bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 4136785: Interpreting Population Mean Treatment Effects in the Kansas City Cardiomyopathy Questionnaire
Authors: Abdel Jawad Mohammad , Jones Philip , Arnold Suzanne , Cohen David , Sherrod Charles , Khan Mirza , Ikemura Nobuhiro , Chan Paul , Spertus John
Published: November 2024

Introduction:
The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a common outcome in heart failure trials. While comparing means between treatment groups improves statistical power, mean effects do not necessarily reflect the clinical benefit experienced by patients.

Objectives:
To evaluate the relationship between mean KCCQ treatment effects in clinical trials and the proportions of patients experiencing clinically important improvements across a range of heart failure etiologies and interventions.

Methods:
We performed a patient-level meta-analysis of 11 randomized trials (9,977 patients) to examine the relationship between mean KCCQ Overall Summary Score (OSS) treatment effects and the absolute differences in the proportions of patients experiencing clinically important (≥5 points) and moderate or larger (≥10 points) improvements. Validation was performed in 7 additional trials.

Results:
Group mean KCCQ-OSS differences were strongly correlated with absolute differences in clinically important changes (Spearman correlations 0.76-0.92). For example, a mean KCCQ-OSS treatment effect of 2.5 points (half of a minimally important difference for an individual patient) was associated with an absolute difference of 6.0% (95% prediction interval [PI] 4.0-8.1) in the proportion of patients improving ≥5 points and 5.0% (95% PI 3.1-7.0) in the proportion improving ≥10 points, corresponding to NNTs of 17 (95% PI 12-25) and 20 (95% PI 14-33), respectively. Similar relationships were observed in the validation studies.

Conclusions:
Inferences on clinical impact based on population-level mean treatment effects are misleading since even small between group differences may reflect clinically important treatment benefits at the patient level. Clinical trials should explicitly describe the distributions of patient-level KCCQ changes to support clinical interpretation of their results.
Abstract 4136796: The effect of replacing typical snacks with pecans on vascular health and diet quality: a randomized controlled trial
Authors: Hart Tricia , Kris-Etherton Penny , Petersen Kristina
Published: November 2024

Background:
Poor diet quality accounts for approximately half of all deaths from cardiometabolic diseases. Food pattern modelling using nationally representative U.S. data suggests that replacing typical snacks consumed with tree nuts will improve diet quality. However, few clinical trials have assessed the potential for tree nuts to improve diet quality. Pecans are rich in polyphenols, which may improve endothelial and vascular function. This study aimed to examine how substitution of usual snack foods with 2 oz/day of pecans affects flow mediated dilation (FMD), carotid-femoral pulse wave velocity (cf-PWV), blood pressure and diet quality after 12 weeks in individuals at increased risk for cardiometabolic disease.

Hypothesis:
Intake of 2 oz/day of pecans in place of habitually consumed snacks will improve vascular health and diet quality compared to habitual intake.

Methods:
In this single-blind RCT, adults (46 ± 13 years, 29.8 ± 3.7 kg/m
2
) with ≥1 criterion for metabolic syndrome who were free from cardiovascular disease, type 2 diabetes and other chronic diseases were included. The experimental group was provided with 2 oz/day of pre-portioned raw, unsalted pecans (~392 kcal) and instructed to replace the snacks they currently consume with the provided pecans. The control group was instructed to continue their usual diet. FMD (primary outcome), cf-PWV, brachial and central blood pressure were measured at baseline and following the intervention period (~12 weeks). At three timepoints (baseline, week 6, and week 12) during the study, participants completed three 24-hour recalls (total 9 recalls). The Healthy Eating Index-2020 (HEI-2020) was calculated to assess diet quality.

Results:
A total of 138 (69 per group) participants were randomized. No between-group difference in FMD, cf-PWV, or blood pressure was observed. The HEI-2020 was 11.1 points higher (95% CI 5.1, 17.2) in the pecan group compared to the usual diet group at week 12. The following HEI-2020 components were improved in the pecan group vs. the usual diet group: total protein foods (0.5 points [95% CI 0.1, 1.0]), seafood and plant proteins (2.5 points [95% CI 1.6, 3.4]), fatty acids (4.1 points [ 95% CI 2.6, 5.5]), and sodium (1.8 points [95% CI 0.3, 3.2]).

Conclusion:
Replacement of usual snacks with 2 oz of pecans improved adherence to the Dietary Guidelines for Americans but did not improve endothelial function, blood pressure, or arterial stiffening.
Abstract 4136804: Effect of Obesity on Arrhythmia Recurrence and Complications following Pulmonary Vein Isolation for Paroxysmal Atrial Fibrillation in the REAL-AF Registry
Authors: Peng Gary , Thorne Christopher , Varley Allyson , Osorio Jose , Goyal Sandeep , Zei Paul
Published: November 2024

Introduction:
Obesity is an important risk factor for atrial fibrillation and its prevalence in the United States is rising. The effect of obesity on outcomes following pulmonary vein isolation in a contemporary setting has not been extensively evaluated.

Research Questions:
- Is higher body mass index (BMI) associated with increased risk of atrial arrhythmia recurrence following pulmonary vein isolation?

- Is higher BMI associated with increased risk of post-procedural complications?

Method:
- The REAL-AF (Real-world Experience of Catheter Ablation for the Treatment of Symptomatic Paroxysmal and Persistent Atrial Fibrillation; ClinicalTrials.gov Identifier: NCT04088071) Registry is a multicenter, prospective observational registry of patients undergoing radiofrequency catheter ablation of atrial fibrillation. We included 2666 patients with paroxysmal atrial fibrillation undergoing index ablation from January 2018 through April 2023. We excluded patients with missing covariates.

- The primary outcome was freedom from atrial arrhythmia following ablation. Rhythm monitoring was standardized using patch monitor at 6 month and 1 year. Time-to-event analysis was performed using a 3-month blanking period.

Results:
- Baseline characteristics are shown in Table 1. The median follow-up was 382 days (IQR: 363-410).

- There was a trend toward higher rate of atrial arrhythmia following ablation for patients in the highest BMI group compared with the reference group (BMI<25) (
BMI≥40:
HR = 1.41 (0.94-2.12), p= 0.092). There was no difference in the rate of atrial arrhythmia for other BMI groups (
BMI 25 - <30:
HR = 0.90 (0.65-1.23), p = 0.5;
BMI 30 - <35:
HR = 0.89 (0.64-1.23), p = 0.5;
BMI 35 - <40:
HR = 0.87 (0.57-1.32), p = 0.5). This trend persisted following adjustment for baseline covariates (
BMI 25 - <30:
HR = 1.01 (0.77-1.33), p > 0.9;
BMI 30 - <35:
HR = 0.97 (0.72-1.32), p = 0.9;
BMI 35 - <40:
HR = 1.01 (0.66-1.55), p > 0.9;
BMI≥40:
HR = 1.57 (0.96-2.57), p =0.071).

- First-pass isolation rates progressively decreased with higher BMI (Table 2).

- Complication rates were low across all BMI groups (Table 2).

Conclusions:
- Severely obese patients with BMI ≥40 experience higher risk of atrial arrhythmia following radiofrequency catheter ablation of paroxysmal atrial fibrillation compared with normal weight individuals. This corresponds with lower rates of first-pass isolation at higher BMI.

- Patients across BMI categories experience similarly low rates of procedural complication.
Abstract 4136805: Type 2 Myocardial Infarction Patients Have Significantly More Days Not at Home
Authors: Kolba Natalie , Hajduk Alexandra , More Verde Luis , Sohal Sumit , Nanna Michael
Published: November 2024

Background:
A Type 2 (T2) myocardial infarction (MI) occurs “secondary to ischemia due to either increased oxygen demand or decreased supply,” while a Type 1 MI (T1) is atherothrombotic. Treatment includes correction of the underlying cause and not catheterization. The current study's aim is to assess the patient-centered outcome of days not at home (DNAH) within a year of discharge among older adults hospitalized with T1 and T2 MI, and to evaluate the distribution of non-home days.

Methods:
Data for this analysis came from a prospective cohort study of adults ≥75 years old hospitalized with MI at 94 U.S. hospitals and linked to Medicare claims and encounter data. MI type was adjudicated according to the Fourth Universal Definition of MI. Patient characteristics were identified via chart review or self-report. DNAH was defined as the number of days dead or in a hospital, skilled nursing facility (SNF), rehab facility, or hospice. Multivariable-adjusted negative binomial regression was used to evaluate the association between MI type and DNAH in the year after discharge.

Results:
Of the 375 participants evaluated in this interim analysis, 264 (70.4%) had T1 MI and 111 (29.6%) had T2 MI. There was no difference in distribution of age, gender, or race. T2 patients were more likely to have heart failure (HF), coronary artery disease (CAD), COPD, and arrythmias. Patients with T2 MI had a median [interquartile range] of 5 [0-71] DNAH in the year after discharge, compared with 2 [0-10] DNAH among patients with T1 MI (p = 0.008). After adjusting for age and comorbidities, T2 patients had 137% more DNAH (IRR = 2.37, 95% CI = 1.43, 3.94, p < 0.001) than T1 patients. The number of days dead or in SNF was significantly higher among patients with T2 MI compared with T1 MI, whereas the association between MI type and increase in days readmitted was borderline (p = 0.06). In the multivariable model, age, HF, and CAD were significantly associated with more DNAH, but COPD and arrhythmias were not.

Conclusion:
Our findings demonstrate that older patients with T2 MI have more days not at home, attributable to death, SNF stays, and to a lesser extent, rehospitalization. Interestingly, accounting for comorbidities did not significantly attenuate this association. Further studies are needed to develop guidelines for medical teams, including evaluating how receipt of cardiac interventions impacts home days in older patients with T1 and T2 MI.
Abstract 4136839: HBI-3000: Pharmacological Conversion of Atrial Fibrillation With Unique Defense Against Excessive QT Interval Prolongation
Authors: Mason Jay , Roy Denis , Elliott Gary , Romano Suzanne , Pollack Charles , Gillings Dr Mireille , Riebman Jerome
Published: November 2024

Background:
HBI-3000 (Sulcardine sulfate) is a new antiarrhythmic drug (AAD) that inhibits multiple cardiac ion channels (INa-peak, INa-late, ICa,L and IKr (hERG)) with uniquely similar potencies. A major AAD limitation is malignant proarrhythmia due to excessive hERG-mediated delay in repolarization, manifested by QT prolongation with proportional J to T peak [JTp] prolongation. While sulcardine inhibits hERG, it also possesses an intrinsic protective mechanism, inhibiting inward INa-late and ICa,L early repolarization currents. In Phase 1 volunteers in sinus rhythm (SR) therapeutic levels of sulcardine not only reduced but reversed the lengthening of the rate-corrected JTp (JTpc), reducing the extent of hERG-related QT prolongation. We investigated this protective JTpc effect in atrial fibrillation (AF) patients at the anticipated clinical dose, and examined the relationships between plasma concentration, QT prolongation, and the JTPc reduction.

Methods:
Ten patients received 350 mg HBI-3000 IV over 30 min in a Phase 2 open-label study of patients with acute AF. Sulcardine plasma concentrations and ECG intervals (from 5-min summary ECGs) were obtained at baseline and several time points. Mean baseline-subtracted, heart rate-corrected QTcF (dQTcF) and JTp (dJTpc; Johannesen’s method) were calculated at each time point. AF patient data were compared to those of volunteers in SR.

Results:
In AF patients, dQTcF prolonged with a linear relationship to plasma concentration as expected (Fig 1A, blue). HBI-3000 IV produced a large linear reduction in JTpc contribution to the QT interval (Fig 1A, red). This is consistent with findings in SR (Fig 1B [350 mg dose] and 1C [360 mg dose]) and unique among AADs that inhibit IKr along with INa-late and/or ICa,L. Calculated dQTcF changes without the JTpc effect were greater than the observed dQTcF (Fig 1A, green) by 27%-76% at Cmax in the three studies.

Conclusions:
HBI-3000 (Sulcardine) exhibits dQTcF prolongation protection in both AF and SR due to a unique pattern of channel fluxes that shortens early repolarization. This shorter dJTp interval acts as a mechanism for effectively limiting excessive QT prolongation and reducing proarrhythmic risk. [Registration: NCT04680026]
Abstract 4137065: Efficacy and Safety of Extracorporeal CPR in Out-of-Hospital Cardiac Arrest Survival and Neurological Integrity: a Meta-Analysis of Randomized Controlled Trials
Authors: Dogan Muhammed Melih
Published: November 2024

Introduction:
Out-of-hospital cardiac arrest (OHCA) remains a significant public health challenge, with conventional cardiopulmonary resuscitation (CPR) often yielding limited success. Extracorporeal CPR (eCPR) has emerged as a potential adjunctive therapy to improve outcomes in OHCA patients.

Purpose:
To evaluate the efficacy and safety of eCPR compared to conventional CPR in OHCA.

Methods:
A comprehensive search of Cochrane CENTRAL, PubMed, Ovid Medline, and Web of Science databases was conducted independently until November 10, 2023. Randomized controlled trials (RCTs) comparing eCPR with conventional CPR in OHCA were included. Primary efficacy outcome was defined as survival to hospital discharge, while primary safety outcome was assessed for bleeding events. Summary effect measures of the primary outcomes were obtained by pooling the data with an inverse variance–weighted random-effects model. A sensitivity analysis was performed regarding whether the conclusions reached might differ substantially if a single study was omitted. Statistical analyses were performed with “meta” package in R (version 4.3.2) and Revman 5.4.

Results:
Four unique RCTs involving 435 patients were included in the analysis. ECCPR was associated with a significantly higher rate of survival at 1 month with good neurological outcome (Risk Ratio [RR] 1.55, 95% Confidence Interval (CI) 1.06 to 2.27, I
2
: 0%) but comparable at survival to hospital discharge (RR 1.10, 95% CI 0.16 to 7.30, I
2
: 47%) compared to conventional CPR. Furthermore, no significant differences were observed between eCPR and conventional CPR groups in survival rates at 3 months (RR 1,33, 95% CI 0.92 to 1.94, I
2
: 64%), survival at 6 months with good neurological outcome (RR 1.39, 95% CI 0.97 to 1.99, I
2
: 0%), and survival at 6 months (RR 2.79, 95% CI 0.33 to 23.28, I
2
: 63%). eCPR demonstrated a statistically significant elevation in bleeding events compared to conventional CPR (RR 4.25, 95% CI 2.37 to 7.64, I
2
: 0%). Sensitivity analysis revealed that none of the studies significantly influenced the pooled risk estimate to any great extent.

Conclusion:
eCPR shows beneficial results in improving short-term survival and neurological outcomes at 1-month post-OHCA. However, it is associated with an elevated risk of bleeding when compared to conventional CPR. Further investigations are imperative to delineate the specific patient populations that stand to gain the most benefit from ECPR intervention.
Abstract 4137135: Trends in Mechanical Circulatory Support After the New Heart Allocation Policy
Authors: Steitieh Diala , Beale Robert , Katznelson Ethan , Minutello Dilan , Feldman Elizabeth , Lu Daniel , Kim Luke , Krishnan Udhay
Published: November 2024

Background:
In October 2018 a new heart allocation policy (NHAP) was implemented, which resulted in patients with Intra-aortic balloon pumps (IABP) being upgraded to status-two. We sought to determine practice pattern changes in mechanical circulatory support (MCS) use as a result of the NHAP.

Hypothesis:
Changes in the new heart allocation policy may lead to shifts in choice of mechanical circulatory support.

Methods:
A retrospective analysis was conducted using the National Inpatient Sample (NIS) between 2017–2020. Hospitalizations for cardiogenic shock were identified, and stratified based on whether the patients were admitted before or after the NHAP. Baseline characteristics were compared between these cohorts, and the primary outcome of interest was the use of MCS and transplant before and after the NHAP. Subgroup analyses included patients only in transplant centers, non-transplant centers, and those who eventually underwent transplant.

Results:
A total of 689,935 hospitalizations were included in the final analysis, of which 279,230 (40.5%) were before the NHAP, and 410,705 (59.5%) were after. In allcomers, hospitalizations after the NHAP were less likely to undergo IABP (Adjusted odds ratio [OR] 0.81, p<0.01) and LVAD (Adjusted OR 0.73, p<0.01). These findings were consistent in most subgroup analyses. Patients who underwent transplant after the NHAP however were more than twice as likely to have received a IABP compared to those admitted prior to the NHAP (adjusted OR 2.58; p<0.01).

Conclusion:
IABP placement after the NHAP increased in patients who underwent transplant, as opposed to allcomers or patients who did not undergo transplant. This change in utilization of MCS may be reflective of perceived benefits and biases in regards to transplantation candidacy.
Abstract 4137138: Incidence and Risk factors of Early Mortality in Symptomatic Acute PE: Recent Insights from the COMMAND VTE Registry-2
Authors: Kobayashi Soichiro , Ogihara Yoshito , Yamashita Yugo , Chatani Ryuki , kaneda kazuhisa , Nishimoto Yuji , Ikeda Nobutaka , Kobayashi Yohei , Ikeda Satoshi , Kim Kitae , Inoko Moriaki , Takase Toru , Tsuji Shuhei , Oi Maki , Takada Takuma , Otsui Kazunori , Sakamoto Jiro , Nishikawa Ryusuke , Sato Toru , Dohi Kaoru
Published: November 2024

Background:
Acute pulmonary embolism (PE) remains a major health burden with substantial morbidity and mortality. Over the past decade, the acute phase management of venous thromboembolism (VTE) has undergone considerable change. These includes a decline in the use of thrombolytic therapy and inferior vena cava filter, the widespread adoption of direct oral anticoagulant (DAOCs), and the increase in early discharge and initial outpatient treatment facilitated by DOACs. Given these advancements, it is crucial to reassess early mortality risk factors in patients with PE.

Objectives:
This study aimed to elucidate the mortality and prognostic factors for 30-day early mortality in patients with acute symptomatic PE in recent years.

Methods:
We utilized the data from the COMMAND VTE Registry-2, a multicenter registry, enrolling 5197 consecutive VTE patients across 31 centers in Japan between January 2015 and August 2020. We selected 2020 patients who presented with acute symptomatic PE. We investigated prognostic factors for early mortality in acute symptomatic PE using the multivariable hazard model.

Results:
In the entire study population, the mean age was 67.3±15.2 years, with 59.3% of patients being women. Active cancer was reported in 26.2%. Massive PE was observed in 7.3% (n=147), sub-massive PE in 42.6% (n=860), and non-massive PE in 44.2% (n=892). During follow-up period of 30 days, 114 patients had died, resulting in the cumulative overall mortality rate of 5.6%. Death was considered to be due to PE in 54 patients (47.4% of deaths). Patients who died within 30-days were more often male and older than those in the survivor group (44.2% vs. 59.9%, P=0.0396) (70.1±15.6 vs. 67.1±15.2, P=0.0368). Multivariable analysis identified active cancer (HR 3.01 [95%CI 2.00-4.53]), hypotension (HR 2.91 [95% CI 1.92-4.40]), tachycardia (HR 2.17 [95%CI 1.42-3.30]), hypoxemia (HR 1.97 [95%CI 1.15-3.37]), leucocytes (<4000, 12000<) (HR 1.80 [95%CI 1.22-2.68]) and age (≥ 80 years) (HR 1.69 [95%CI 1.10-2.58]) were independent prognostic factors for early mortality in acute symptomatic PE.

Conclusions:
In this large VTE registry from recent years, several independent prognostic factors for 30-day early mortality in acute symptomatic PE were identified, consisting of active cancer, hypotension, tachycardia, hypoxemia, leucocytes (<4000, 12000<) and age (≥ 80 years).
Abstract 4137144: Return to Cath Lab: Chest Pain Resolution after Right Coronary Artery Chronic Total Occlusion Intervention
Authors: Jason Max , McCallister Reid , Mertens Amy
Published: November 2024

Introduction:
Subacute stent thrombosis (ST) is related to high rates of cardiac reinfarction. We present a case of reinfarction from ST. The patient’s chest pain (CP) was not alleviated with initial revascularization of his left circumflex (LCx) ST, requiring PCI to his right coronary artery (RCA) chronic total occlusion (CTO). This is a novel approach to CTO PCI which is traditionally a non-urgent procedure.

Case:
A 53-year-old male with a history of coronary artery disease and surgical turndown presented to the ED with CP. Two weeks prior he had impella guided LM bifurcation PCI with DES and ramus intermedius (RI) angioplasty (PTA) but was nonadherent to clopidogrel. He had a BP of 127/85, HR of 65, and was on room air. Exam was unremarkable. His EKG was in sinus rhythm with S-T depressions ~1mm in leads V1-V4 concerning for posterior infarction. HS-troponin (HST) was 60. Angiography (CA) showed thrombotic occlusion of his LCx DES (Fig 1a) and an RCA CTO (Fig 1c). Optical coherence tomography (OCT) revealed DES struts overlying the ostial LCx concerning for mechanical deformation from carinal shift. OCT guided PTA and laser thrombectomy (LT) of the LCx led to TIMI-3 Flow. LT and kissing balloon inflation (BI) was performed on the LAD and LCx to reshape the carina. HST peaked at 116,012. He had CCS Class IV CP despite medical therapy and returned for re-look CA with TIMI-3 flow in the left-sided circulation without thrombus (Fig 1b). He had PCI to his distal RCA CTO with two DES and TIMI-3 flow in the RCA (Fig 1d). He did not have recurrence of CP.

Discussion:
Bifurcation PCI leads to challenges from anatomic reconfiguration, metallic DES deformity, and changes in blood flow leading to increased risk of distal ST. This patient’s CA demonstrated LM DES material overlying the LCx from carinal shifting which likely led to interrupted flow dynamics. His LCx ST was partly due to this stasis and his clopidogrel nonadherence. Despite PCI of his LCx his CP remained with poor collateral flow from the left circulation. While CTO procedures are typically done non urgently, emergent intervention on our patient’s RCA CTO led to complete resolution of his CP and clear benefit for symptomatic management.
Abstract 4137165: Changes in Contrast Volume among Patients Undergoing Percutaneous Coronary Intervention: a Report from NCDR CathPCI registry
Authors: Ikemura Nobuhiro , Chan Paul , Cohen David , kennedy kevin , Uzendu Anezi , Kohsaka Shun , Spertus John
Published: November 2024

Background:
Acute kidney injury (AKI) is the most common complication after percutaneous coronary intervention (PCI) and can be mitigated by using less iodinated contrast. The National Cardiovascular Data Registry (NCDR) supports quality improvement initiatives by providing quarterly, risk-adjusted, institutional AKI rates. However, it remains uncertain whether these efforts have reduced procedural contrast volume, particularly in high-risk patients.

Aims:
Examine temporal trends in contrast volume during PCI across different pre-procedural AKI risk strata.

Methods:
Within the NCDR CathPCI Registry, we identified PCIs performed between April 1, 2018, and December 31, 2022, and examined changes in mean contrast volume over time across different pre-procedural AKI risk strata defined by the validated NCDR AKI risk model. A multivariable hierarchical model, with the physician as a random effect, was constructed to assess the trend in contrast volume use over time.

Results:
Among 3,126,559 patients undergoing PCI (mean age = 66.8 ± 11.7 years, 69.4% men, and 39.9% elective procedures), contrast volume declined from a mean of 168.1±77.6 ml in Q2 2018 to 149.8±71.2 ml in Q4 2022 (
p
< 0.001 for trend) with the trend being consistent across AKI risk strata (
Figure
). After adjusting for patient and pre-procedural characteristics, the contrast volume declined by 18.9 ml (95%CI 19.1 to 18.6,
P
<0.001) between 2018 and 2022. Despite marked physician variability in mean contrast use, the lowest mean contrast doses were observed in patients at greatest AKI risk (>15%).

Conclusions:
PCI contrast administration has declined over time, and the average exposure was lowest in patients at highest risk for AKI, suggesting improved efforts to reduce AKI over time.
Abstract 4137169: Artificial Intelligence-Enabled Electrocardiography For The Prediction of Future Type 2 Diabetes Mellitus
Authors: Pastika Libor , Patlatzoglou Konstantinos , Sieliwonczyk Ewa , Barker Joseph , Zeidaabadi Boroumand , McGurk Kathryn , Khan Sadia , Mandic Danilo , Ware James , Peters Nicholas , Kramer Daniel , Waks Jonathan , Sau Arunashis , Ng Fu Siong
Published: November 2024

Background:
Undiagnosed diabetes and prediabetes present a significant global health challenge. Artificial Intelligence-enabled electrocardiography (AI-ECG) has shown promise in identifying subtle ECG changes in a wide range of subclinical diseases. Opportunistic ECG screening could identify prediabetic patients, enabling early interventions to prevent T2DM and adverse cardiovascular events.

Aims:
To develop the AI-ECG Risk Estimator to diagnose prevalent T2DM and predict future T2DM (AIRE-DM)

Methods:
AIRE-DM was trained on a real-world secondary care cohort from Beth Israel Deaconess Medical Center (BIDMC) of 1,163,401 ECGs and externally validated in the UK Biobank (UKB, N = 65,606). AIRE-DM employs a residual neural network architecture with a discrete-time survival loss function.

Results:
AIRE-DM accurately identifies prevalent T2DM (AUROC: BIDMC – 0.712 (0.705-0.719), UKB - 0.731 (0.725 - 0.741) and predicts future T2DM (C-index: BIDMC - 0.666 (0.658-0.675), UKB 0.689 (0.663-0.715). In subjects without T2DM, the high-risk quartile shows a markedly increased risk of future T2DM (HR: BIDMC - 4.67 (4.01-5.45), UKB - 10.10 (5.87-17.40), adjusted for age and sex. Adding AIRE-DM to clinical risk factors in BIDMC and to the American Diabetes Association (ADA) score in the UKB significantly enhanced predictive accuracy for future T2DM (C-index improvement: BIDMC - 0.0359 (0.0354-0.0363), UKB: 0.0337 (0.0324-0.0350), continuous net reclassification index: BIDMC - 0.407 (0.360-0.445), UKB - 0.391 (0.259-0.503)).

Using phenome- and genome-wide association studies, we identified biologically plausible associations for AIRE-DM, including glucose regulation, cardiac morphology, diastolic dysfunction, arterial stiffness and lipid metabolism. We identified variants adjacent to
CASQ2
,
TBX3
,
NOS1AP
,
TKT
,
VGLL2
and
PRDM6
, which are known regulators of cardiac morphology, arterial stiffness and glucose metabolism.

Conclusion:
AIRE-DM can predict future T2DM in non-diabetics and enhances T2DM risk prediction when integrated with clinical risk scores. Its application holds promise for early identification of individuals at high risk of T2DM, enabling early lifestyle and pharmacological interventions.
Abstract 4137257: Hepatocyte growth factor -mediated Angiogenesis supersession in Hyperhomocysteinemia
Authors: Huang Xiao , Cao Tianyu , Wang Hong
Published: November 2024

Background:
Homocysteine (Hcy) is a well-established cardiovascular risk factor. Elevated homocysteine, or hyperhomocysteinemia (HHcy), inhibit the growth of endothelial cells and stimulate vascular smooth muscle cell proliferation. However, the mechanisms of HHcy disrupts angiogenesis remain unclear. Here we examine the molecular pathways involved in HHcy-impaired angiogenesis.

Method:
We generated
Tg-hCBS+ Cbs-/-
mice by crossing
Cbs
knockout mice and
Tg-hCBS
mice where human
CBS cDNA
was regulated by a zinc-inducible metallothionein promoter. The model exhibited severe HHcy (＞115 μmol/L). We conducted both in vivo and in vitro experiments, including vasculogenesis assays of retinal and heart tissues, aortic ring assay, and tube formation. Retinas were stained with Isolectin B4 and imaged using a confocal microscope. The Human Angiogenesis RT
2
Profiler™ PCR Array was used to profile 84 key angiogenesis-related genes. Homocysteine metabolites in Cbs mice were measured by HPLC. ChIP-seq data were analyzed using Chip Atlas. Additionally, 91 patients went through coronary angiography were enrolled from the Second Affiliated Hospital of Nanchang University. Participants with CTFC, greater than 27 frames per second were identified as having slow coronary arteries flow (SCF).

Results:
HHcy caused SCF in patients and impaired vasculogenesis in the retinas of newborn and 12-week-old
Tg-hCBS Cbs-/-
mice. Capillary density in the hearts of adult
Tg-hCBS Cbs-/-
mice was reduced. HHcy suppressed tube formation and aortic ring microvessel growth in a concentration-dependent manner. The PCR array revealed significant gene expression changes in Hcy treated human aortic endothelial cells. Notably, genes encoding hepatocyte growth factor (HGF), collagen type IV alpha 3, epiregulin, interferons, and leukocyte cell-derived chemotaxin 1 were downregulated by at least four-fold. In an acute myocardial infarction model, HGF expression was further reduced, and HGF treatment rescued Hcy-inhibited tube formation and microvessel growth. Hcy and S-adenosylhomocysteine levels were negatively correlated with plasma HGF levels. ChIP-seq data identified homocysteine-responsive hypomethylation in ETF, TFII, FOXP3, RXRa, and c-Jun Hcy-hypomethylation Box (-2701/0).

Conclusion:
HHcy impair angiogenesis via HGF inhibition, which has a rescue effect. Hypomethylation caused by Hcy affects the methylation status of specific CpG sites within the Hcy-hypomethylation box of the HGF gene.
Abstract 4137264: Subclassification of Peripheral Artery Disease Based on Muscle Force: Leg Failure with Reduced Muscle Force and Leg Failure with Preserved Muscle Force
Authors: Tian Yuqian , Hakim Ali , fallahtafti Farahnaz , Moulton Michael , Koutakis Panagiotis , Thompson Jonathan , Cook Jason , Kim Julian , zhu zhen , Despiegelaere Holly , Haynatzki Gleb , Myers Sara , Pipinos Iraklis
Published: November 2024

Introduction:
All claudicating patients with peripheral artery disease (PAD) exhibit leg failure, as evidenced by distinct walking impairment. However, based on a detailed evaluation of leg biomechanics, some claudicating patients maintain preserved leg muscle strength, while others demonstrate reduced strength. In this study, we aim to compare the clinical and physiological characteristics of the two groups.

Methods:
Fifty-four claudicating patients were categorized into two groups: leg failure with preserved muscle force (LEF-PF) versus leg failure with reduced muscle force (LEF-RF), based on the peak torque (PT) from performing maximum isometric plantar flexion contractions on a Biodex system. All patients underwent history and physical exam, measurement of leg hemodynamics, walking performance and quality of life, and gastrocnemius biopsy to evaluate the histology and biochemistry of the affected leg muscles. We used independent samples T test and chi-square test to compare the two groups.

Results:
LEF-PF (N=19, PT 92±15 Nm) and LEF-RF (N=35, PT 49±13 Nm) had similar demographic and comorbidity profiles. While ankle-brachial index didn't differ between the two groups, during the reactive hyperemia test, ankle pressure of LEF-RF dropped more significantly (p=0.021) upon occlusion release and took longer to recover (p=0.023). Both groups performed similarly on the Gardner Treadmill test, but LEF-PF performed better in the 6-Minute Walking test (p=0.062). LEF-PF also trended towards higher scores on the modified falls efficacy scale (p=0.056). Histologically, gastrocnemius muscle from LEF-PF had larger myofibers, while biochemically, they exhibited lower mitochondrial respiratory activity dependent on complex-II compared to LEF-RF.

Conclusion:
Our study presents a novel approach to understanding the physiology of claudication, focusing on the strength of the ischemic muscles. Despite comparable demographics and hemodynamics at rest, notable differences separate the two groups during stress-induced hemodynamics, walking performance, myofiber histology, and mitochondrial biochemistry. Further investigations are necessary to elucidate the underlying mechanisms behind the differences in muscle strength among patients with claudication. Such insights may enhance our understanding of PAD physiology and potentially correlate with variations in mortality rates, progression to more advanced PAD stages, and responses to different therapeutic interventions.
Abstract 4137296: Single-cell Atlas of Human Epicardial Adipose Tissue Reveals Aging IL4R
+
Naive B cell Contributing To Atrial Fibrillation
Authors: Huang Shengkang , Yang Ziang , Fang Chenglong , Zhao Wei , Feng Wei
Published: November 2024

Background:
Numerous recent evidence suggested a role of epicardial adipose tissue (EAT), the visceral fat depot of the heart, in the development of Atrial Fibrillation (AF). However, the cellular and molecular mechanisms underlying the association remain elusive.

Methods:
We performed single-nucleus RNA sequencing on eleven EAT samples collected from 2 groups of subjects: patients with nonvalvular AF undergoing coronary bypass surgery for severe CAD (n=7), and a control group of patients without concomitant AF (n=4). Comparative analyses were performed between the groups, including cellular compositional analysis, cell type–resolved transcriptomic changes, and functional analysis.

Results:
Unsupervised clustering of 92734 nuclei identified 11 clusters, encompassing all known cell types in the adipose tissue. Pseudobulk differential expression analysis between the AF and control groups revealed pronounced differences in a select subset of genes located on the X and Y chromosomes, including XIST and TSIX. Subsequent pathway analysis identified that the most significantly impacted pathways were those associated with immune cell functions. Meanwhile, differences in cellular composition and transcriptomic profiles, particularly concerning B cells, were observed between normal and AF conditions, highlighting distinct immune cell dynamics. Comparison of pathways across different B cell states revealed the enrichment of distinct pathways within each state, including those involved in cellular senescence, antigen processing and presentation, and programmed cell death signatures. Notably, aging IL4R
+
naive B cell and inflammatory ITGB1
+
memory B cell were identified as important regulators potentially involved in functional changes of EAT and AF pathogenesis.

Conclusions:
We built a complete single-nucleus transcriptomic atlas of human EAT in normal and AF conditions. Our study lays the foundation for developing novel therapeutic strategies for treating AF by targeting and modifying B cell functions within EAT.
Abstract 4137339: Application of PLGA-PEG-PLGA Thermosensitive Hydrogel Loaded with Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes and Ginsenoside Rb3 in the Treatment of Acute Myocardial Infarction
Authors: Xiang Kun , Zheng Zilong , Li Yichen , Tang Weijie , Chen Wangping , Yang Jinfu , Fan Chengming
Published: November 2024

Background:
Ginsenoside Rb3 (GSRb3) is a traditional Chinese medicine monomer. We aim to investigate the effects of GSRb3 on the proliferation of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and the reparative effects of PLGA-PEG-PLGA thermosensitive hydrogel loaded with hiPSC-CMs and GSRb3 (NP
GSRb3
@Gel+iCM) on myocardial infarction (MI).

Methods:
1. Western Blot, RT-qPCR, cell immunofluorescence staining, and CCK-8 assays were employed to assess the proliferative effects of different concentrations of GSRb3 on neonatal mouse primary cardiomyocytes (NCMs) and hiPSC-CMs. 2. Transcriptomic gene sequencing technology was utilized to investigate the mRNA expression changes of hiPSC-CMs induced by GSRb3; The NP
GSRb3
@Gel+iCM was injected into the left ventricular myocardium of the MI mice; the same volume injections of hiPSC-CMs (iCM group) and PLGA-PEG-PLGA thermosensitive hydrogel loaded with GSRb3 (NP
GSRb3
@Gel group) served as control; Additionally, MI model group without additional treatment and sham group were established. 3. At 4 weeks post-MI, echocardiography, Sirius Red/Fast Green staining and immunofluorescence staining were utilized to evaluate the heart function, infarction size and survival rate of transplanted hiPSC-CMs.

Results:
GSRb3 inhibit the apoptosis of NCMs while promote proliferation of NCMs and hiPSC-CMs significantly. After 4 weeks of treatment, the engraftment rate of hiPSC-CMs in NP
GSRb3
@Gel+iCM group (36.7%) was 4.8 times that of iCM group (7.7%); Compared to the MI group, NP
GSRb3
@Gel group and iCM group, NP
GSRb3
@Gel+iCM group showed significant improvement in cardiac function; The myocardial repair effect in NP
GSRb3
@Gel+iCM group was significantly superior to NP
GSRb3
@Gel group and iCM group, with a 47% reduction in infarct size compared to MI group, and further reduction in left ventricular anterior wall thickness compared to NP
GSRb3
@Gel group and iCM group.

Conclusion:
GSRb3 promotes the proliferation of hiPSC-CMs both in vitro and in vivo. NP
GSRb3
@Gel+iCM significantly increase the engraftment of hiPSC-CMs, promote angiogenesis, reduce infarction size, inhibit left ventricular remodeling and improve cardiac function.
Abstract 4137364: Sex differences in the right ventricle in the Sugen-Hypoxia rat model of pulmonary arterial hypertension
Authors: Coyle Chelbi , MacLean Margaret , Tian Lian
Published: November 2024

Background:
An unexplained estrogen puzzle exists in pulmonary arterial hypertension (PAH): PAH occurs ~4 fold more frequently in women than men; however, women with PAH have better right ventricular (RV) function and survival than the men. Sex differences and the associated mechanism in RV in PAH are not well understood.

Aim:
To characterize sex differences in RV function and structure in PAH.

Methods:
Sprague-Dawley rats were injected with Sugen (SU5416, 25mg/kg), and subjected to 3 weeks of hypoxia, followed by 5 weeks of normoxia. Control rats received vehicle and stayed in normoxia for up to 8 weeks. RV pressure-volume, mitochondrial properties, weight, myocyte size, cell proliferation, and interstitial and perivascular (right coronary arteries, RCA) fibrosis were obtained.

Results:
Sugen-Hypoxia (SuHx) caused significant increases in RV systolic pressure (RVSP) and effective arterial elastance (Ea) in both sexes (P<0.05), but caused slightly greater increase in RV end-systolic elastance (Ees) in females vs males, leading to a preserved RV-pulmonary artery coupling (Ees/Ea) in females and a significant decrease in Ees/Ea in males (P<0.05). SuHx caused a significant increase in RV diastolic pressure only in males (P<0.05), which is associated with significantly higher amount of RV interstitial fibrosis in males vs females. In addition, SuHx caused significant increase in cell proliferation in both sexes (P<0.05) though with slightly greater in crease in males, which is well correlated with RV interstitial fibrosis. Whilst there was no sex difference in RV hypertrophy in SuHx rats as indicated by both fulton index and myocyte size, female RV had smaller myocytes than males at baseline, indicating a greater increase in myocyte size in response to SuHx. Finally, there was a significant increase in RCA fibrosis in male SuHx rats (P<0.05) but not in females, potentially leading to a greater degree of ischemia in male SuHx RV, and this is consistent with impaired mitochondrial properties (decreased mitochondrial fusion, membrane potential an superoxide) in male SuHx rat RV (P<0.05) but preserved mitochoindrial properties in females.

Conclusions:
SuHx resulted in similar level of RV afterload in both sexes, but compared to males, RV in females responded differently in both function (Ees and mitochondrial properties) and structure (myocyte size and fibrosis). Future studies on the associated mechanism are needed to gain therapeutic insight for RV in PAH.
Abstract 4137516: Disparities in Participation: Analyzing Age, Sex, Race, and Ethnicity in Atrial Fibrillation Clinical Trials in the United States
Authors: Bejjani Antoine , Akiki Elias , Azzo Joe David , Maalouf Elisia , Kadi Tamara , Ghusn Wissam
Published: November 2024

Introduction:
Atrial fibrillation (AF) is a prevalent cardiovascular disease that significantly impacts public health in the United States. Although numerous clinical trials aim to optimize AF management, concerns about demographic disparities in trial participation persist. This study assesses the representation of age, sex, race, and ethnicity among participants in AF trials conducted in the US, highlighting potential biases that could affect the generalizability of trial outcomes.

Methods:
An extensive review of clinical trials registered on ClinicalTrials.gov involving patients with AF up to April 2024 was performed. The search was filtered to include all completed interventional trials across phases 2 to 4 without restrictions on the initiation or completion dates. Data were extracted concerning mean age, age distribution, sex, and the racial and ethnic composition of the trial participants.

Results:
From the 173 trials analyzed, a total of 1,355,239 participants were included, with an average age of 64.7 years. The demographic breakdown revealed a participant pool consisting predominantly of older adults (>65 years: 70.8%), with a significant underrepresentation of the younger age group (18-65 years: 29.2%). Males constituted 65.2% of the trial population, highlighting a gender imbalance. Racially, 74.1% of participants were White, while African Americans (7.7%) and Asians (5.9%) and other racial groups were notably underrepresented. Ethnic disparities were also evident, with Hispanic participants making up only 11.5% of the study population.

Conclusion:
The findings demonstrate significant disparities in the age, sex, race, and ethnic backgrounds of AF clinical trial participants in the US. These imbalances could potentially limit the applicability of trial results across the broader, diverse population. Efforts to enhance the diversity of clinical trial cohorts are essential to ensure more equitable health outcomes and the universal applicability of clinical research findings. Future strategies should focus on targeted recruitment and inclusive study designs to address these disparities.
Abstract 4137564: Management of Atrial Flutter (AFL) Using Intrinsic Antitachycardia Pacing (iATP) Protocol
Authors: Silverstein Joshua , Gupta Manasvi , Duan Chaojing , Phalunas Caitlin , Shaw George , Liu Emerson , Cherian Tharian , Belden William , Friehling Mati , Belden Elizabeth , Lathia Minesh , Bailey Grace , Thosani Amit
Published: November 2024

Background:
The recently introduced iATP algorithm augments traditional ventricular antitachycardia pacing (ATP) with programmed stimulation (PS) resulting in greater efficacy terminating ventricular tachycardia than traditional ATP in avoiding ICD shocks. The use of iATP in the atrium may similarly enhance termination of atrial arrhythmias, avoiding prolonged arrhythmia burden or need for cardioversion.

Objective:
To compare efficacy of 3 atrial ATP protocols (PROT[GS1] ) in either converting AFL to sinus rhythm or accelerating AFL to atrial fibrillation (AF).

Methods:
Patients presenting in AFL for ablation were recruited. Patents underwent all three pacing protocols, twice, and in random order (6 times total).

1. PROT 1 – Ramp pacing at 91% of tachycardia cycle length (TCL) for 13 beats with 5 or 10ms decrement, avoiding pacing cycle length (CL) <160 ms.

2. PROT 2 – Ramp pacing at 81% of TCL for 13 beats again with 5 or 10ms decrement, avoiding CL <160 ms.

3. PROT 3 (iATP) – Drive train of 88% of TCL for 15 beats with singles, doubles, and triples down to atrial effective refractory period.

If AFL terminated, it was re-induced with PS or burst pacing.

Termination and CL acceleration to AF are defined as the positive effect. No effect is defined as the negative effect. CL acceleration and termination were treated similarly in the analysis because AF is clinically easier to manage than AFL.

Results:
Of the 21 patients enrolled, 17 completed the entire protocol. 4 patients (excluded from analysis) did not complete the protocol due to non-inducibility following AFL termination. The TCL of the AFL ranged from 190ms to 290ms. PROT 1 terminated AFL 6 out of 34 attempts (17.6%). PROT 2 terminated AFL 7 out of 34 attempts (20.5%). iATP terminated AFL 13 out of 34 attempts (38%). It also accelerated AFL more frequently than the other two protocols (PROT 1:1, 2:4, 3:8).

Conclusion:
Atrial iATP was significantly more effective in either terminating or accelerating AFL, compared to ramp pacing protocols.
Abstract 4137682: Genome wide association study for residualized apolipoprotein B elucidates its role in coronary artery disease risk
Authors: Zhang Selena , Koyama Satoshi , Haidermota Sara , Hornsby Whitney , Honigberg Michael , Ellinor Patrick , Natarajan Pradeep
Published: November 2024

Background:
Recent studies have shown apolipoprotein B (ApoB), the principle atherogenic lipoproteins, to have greater predictive ability for coronary artery disease (CAD) risk over standard lipid parameters. Moreover, discordantly high ApoB relative to Low-density lipoprotein cholesterol (LDLC) has repeatedly been associated with increased CAD risk.

Aim:
Given the strong genetic effects of ApoB and LDLC, we sought to characterize the discordance between ApoB and LDLC by genetics to obtain mechanistic insights into this emerging risk factor.

Method:
We derived residualized-ApoB regressing ApoB on LDLC in European-like populations (N = 383,500) in the UK Biobank. Using residualized-ApoB as an outcome, we explored clinical associations and conducted genome wide association study (GWAS).

Result:
Residualized-ApoB only modestly correlated with ApoB and LDLC (Spearman’s rho = 0.248 and -0.0079 respectively). We observed increased residualized-ApoB in males and individuals with lipid lowering therapy. Increased residualized-ApoB was associated with increased risk for CAD [Odds Ratio; 1.25 (95% Confidence interval 1.23-1.27)] independent from LDLC, ApoB, and Triglycerides. By GWAS, we observed significant heritability for residualized-ApoB [h
2
= 12.3 (SE 0.012)] and 195 significantly associated genetic loci (
P
< 5 × 10
-8
). Only 59 of these lead variants were associated with ApoB or LDLC. We also found different effects in ApoB-related loci. For example, ApoB-increasing alleles at
APOB
(rs533617) and
APOE
(rs7412) loci increased residualized-ApoB but ApoB-increasing alleles at
ABCG8
(rs4245791) and
HAPLN4-TM6SF2
(rs150641967) loci decreased residualized-ApoB.

Conclusions:
Exploiting genetics, we determined significant heritability of residualized-ApoB which was partially correlated with ApoB/LDLC. We identified distinct effects of genetic variants on residualized-ApoB. Our results provide the clues for further precise understanding of regulatory mechanisms between ApoB and LDLC.