follow-up, after adjusting for age and LAVI, higher LAstiffn remained associated with AF recurrence in women (P=.02, HR 2.82 per unit change, 95% CI, 1.08-6.72; Figure 2, right), but not in men (P=.30). Conclusions LAStiffn is higher in women vs. men and correlates with burden of comorbidities, aging, diastolic dysfunction and pulmonary hypertension, possibly reflecting more extensive LA myopathy, and potentially contributing to sex differences in AF recurrence.Figure 1Table 1

Abstract Background Cancer therapy-related cardiac dysfunction, which commonly includes varying degrees of asymptomatic ventricular dysfunction and/or heart failure, is the main adverse effect of anticancer therapy. The mechanism by which it develops is still quite uncertain. In recent years several genetic association studies have identified common genetic variants associated with cardiotoxicity in genes related to DNA damage, drug transportation and metabolism, antioxidant mechanism, sarcomere dysfunction and impaired iron metabolism, but the evidence is still limited. Rare variants in familial cardiomyopathies genes have also been identified. Purpose This uncertainly requires larger studies to identify genetic variants allowing to predict the risk of cardiotoxicity. In this sense, we carry out a genome-wide association meta-analysis to identify genetic variants associated with cancer therapy-related cardiac dysfunction. The development of a risk predictor model combining clinical and genetic factors would make it possible to anticipate the adverse effects of this therapy. Methods Genome wide meta-analysis was performed with a total of 594 patients from the CARDIOTOX registry and 3545 healthy individuals from the National DNA Bank, together with three previously published independent cohorts with 1446, 227 and 52 individuals receiving cancer therapy. Patients were classified with different cardiotoxicity degrees based on the CARDIOTOX registry and exhaustive clinical information was obtained from medical records. The study was ethically approved by local institutional review boards and all participants provided written informed consent. DNA samples were genotyped and imputed to perform a GWAS meta-analysis for case-control (n=5864) and extreme phenotypes (n=5317) looking for genetic variants that predispose to developing cancer therapy-related cardiac dysfunction. A functional characterization of the significant loci was performed by colocalization with eQTLs. Results The case-control analysis showed 17 loci that achieved suggestive significance (< P=1 x10-5) (Figure 1). The rs6765460, an intergenic variant between TPRG1 and TP63 genes, had the strongest relationship with the development of cardiotoxicity (P=1.89x10-7). The extreme phenotypes analysis showed additional 8 loci that achieved suggestive significance. The rs12904266, an intron variant of SLCO3A1, had the strongest relationship with severe cardiotoxicity (P=3.20E-07). eQTLs colocalization of the significant loci revealed association with genes involved in the mitochondria, inflammation, immune system, and fibrosis. Conclusions Our GWAS meta-analysis identified 25 novel genetic variants that may be associated with cancer therapy-related cardiac dysfunction. Genotyping of these markers could be considered in a genetic risk score which, together with the already known clinical risk factors, would improve the cardiotoxicity prediction in cardio-oncology units.Figure 1.Miami plot with P values

Abstract Background Catheter ablation has emerged as the first-line therapy for management of ventricular tachycardia (VT) over the last decade. There is a reluctance for older patients to be referred for catheter ablation with concerns for complications and poor outcomes. Purpose The purpose of the study was to assess the safety and outcomes of catheter ablation for VT in patients more than 74 years of age in comparison to younger patients. Methods A single-center retrospective study of 200 procedures in 168 patients undergoing catheter ablation for scar-related VT was conducted. Data collected included demographics, comorbidities, medications, relevant laboratory abnormalities, electrocardiograms, Holter, device electrograms, structural data including echocardiograms and cardiac magnetic resonance imaging, detailed procedural characteristics, and outcomes. Results The mean age in the older cohort was 77.7 ± 3.7 years compared to 57.6 ± 13.1 years in the younger group (p < 0.01) [Figure 1]. The geriatric patients had more males (93.6% vs. 75.8%) and had greater proportion of comorbidities including congestive heart failure (89.4% vs. 66.7%), hypertension (91.5% & 56.9%), atrial arrhythmias (66.0% vs. 43.1%), chronic kidney disease (68.1% vs. 31.4%), prior myocardial infarction (53.2% vs. 24.2%), and stroke (21.3% vs. 8.5%). The older patients were on more antiarrhythmic drugs at baseline. During the procedure, the number of cases with VT induction and hemodynamic stability was similar in older and younger groups. In cases where VT was induced, the older patients had a greater number of VTs induced (2.7 ± 3.0 vs. 1.9 ± 1.8), with slower cycle lengths (454.9 ± 122.6 vs. 379.3 ± 108.1 milliseconds). There was no difference noted in the procedural complications between the two groups. Older patients were more likely to be discharged on antiarrhythmic medications (87.2% vs. 71.2%) and had higher long-term mortality (29.8% vs. 7.8%). The older group was less likely to have a repeat ablation procedure (8.5% vs 24.2%). There was no difference in long-term VT-free survival rates among the two groups [Figure 2]. Conclusion Patients more than 74 years of age undergoing catheter ablation for structural VT have a greater comorbidity burden but demonstrate similar procedural complications and VT-free survival rates, when compared to the younger cohort.Figure 1Figure 2

Abstract Background/Introduction Arrhythmogenic mitral valve prolapse syndrome (AMVPS) is a female-predominant sudden cardiac death (SCD)-predisposing disorder characterized clinically by myxomatous mitral valve prolapse (MVP), inferolateral T-wave inversions and complex ventricular ectopy. However, insights into the pathogenesis and potential genetic basis of AMVPS are currently lacking. Purpose Considering recent case reports that suggest a potential role for genetic cardiomyopathies in the pathogenesis of AMVPS, we sought to determine the yield of pathogenic/likely pathogenic (P/LP) genetic variants in strong evidence cardiomyopathy-susceptibility genes amongst AMVPS patients who underwent clinical genetic testing. Methods In this retrospective study, the medical records of 4,907 patients referred to our cardiovascular genetics clinic was used to identify those patients with a clinical phenotype consistent with AMVPS. After exclusion of individuals with severe mitral valve regurgitation, pertinent clinical, electrocardiographic, imaging and genetic testing data was extracted from the electronic record. For those AMVPS that underwent a form of genetic testing that encompassed 23 Clinical Genome Resource-defined strong/definitive evidence cardiomyopathy-susceptibility genes, ultra-rare (minor allele frequency ≤ 0.00005 in the Genome Aggregation Database [n=141,456 individuals]) non-synonymous variants identified within these genes were adjudicated independently as P, LP or variant of uncertain significance with the assistance of Varsome. The frequency of P/LP variants was then compared to a previously published cohort of 973 ostensibly healthy control exomes. Results Overall, 56 unrelated patients with suspected AMVPS were identified (82% female; average age at presentation of 31 ± 13 years; 32% with a family history of MVP and/or SCD). Of these, 24/56 (43%) underwent a form of clinical genetic testing that encompassed the pre-defined panel of cardiomyopathy-susceptibility genes. In comparison to control exomes (n=973), P/LP variants in strong/definitive evidence cardiomyopathy-susceptibility genes were over-represented in AMVPS patients [4/24 (16.7%) vs 20/973 (2.1%); p=0.002]. Interestingly, this enrichment was driven in large part by an excess number of A-band-localizing P/LP truncating variants in TTN-encoded titin in AMVPS cases [3/24 (12.5%) versus 4/973 (0.4%); p=0.0004]. Conclusion This study provides further evidence that a subset of AMVPS may arise secondary to a "two-hit" model whereby an underlying cardiomyopathic genetic substrate is exacerbated by the mechanical force generated by genetically unrelated myxomatous MVP resulting in maladaptive and ventricular arrhythmia-predisposing fibrosis within the inferobasal left ventricle and posteromedial papillary muscles. Larger studies are needed to better understand the potential role of genetic testing in the diagnosis, risk-stratification and management of patients with suspected AMVPS.

Abstract Background Premature ventricular contractions (PVCs) are the most common arrhythmia affecting the ventricle. Frequent PVCs are associated with the development of PVC-cardiomyopathy (CM). It is known that the PVC burden has a direct correlation to the severity of left ventricular (LV) dysfunction. However, only 5% of patients with frequent PVCs (>10,000 per day) have associated PVC-CM. Thus, selecting patients for therapy options with drugs or catheter ablation is challenging, especially, when patients are asymptomatic with the PVCs. Purpose To train a deep learning model to predict the probability of low LV ejection fraction (LVEF) in patients with PVCs on a 12-lead electrocardiogram (ECG). Methods Using 69,440 paired 12-lead ECGs (containing at least one PVC), and echocardiogram data, including the left ventricular ejection fraction at Mayo Clinic, we trained a convolutional neural network to identify patients with ventricular dysfunction, defined as ejection fraction ≤35%, using the ECG data alone. ECGs were acquired at a sampling rate of 500 Hz using a Marquette ECG machine (GE Healthcare) and stored using the MUSE data management system for later retrieval. Comprehensive 2-D or 3-D and Doppler echocardiography were available for all patients. We trained a convolutional neural network using the Keras framework with TensorFlow (Google). The ECG-echocardiogram pairs were divided into a 60:20:20 training:validation:test split. Results The mean age of the patients used to train the model was 69.9 ± 13.0 years, and 65.2 percent of patients were male. The mean LVEF for this population was 52 ± 14.9 %, and the proportion of patients with low LVEF was 16.8 percent. The model yielded values for area under the curve, sensitivity, specificity, and accuracy of 0.897, 0.830, 0.813, and 0.816, respectively (Figure 1). A representative example of model prediction of normal LVEF and low LVEF is shown in Figure 2. Conclusion Using large-scale data, we have trained a highly accurate convolutional neural network with excellent predictive accuracy for LV systolic dysfunction using the surface ECG. Such a tool would be invaluable for cardiologists when risk-stratifying patients with frequent PVCs, especially those that are asymptomatic. Patients at risk will benefit from early referral to electrophysiologists for drug therapy and catheter ablation to mitigate the risk of PVC-CM.Figure 1Figure 2

Abstract Background The co-stimulatory CD40–CD40 ligand axis is central in atherogenesis. Upon activation, CD40 recruits tumor necrosis factor receptor-associated factors (TRAFs) to induce downstream signaling. Murine studies with mutated CD40-TRAF binding sites in macrophages have shown that the CD40-TRAF6, rather than CD40-TRAF2/3/5, axis is crucial for atherosclerosis. We thus synthesized the small molecule inhibitor TRAF-STOP 6877002, that selectively blocks CD40-TRAF6 signaling. 6877002 successfully reduced the onset and development of atherosclerosis by reducing monocyte recruitment and macrophage activation in ApoE-/- mice without having immunosuppressive side effects. Purpose To assess whether 6877002 is a suitable candidate to pass the translational pipeline towards a clinical application. Methods Elaborate in vitro and in vivo assays evaluating the pharmacological properties and potential toxicity of 6877002. Results Together with Cyprotex, we performed in vitro assays examining the ADME profile of 6877002. In an intestinal permeability assay, 6877002 had low to moderate resorption with no significant efflux, suggesting it is not a substrate for the efflux transporters Pgp/BCRP or MRP2. A plasma protein binding assay showed very low unbound 6877002 fractions, indicating that it is highly bound to plasma proteins. The potential to inhibit cytochrome P450 enzymes was assessed using human liver microsomes in the presence of enzyme-specific probe substrates. While 6877002 inhibited CYP1A2 (IC50=4.01 µM), no potential for inhibiting other CYP isoforms was detected, suggesting low drug-drug interaction potential. To screen for putative cardiovascular risks, hERG ion channel inhibition was assessed and no IC50 could be determined. Hepatic clearance was rapid in mice, rats and dogs, while minipig and human hepatocytes had lower intrinsic clearance. Together with Aptuit, we developed suitable formulations for oral and i.v. administration. In vivo pharmacokinetics studies in rats showed low bioavailability (8.43%) and rapid clearance of orally administered 6877002 compared to i.v. injected 6877002, likely – and in line with our in vitro data – due to fast first-past effect in mouse hepatocytes and uptake by macrophages. To explain the high efficacy of 6877002 despite its rapid metabolism, we assessed whether 6877002 has active metabolites that bind the CD40-TRAF6 pocket and performed an LC-MS/MS-based metabolite profiling. We detected 17 metabolites. Further MD simulations confirmed that Metabolite (M)4, the most abundant metabolite, binds the CD40-TRAF6 pocket, reflected by the highest binding mode (-19.6; defined as Binding Free Energy derived from 40-50 ns of MD run as compared to -16.5 for 6877002). Similar to 6877002, M4 reduced atherosclerosis by 54% in Western diet-fed ApoE-/- mice, indicative of M4 being an active metabolite. Conclusion CD40-TRAF6 inhibitors are an attractive strategy to combat atherosclerosis with high translational potential.

Abstract Background Atherosclerosis is a chronic inflammatory disease, characterized by the formation of luminal plaques in arteries. Atheroprogression is accompanied by strong immune activation, during which T cells play a pivotal role. Genes driving T-cell activation are regulated by the polycomb repressive complex 2(PRC2), whose major component is the Enhancer of Zeste Homolog 2(EZH2), responsible for the methylation of Histone 3 Lysine 27(H3K27me3) epigenetic mark. Purpose We hypothesize that EZH2 mediates T-cell activation and modulates T-helper (Th) cell polarization, thus atherogenesis. Methods To study the effect of EZH2 in atherosclerosis, we backcrossed mice with Ezh2 flanked by loxP-sites sensitive to Cre-mediated inactivation in T cells to apolipoprotein E (Apoe-/-)mice and fed a high cholesterol diet to have hyperlipidemic Ezh2fl/flCd4CreApoe-/-mice and controls. Atherosclerotic plaque progression and immune cell phenotyping were assessed by histology, flow cytometry (FC), gene and protein expression analysis and single cell (sc)RNA-sequencing (Seq) as well as by functional in vitro assays. Results T cell-specific EZH2 deficiency resulted in a significant reduction in H3K27me3 in T-cells. Female Ezh2fl/flCd4Cre mice developed 34% less atherosclerotic plaques in the aortic root compared to wildtype (WT) littermates. FC analysis of spleen and lymph nodes of Ezh2fl/flCd4Cre mice revealed a shift from naive to effector CD4+ T cells, and the majority were Th2 cells (p<0.0001). Accordingly, plasma levels of lL4 and aortic IL4 transcripts were increased in Ezh2fl/flCd4Cre mice(p=0.05 and p=0.0079, respectively). Functional analysis revealed that splenic CD4+ T cells from Ezh2fl/flCd4Cre mice showed decreased migratory capacity towards the chemokines CXCL10, CCL17, CCL22, CCL19. To unravel mechanisms driving the type 2 immune response, bulk RNA-Seq of CD4+ T cells and scRNA-Seq of splenic CD3+ T cells from Ezh2fl/flCd4Cre and WT mice revealed that CD4+ T cell EZH2 deficiency caused upregulation of promyelocytic leukemia zinc finger (Plzf), a transcription factor of NKT cells of the NKT2 subtype, characterized by high IL4 production. Via FC we confirmed the increase in splenic NKT cells in Ezh2fl/flCd4Cre mice. Likewise, Plzf aortic mRNA levels were also significantly increased(p=0.002). To exploit the translational potential of T cell-specific EZH2 targeting, we treated Jurkat T cells with EZH2 inhibitors, the FDA-approved drug Tazemetostat and GSK126. Corroborating our in vivo data, EZH2 inhibitor-treated cells showed decreased H3K27me3 and 70% reduced migration towards the chemokine CXCL12. Conclusions Our study demonstrates that CD4+ T-cell specific EZH2 deficiency impairs T cell-migration and skews the immune response towards a type 2 response, resulting in protection against atherosclerosis. We aim at investigating whether the epigenetic mark H3K27me3 in T cells may be a promising therapeutic target for future cardiovascular immunotherapies.

Abstract Background Atherosclerotic cardiovascular disease (ASCVD), of which coronary artery disease (CAD) is the primary manifestation, is the leading cause of death worldwide. The AHA/ACC Pooled Cohort Equation (PCE) facilitates risk stratification and initiation of primary prevention of ASCVD, however their performance is suboptimal. Purpose We develop an artificial intelligence-based electrocardiogram (ECG) analysis (AI-ECG) algorithm to detect different stages of CAD and assessed the value of AI-ECG over PCE to predict incident myocardial infarction (MI) and survival over 3-years. Methods Using electronic health record data from approximately 7 million patients seen at over 70 hospitals and clinics across 5 states in the USA, we created independent AI-ECG models to identify elevated coronary artery calcium (CAC) by computer tomography, the presence of obstructive CAD by stress test or angiography, and left ventricular regional akinesis by echocardiogram, presumed to represent prior MI. Deep structured data, AI-enabled natural language processing of unstructured data were used to ensure cohort, and physician review of labeling were used to ensure cohort accuracy. These models were ensembled into a single model that was used to assess the utility of AI-ECG for predicting new occurrence MI in PCE- and age-stratified cohorts of patient with no prior history of ASCVD, over a 3-year timeframe using Cox’s proportional hazards analysis. Results A total of 6,080 patients (15,192 ECGs) were labeled positive for CAC ≥ 300, 12,561 patients (18,915 ECGs) positive for obstructive CAD, and 10,767 patients (23,870 ECGs) positive for regional akinesis. AI-ECG for identifying elevated CACS, obstructive CAD, and regional akinesis achieved AUROCs of 0.86, 0.80, and 0.93, respectively. All AI-ECG models identified increased 3-year risk for MI and death in AI-ECG positive versus AI-ECG negative patients and subgroups with 2 or 3 positive results had stepwise increased risk (Figure A). In a 3-year survival analysis of all-comer patients, the hazard ratio for those that tested positive on 1, 2, or 3 versus 0 positive disease-specific models were 1.61 (1.53-1.69). 2.40 (2.27-2.55), 3.42 (3.21-3.65), respectively. Risk stratification was also observed in cohorts without prior ASCVD stratified by low and high PCE-derived 10-year ASCVD risk (Figure B) and in cohorts stratified by age, including under the age of 40. Conclusions AI-ECG has potential to address unmet need for accessible risk stratification in patients in whom PCE under, over, or insufficiently estimate ASCVD risk, and in whom risk assessment over periods of time shorter than 10 years is desired.

Introduction Epidural steroid injections and epidural blood patches commonly involve the injection of a small amount of radiocontrast media under fluoroscopy to properly identify the target tissue or anatomic space and prevent off-target or intravascular delivery of therapeutic or diagnostic drugs. Iodinated low osmolar non-ionic contrast media is the standard preparation used as it is considered safe and cost-effective, but gadolinium-based preparations have been used as an alternative for patients with an ‘iodine’-related or radiocontrast media allergy label to prevent hypersensitivity reactions. The risk of neurotoxic events when gadolinium is inadvertently injected into the intrathecal space has been reported in recent years, raising concerns when gadolinium-based contrast media is used in lieu of iodinated low osmolar non-ionic contrast media. Methods A retrospective review was conducted of patients who received gadolinium-based contrast media for procedures with risk of inadvertent intrathecal access from January 1, 2019 to May 1, 2022. Information on patient demographics, allergy label information, and procedure description was documented for all patients who received gadolinium-based contrast media for axial spine procedures (including epidural steroid injections, epidural blood patch procedures, and selective nerve root blocks), and all side effects reported within 1 month of the procedure were recorded. Saved fluoroscopy images of all procedures for which there was concern for possible gadolinium-based contrast media-related side effect were reviewed for evidence of inadvertent intrathecal gadolinium-based contrast media administration. Descriptive statistical analysis was performed using REDCap and IBM SPSS Statistics V.28. Results We identified 508 patients who received gadolinium-based contrast media during a fluoroscopically guided axial spine procedure. These patients underwent 697 epidural procedures and 23 patients were identified as experiencing an adverse event that could be consistent with possible, probable, or clear signs of exposure to intrathecal gadolinium. Our calculated adverse event rate was 3.3%. Ten patients required additional medical evaluation or treatment. Discussion Almost all patients in our cohort had an allergy label on their chart that guided the provider to switch to gadolinium-based contrast media, but most were incomplete, ill-defined, or related to allergy to iodine but not iodinated contrast media. Such practice is not recommended based on current guidelines. The current study raises concern regarding the use of gadolinium-based contrast media in axial spine procedures, with the risk of potential severe adverse events, without evidence-based need for avoiding iodinated contrast media.

Abstract Background Right ventricular (RV) dysfunction is common in heart failure with preserved ejection fraction (HFpEF), portends worse prognosis, and is believed to be caused by contractile impairment and remodeling due to afterload mismatch from pulmonary hypertension (PH). The goal of this study was to examine the right heart in patients with HFpEF and resting mean pulmonary arterial (PA) pressure (MPAP)≤20 mmHg. Methods and results Among 621 patients with HFpEF undergoing comprehensive echocardiography and invasive cardiopulmonary exercise testing, 159 (26%) had resting MPAP≤20 mmHg (HFpEFMPAP≤20mmHg). In comparison to 73 controls, they were more obese, had more coronary disease and atrial fibrillation. After adjusting for BMI, there were no differences in plasma volume but NTproBNP was higher and peak oxygen consumption lower in HFpEFMPAP≤20mmHg than in controls (p = 0.002, <0.001, respectively). While RV dimension was similar, tricuspid annular plane systolic excursion and RVs’ were lower in HFpEFMPAP≤20mmHg (18±5 vs. 22±4 mm, p = 0.005; 10±2 vs. 12±2 cm/s, p = 0.047, respectively). HFpEFMPAP≤20mmHg and controls displayed similar pulmonary vascular resistance, MPAP and right atrial pressure at rest, but during exercise, MPAP and right atrial pressure were higher in patients with HFpEFMPAP≤20mmHg (41±10 vs. 33±10 mmHg; 18±7 vs. 12±4 mmHg, p<0.001, respectively). PA compliance was lower at both rest and exercise (rest 4.1±2.1 vs. 5.0±1.8; exercise 2.9±1.4 vs. 3.2±1.4 ml/mmHg, p<0.001, for both). Conclusion Right heart dysfunction is present in patients with HFpEF even in the absence of frank PH. These patients display greater pulsatile RV loading by PA compliance even as resistance is not markedly elevated. These data support further study into novel therapies targeting pulsatile RV afterload in HFpEF.