bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 13092: Macrophage Specific IGF1 Overexpression on ApoE Deficient Mice Decreases Atherosclerosis, Reduces CXCL12 Chemokine Expression, and Increases Cholesterol Efflux
Authors: Snarski Patricia , Sukhanov Sergiy , Yoshida Tadashi , Danchuk Svitlana , Shai Shaw-Yung , Bysani Chandrasekar , Delafontaine Patrice
Published: April 2024

Increased bioavailability of Insulin Like Growth Factor I (IGF1) has been shown to reduce cardiovascular events. Systemic IGF1 administration in ApoE deficient (Apoe
-/-
) mice fed a high fat diet reduced atherosclerosis and reduced plaque macrophages. Results of our previous
in vitro
experiments suggest that macrophages play a predominant role in mediating IGF1 effects in atherosclerotic plaque. We hypothesized that increasing IGF1 levels strictly in macrophages will prevent atherosclerosis. After breeding a novel macrophage-specific IGF1 overexpressing transgenic mouse to an Apoe
-/-
background (MF-IGF1 mice), we assessed atherosclerotic plaque burden, stability, and monocyte recruitment. Macrophage IGF1 overexpression downregulated plaque burden by 30% (P<0.01), reduced plaque macrophages by 47% (P<0.001) and promoted a stable plaque phenotype. Monocyte recruitment was reduced by 70% (P<0.05) in MF-IGF1 mice and was associated with a decrease in circulating levels of CXC Chemokine Ligand 12 (CXCL12) (27% reduction, P<0.05). CXCL12 protein levels were reduced in plaque and peritoneal macrophages in MF-IGF1 mice. IGF1 completely blocked oxidized low-density lipoprotein (oxLDL)-dependent increase of CXCL12 mRNA transcription (98% reduction, P<0.01) and IGF1 treatment reduced CXCL12 protein (56% decrease, P<0.001)
in vitro.

ATP-binding cassette transporter A1 (ABCA1) is the key cholesterol transporter mediating macrophage cholesterol efflux and CXCL12 reduces its expression. We found that peritoneal macrophages isolated from MF-IGF1 mice have a 2 fold increase in ABCA1 protein levels. We loaded peritoneal macrophages with oxLDL to measure changes in cholesterol efflux and found that MF-IGF1 mice have a 42% increase in efflux (P<0.01). We also found a 27% increase in cholesterol efflux in IGF1 (100 ng/mL) treated THP-1 cells (P<0.01) with Apolipoprotein AI as a cholesterol acceptor. Overall, our results indicate that macrophage IGF1 reduces atherosclerosis and decreases CXCL12, a chemokine newly implicated in atheroprogression. IGF1 potentially exerts its atheroprotective effect via this reduction in CXCL12 by reducing monocyte recruitment and by increasing ABCA1, thereby increasing cholesterol efflux capacity.
Abstract 13167: Multiscale Mechanisms of Right Ventricular Injury in Bronchopulmonary Dysplasia
Authors: Freeman Madison J , Hacker Timothy A , Goss Kara N , Chesler Naomi C
Published: April 2024

Introduction:
Bronchopulmonary dysplasia (BPD) is the most common complication of premature birth. Whether right ventricular (RV) injury or chronically increased afterload are more responsible for long-term RV dysfunction in BPD is unknown. We aim to determine key drivers of RV dysfunction in BPD using both experimental data and a computational model. We hypothesize that decreased mitochondrial energetics and active force generation are critical contributors.

Methods:
Male and female Sprague-Dawley rats were delivered at term to timed-pregnant dams and exposed to either room air (Nx) or 85% fraction inspired O
2
(Hx) for 4, 8, or 14 days. Multiscale experimental data was obtained at postnatal day 21 and used to parameterize the previously published computational model of the heart and circulation, which integrates myocardial mechanics and mitochondrial energetics.

Results:
Despite increased RV afterload in the 8-and 14-day exposure groups (Fig. 1A) and significant RV hypertrophy in the 14-day group (Fig. 1B), there was no change in ejection fraction (EF) due to high variability (Fig. 1C). We used the computational model to explore how multiscale features of RV injury impact RV EF (Fig. 1D). Whereas decreased mitochondrial function, decreased cross-bridge maximum force, and increased RV afterload further reduce predicted RV EF in the 14-day Hx rat with the lowest EF (red symbol) and RV EF in the 14-day Nx rat with the highest EF (blue symbol), EF can be restored in a simulated reversal of these injuries in the Hx rat.

Conclusions:
Our approach provides valuable insight into key features of RV injury in BPD. Different degrees and combination of injuries at multiple scales can explain functional heterogeneity and may enable more accurate predictions of long-term RV dysfunction. Figure 1: Measurements of (A) RV afterload, (B) RV Fulton index and (C) RV EF as well as computational model predictions of (D) RV EF for one 14D Hx (red) and one 14D Nx rat (blue).
Abstract 13683: Corticosteroids and the Risk of Atrial Fibrillation in Hospitalized COVID-19 Patients
Authors: Lee Yi , Jehangir Qasim , Poisson Laila , Latack Katie , Krishnamoorthy Geetha , Sule Anupam , Song Shiyi , Apala Dinesh Reddy , Halabi Abdul R , Patel Kirit , Wang Dee Dee
Published: April 2024

Introduction:
Some studies suggest an increased incidence of atrial fibrillation (AF) in patients receiving corticosteroids, whereas others suggest a preventive effect of steroids. Data on the impact of steroids on the incidence of new-onset AF in hospitalized COVID-19 patients is lacking.

Methods:
This retrospective, multicenter cohort study included patients ≥ 18 years admitted to one tertiary care and five community hospitals for treatment of COVID-19 infection between 3/1/2020 and 3/31/2021. Subjects were stratified based on steroid exposure during hospitalization: group 1 (full-dose) received cumulative dosage including dexamethasone ≥ 6 mg/day, methylprednisolone ≥ 80 mg/day or hydrocortisone ≥ 50 mg/day for ≥ 3 days, group 2 (low-dose) did not receive the aforementioned dosage, and group 3 had no steroid usage. Patients with a history of AF and length of stay < 3 days were excluded.

Results:
Among 4578 (1556 in group 1, 1046 in group 2, 2156 in group 3) patients (mean age 65.4 ± 61 years, 50.4 % females), 542 patients developed new-onset AF. 523 (24.3%) patients in group 1, 97 (9.3%) in group 2, and 125 (8%) in group 3 died during hospitalization. In multivariable logistic regression models adjusted for hypoxia and significant baseline demographics (age, sex, body mass index, hypertension, pulmonary disease, chronic kidney disease, liver disease, and cerebrovascular accident), we found that group 1 had a higher incidence of AF compared to group 3 (adjusted relative risk [aRR] 1.59; 95% CI 1.27 - 1.99; p < 0.001) and group 2 (aRR 1.39; 95% CI 1.09 - 1.77; p = 0.007). The group 2 vs group 3 (aRR 1.14; 95% CI 0.87 - 1.50; p = 0.347) comparison did not reach statistical significance (Figure).

Conclusions:
Corticosteroids, the mainstay of treatment of hypoxic COVID-19 patients, are associated with an increased risk of developing AF. This suggests that steroids have a potential direct arrhythmogenic effect in COVID-19 patients.
Abstract 13694: Remote Cardiovascular Health Program Improved Risk Factor Control in Patients With Diabetes
Authors: Blood Alexander J , Chaney Kira , Zelle David , Gordon William , Gaziano Thomas A , Plutzky Jorge , Fisher Naomi D , Cannon Christopher P , Scirica Benjamin M
Published: April 2024

Introduction:
Patients with diabetes are at significantly increased risk of developing future cardiovascular events. Systematic approaches to optimally control cholesterol and blood pressure (BP) can reduce the morbidity and mortality associated with diabetes.

Methods:
The Digital Care Transformation (DCT) program screens and refers patients for remote cholesterol and hypertension management and subsequently educates, starts and titrates medications and monitors laboratory values through expert-designed algorithms. Patients referred into the DCT program who had established diabetes were assessed to understand therapy decisions and BP and cholesterol outcomes.

Results:
3,294 patients with known diabetes have been enrolled from the DCT program. 249 patients have completed only BP management, 951 completed only cholesterol management and 58 completed both programs. ~26% of patients in both programs also had ASCVD. Mean office BP measurements were146/79 mmHg. Patients without white coat hypertension had a weekly average home BP of 134/77 mmHg. Patients in BP management who were hypertensive on home monitoring and completed the program attained a mean BP fall of 9.3/5.4 mmHg, with a mean 2.9 medication changes over an average of 3.9 months. Patients in cholesterol management had a mean baseline LDL cholesterol of 118 mg/dL. These patients underwent 1.5 medication changes to attain a mean 50.6 mg/dL LDL-c reduction over an average of 4.2 months.

Conclusions:
A population health management tool implemented by an algorithm-based medication management approach can appropriately prescribe therapy and improve hypertension and cholesterol control in patients with diabetes. Patients at high risk of developing a future cardiovascular events can reduce their risk through the DCT program. Further study is warranted to assess the cost-effectiveness of these interventions at scale.
Abstract 13735: Classic Pattern Dyssynchrony Score: A Predictor of Response to Cardiac Resynchronization Therapy in Pediatric and Congenital Heart Disease
Authors: Chubb Henry , Dubin Anne M , Lopez Leo , Klas Berthold , Kaplinski Michelle , Ceresnak Scott R , Motonaga Kara , Goodyer William R , Trela Anthony , Hanisch Deb , McElhinney Doff B , Friedberg Mark K
Published: April 2024

Introduction:
Cardiac resynchronization therapy (CRT) is associated with an improvement in survival in selected pediatric and congenital heart disease (CHD) patients. However, there is minimal data to guide the identification of CRT responders in these challenging subgroups, even though implant is more complex and entails a longer lifetime legacy of device-related complications.

Hypothesis:
Echocardiographic measures of dyssynchrony predict response to CRT in this patient population

Methods:
This single-center study included all CRT pediatric and/or CHD patients (implant date 2004-2018). Response to CRT was defined as change in systemic ventricle ejection fraction (SVEF) on an ordinal scale (worsened/no change/improved). Multiple established echo indices (conventional and strain-derived) were assessed prior to implant. In addition, a novel ‘CPD-Score’, using an automated assessment of the presence of each of the four Classic Pattern Dyssynchrony (CPD) criteria on strain imaging (septal flash, lateral stretch, early peak septal strain, late peak lateral strain), was created. (Figure)

Results:
Of 127 CRT recipients, 91 met inclusion criteria (age 11yr (IQR 3-22yr), baseline SVEF 36±15%). In 62 (68%), SVEF improved following CRT (15 (16%) no change, 14 (15%) deteriorated). The presence of a septal flash was the best conventional echo predictor of response (PPV 78%). Conventional, strict, CPD also had high PPV for CRT response (72%) but was identified in only 9 (10%) patients. ‘CPD-Score’ offered a more graded response and higher PPV. A score of ≥3 was observed in 21 patients with PPV 96% (CPD-Score≥2 in 48 patients, PPV 83%). On stepwise multivariate ordinal regression, CPD-Score was independently associated with response (p= 0.02).

Conclusion:
CRT in pediatric and CHD patients is associated with an improvement in SVEF for the majority of recipients. Those with multiple features of CPD (‘CPD-Score’) are most likely to have an improvement in EF following CRT.
Abstract 13762: In-Hospital Outcomes of Mechanical Circulatory Support in MitraClip Implantation
Authors: Jehangir Qasim , Lee Yi , Kakouros Nikolaos , Abdel-Hafez Osama , tirunagari Deepthi , Shah Ruchit , Apala Dinesh Reddy , Jena Nihar , Abdou Asrar , Salih Mohammed , Halabi Abdul R , Patel Kirit , Qureshi Waqas
Published: April 2024

Introduction:
MitraClip, an efficacious strategy for patients with heart failure and severe mitral regurgitation, can be complicated by acute circulatory collapse in rare instances. Data on the use of mechanical circulatory support (MCS) in these patients is scarce.

Methods:
Using the Nationwide Inpatient Sample Database from 2016 to 2018, we identified patients who underwent MitraClip insertion and required MCS using ICD-10 codes. The MCS devices included intra-aortic balloon pump (IABP) (group 1), Impella (group 2), and extracorporeal membrane oxygenation (ECMO) (group 3). Patients <18 years and those requiring more than one device use were excluded. The primary outcome was in-hospital mortality and secondary outcomes were myocardial infarction (MI), cerebrovascular accident, sepsis, and major bleeding.

Results:
Our analysis included 17,070 MitraClip patients (based on weighted sample) with 360 requiring MCS devices (IABP N=270, Impella N=75, ECMO N=15). Patients who required Impella were older than those who required ECMO and IABP (mean age group 1 75.8 ± 11.3, group 2 78.3 ± 10.1, group 3 77.1 ± 8.9; p < 0.0001). The utilization of MCS devices was different among races (Whites 80.8%, African Americans 7.6%, Hispanics 6.53%; p = 0.0078) but not among gender (males 52.3%; p = 0.8467). Incidence of in-hospital mortality was highest in Impella (group 1 31.5%, group 2 46.7%, none in group 3; p < 0.001) (Figure). The multivariate logistic regression model adjusted for MCS devices, age, race, sex, hypertension, diabetes, cardiopulmonary disease, kidney disease (CKD), liver disease, peripheral arterial disease, and arrhythmias indicated that the use of IABP, Impella, CKD, and liver disease were independent predictors of in-hospital mortality.

Conclusions:
In MitraClip, the use of ECMO was associated with a higher incidence of major bleeding and sepsis when compared to Impella and IABP, however, Impella use was associated with higher in-hospital mortality and MI.
Abstract 13767: Reaching the LDL-Cholesterol Target Recommended by the Guidelines: Be Ambitious to Get the Maximum Benefit
Authors: Casula Matteo , Taietti Ivan , Galazzi Marco , Zeqaj Iris , Fortuni Federico , Cornara Stefano , Somaschini Alberto , Leonardi Sergio , Camporotondo Rita , Totaro Rossana , Ferlini Marco , Gnecchi Massimiliano
Published: April 2024

Introduction:
There is no agreement among international guidelines (GL) on the recommended therapeutic target for LDL cholesterol in secondary prevention (SP).

Hypothesis:
The aim of this study was to determine the risk of major adverse cardiovascular events (MACE) during follow-up in a real-world SP population according to the achievement of a purely numerical threshold (i.e. LDL<1.8mmol/L [Canadian 2021 GL], group A) or a target that also considers a relative reduction in LDL levels (i.e. LDL reduced ≥50% from baseline and <1.8mmol/L [AHA/ACC 2018 GL] or <1.4 mmol/L [ESC 2019 GL], group B).

Methods:
We conducted a retrospective analysis of a monocentric observational registry prospectively enrolling patients admitted for STEMI between 2011 and 2019. The combined endpoint of MACE included all-cause death, non-fatal MI, non-fatal stroke, and unplanned revascularization. The lowest LDL value collected between 1 and 12 months after the index event was used to define the achievement of the target. We conducted a Kaplan-Meier analysis comparing patients who achieved different GL-recommended targets.

Results:
A total of 1199 patients (23% female) were included. Median age was 63 (54-72) years, 56% had hypertension, 17% diabetes, and 38% were smoker. Baseline LDL was 3.2 (2.5-3.8) mmol/L; 83% of patients were treated with statin therapy alone, and 17% with the addition of ezetimibe. Median follow-up was 53 (32-70) months. The Canadian, AHA/ACC and ESC targets were achieved in 842 (70%), 506 (42%) and 308 (26%) patients respectively; MACE-free analysis based on the target achieved is presented in FigA. The net incidence of MACE was 29% in group A vs 15% in group B (HR 1.97; 95%CI 1.36-2.85; P log-rank=0.0003; NNT=7; FigB).

Conclusions:
Our data from a real-world cohort of secondary prevention patients emphasize the importance of achieving a guideline-recommended target that also considers a relative reduction in LDL levels (i.e. LDL ≤50% from baseline) in order to reduce MACE.
Abstract 13775: Determinants and Prognostic Implications of Improved and Non-Improved Left Ventricular Ejection Fraction in Chronic Heart Failure
Authors: Nordbeck Peter , Liu Dan , hu kai
Published: April 2024

Introduction:
Clinical implications of improvement in left ventricular ejection fraction (LV EF) are not well investigated.

Hypothesis:
To evaluate determinants and prognostic value of longitudinal changes in ejection fraction among chronic heart failure (HF) patients with reduced EF (HFrEF, EF ≤40%) and to determine risk factors of adverse outcomes among HFrEF patients with or without improve EF

Methods:
573 consecutive hospitalized HFrEF patients (aged 66±13years, male 75.6%) with baseline (BL) and follow-up (FUP) echocardiography examinations (interval at least ≥12 months) were included. Patients were divided into improved EF (iEF, ≥5% increase in FUP_EF, n=335) or non-improved EF (niEF, <5% increase in FUP_EF, n=238). Primary endpoints included all-cause death, cardiovascular (CV) death, and CV rehospitalization.

Results:
Lower BL_EF (≤30%, OR 2.70, P<0.001), smaller LV end-diastolic dimension (<65mm, OR 2.62, P<0.001), and absence of coronary artery disease (CAD, OR 1.73, P=0.006) independently associated with EF improvement in this cohort. During follow-up (median 27 months), overall mortality (20.3% vs. 38.2%), CV mortality (9.0% vs. 19.7%), CV rehospitalization rate (25.4% vs. 45.0%), and HF rehospitalization rate (8.4% vs. 20.6%) were all significantly lower in iEF group than in niEF group (all P<0.001). After adjustment for age, sex, and other confounders associated with CV events, iEF remained independently associated with lower overall mortality (HR 0.50, P<0.001), CV mortality (HR 0.43, P<0.001), CV and HF rehospitalization (HR 0.44 and 0.34, P<0.001). For HFrEF patients with iEF, elevated C-reaction protein and NT-proBNP levels were related to increased risk of CV events. For HFrEF patients with niEF, elevated NT-proBNP, reduced longitudinal systolic function, and enlarged RV were independently related to increased risk of CV events.

Conclusions:
Improvement in LV EF during follow-up is a powerful determinant of reduced overall mortality, CV mortality, and CV rehospitalization in HFrEF patients independent of age, sex and other identified risk factors.
Abstract 13781: Megakaryocytes Participating in Thrombosis Under Inflammatory Stress and Sepsis: Direct Pathological Evidence in Two Cases
Authors: Zhang Hua , zeng kuan , Li Liang , Zhang Lu , Li Jianfen , Yang Mo , Yang Yanqi
Published: April 2024

Introduction:
Megakarycytes (MKs) produce platelets (PLTs) which enter the circulation and play its roles in hemostasis and thrombosis. However, direct pathological evidence that MKs participate in thrombosis has not been reported in clinical practice. We describe here direct observations in two cases where MKs were found in thrombosis in coronary artery and in the right atrium under open-heart surgery.

Hypothesis:
MKs might be mobilized into circulation and directly participate in and magnify thrombosis under sepsis, inflammatory stress and full heparinization.

Methods:
Case one was a 51-year-old male with ischemic cardiomyopathy, coronary stenoses and severe mitral insufficiency who underwent coronary artery bypass grafting (CABG) and mitral annuloplasty under cardiopulmonary bypass (CPB). A thrombus was pulled out from the right atrium when an atrial cannula was removed under full heparinization. Case two was a 53-year-old male with known mitral endocarditis and acute anterior myocardial infarction. Acute coronary angiogram after admission showed thrombosis in the left anterior descending (LAD) branch. The patient underwent emergency thrombectomy, CABG and mitral valve replacement with CPB. The thrombus was completely removed from the LAD through a small incision. Both thrombi, valve tissue and vegetation were sent for pathological examination with HE and CD41-IHC staining on paraffin sections.

Results:
Large number of giant polyploidy MKs surrounded by PLTs were seen in different areas in the thrombi of MKs-PLTs-fibrin networks from the right atrium and LAD. The coronary thrombus was consisted of MKs, PLTs and red cells in fibrin networks while the infected vegetation was consisted dominantly of inflammatory cells, bacterial legions and fibrin.

Conclusions:
MKs may enter both venous and arterial circulation, actively participate in thrombosis under inflammatory stress and sepsis, and be capable of escaping from inhibition of full heparinization.
Abstract 13800: The CardioNerds Case Report Series: The Role of Asynchronous Medical Education in Cardiovascular Training
Authors: Desai Karan , Ambinder Daniel , Reza Nosheen , Menon Venu , Goyal Amit
Published: April 2024

Background:
The COVID-19 pandemic created numerous challenges for graduate medical education, including defining the role of asynchronous virtual education in general cardiovascular (CV) fellowship training. The CardioNerds podcast introduced the CardioNerds Case Report (CNCR) series to provide continued high-quality cardiovascular education during the pandemic. Moving forward, the role and value of asynchronous education, and specifically medical podcasts, remain unknown.

Methods:
The CNCR series included a wide range of case-based episodes involving cardiology fellows, content experts, and program leadership from participating programs. Every accredited general cardiology fellowship program in the United States was invited. A survey assessing attitudes on a likert scale towards cased-based cardiology podcasts and medical podcasts was administered to all participating programs.

Results:
44 cardiology fellowship programs participated in the CNCR series representing 137 fellows and 59 program directors and leaders (PDs). At this time, 76% of fellows and 63% of program directors have responded. 90% of both fellows and PDs agreed that the CNCR series was an effective way to teach core CV concepts and 74% of fellows felt that contributing to the CNCR series improved their clinical reasoning skills. 70% of PDs and 94% of fellows felt that medical podcasts in general added to their knowledge base. Fellows were more likely to strongly agree that medical podcasts changed their clinical practice compared to PDs (46% vs 8%, p = 0.02).

Conclusion:
Medical podcasts are becoming increasingly popular in cardiovascular education and training. Specifically, the CNCR platform has been well received by fellowship programs and has potentially influenced clinical practice. CV training programs and professional societies should invest in ensuring high quality medical podcasts are incorporated into CV training moving forward to supplement traditional CV education.
Abstract 13801: Predictive Value of Apical Sparing on Echocardiography for Cardiac Amyloidosis
Authors: Guo James W , Witting Celeste , Bavishi Aakash , Jankowski Madeline , Maganti Kameswari
Published: April 2024

Introduction:
In prior studies of patients with left ventricular thickness, the 2D speckle tracking strain echocardiography (STE) finding of relative apical sparing of longitudinal strain (RALS) was associated with a high sensitivity and specificity for diagnosing cardiac amyloidosis (CA). Use of STE is increasing, but the positive predictive value (PPV) of RALS for identifying CA among other etiologies in a large, contemporary patient population is unknown.

Hypothesis:
While RALS will still carry high predictive value for diagnosing CA, a significant proportion of patients will have other identifiable etiologies.

Methods:
We retrospectively reviewed 97 patients with RALS (defined as strain ratio ≥ 2.0) on echocardiography between June 2017 and June 2020 who had workup for CA, with cardiac MRI,
99m
Technetium-pyrophosphate scan, serum/urine protein electrophoresis, and/or biopsies. These patients were then categorized into 4 groups relative to suspicion for CA (confirmed, suspicious, unlikely, ruled out). Patients without CA (unlikely/ruled out) were screened for comorbidities, including potential etiologies of RALS.

Results:
Of the 97 patients included, 40 (41%) were women and 39 (40%) were black. 17 (18%) had confirmed and 8 (8%) had suspicious CA while 72 (74%) had unlikely or ruled out CA. Of the confirmed cases, 10 (10%) were diagnosed with TTR amyloidosis and 7 (7%) were diagnosed with AL amyloidosis. The PPV of RALS for CA was 26% (25/97). Among the 72 patients with RALS without CA, 17 (24%) had no comorbidity, 4 (6%) had chronic kidney disease (CKD), 17 (24%) had hypertension (HTN), 16 (22%) had CKD and HTN, 2 (3%) had a malignancy treated with chemotherapy, 1 (1%) had aortic stenosis (AS), and 15 (24%) had multiple comorbidities (Figure 1).

Conclusions:
In a patient population with non-selective use of STE, the PPV of RALS for CA was 26%. Given the increasing use of STE, recognition of other etiologies of RALS should be noted.
Abstract 13850: Proteomic Profiling to Identify Pre-Transplant Biomarkers of Renal Failure After Heart Transplantation
Authors: Truby Lauren K , Kwee Lydia , Shaw Brian , Agarwal Richa , Devore Adam D , Knechtle Stuart , Luo Xunrong , Patel Chetan B , Chen Dongfeng , Bowles Dawn E , Milano Carmelo A , Holley Christopher L , Shah Svati H
Published: April 2024

Introduction:
In patients being considered for heart transplantation (HT), differentiating reversible kidney injury due to cardiorenal syndrome from irreversible renal disease that will necessitate simultaneous heart-kidney transplant (sHK) remains a clinical challenge.

Hypothesis:
We hypothesized that pre-transplant proteomic profiling could identify novel biomarkers of post-transplant renal failure in HT recipients and, in so doing, identify those patients who may derive benefit from sHK evaluation.

Methods:
We performed targeted proteomic profiling of serum samples collected within the 24 hours prior to HT or sHK. Using a multivariable logistic regression including relative protein expression, age, and sex with adjustment for batch effect, we identified those pre-transplant proteins that were differentially expressed between patients who received HT and sHK. Proteins that met FDR significance in this multivariable model were then tested for association with post-transplant RRT in isolated HT recipients. Patients with known intraoperative hemodynamic insult as a result of primary graft dysfunction were excluded from this analysis. This model was adjusted for age, sex, and MDRD eGFR. ROC analysis was performed to test the performance of the final protein model.

Results:
Pre-transplant expression of 97 proteins was noted to be significantly different at the FDR p <0.05 level in sHK recipients (n=12) when compared to HT (n=231) recipients in the multivariable model. We identified 205 isolated HT recipients, among whom 33 required post-HT RRT. Among these 97 candidate We identified a total of 15 proteins, many of which have previously been associated with acute and chronic kidney injury, including KIM1, FABP4, PAR-1, VSIG2, and GDF-15, that were significantly associated with post-HT RRT after adjustment for age, sex, and pre-transplant eGFR. In ROC analysis in our cohort, the AUC of the 15-protein model was 0.82.

Conclusions:
Proteomic profiling of pre-transplant serum of HT recipients may identify HT candidates at high risk for post-transplant RRT. Individually and in aggregate, these 17 proteins warrant additional investigation as novel biomarkers that may identify patients who would benefit from sHK evaluation.
Abstract 13853: A Fully Automated Deep Phenotyping of Late Gadolinium Enhancement Cardiac MRI for Predicting Heart Failure Progression in Hypertrophic Cardiomyopathy
Authors: Fahmy Ahmed S , Rowin Ethan J , Manning Warren J , Maron Martin S , Nezafat Reza
Published: April 2024

Introduction:
Myocardium scar volume in late gadolinium enhancement (LGE) MRI is associated with cardiac adverse outcomes in hypertrophic cardiomyopathy (HCM). However, scar quantification is time-consuming and challenging. Also, LGE contains information about scar heterogeneity, location, and shape not readily quantified by current LGE analyses.

Hypothesis:
Automated deep phenotyping of LGE images can extract novel imaging markers of heart failure (HF) progression in HCM.

Methods:
We developed a deep convolutional neural network (CNN) (Fig 1) to extract LGE image features associated with progressive HF in HCM. We developed the CNN using data for 572 HCM patients (183 F; 51±16 years) evaluated at Tufts medical center. The CNN input was 5 LGE images and the output was the probability of developing a HF outcome (defined as a change of New York Heart Association class I/II at baseline to class III/IV during follow-up). The dataset was split into training, 50%, validation, 25%, and independent testing, 25%. We trained the CNN for 50 epochs (learn-rate = 0.001, batch size = 12, class-weighted cross-entropy loss). To avoid overfitting, the model that best predicted HF outcomes in the validation cohort was used as the final model. We compared the CNN model to a single-variable logistic regression (LR) model (L2 regularization, class-weighted loss) that predicts HF outcomes using scar volume (manually quantified by an expert reader).

Results:
Progressive HF occurred in 96 (17%) patients during follow-up (4±2 years). In the testing cohort (n = 138), CNN correctly predicted HF in 60% of patients with positive HF outcomes (n = 22; specificity 77%, accuracy 73%, AUC = 0.73). Using the same dataset, the LR classifier showed much lower HF prediction power with AUC = 0.54 (accuracy 38%, specificity 30%).

Conclusions:
Deep phenotyping of LGE allows accurate prediction of progressive HF in HCM patients and outperforms classical LR models that use scar volume as a sole predictor of HF.
Abstract 13928: Asymmetric Dimethylarginine (ADMA) Mediates the Effect of miRNA-762 on All-Cause Mortality in Patients With Coronary Artery Disease
Authors: Jarzebska Natalia , Tselmin Sergey , Kleber Marcus , Maerz Winfried , Jin Hong , Stefan Bornstein , Mangoni Arduino A , Weiss Norbert , Rodionov Roman
Published: April 2024

Introduction:
Plasma concentrations of the endogenous L-arginine homologue asymmetric dimethylarginine (ADMA) independently predict cardiovascular and all-cause mortality. We sought to identify miRNAs that mediate the effects of ADMA on mortality or influence mortality through regulation of ADMA concentrations.

Methods:
In 993 participants of the Ludwigshafen Risk and Cardiovascular Health study (age 63.0±10.5 years, 31.4% females and 74.7% with coronary artery disease (CAD)) we measured ADMA and miRNAs concentrations in citrate plasma and investigated associations between them and with all-cause mortality.

Results:
miRNA-762 was positively and significantly correlated with ADMA concentrations (p=0.0013) and with all-cause mortality after adjusting for age and sex (HR (95%CI: 1.51(1.26-1.81); p=7.37E-06). The association remained significant after additionally adjusting for body mass index, CAD, arterial hypertension, diabetes, smoking, lipids, C-reactive protein, fibrinogen, renal function, homocysteine and medication (p=0.04). Mediation analyses showed that ADMA mediated 67% of the effect of miRNA-762 on mortality while miRNA-762 only mediated 8% of the effect of ADMA.

Conclusions:
miRNA-762 is an independent predictor of all-cause mortality in patients with CAD. The effects of miRNA-762 on mortality might be at least partially mediated by ADMA. miRNA-762 has been recently shown to regulate apoptosis in cardiomyocytes in myocardial infarction. We are currently investigating the effects of miRNA-762 on ADMA metabolism and stress responses in cultured cardiomyocytes and endothelial cells.
Abstract 13947: Catheter-Induced Ectopy During Ventricular Electroanatomical Mapping: Simply Annoying or Potentially Useful?
Authors: Kawamura Iwanari , Reddy Vivek Y , Turagam Mohit , Musikantow Daniel , Chu Edward , Miller Marc , Whang William , Dukkipati Srinivas , Koruth jacob s
Published: April 2024

Background:
During ventricular catheter mapping to guide catheter ablation of scar-related ventricular tachycardia (VT), creating an electroanatomical map can be frustrated by catheter-induced ventricular ectopy. However, we observed anecdotally that catheter-induced ventricular ectopy may unmask local abnormal ventricular activities (LAVA). The aim of this study was to compare LAVA characteristics between catheter-induced ventricular ectopy and intrinsic ventricular conduction in post-infarction patients undergoing electroanatomic mapping.

Methods:
We performed a retrospective review of electroanatomical maps from 136 consecutive post-infarction VT patients who had undergone mapping using a contact force-sensing catheter (Thermocool STSF & CARTO, Biosense Webster Inc). Patients who had any diagnostic catheters inside the ventricular were excluded. From 8 patients, 1154 discrete points were screened during sinus rhythm or right atrial pacing, and 443 points were identified to have ectopic and intrinsic beats - confirmed to be colocalized using show-catheter functionality.

Results:
Among 443 points, LAVA were identified in 151 points - either during catheter-induced ectopy or intrinsic rhythm. The interval from onset of QRS to ventricular electrogram (EGM) were measured: ectopy revealed negative values compared to intrinsic rhythm (-43.5 (-65.5, 0) vs 18.5 (0, 35.0), P<0.001). Catheter-induced ectopy had significantly longer EGM duration (206.0ms (161.0, 285.0) vs 140.0 (123.8, 168.3), P<0.001) and smaller EGM amplitude (0.59mV (0.34, 0.82) vs 0.66 (0.36, 1.06), P=0.003) compared to intrinsic rhythm. For 77 of 151 (51.0%) points, LAVA potentials were unmasked
only
during catheter-induced ectopy.

Conclusions:
During mapping of infarcted ventricles, catheter-induced ectopy offers potential insights into the underlying tissue, warranting further investigation as a guide to VT ablation.
Abstract 13952: A Novel Genetic Mini-Pig Model of Cardiac Myosin-Binding Protein C (MYBPC3) Dysfunction: Evidence for Altered Sarcomere Structure and Systolic/Diastolic Functional Reserve
in vivo
Authors: del Rio Carlos L , Ma Weikang , Ryba David , Gong Henry , Henze Marcus , Gollapudi Sampath K , Anderson Robert , Nag Suman , Rogers Christopher , Irving Thomas
Published: April 2024

Introduction:
Mutations in MYPBC3, the gene encoding cardiac Myosin-Binding Protein C (cMyBP-C), a regulatory sarcomeric protein, are known to play a pathogenic role in hypertrophic cardiomyopathy (HCM). However, the molecular bases for this pathophysiology remain poorly understood. Here, a novel large-animal MYPBC3-mutant model was developed and characterized to determine the association between myofilament abnormalities induced by cMyBP-C dysfunction and the resulting in vivo phenotype.

Methods:
A missense (early stop) E330X MYPBC3 mutation was introduced in Yucatan mini-pigs. Young heterozygous mutants (C3) and age-matched wildtype (WT) herd-mates were studied.
In vivo
imaging (MRI) and invasive hemodynamics were performed along with ex vivo measurements of tension dynamics, sarcomere structure (x-ray diffraction), and ATP turnover rates, including the population of myosin heads in the super-relaxed state (SRX) in LV fibers/tissues. Load-independent systolic and diastolic function (via LV pressure-volume relationships), and β-adrenergic receptor (β-AR) cardiac reserve (dobutamine 5 ug/kg/min IV) were assessed in vivo.

Results:
Relaxed C3 fibers showed reduced ordering of the myosin heads around the thick filament and a sensitizing shift of myosin-heads towards actin. However, C3 pigs showed normal Ca2+ sensitivity ex vivo with mildly decreased systolic function at rest in vivo (LVEF: 49 ± 1 vs. 56 ± 2%; vmax: 31 ± 1 vs. 38 ± 5 1/s; Ees: 8.5 ± 1.0 vs. 10.2 ± 1.5 mmHg/mL; all P < 0.05 vs. CTRL). Upon β-AR stimulation, C3 pigs became hypercontractile (Ees: 18.0 ± 3.1 vs. 14.3 ± 2.8 mmHg/mL in CTRL, P <0.05) showing markedly increased (P<0.05) end-diastolic stiffness (Eed: 1.7 ± 0.4 vs. 1.3 ± 0.3 mmHg/mL in CTRL) and pressures; C3 fibers showed SRX dysregulation dependent on the phosphorylation state.

Conclusions:
MYPBC3 mutant mini-pigs showed a complex phenotype, characterized by myofilament abnormalities
ex vivo
and β-AR dependent hypercontractility and diastolic dysfunction
in vivo
. Taken together, these data generated in a translationally-relevant novel large-animal model further support the role of cMyBP-C as a key regulator of contraction and relaxation, but also can provide insights into the pathophysiology of HCM.
Abstract 13960: Socioeconomic and Environmental Exposures (Socio-Enviromics) and Cardiometabolic Health in the United States
Authors: Al-Kindi Sadeer , Bevan Graham , Madabhushi Anant , Levy Phillip , Nasir Khurram , Munzel Thomas , Brook Robert D , Rajagopalan Sanjay
Published: April 2024

Introduction:
Environmental exposures and socioeconomic status may have complex interactions at the neighborhood level with respect to contributionto cardiovascular disease. We sought to understand the association between integreated social/environmentalexposures (socio-enviromics) with geospatial variation in various chronic cardiometabolic and pulmonary conditions in the United States.

Methods:
We mapped 27 census tract (CT)-level multi-source environmental exposure and socioeconomic variables throughout more >70,000 census tracts in the US. We trained a regression-based machine learning model using 80% training and tested it on 20% hold-out test to predict CT-level estimated prevalence of various risk factors and chronic diseases. We additionally tested the association between the predicted prevalence of coronary artery disease (socio-enviromic score) with major adverse cardiovascular events (MACE) in a prospective cohort of 45,188 individuals who underwent coronary artery calcium (CAC) score testing using cox regression model.

Results:
Enviromics/SocioEnviromics explained significant proportion of variation in prevalence of health conditions (figure). In the CAC cohort, socio-enviromic score was associated with MACE independently of age, sex, race and CAC (HR 1.12 [1.08-1.17], P<0.001). The association between socioenviromic score and MACE was stronger among individuals with lower CAC (socioenviromic score * CAC P
interaction
=0.01).

Conclusions:
A significant proportion of the census-tract level prevalence of cardiometabolic conditions can be explained by geographic variation in socio-enviromics, and an integrated socio-enviromic score is associated with MACE at the individual level, independently of CAC. The impact of integrated socio-enviromics in individual cardiovascular risk prediction should be studied in prospective cohorts.
Abstract 13974: Mitochondrial Chaperonin CLPB Determines MICU1 Protein Turnover and Mitochondrial Calcium Overload in Ischemia-Reperfusion Injury
Authors: Tomar Dhanendra , McGregor Ryan , jadiya pooja , Hildebrand Alycia , Elrod John W
Published: April 2024

Background:
Mitochondrial calcium uptake 1 protein (MICU1) fine-tunes mitochondrial calcium (
m
Ca
2+
) uptake across the inner mitochondrial membrane (IMM) by regulating the open probability of the mitochondrial calcium uniporter channel complex (mtCU). The loss of MICU1 is associated with numerous chronic disease states and contributes to mitochondrial calcium overload. Here we report that in response to hypoxia, MICU1 protein turnover is higher compared to all other mtCU components, suggesting a dynamically regulated post-translational system controls MICU1 expression.

Methods:
Biotin-based proximity labeling and liquid chromatography- mass spectrometry proteomics, protein biochemistry, live-cell Ca
2+
imaging, confocal and super-resolution imaging, CRISPR/Cas9 based gene editing, AAV9 based gene delivery, and mouse left coronary artery ligation for myocardial ischemia-reperfusion (IR) injury were utilized to discern the role of CLPB in MICU1 turnover,
m
Ca
2+
overload, and IR injury.

Results and Conclusions:
To identify the components regulating MICU1 protein turnover, we performed an unbiased proteomics screen utilizing MICU1 fused to BioID2, a biotinylation proximity labeling strategy combined with avidin-based isolation and mass spectrometry. We identified caseinolytic peptidase B protein homolog (CLPB), a mitochondrial chaperonin/disaggregase, as a potential determinant of the MICU1 protein turnover. We confirmed that CLPB lacks proteolytic activity using in vitro protein degradation assays. Next, to identify the CLPB partner protease, we performed a subsequent BIOID2 screen of the CLPB interactome. We identified that in response to hypoxia, the intermembrane space (IMS) localized protease YME1L was necessary for MICU1 protein turnover. Subsequent experiments suggest that CLPB regulated MICU1 protein turnover is a critical molecular event in the onset of cell death in the context of cardiac injury. As knockdown of CLPB is sufficient to decrease infarct size and protect against cardiac ischemia reperfusion injury in mice. In conclusion, we detail a previously unknown protein-quality control system regulating MICU1 and influencing mitochondrial calcium uptake and downstream cellular events.
Abstract 13980: The Association of Education and Household Income With the Lifetime Risk of Incident Atrial Fibrillation: The Framingham Heart Study
Authors: Ataklte Feven , Huang Qiuxi , Kornej Jelena , Mondesir Favel L , Benjamin Emelia J , Trinquart Ludovic
Published: April 2024

Introduction:
Social determinants of health, in particular education and income, influence the incidence, management, and outcomes of cardiovascular diseases including atrial fibrillation (AF). However, data are limited on the effect of socioeconomic status on the lifetime risk of incident AF. We assessed the association of income and education with lifetime risk of AF in the Framingham Heart Study (FHS).

Methods:
We selected 2172 FHS participants (51% women) who were free of AF at the index age of 55 years. We assessed educational attainment (some college or more) at the last exam prior to index age and household income ($40k/50k/55k or more depending on the FHS cohort). We estimated the lifetime risk of AF as the cumulative incidence of AF, accounting for the competing risk of death, at age 95 years. We analyzed strata defined by education and household income separately, and by combining education and household income. We adjusted analyses on sex, height, weight, systolic and diastolic blood pressure, current smoking, use of antihypertensive medication, diabetes, history of myocardial infarction, and history of heart failure.

Results:
Over a mean follow-up of 13 years, 265 participants developed incident AF. The lifetime risk of developing AF was 32.5% (95%CI, 26.5% to 38.5%) and 32.5% (95%CI, 28.7% to 38.3%) among participants with lower and higher education attainment (p=0.98). The lifetime risk of developing AF was 32.1% (95%CI, 26.7% to 37.5%) and 31.8% (95%CI, 26.6% to 36.9%) among participants with lower and higher household income (p=0.79). There was no evidence of an interaction between education and income on lifetime risk of AF (p = 0.84). Results were similar in subgroups of women and men.

Conclusions:
In our community-based sample, there was no evidence of association between education or household income and lifetime risk of AF
Abstract 13994: Single-Dose Intervention With Rapamycin at Reperfusion Preserves Cardiac Function Through Attenuation of Inflammation and Increased Cardiomyocyte Proliferation in Diabetic Rabbit- Role of Hippo Pathway
Authors: Samidurai Arun , Ockaili Ramzi A , Kraskauskas Donatas , Roh Sean , Kukreja Rakesh C , Das Anindita
Published: April 2024

Background:
Rapamycin (RAPA, mTOR inhibitor) given at reperfusion protects diabetic rabbit hearts against ischemia/reperfusion (I/R) injury by reducing infarct size and apoptosis. We hypothesized that RAPA administration may preserve post-ischemic cardiac function through decreased inflammation and increased cardiomyocyte proliferation with regulation of YAP- the effector of Hippo pathway).

Methods and Results:
Diabetes (DM) was induced by administration of alloxan monohydrate (125 mg/kg, i.v.) in New Zealand rabbits (n=12; body weight≈3 kg, 4-month-old). Four weeks after alloxan treatments, conscious diabetic rabbits (maintaining blood glucose>250 mg/dL) were subjected to 45 min of ischemia and 10 days of reperfusion (R) by inflating/deflating previously implanted hydraulic balloon occluder. RAPA (0.25 mg/kg, i.v.) or DMSO (vehicle) was infused 5 min before onset of R. Post-I/R cardiac function in diabetic rabbit, assessed by echocardiography, showed significant improvement of ejection fraction (EF,
Fig. A
). Left ventricular fibrosis (
Fig. B
, evaluated by picrosirius red staining) was attenuated following treatment of RAPA in diabetic rabbits. Immunofluorescence staining revealed the attenuation of post-I/R inflammasome formation with RAPA treatment as shown by reduced ASC aggregation (apoptosis speck-like protein with a caspase recruitment domain) in cardiomyocytes (
Fig. C
). RAPA suppressed the phosphorylation of YAP in cytosol of cardiomyocytes (
Fig. D
). Proliferation markers, Ki-67 positive and phospho-Aurora B Kinase positive cells indicated cardiomyocytes were in G2-M phase in RAPA-treated diabetic rabbits after I/R injury (
Fig. E
).

Conclusion:
RAPA treatment at reperfusion preserves cardiac function and improves cardiomyocyte proliferation with attenuation of inflammation and possibly regulation of Hippo pathway following I/R injury in diabetes.
Abstract 13995: Proarrhythmic Electromechanical Heterogeneities in Patients With
KCNJ2
Mutations
Authors: Deissler Peter M , Stoks Job , van Rees Bianca , Lewetag Raphaela , Koopman Pieter , Gommers Suzanne , Holtackers Robert J , Claes Godelieve R , Cluitmans Matthijs J , Geukens Robert , Heinzel Frank R , Odening Katja E , Volders Paul G , Ter Bekke Rachel
Published: April 2024

Introduction:
Loss-of-function mutations of the
KCNJ2
gene encoding the inward-rectifier potassium channel,
I
K1
, are associated with QT prolongation, prominent U waves, abnormal impulse formation and ventricular tachycardia (VT), besides non-cardiac manifestations. The electromechanical consequences of genetic
I
K1
dysfunction are unknown.

Hypothesis:
We hypothesize that
I
K1
dysfunction leads to increased electrical and mechanical dispersion and electromechanical (EMW) negativity. Dynamic heterogeneity of these functional parameters may conspire to arrhythmia.

Methods:
High-resolution mapping using ECG imaging, speckle-tracking echocardiography and/or tissue-phase mapping CMR were performed in genotyped
KCNJ2
-mutation carriers, besides standard 12-lead and ambulatory recording.

Results:
Five patients (44±13 years; 2 females) were included;
KCNJ2
p.(Val93Ile), p.(Arg218Gln), p.(Thr75Arg), p.(Lys49Arg), p.(Gly144Ala). Three had experienced polymorphic VT/VF. Multifocal ventricular ectopic burden averaged 13%. Mean QTc/QTUc were 446±42/610±78 ms, with U-waves of 149±18 ms and 0.087±0.045 mV. ECG-imaging revealed increased epicardial recovery time gradients (168±58 ms/cm), with LV- and RV-contractile heterogeneities by strain: Delta contraction duration (CD) LV 213±77 ms, standard deviation (SD) 58±14 ms; RV Delta CD 30±22 ms, SD 13±9 ms. Abnormal postsystolic shortenings (Fig.), prolonged isovolumic relaxation times (103±25 ms) and reduced diastolic peak velocities (-7.2±1.7 cm/s) indicated impaired early relaxation. The EMW was -51±35 ms with more pronounced negativity in symptomatic patients (-74 vs. -17 ms).

Conclusions:
Genetic
I
K1
dysfunction underlies nonuniform mechanical heterogeneities in contraction and relaxation, besides repolarization and resting membrane-potential instability. Significant EMW negativity further promotes ventricular ectopy, potentially precipitating VT.