bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 15548: Rare Association of Arrhythmogenic Left Ventricular Cardiomyopathy Phenotype of Titin Mutation of Uncertain Significance
Authors: Abbas Syed Faiz , Babayale Omofolarin , Chand Swati , Rai Devesh , baibhav bipul
Published: June 2023

Case Presentation:
A 67-year-old female presented to the office with exertional dyspnea, atypical chest pain, palpitations, and dizziness. She had a past medical history of hypertension, hyperlipidemia, mitral valve prolapse, and moderate mitral regurgitation. Her EKG identified multiple PVCs requiring the placement of a Holter monitor, a PVC burden of 31,441 beats (15%) was captured with variable morphology. TTE showed mild global hypokinesis of the left ventricle and ejection fraction (EF) of 40%. Coronary arteries were normal on cardiac catheterization. Cardiac magnetic resonance revealed epicardial late gadolinium enhancement suggestive of fatty infiltration of the distal lateral wall of the left ventricle (LV) indicative of Arrhythmogenic left ventricular cardiomyopathy (ALVC). The basal anterolateral wall of the LV appeared thin and dyskinetic, and the right ventricle was normal in size and function. Optimal medical therapy was initiated with metoprolol, sacubitril/valsartan, dapagliflozin, and spironolactone. A dual-chamber ICD was placed for primary prevention. Over time with medical management, her PVC burden reduced, and LVEF improved to 50%. A multigene panel for cardiomyopathies identified a mutation in titin (TTN) gene variant of unknown significance.

Discussion:
Previously thought to affect only the right ventricle, arrhythmogenic cardiomyopathy (ACM) is a rare genetic disease characterized by fibrofatty replacement of the ventricular myocardium. ALVC refers to the predominant LV dominant phenotype of this disease. The most frequent genetic mutations occur in the genes plakophilin (PKP2), desmoplakin (DSP), and desmoglein (DSG2). However, we report a case of ALVC in the setting of titin (TTN) gene variant, which is a gene usually implicated in dilated cardiomyopathy. However, the clinical significance of the TTN gene variant identified in our patient remains unclear as more studies are needed to link it to the phenotypic findings.
Abstract 15563: Analysis of the Ventricular Fibrillation Waveform Can Guide Resuscitation in Cardiac Arrest by Identifying the Precipitating Cause and Estimating the Underlying Hemodynamics
Authors: Prisco Anthony R , Kosmopoulos Marinos , Sebastian Pierre , Gandhi Manan , Benditt David G , Theodorou Evangelos , Yannopoulos Demetris
Published: June 2023

Background:
Patients presenting with out of hospital cardiac arrest (OHCA) and prolonged (>30 min) cardiopulmonary resuscitation (CPR) face nearly 100% mortality. In patients presenting with ventricular fibrillation (VF), coronary ischemia is thought to be the cause in up to 60%. As conventional CPR does not reverse a coronary ischemia, CPR often must be done until a patient can be brought to a cardiac catheterization laboratory (CCL) where the underlying cause (acute ischemia) can be treated. In a porcine model of cardiac arrest, we have previously demonstrated that machine learning (ML) targeting invasive hemodynamic monitoring, could significantly improve CPR quality. To advance the clinical relevance of the machine-controlled CPR methods, we developed ML algorithms that can diagnose coronary ischemia during VF, and infer the underlying hemodynamics while performing CPR.

Methods:
In a porcine model of cardiac arrest, VF was induced via high-grade coronary occlusion (ischemia) or electrical stimulation (dysrhythmia). The animals (n = 72) were left in VF for 3 minutes prior to intervention and the ECG waveform was collected. The VF signal was converted to the frequency domain using a fast-fourier transformation and an ensemble classifier was developed to detect underlying ischemia. CPR was then initiated and the VF waveform was continuously monitored along with the coronary perfusion pressure (CPP). We then developed a 20-layer convolutional neural network (CNN) to non-invasively infer the CPP from a 10-second VF waveform.

Results:
Animal studies were split into training and test sets. When using the developed ML technique to detect ischemia from the VF waveform, evaluation of the test set yielded an area under the curve (AUC) of 0.81 on a ROC. When we used the CNN to infer the underlying hemodynamics, we demonstrated a high correlation between measured and predicted CPP in the test set. The AUC for the ROC when predicting a CPP of >15 mmHg was 0.85.

Conclusion:
Survival for patients with OHCA secondary to coronary ischemia will improve with rapid diagnosis and high quality CPR. Our results demonstrate the proof-of-concept that the VF waveform contains features that can guide resuscitation for cause identification and hemodynamic improvement.
Abstract 15564: Transcriptional Profiling Unveils New Molecular Subgroups of Adaptive and Maladaptive Right Ventricular Remodeling in Pulmonary Hypertension
Authors: Khassafi Fatemeh , Chelladurai Prakash , Nayakanti Sreenath R , Martineau Sandra , Tello Khodr , Sommer Natascha , Omura Junichi , Breuils Bonnet Sandra , Kuenne Carsten , Guenther Stefan , potus francois , Boucherat Olivier , Provencher Steeve , Savai Rajkumar , Seeger Werner , Looso Mario , Bonnet Sebastien , Savai Pullamsetti Soni
Published: June 2023

The right ventricle (RV) function plays a crucial role in the prognosis and functional outcome of PAH (Pulmonary Arterial Hypertension) patients. However, RV remodeling and its underlying mechanisms in PAH, and the molecular phenotype of RV in different disease conditions are poorly understood. Therefore, we designed this study to deeply investigate molecular changes underlying right ventricular remodeling and dysfunction in PAH. To this aim, we generated RNA-seq data from 40 patients' RV tissues, clinically classified in adaptive versus maladaptive RV hypertrophy. Using an unsupervised clustering-based analysis, we identified “early” and “late” subgroups in both diseased RV states, associated with patients’ hemodynamic profiles. We then demonstrated that the compensated RV is characterized by an upregulation of cell cycle-associated genes and mitochondrial respiration, whereas excessive levels of extracellular matrix components were central in the decompensation phase. However, dysregulation of fatty acid β-oxidation characterized the early decompensation phase. Furthermore, a comparative analysis from 30 RV samples of monocrotaline (MCT)-induced rat model largely confirmed the stage-specific molecular phenotypes, along with subgroups identification. Finally, we assessed the circulating levels of several dysregulated proteins in two independent cohorts of PAH patients and introduced a panel of five ECM-related proteins that had a significant alteration in patients with compensated vs. decompensated RV in both cohorts. Among those, NID1, C1QTNF1, and CRTAC1 demonstrated higher importance in predicting the development of maladaptive RV hypertrophy in both cohorts, while the correlation of their expression with cardiac functions confirmed their potential biomarker capacity in the prognosis of PAH-associated RV hypertrophy and failure. In conclusion, this comprehensive transcriptome study revealed new subgroups of human RV hypertrophy beyond the clinical measurements, while combination with proteome analysis proposed a panel of potential PAH biomarkers related to patients' RV function. Furthermore, our comparative analysis of two species supports the relevance of current animal models to explore new targets.
Abstract 15589: Evaluating Methods to Mitigate the Bias for Machine Learning-Based Cardiovascular Risk Model
Authors: Li Fuchen , Zhao Juan , Wu Patrick , Ong Henry H , Wei Wei-qi , Peterson Josh F
Published: June 2023

Introduction:
Cardiovascular disease (CVD) is the leading cause of death in the U.S. and globally. Predictive models are essential for identifying high CVD-risk patients. Machine learning (ML) models have been used to develop predictive models. However, the dataset generalized for training ML models could involve a systematic bias (e.g., sampling bias), which could bias the model. The study investigated the performance of different methods to reduce bias for 10-year CVD prediction models among demographic groups (White and Black, Male and Female).

Methods:
We used a large cohort derived from VUMC de-identified EHR data, including outpatients with follow-up visits between 2007 and 2017. Logistic regression (LR), random forests (RF), and gradient boosting trees (GBT) were trained. Predictors included traditional CVD risk factors, labs, prior diagnosis, and medications. Fairness metrics were equal opportunity difference (EOD) - a difference of true positive rate (0 indicates fairness), and disparate impact (DI) - a ratio of predicted CVD (1 indicates fairness) among groups. Three de-biasing methods were applied, removing protected attributes (i.e., race, gender) from the model, resampling the training set by sample size, and by the proportion of CVD.

Results:
The study included 109, 490 individuals (9,824 CVDs) with mean (SD) age of 47.4 (14.7) years (White 86.3%, Black 13.7%, Male 35.5% and Female 64.5%). Models had a slight bias across race groups but a large EOD and DI across genders (i.e. models has higher prediction accuracy in Male than Female). After debiasing, EOD and DI were significantly improved for genders (Fig. 1). Resampling by size reduced bias while retaining accuracy (e.g. 0.78 AUROC for GBT).

Conclusions:
Among the VUMC cohort, despite the high proportion of women, ML models had a lower prediction accuracy for the women group. Resampling the training set data reduced the bias, but it should be used with caution depending on the magnitude and nature of the bias.
Abstract 15591: Acute Dantrolene Treatment Reverses Arrhythmogenic Substrate and Reduces Triggers Induced by Ryanodine Receptor 2 Hyperactivity in Human Hearts
Authors: George Sharon Ann , Efimov Igor R
Published: June 2023

Introduction:
Ryanodine receptor 2 (RyR2) hyperactivity is commonly observed in structural heart diseases that are a result of ischemia or heart failure. It results in abnormal calcium handling and calcium leak that can trigger arrhythmias. Dantrolene, a RyR inhibitor, is used to prevent calcium leak from RyR1 in skeletal muscles.

Hypothesis:
Suppressing RyR2 hyperactivity with acute dantrolene treatment can reduce arrhythmia burden in human hearts.

Methods:
Human donor hearts that were not used in transplantation were obtained and 1 cm
3
cubes were isolated from the left ventricle. Slices at 400 μm thickness were generated from these cubes, pinned and perfused with Tyrode’s solution in a recording tissue chamber. Pseudo-ECGs were recorded with ECG electrodes and the slices were optically mapped to measure conduction velocity (CV), action potential duration (APD) and calcium transient duration (CaTD). After an initial 30 min equilibration period, baseline optical recordings were obtained. Slices were then treated with 1) Isoproterenol (Iso, 250 nM) to stimulate β-adrenergic receptors, 2) Caffeine (200 μM) for RyR2 receptor activation and 3) Dantrolene (10 μM), sequentially. Dual optical recordings, Vm and Ca, were obtained after each treatment.

Results:
Substrate: Iso reduced APD (425±36 vs 394±43, p=0.03), as expected, and addition of Caffeine restored APD to baseline. More importantly, addition of Dantrolene prolonged APD even further (460±90, p=0.04). CaTD was also similarly reduced by Iso (445±48 vs 387±25, p=0.04) and restored to baseline by Caffeine+Iso. No significant changes in CV were measured under any condition. Trigger: In slices where PVCs were inducible, Caffeine+Iso increased occurrence of PVCs (20 vs 53 PVCs/min) while addition of Dantrolene reduced PVC incidence (18 PVCs/min).

Conclusions:
Dantrolene treatment, acutely reversed proarrhythmogenic substrate and reduced triggers and could therefore be a suitable approach for anti-arrhythmic therapy in patients with structural heart disease. Additionally, human LV slice preparation is useful in antiarrhythmic drug studies.
Abstract 15595: Whole Genome Sequencing to Identify Predictors of IVIG Response in Kawasaki Disease
Authors: Shrestha Sadeep , Wiener Howard , Kajimoto Hidemi , srinivasasainagendra vinodh , Ledee Dolena , Chowdhury Sabrina , Beckley Mikayla , Padilla Luz , Dahdah Nagib , Tiwari Hemant K , Portman Michael A
Published: June 2023

Introduction:
Kawasaki Disease (KD) leads as a cause of acquired cardiovascular disease among children in developed countries. Around~20% of patients are refractory to high-dose intravenous immunoglobulin (IVIG), the standard treatment, and are at high risk of developing coronary artery aneurysms.

Hypothesis:
Whole genome sequencing (WGS) will identify specific predictors of non-response and inform the mechanism of IVIG action.

Methods:
KD patients were diagnosed by the American Heart Association and the American Academy of Pediatrics (AHA/AAP) criteria and treated by AHA guidelines. IVIG refractoriness was defined by persistent or recurrent fever (>38C)>36 hours after completing infusion. We performed a case-control study with WGS on DNA from saliva or blood from 107 responders versus 103 non-responders. After processing informatics using the pipeline of Genome Analysis Toolkit (GATK), additive genetic models were assessed for all common variants using logistic regression. We adjusted for age, gender, and race based on principal components. We also conducted SNP-set (Sequence) Kernel Association Test (SKAT) with common and rare variants in the gene regions with the most statistically significant SNP results.

Results:
Average sequencing depth was 30x and with a total of 34,548,910 variants. While SNPs in genes previously indicated in the IVIG pathway were confirmed, multiple novel SNPs in various gene regions were also statistically significant (often p< 10-6; Figure-Manhattan plot). SKAT analysis suggested joint effects of multiple SNPs in individual gene regions.

Conclusions:
We confirmed SNPs in genes from previous reports and identified multiple novel ones, indicating plausible previous unsuspected IVIG mechanisms pathways. Potentially, functional disruption of these genes could lead to non-response. Further, a panel of these SNPs can be a prognostic tool for identifying at-risk KD patients that require therapy intensification.
Abstract 15606: Diabetes is Associated With Increased Risk of Major Adverse Cardiovascular Events in Patients Covid-19: A Retrospective U.S. Multicenter Cohort Study
Authors: Khairani Candrika D , Bejjani Antoine , Carroll Brett , Welker James , Bonaca Marc P , Hsia Judith A , Goldhaber Samuel Z , Piazza Gregory
Published: June 2023

Introduction:
Diabetes mellitus (DM) increases the risk of adverse outcomes in patients with COVID-19. Whether this is driven by a higher rate of thrombotic complications or cardiovascular events in patients with COVID-19 has rarely been explored.

Methods:
We analyzed a retrospective cohort of 6920 consecutive patients ≥ 18 years old with confirmed SARS-COV-2 polymerase chain reaction testing from March 2020 to April 2020 using a US multicenter registry. Main outcomes of interest were 30-day of adjudicated major adverse cardiovascular events (MACE), major arterial and venous thromboembolic (VTE) events, and symptomatic VTE. MACE included VTE, catheter related thrombosis, myocardial infarction, stroke, major adverse limb events, heart failure hospitalization, atrial fibrillation (AF), and myocarditis.

Results:
Of 1252 patients with DM, 49.4% were women, 50.9% were non-white, and 26.2% were Latinx. Mean BMI of patients with and without DM was similar (34.2 vs 33.4 kg/m2,
p
=0.91). Compared with patients without DM, those with DM were older (50.3±15.4 years. vs 39.6±19.7,
p
<0.001), had higher rates of hypertension, AF, hospitalization (76.4% vs 23.1%, 5.0% vs 1.0% and 60.8% vs 28.4%,
p
<0.001, respectively). Thirty days after COVID diagnosis, patients with DM had a higher rate of MACE (12.7% vs 3.9%,
p
<0.001), major arterial or venous thromboembolism (8.5% vs 3.1%,
p
<0.001), symptomatic VTE (6.5% vs 4.7%,
p
<0.001
),
and death (11.9% vs 4.7%,
p
<0.001) compared with patients without DM (Panel A). After adjusting for age, gender, hypertension, COVID-19 admission, peripheral artery disease, and coronary artery disease, patients with DM had increased risk of MACE (aOR 1.39 95% CI 1.09-1.78), but not of major adverse arterial or VTE events (aOR 1.24 95% CI 0.93-1.65), symptomatic VTE (aOR 1.34 95% CI 0.98-1.86), or death (aOR 1.13 95% CI 0.87-1.47) (Panel B).

Conclusions:
In patients with COVID-19, DM is independently associated with increased risk of MACE.
Abstract 15612: Association Between ECG-Derived Age With Coronary Artery Calcium
Authors: Sheffeh Mohammad Ali , Medina-Inojosa Jose R , Medina-Inojosa Betsy , Attia Zachi , Bianchettin Rosana , Baez Suarez Abraham , Lerman Amir , Friedman Paul , Lopez-Jimenez Francisco
Published: June 2023

Introduction:
We have previously shown that ECG-derived age (ECG-Age) predicts all-cause and cardiovascular (CV) mortality, reflecting physiologic age. We hypothesized that ECG-Age minus chronological age (Age-Gap) would be associated with coronary artery calcium (CAC) assessed by computer tomography.

Methods:
We developed a neural network model to predict ECG-Age using 12 lead ECGs from 399,750 training, 99,977 validation and 275,056 testing patients. We then applied the algorithm to 41,202 consecutive patients that from 1997-2020 underwent clinically indicated CAC and ECG within 1 year. Major modifiable CV risk factors were collected as part of preventive cardiology or general medical evaluations. Exclusion criteria were statin therapy, pacemakers, or history of coronary artery disease.

Results:
We included 41,202 subjects (68.5% males, 83.6% Caucasian), mean chronological age was 55.2±9.1 yrs and the ECG-Age was 56.01±9.3 yrs. The mean Age-Gap was -0.78±7 yrs, R
2
=0.78, p<0.0001. Mean CAC score was 140.2±532.3, and 21,483 (52%) had CAC >0. After adjustment for age and sex, those older by ECG (defined as having a positive Age-Gap) were more likely to have CAC>0 (OR 1.35, 95% CI 1.34-2.37 for those with >1 but <2 SD of a positive Age-Gap; and OR 1.80, 95% CI 1.34-2.37 for those with ≥2 SD of a positive Age-Gap), while those younger by ECG were less likely to have any CAC (OR 0.70, 95% CI 0.57-0.87 for those with >1 but <2 SD of a negative Age-Gap; and OR 0.75, 95% CI 0.67-0.84 for those with ≥2 SD of a negative Age-Gap), respectively. This association remained significant after multivariate adjustment,
Fig. A
and increased with CAC burden,
Fig. B
, all
P
for trend <0.01.

Conclusions:
The difference between physiologic AI-ECG age and chronologic age, something likely representing rate of biological aging, is associated with presence of CAC, further supporting the hypothesis that AI-ECG age can identify people more likely to have subclinical coronary atherosclerosis.
Abstract 15619: Smoking Towards Prinzmetal
Authors: Stewart Jonathan , Kapoor Kunal , AHMED SHAFEEQ , Kaszala Karoly
Published: June 2023

Background:
Vasospastic (Prinzmetal) angina is a result of coronary vasospasm leading to myocardial ischemia. It is defined by nitrate responsive angina, transient ischemic ECG changes, and coronary vasospasm. In this report, we highlight coronary angiographic findings of Prinzmetal angina and underscore tobacco use as a known risk factor.

Case Presentation:
A 62-year-old male with hypertension and tobacco use presented with acute substernal chest pain. Laboratory testing revealed elevated troponin to 17.4 mg/mL and ECG with new T-wave inversions in the lateral leads. Coronary angiogram revealed non-obstructive coronary artery disease (CAD) (Figure 1). He was discharged on medical therapy and instructed to stop smoking. Four days later, he returned with one day of chest pain that improved with sublingual nitroglycerin. Repeat troponin was elevated to 46.9 ng/mL and ECG revealed ST depressions in V2-V6. Repeat coronary angiogram revealed 99% narrowing in the proximal left circumflex (LCx) (Figure 2). Intra-arterial nitroglycerin administration led to resolution of the LCx narrowing (Figure 3).

Conclusion:
Prinzmetal angina can be precipitated by tobacco use. Clinicians ought to maintain a high degree of suspicion for Prinzmetal angina as an etiology of cardiac ischemia in patients who have non-obstructive CAD and concomitant tobacco use.
Abstract 15623: Arrhythmia Burden and Associated Outcomes Among Patients With Myelodysplastic Syndromes
Authors: Oyenubi Olamide , Momoh Omolegho , Hirst Priscila , Benjamin Patrick , Pomerantz Daniel , Chan Marvyn Allen G , Jesmajian Stephen
Published: June 2023

Background:
Arrhythmias are an increasingly recognized comorbid condition among patients with cancers. However, there is little research on the relationship between conduction abnormalities and in-hospital outcomes in patients with myelodysplastic syndrome (MDS). This analysis explores the burden of cardiac arrhythmias and associated outcomes in hospitalized MDS patients.

Methods:
Nationwide Inpatient Sample from 2017 to 2019 was used. MDS-associated hospitalizations with concurrent arrhythmia were identified using appropriate ICD-10 CM codes and compared to MDS-associated hospitalizations without arrhythmia. Primary outcome was all-cause in-hospital mortality. Secondary outcomes were in-hospital length of stay and total costs.

Results:
About 21% (n=4065) of MDS patients were diagnosed with an arrhythmia. Atrial tachycardias were most common (87%). Frequency of bradyarrhythmias, ventricular tachycardias, and unspecified arrhythmias were 10.7%, 10.4%, and 0.8%, respectively. The MDS-arrhythmia cohort were significantly older (78 vs 71 years), had higher number of comorbidities (>3 Charlson Comorbidity Index score: 45.5% vs 30%), and were more likely men (57.8% vs 52.7%) (P < 0.001). The MDS-arrhythmia cohort demonstrated higher all-cause mortality (10.6% vs. 5%) and had increased odds of in-hospital death after adjusting for sociodemographic and hospital level factors (AOR 2.2, 95% CI 1.59-2.91) (P < .001). Hospital length of stay (8.5 vs. 8.0 days) and hospital charges ($104267 vs. $105654) were similar across both groups.

Conclusions:
Concurrent arrhythmias were associated with worse survival outcomes for patients with MDS. Understanding the mortality associated with arrhythmias in MDS patients may have clinical implications when planning treatment options in which cardiotoxicity is an adverse event. Awareness of the frequency and risk factors for arrhythmias in MDS patients may encourage the early introduction of cardiac monitoring for arrhythmias in hospitalized patients with MDS.
Abstract 15624: The Impact of One versus Three Readings on Pediatric Hypertension Diagnosis is Mediated via Diastolic Blood Pressure
Authors: Riar Sandeep , Lee Brian
Published: June 2023

Introduction:
Blood pressure (BP) is affected by many factors. In pre-teen children, the hypertension (HTN) threshold is about 4 mmHg higher for systolic and about 3 mmHg for diastolic BP. Single BP reading is the norm in real life clinical practice even as HTN guidelines and research use multiple BP readings. There is limited data on the within-visit BP variability in children. The National Health and Nutrition Examination Survey (NHANES) is a population-based survey and 3 BP readings are obtained using a standardized protocol. We aimed to study the difference between single versus 3 BP readings using NHANES data.

Methods:
In the 2017-2018 NHANES, participants aged 8 years and older underwent BP measurement using 2 protocols. The auscultation protocol (AP) was administered by a physician using a mercury sphygmomanometer. The oscillometric protocol (OP) was administered by a health technician using an Omron HEM-907 XL device. We included participants 8 to 17 years old with 3 AP and 3 OP BP readings for comparison and excluded those with DBP of zero.

Results:
There were 1126 subjects who met inclusion criteria. The proportion of SBP readings with a difference of at least 5 mmHg between the initial and subsequent 2 BP readings was greater with OP but greater with AP for DBP (Table 2). Similar trend was noted with comparison of initial and mean of all 3 BP readings. Coefficient of variation was higher for DBP than SBP. The proportion of patients with hypertension range BP was significantly higher for DBP than for SBP (table 3).

Conclusions:
Diastolic BP shows more variability with multiple measurements. Hypertension range BP was noted more often with the initial DBP measurement than with 3 BP readings.
Abstract 15637: Detection and Characterization of Fibrin/Amyloid Microclots in Patients With Post-Acute Sequelae of Covid-19
Authors: Walker Melanie , Federico Emma M , Kell Douglas B , Dupont Christopher , Proal Amy , Pretorius Etheresia
Published: June 2023

LongCovid or Post-Acute Sequelae of COVID-19 (PASC) is a diagnosis given to patients who experience a wide range of debilitating chronic symptoms after infection with SARS-CoV-2. The majority of individuals are PCR negative, indicating microbiological recovery. There are currently few LongCovid/PASC blood-based biomarkers. We used fluorescence microcopy to identify unique fibrin/amyloid micro-thrombosis and hyperactivated platelets in individuals with PASC. These fibrin/amyloid microclots may impede blood flow to tissue.

Methods:
Whole blood was collected in citrate tubes from 30 matched healthy subjects and 30 PASC subjects. Platelet poor plasma (PPP) was prepared by centrifugation and stored at -80 °C. PPP was then exposed to thioflavin T (ThT), a fluorescence marker known to bind to and open hydrophobic areas on damaged amyloidogenic protein. Samples were viewed with fluorescence microscopy using a 63x/1.4 Oil DIC M27 objective (excitation wavelength 450nm-488nm, emission 499nm- 529nm). After a double-trypsin PPP digestion method, proteomic analysis of the PPP samples was performed.

Results:
Significant microclot load was observed in the PPP of participants with PASC compared to healthy participants (Fig. 1). Proteomic analysis revealed the presence of inflammatory molecules within digested microclots.

Conclusion:
Preliminary results suggest that the presence of microclots in PPP may be used as a diagnostic biomarker for the PASC. Characterization of inflammatory molecules and antibodies trapped within microclots might provide insight into the pathogenesis of PASC and serve as a basis for novel treatment strategies or preventative medicine.

Figure:

Representative specimens
A)
Microclots in healthy plasma.
B)
Microclots in PASC plasma.
Abstract 15638: Proinflammatory and Proangiogenic State Promotes Malignant Melanoma Progression in Mouse Model of HFpEF
Authors: Lang Liwei , Buncha Vadym , Bagi Zsolt A
Published: June 2023

Epidemiological studies have shown that the incidence of various cancers, such as malignant melanoma is higher in patients with heart failure (both HFrEF and HFpEF) than in age-matched population, but the underlying mechanisms remain unknown. We hypothesized that in HFpEF a chronic systemic inflammation promotes malignant melanoma progression. To test this hypothesis orthotopic melanoma xenograft model was employed in a mouse model of HFpEF. Mice with uninephrectomy, aldosterone infusion (UNX-Aldo) with osmotic minipump (Alzet, 0.30 μg/h), and high salt ingestion (1% in drinking water) develop left ventricle diastolic dysfunction as indicated by a significantly (p<0.05) reduced E/A ratio (E=early, A=late mitral inflow peak velocities), increased E/e’ ratio, isovolumic relaxation time and E wave deceleration time, with no change in the ejection fraction. Mouse melanoma B16F10 cells labelled with firefly luciferase was injected in the mouse ear of UNX-Aldo and control mice. Using in vivo bioluminescence imaging we found a significantly augmented tumor growths in the UNX-Aldo mice. UNX-Aldo mice display a robust increase in several serum inflammatory mediators, cytokines and chemokines, such as IL-1, IL-6, TNF, IFN-γ, MCP-1, CD14, CCL12, CXCL13/16, as well as decreases in anti-inflammatory cytokines, such as IL-10, as measured in a Proteome Profiler cytokine array. In addition, UNX-Aldo mice had increased level of multiple angiogenic growth factors, such as IGFBP-1 and GM-CSF. Flow cytometry analysis also revealed and elevated number of tumor-associated, CD11b+F480-Ly6G+CXCL1+ neutrophils in the grafted tumors in UNX-Aldo mice. Collectively, our results indicate that pro-inflammatory and proangiogenic state in experimental HFpEF exacerbates melanoma tumor growth.
Abstract 15640: Histomic-Based Clot Structure Quantification for Prediction of Ischemic Stroke Etiology
Authors: Patel Tatsat Rajendra , Santo Briana , Jenkins TaJania , Waqas Muhammad , Monteiro Andre , Baig Ammad , Levy Elad , Siddiqui Adnan H , Kolega John , Tomaszewski John , Tutino Vincent M
Published: June 2023

Introduction:
Determining stroke etiology is paramount to clinical management and prevention of recurrent strokes. Although stroke patients undergo extensive post-treatment work-ups, 30-40% of cases remain cryptogenic.

Hypothesis:
Engineered histomic features from digital pathology images of stroke blood clots collected during mechanical thrombectomy (MT) can be used to delineate stroke etiology.

Methods:
For clots retrieved from patients undergoing MT, etiology was determined by the trial of Trial of Org 10172 in Acute Stroke Treatment (TOAST) score. After sectioning and H&E staining, clot components (red blood cells-RBCs, fibrin-platelet regions-FP, and white blood cells-WBCs) were segmented from whole slide images. Histomic features were engineered to capture the structural distribution of RBC/FP regions throughout the clot. To measure clot WBC diversity, WBC instances were clustered into WBC “classes” based on texture, and summarized as a class frequency distribution (CFD). The three most significant RBC/FP and WBC features between large artery atherosclerosis (LAA) and cardioembolic (CE) cases were used to train a complement Naïve Bayes (CNB) model, which was then implemented to predict the etiology of cryptogenic cases.

Results:
In our data (n=53), 31 clots were CE, 8 were LAA, 4 were from strokes of other determined etiology, and 10 were cryptogenic. 17 significant RBC/FP features and 3 significant WBC CFDs were different between CE and LAA. The trained CNB model accurately classified CE vs. LAA with a validation AUC of 0.87±0.03, exhibiting superior performance to a model trained using common clot percent cellular composition metrics (AUC=0.69±0.16). Furthermore, we showed the potential to classify cryptogenic cases as CE or LAA.

Conclusions:
This first-of-its-kind, biologically-informed clot histomic pipeline captured significant information that may augment clinical and laboratory features used in stroke etiology classification.
Abstract 15650: Relationship Between Lipoprotein (a) and Aortic Vulnerable Plaques Detected by Non-Obstructive General Angioscopy
Authors: Kojima Keisuke , Koyama Yutaka , Ebuchi Yasunari , Murata Nobuhiro , Okumura Yasuo
Published: June 2023

Background:
Although atherosclerotic disease including myocardial infarction had decreased with lipid-lowering therapy for LDL cholesterol, atherosclerotic risk factors as residual risks without low-density lipoprotein are pointed out. Especially, lipoprotein (a) had been reported as one of the cardiovascular risks. Non-obstructive general angioscopy (NOGA) can meticulously visualize directly aortic atherosclerosis. NOGA-derived aortic vulnerable plaques had been reported to be related to future cardiovascular events. However, the relationships between serum lipoprotein (a) value and NOGA-derived aortic plaques had not been fully investigated yet.

Methods and Results:
We investigated consecutive 165 cases with coronary artery disease evaluated for the aorta by NOGA. Atherosclerotic lesions of the aorta were screened using NOGA immediately after coronary arteriography. NOGA examination evaluated the presence of aortic ruptured plaques which were "puff-chandelier rupture" appearance as previously reported. The mean age was 68 years and the median lipoprotein (a) value was 16 [9-27]. The median number of plaque ruptures was 1 [0-3], and 60% of cases had at least one plaque rupture. In a logistic regression analysis for the presence of aortic plaque rupture, the serum lipoprotein (a) value was associated with NOGA-derived aortic plaque rupture (odds ratio, 1.01 [1.0-1.03], p < 0.05). The study patients were divided into three groups according to the tertile of serum lipoprotein (a) value [1st tertile: 0-11 mg/dl, 2nd tertile: 12-24 mg/dl, 3rd tertile 25 mg/dl <], the first tertile had the lowest prevalence of plaque rupture (the presence of plaque rupture: first tertile 50%, second tertile 71%, third tertile 72%, p = 0.03).

Conclusion:
Serum lipoprotein (a) value was related to the presence of the aortic plaque rupture. Further studies are needed to elucidate the effect of the low lipoprotein (a) on the prevention of aortic vulnerable plaques.
Abstract 15665: Pod-Based Electronic Cigarette Use Alters Measures of Heart Rate Variability
Authors: Akubo Chelsea , Majid Sana A , Weisbrod Robert M , Srivastava Sanjay , Fetterman Jessica L , Conklin Daniel J , Robertson Rose M , Bhatnagar Aruni , Keith Rachel J , Hamburg Naomi M
Published: June 2023

Background:
Previous studies demonstrate changes in autonomic function with combustible and earlier generation electronic cigarette (ecig) use. We sought to explore the effects of nicotine salt containing pod-based ecigs on autonomic regulation in young adult regular users by analyzing indices of heart rate variability (HRV).

Methods:
We enrolled healthy adults (18-45 yo) who were self-reported tobacco nonusers, pod-based ecig users, or combustible cigarette users. Participants were asked to refrain from tobacco product use at least 6 h before the study visit. Indices of HRV: standard deviation of the NN intervals (SDNN) and the root mean square differences of successive NN intervals (RMSSD, measure of parasympathetic function) were measured by Sphygmacor before and 10 minutes after structured use of participants’ own product. Measurements of urinary levels of cotinine, a nicotine metabolite, and 3HPMA, an acrolein metabolite, were made 1 h after product use.

Results:
In 133 subjects (age 26±5, 49% women), baseline HRV measures were comparable among tobacco non-users (N=39), pod-based ecig users (N=64), and combustible cigarette users (N=30). Analyses adjusted for age and sex demonstrated that acute pod-based ecig use reduced SDNN compared with non-use (-5.9±2.6ms vs 6.5±3.2ms, P=0.004) and similar to the effect of combustible cigarette use (-10.2±3.8ms, P=0.37). Moreover, acute pod-based ecig use reduced RMSSD compared with non-use (-5.6±3.3ms vs 5.4±4.1ms, P=0.04) and similar to the effect of combustible cigarette use (-10.9±4.9ms, P=0.38). Urinary cotinine, reflective of nicotine exposure, was associated with decreases in SDNN and RMSSD (r=-0.33, P=0.001; r=-0.29,P=0.003, respectively) whereas 3HPMA associated with SDNN and showed a trend toward association with RMSSD (r=-0.27, P=0.006; r=-0.18, P=0.06, respectively).

Conclusion:
Our data demonstrate an association between acute use of pod-based ecigs and altered cardiac autonomic function in association with the level of nicotine and acrolein exposure.
Abstract 15670: Clinical Relevance of a Polygenic Susceptibility to Dilated Cardiomyopathy
Authors: Gaziano Liam , Biddinger Kiran , Jurgens Sean J , Choi Seung H , Lubitz Steven A , Ellinor Patrick T , Aragam Krishna
Published: June 2023

Introduction:
Both rare and common genetic variants have been associated with dilated cardiomyopathy (DCM), but their contributions to DCM risk in the context of clinical factors remains unexplored.

Methods:
In the UK Biobank, we identified carriers of rare, monogenic variants of relevance to DCM (ClinGenLOF), and also computed a genome-wide, common-variant (polygenic) score (GPS) based on imaging-derived measures of left ventricular structure and function. We evaluated the contributions of ClinGenLOF status, the GPS, and clinical factors to incident DCM through measures of relative risk, phenotypic variance explained (i.e. population attributable fraction, PAF), and discrimination.

Results:
In 160,485 UK Biobank participants, mean age was 56.5 (SD 8.1), 89,888 (56%) were female, and 226 developed DCM during a median of 10.9 years of follow-up. ClinGenLOF carriers had the highest hazards of disease (HR=14.5, 95%CI: 9.43 to 22.11), followed by atrial fibrillation (HR=3.25, 95%CI:1.94 to 5.48), and chronic kidney disease (2.56 95%CI:0.81 to 8.12). In contrast, hypertension accounted for the greatest proportion of DCM risk in the population (PAF=23.2%) followed by having a high (>80th percentile) polygenic score (PAF= 17.9%). On top of a reference model, improvements in discrimination were individually greatest with addition of ClinGenLOF status (delta C-index = 0.049) or the GPS (delta C-index = 0.031), comparable to the addition of all clinical factors combined (delta C-index = 0.032;
Figure
). When added sequentially to a model inclusive of clinical factors, ClinGenLOF status (delta C-index = 0.046) and GPS (additional delta C-index = 0.021) further improved discrimination.

Conclusions:
Rare, monogenic variants, a polygenic score, and clinical factors all contribute substantially to risk of DCM. Considering cumulative genetic (monogenic and polygenic) risk on top of clinical factors improves the prediction of incident DCM in the general population.
Abstract 15681: Impact of Dietary Sodium Restriction on Heart Failure Outcomes: A Systematic Review and Meta-Analysis
Authors: Siddiqi Tariq J , Usman Muhammad Shariq S , Siddiqi Ahmed K , Rashid Ahmed Mustafa , Kamimura Daisuke , Shafi Tariq , Testani Jeffrey M , Pandey Ambarish , Mentz Robert J , Butler Javed , Hall Michael E
Published: June 2023

Introduction:
Although heart failure (HF) guidelines emphasized dietary sodium restriction, the recommendation was based on limited evidence. We analyzed the impact of dietary sodium restriction on HF outcomes and quality of life (QoL) by systematically reviewing the available literature to-date.

Methods:
MEDLINE and SCOPUS were queried from inception till April 2022 for randomized controlled trials (RCTs) and observational studies with sodium restriction (≤1500-3000mg) as an intervention/comparator and assessing its impact (or association) on HF outcomes. Data about HF-related hospitalizations, all-cause mortality and QoL (via the Kansas City Cardiomyopathy Questionnaire) was extracted, pooled and analyzed. Forest plots were created based on random effects model.

Results:
Twelve studies (n= 4637 patients) were included in our analysis with a median follow-up time of 6 months. The pooled analysis demonstrated no difference in HF hospitalizations between the sodium-restricted and unrestricted groups (OR = 1.30 [0.81-2.10] P<0.28) (Figure 1a). However, a significantly higher risk of all-cause mortality was observed associated with sodium-restriction (OR = 1.68, 95% CI: 1.26-2.24, P< 0.0004) (Figure 1b). Dietary sodium restriction was not associated with QoL (mean difference = 0.14, 95% CI: -0.07-0.35, P< 0.18). (Figure 1c).

Conclusions:
Our observations suggest that sodium restriction in patients with HF may not improve QoL or reduce hospitalizations, but is associated with increased risk of mortality.
Abstract 15698: Logistic and Machine Learning Approaches to Identify Predictors of Venous Thromboembolism in Covid-19 Patients
Authors: Sacioto Manuela F , Silveira Warley C , Rezende Suely , Paiva Bruno B , Pires Magda C , Valiense Cláudio , Gonçalves Marcos A , Pereira Polianna D , Marcolino Milena
Published: June 2023

Introduction:
Venous thromboembolism (VTE) has a significantly higher incidence in COVID-19 patients when compared to other acute viral infections. The evidence on the risk factors of VTE in COVID-19 inhospital patients is still inconsistent. The information is of utmost importance, as a path to promote prevention, early diagnosis and treatment.

Hypothesis:
VTE predictors may be identified through logistic regression (LR) and machine learning (ML) approaches.

Methods:
This multicenter cohort study included consecutive COVID-19 adult patients from 16 hospitals, admitted between March and September, 2020. Deep venous thrombosis and pulmonary embolism were confirmed by objective imaging. LR analysis, tree-based boosting and bagging were used to investigate the association of variables upon hospital presentation with VTE.

Results:
Among 4,120 patients (median age 61 [interquartile range 48-72] years-old, 55.5% men, 39.3% admitted to intensive care unit), VTE was confirmed in 6.7%. In multivariate LR analysis, obesity (OR 1.50, 95%CI 1.11-2.02); being an ex-smoker (OR 1.44, 95%CI 1.03-2.01); surgery ≤ 90 days (OR 2.20, 95%CI 1.14-4.23); axillary temperature (OR 1.41, 95%CI 1.22-1.63); D-dimer ≥ 4 times above the upper limit of reference value (OR 2.16, 95%CI 1.26-3.67), lactate (OR 1.10, 95%CI 1.02-1.19), C-reactive protein levels (CRP, OR 1.09, 95% CI 1.01-1.18); and neutrophil count (OR 1.04, 95%CI 1.005-1.075) were independent predictors of VTE. Temperature at hospital presentation, SF ratio, neutrophil count, D-dimer, CRP and lactate levels were also identified as predictors by ML methods.

Conclusions:
By using ML and LR analysis, we showed that D-dimer, axillary temperature, neutrophil count, CPR and lactate levels are risk factors for VTE in COVID-19 patients. ML approaches were able to identify additional predictors. We suggest that patients presenting those risk factors at hospital admission should be more closely monitored for VTE development.
Abstract 157: Diagnostic Test Accuracy Of The ST-segment Elevation Myocardial Infarction Equivalents In Electrocardiogram After Return Of Spontaneous Circulation Among Out-of-hospital Cardiac Arrest Patients Without ST-segment Elevation
Authors: Yoshimura Satoshi , Kiguchi Takeyuki , Irisawa Taro , Park Changhwi , Yamada Tomoki , Nishimura Tetsuro , SOGABE TAKU , Onoe Atsunori , Yusuke Ito , Morooka Takaya , Kitamura Tetsuhisa , Iwami Taku ,   CRITICAL study group
Published: June 2023

Background:
Out-of-hospital cardiac arrest (OHCA) patients with acute coronary syndrome (ACS) needs emergent coronary angiography and subsequent percutaneous coronary intervention to improve their outcomes. ‘STEMI equivalents’ in electrocardiogram (ECG) are known to help the diagnosis of ACS. However, these findings have not been sufficiently evaluated among OHCA patients. This study aimed to evaluate the diagnostic test accuracy (DTA) of ‘STEMI equivalents’ to identify ACS among OHCA patients without ST-segment elevation.

Methods/Results:
Nine emergency medical departments among the Comprehensive Registry of In-Hospital Intensive Care for OHCA Survival (CRITICAL) study in Osaka, Japan collected the patients' first 12 leads ECGs after return of spontaneous circulation (ROSC) from 2012 to 2017. Patients with non-traumatic OHCA aged >=18 years old with ventricular fibrillation / pulseless ventricular tachycardia as first documented rhythm or rhythm at hospital arrival were included. Of them, patients without ST-segment elevation nor complete left bundle branch block were extracted. The DTAs; sensitivity, specificity, positive likelihood ratio (LR+), and negative and likelihood ratio (LR-) of STEMI equivalents (i.e., Isolated T-wave inversion, Wellens signs) for the diagnosis of the ACS were evaluated. ACS was diagnosed by the physicians in each hospital based on the coronary angiography.

Results:
A total of 143 cases were included in the analysis and 79 patients were diagnosed as ACS. Isolated T-wave inversion was found in 7 (3.2%) patients in the ACS group and 3 (8.8%) in the non-ACS group. The Wellens signs was present in 5 (6.3%) and 5 (7.8%) patients, respectively. The isolated T-wave inversion and the Wellens signs had high specificity with 0.95 (95% CI: 0.87-0.99) and 0.92 (95% CI: 0.82-0.97), whereas these findings had low LR+ with wide range of 95% CI with 1.89 (95% CI: 0.51-7.02), and 0.81 (95% CI: 0.25-2.68), respectively.

Conclusion:
In this study, the DTA of STEMI equivalents of single 12 leads ECG alone were not sufficient for the diagnosis of ACS after ROSC among OHCA patients without ST-segment elevation. Further investigation of the DTA evaluation considering the measurement timing and the change of the ECG is needed.
Abstract 15700: ALK1-Mediated Smad1 Activation in a Myofibroblast Subset Protects the Infarcted Heart From Adverse Remodeling and Excessive Fibrosis
Authors: Hanna Anis , Frangogiannis Nikolaos
Published: June 2023

Cardiac fibroblasts acquire inflammatory, proangiogenic, or matrix-synthetic phenotypes following MI and play a pivotal role in repair and remodeling of the infarcted heart. Members of the Transforming Growth Factor (TGF)β superfamily (including TGFβs and BMPs) are activated following MI and regulate fibroblast phenotype and cardiac fibrosis. Canonical TGFβ signaling is mediated through the receptor-activated Smads: TGF-βs activate Smad2/3, whereas BMPs predominantly stimulate Smad1/5 cascade. Smad3 signaling plays an important role in activation of infarct myofibroblasts; however, the role of the Smad1 pathway remains unknown. We hypothesized that fibroblast-specific actions of Smad1 regulate repair and remodeling in the infarcted myocardium. In a mouse model of non-reperfused infarction, Smad1 was activated in a subset of cardiac myofibroblasts not only by BMPs, but also by all three TGF-β isoforms. TGF-β activation of Smad1 was dependent on both ALK1 and ALK5 signaling. Analysis of single cell RNA-seq data suggested that ALK1 is a marker of a myofibroblast subset exhibiting anti-fibrotic properties. In order to examine the role of fibroblast Smad1 in vivo, we generated mice with myofibroblast-specific Smad1 loss (MFS1KO). Echocardiography showed that MFS1KO mice have accentuated systolic dysfunction and LV dilation 7-28 days after MI
(p<0.01, N=13-49)
. Worse adverse remodeling in infarcted MFS1KO hearts was associated with scar expansion, higher myofibroblast density and accentuated fibrosis. Smad1 knockdown in cardiac fibroblasts increased mRNA levels of structural and matricellular genes while reducing matrix metalloproteinase synthesis. RNA-seq showed that Smad1 loss activates pathways involved in matrix regulation and collagen biosynthesis, and suggested that Smad1 may exert anti-fibrotic actions through inhibition of TGF-β/Smad3 axis, p53, and IL4/STAT6 pro-fibrotic cascades. In conclusion, Smad1 activation in a subset of anti-fibrotic infarct myofibroblasts restrains cardiac fibrosis and protects from adverse remodeling by inhibiting key pro-fibrotic pathways. These findings suggest that Smad1 activation in fibroblasts may be a promising strategy to restrain cardiac fibrosis in infarcted and failing hearts.