bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 12117: Machine Learning to Probe Variability in Patient Outcomes After Atrial Fibrillation Ablation - The Stanford AF Registry (start)
Authors: Deb Brototo , bhatia neal , Rogers Albert J , Baykaner Tina , Chang Hui Ju , Clopton Paul L , Ganesan Prasanth , Feng Ruibin , Ruiperez-Campillo Samuel , Turakhia Mintu , Perino Alexander C , Perez Marco V , Zei Paul , Badhwar Nitish , Badhwar Nitish , Brodt Chad , Narayan Sanjiv M , Wang Paul J , Viswanathan Mohan N
Published: June 2023

Introduction:
A major challenge in improving atrial fibrillation (AF) ablation is the variability in outcome between patients, which is not captured by traditional biostatistics.

Hypothesis:
We hypothesized that machine learning (ML) can be used to probe phenotypes of variable response to AF ablation.

Methods:
We studied 632 patients with drug-refractory AF, enrolled prospectively for a uniform strategy of PVI plus map-guided AF ablation at Stanford Health. We applied unsupervised ML to 64 variables to identify features associated with freedom from AF or atrial tachycardia (AT) at 3 years.

Results:
Patients (N=632) were 65±10 years, 28.2% female, BMI 30.2±6 kg/m2, 59.7% with non-paroxysmal AF, and 70.0% at de novo ablation. At 1-year, freedom from AF and AF/AT were 77.5% (95% CI interval: 74.2%, 80.9%) and 70.1% at 1 year (66.5%, 73.8%). At 3 years, they were 55.5% (51.2%, 60.1%) and 48.6% (44.3%-53.3%) respectively, regardless of antiarrhythmic drugs (P=0.23). Unsupervised ML revealed 3 phenotypic clusters that crossed conventional AF labels (Fig1). An
Early AF
cluster had best outcomes (1Y/3Y: 79.6 /53.5%); a
Non-remodeled
AF cluster (69.8/52.0%) had most comorbidities, a substantial number of non-paroxysmal AF patients, yet better outcomes than a cluster characterized by atrial or ventricular
Remodeling
(66.4/42.3%) (p=0.028) (Table 1).

Conclusions:
In a large prospective AF registry, ML revealed clusters for outcomes, spanning conventional clinical labels and highlighting that patients with comorbidities may have good outcomes if they lack structural remodeling, and that electrical and structural remodeling may follow independent courses between patients.
Abstract 12121: Integrating Ketone Bodies in Multi-Marker Risk Prediction of Incident Heart Failure in the Multi-Ethnic Study of Atherosclerosis (MESA)
Authors: Chevli Parag A , Selvaraj Senthil , Hammoud Aziz , Connelly Margery A , Defilippi Christopher , Ac Lima Joao A , Khan Sadiya S , Herrington David M , Shapiro Michael D , Vaduganathan Muthiah
Published: June 2023

Introduction:
The Universal Definition of Heart Failure (HF) has incorporated N-terminal proB-type natriuretic peptide (NT-proBNP) and high-sensitivity troponin (hs-cTnT) as markers to identify “stage B” HF (asymptomatic left ventricular dysfunction). Plasma ketone bodies (KB) have demonstrated an association with disease severity in HF patients. A multi-biomarker risk score may improve risk stratification of incident HF in the community.

Methods:
Participants free of CVD from the Multiethnic Study of Atherosclerosis (MESA) at the baseline visit were included. A multi-biomarker score was developed incorporating NT-proBNP ≥ 125 pg/mL, hs-cTnT ≥ 14 ng/L, and total KB ≥ 75
th
percentile (316 μmol/L), with 1 point allocated for each abnormal marker. A multivariable Cox model was used to assess the association between multi-biomarker risk score categories and the risk of incident HF. The 5- year Kaplan Meier estimates for incident HF was determined for each biomarker score.

Results:
Among 6748 participants there were 383 incident HF events over a median follow-up of 15.7 yrs. Total KB displayed a poor correlation with other biomarkers (r<0.06 for all). The addition of KB to the current standard of care to identify pre-HF (either elevation in NT-proBNP and/or hs-cTnT) improved risk prediction (C-statistic 0.70 vs. 0.73). The 3-biomarker score demonstrated good discrimination for predicting 5-year HF risk [C-statistic 0.74 (95%CI 0.70-0.78)]. A graded association was observed between biomarker score groups and the risk of HF independent of established clinical factors (
Figure
). 8% of participants with biomarker score ≥2 developed HF within 5 yrs, while those with biomarker scores≤1 faced very low risk (≤2% over 5 yrs).

Conclusions:
The addition of plasma KB to a clinical risk score using routinely collected biomarkers of cardiac injury and stress may further personalize risk estimation and reduce misclassification of those at risk of incident HF.
Abstract 12170: A National Heart Failure Initiative is Associated With Improved Use of Guideline-Directed Medical Therapies
Authors: Cherkur Sruthi , Kiser Robin Y , Serdynski Lynn , Saunders Rhoda , Sterzing Christina , Macheska Kelly L , Scharnott Michelle C , Bolles Michele M , Chahoud Georges , Mody Kanika , SALTZBERG MITCHELL , Sauer Andrew J , Spencer Steven , Spertus John A , Wald joyce , Fonarow Gregg C , Yancy Clyde W
Published: June 2023

Background:
Heart Failure (HF) is projected to impact over 8 million people by 2030. Guideline-Directed Medical Therapy (GDMT) reduces mortality and morbidity, but many eligible patients are not receiving the recommended medications. The 2022 ACC/AHA/HFSA Guideline for the Management of HF highlight the importance of SGLT2i and ARNi, which continue to be underused in eligible HFrEF patients.

Methods:
IMPLEMENT-HF (I-HF), a national HF quality improvement initiative focusing on early adoption of GDMT, aims to improve use of SGLT2i and ARNi for HFrEF patients.

I-HF creates a transformative learning collaborative and resource repository across seven U.S regions to promote education and adherence to GDMT, that includes sharing models of clinical care, targeted training, resource development, and quality improvement consultation.

Participation in a learning collaborative allows for sharing of interventions, such as adding SGLT2i on formulary, optimizing EHR tools for GDMT (best practice alerts, disease-specific order sets, dot phrases), provider education, and patient resources to address medication affordability.

Sites receive educational materials, including webinars, pocket guideline booklets, and guideline reminder cards to reinforce GDMT.

Participating hospitals collect GDMT data in Get With The Guidelines®-Heart Failure (GWTG-HF).

ARNi and SGLT2i at discharge was analyzed from baseline (Q1 & Q2 2021 aggregate) through Q1 2022.

Results:
Data from 62 sites (16,533 HF patient records) showed that use of ARNi at hospital discharge increased from baseline 46% to 58% in Q1 2022, +12%,
p
value <0.001. SGLT2i use at discharge increased from 8% to 26%, +18%,
p
value <0.001 (Figure 1).

Conclusions:
Among centers participating in the I-HF initiative, early findings suggest there has been a rapid increase in use of SGLT2i and ARNi at discharge for HFrEF patients. Further study is needed to assess post-discharge GDMT use, adherence, and clinical outcomes.
Abstract 12176: Incidence and Risk Factors for Takutsubo Syndrome After Inpatient Chemotherapy : Nationwide Readmissions Database Analysis
Authors: Parekh Jay , Jang Sun-Joo A , Yerlikaya Aslihan , Kim Eejung , Park Jong Chul , Yeo Illhwan , Guha Avirup , Ahmad Tariq
Published: June 2023

Backgrounds:
Takotsubo syndrome (TTS) is known to be associated with malignancy. However, the exact etiology of TTS in cancer patients is still unclear. There have been several reports of TTS development from the exposure to cancer therapies. We aimed to identify risk factors for the early development of TTS among patients receiving inpatient chemotherapy or immunotherapy.

Methods:
Patients who were admitted primarily for chemotherapy or immunotherapy were selected from the Nationwide Readmissions Database of the United States. TTS during index hospitalization or within 30 days after discharge was identified by International Classification of Diseases - 10th Version-Clinical Modification codes. Patients who had acute coronary syndrome or coronary revascularization were excluded. Clinical and hospital characteristics in patients with or without TTS were compared.

Results:
Between January 2016 and November 2019, a total of 599,921 cancer patients who received chemotherapy or immunotherapy were included in the analysis. Total 295 patients (0.049%) were found to have TTS during hospitalization or within 30 days after discharge. Patients with TTS were older and more frequently had women, hypertension or chronic lung disease vs those without TTS. Leukemia was more frequent in patients with TTS (38.5%) vs in patients without TTS (24.3%) (P<0.001). Multivariable risk adjustment showed that cancer type of Leukemia (adjusted odds ratio (aOR) 2.08, 95% confidence interval (CI) 1.44 to 2.99, P<0.001), old age (aOR per year 1.02, 95% CI 1.01 to 1.03, P<0.001), women (aOR 2.00, 95% CI 1.42 to 2.82, P<0.001) and disposition to facilities (aOR 1.50, 95% CI 1.03 to 2.19, P=0.037) were independently associated with the early TTS development after inpatient chemotherapy or immunotherapy.

Conclusions:
The presence of leukemia, advanced age, women and disposition to facilities were significantly associated with early TTS. Further risk stratification among patients receiving chemotherapy or immunotherapy may be helpful to identify patients at risk of TTS
Abstract 12178: Extracellular Vesicle-Encapsulated AAVs for Therapeutic Gene Delivery to the Heart
Authors: La Salvia Sabrina , Li Xisheng , Liang Yaxuan , Adamiak Marta , Kohlbrenner Erik , Lopez-Gordo Estrella , Phan Anh , Raisinghani Nikhil , zhang shihong , Gonzalez Kozlova Edgar , Dubois Nicole , Dogra Navneet , Hajjar Roger , Sahoo Susmita
Published: June 2023

Background:
Adeno-associated virus (AAV) has emerged as one of the best tools for cardiac gene delivery due to its cardiotropism, long-term expression, and safety. However, a significant challenge to its successful clinical use are pre-existing neutralizing antibodies (NAbs), which bind to free AAVs, prevent efficient gene transduction and reduce or negate therapeutic effects. Here we describe extracellular vesicle-encapsulated AAVs (EV-AAVs), secreted naturally by AAV-producing cells, as a superior cardiac gene delivery vector that delivers more genes and offers higher NAb resistance.

Method:
We developed a two-step density-gradient ultracentrifugation method to isolate highly purified EV-AAVs.

Results:
Using cardiotropic AAV serotypes 6 and 9 and several reporter constructs, we demonstrated that EV-AAVs deliver significantly higher quantities of genes than AAVs in the presence of NAb, both to human left ventricular and hiPSC cardiomyocytes in vitro, and to mouse hearts in vivo. Intramyocardial delivery of EV-AAV9-SERCA2a to infarcted hearts in pre-immunized mice significantly improved ejection fraction and fractional shortening compared to AAV9-SERCA2a delivery. These data validated NAb evasion by and therapeutic efficacy of EV-AAV9 vectors. Interestingly, in vivo trafficking studies in mouse hearts showed significantly higher expression of EV-AAV9-delivered genes in cardiomyocytes compared to non-cardiomyocytes, even with comparable cellular uptake. Using cellular sub-fraction analyses and pH-sensitive dyes, we discovered that EV-AAVs were internalized into acidic endosomal compartments of cardiomyocytes for releasing and acidifying AAVs for their nuclear uptake.

Conclusion:
Together, using six different in vitro and in vivo model systems, we demonstrate significantly higher potency and therapeutic efficacy of EV-AAV vectors compared to free AAVs. These results establish the potential of EV-AAV vectors as a gene delivery tool to treat heart failure.

1
Abstract 12213: A Description of Left Atrial Appendage Morphologies by Race
Authors: Lee Madeline , Quinn Alexander , Bocchese Matthew , Garber Rebecca , Patil Pravin , Dewland Thomas A , Whitman Isaac R
Published: June 2023

Introduction
: The left atrial appendage (LAA) is the origin of most thromboemboli in patients with atrial fibrillation (AF). Certain LAA morphologies are associated with higher risk of thrombus formation and stroke. Blacks with AF suffer more ischemic strokes than non-Blacks despite adjustment for conventional stroke risk factors and differences in anticoagulation prescription. The association of certain LAA morphologies with race as a contributing explanation for the racial difference in stroke risk has not been examined. We hypothesized that, among those with AF, Blacks have higher risk LAA morphologies compared to non-Blacks.

Methods
: We performed a retrospective analysis of consecutive patients with AF who underwent a contrast-enhanced CT scan in preparation for Watchman device placement to determine LAA morphology. Based on prior literature, we assigned a score to each morphology based on relative risk of stroke associated with each morphology: chicken wing, 1 (lowest risk, reference); windsock or cactus, 4; and cauliflower, 8. Mean scores among Blacks vs non-Blacks, defined as White, Asian, or Hispanic, were compared using Students T-test.

Results
: Among 85 patients (Black, n=36), there was no significant difference in the proportion of individuals with the low risk chicken wing morphology between races (29% Black versus 36% non-Black, p = 0.69). However, Blacks were more likely to have the high risk cauliflower morphology (n=5, 6% versus n=1, 1%, p=0.04). The summative mean score for morphology-associated stroke risk was higher among Blacks (2.1 vs 2.5, p=0.017) (
Figure
).

Conclusions
: Black patients with AF had higher-risk LAA morphologies compared to non-Black patients. These findings may explain the previously observed racial differences in AF-associated stroke risk.Figure: Distribution of LAA morphologies by Black versus Non-Black and difference in summative relative risk between Black and Non-Black patients.
Abstract 12217: Effect of Repeated Binge Drinking in Mid-Life Adults on Vascular Function
Authors: Pusec Carolina M , Hibner Brooks A , Drab Yuliya , Piano Mariann R , Phillips Shane A , Hwang Chueh-Lung
Published: June 2023

Introduction:
Age-related changes in vascular function, including endothelial dysfunction and arterial stiffening, contribute to the development of cardiovascular disease. “Mid-life adults”, defined as age 50-64, begin to show signs of vascular aging. One in five mid-life adults engage in binge drinking and our previous studies in young adults showed that repeated binge drinking was associated with endothelial dysfunction and arterial stiffening. However, it is unclear how binge drinking influences vascular function in aged individuals. Therefore, the purpose of this study is to investigate endothelial function and arterial stiffness in mid-life adults who binge drink regularly (binge drinkers) compared to those who did not drink alcohol (alcohol abstainers).

Methods:
Twelve apparently healthy mid-life men and postmenopausal women, with no smoking history were included in this study (mean±SEM, age: 57±1 years, body mass index: 26.0±0.8 kg/cm
2
, systolic blood pressure: 119±5 mmHg). Alcohol use was assessed by the Alcohol Use Disorders Identification Test (AUDIT) and dried blood spot phosphatidylethanol. Endothelial function was assessed by brachial artery response to reactive hyperemia (flow-mediated dilation, FMD) via ultrasonography. Arterial stiffness was assessed by carotid to femoral pulse wave velocity (cfPWV) via use of the cuff-based SphygmoCor Xcel.

Results:
Binge drinkers (n=6) had an AUDIT score≥5 (11.8±2.1) and positive phosphatidylethanol level (162±103 ng/mL), while alcohol abstainers (n=6) had an AUDIT score≤1 (0.8±0.2) and negative phosphatidylethanol level. Compared to alcohol abstainers, binge drinkers had a lower brachial artery FMD (alcohol abstainers vs. binge drinkers: 9.8±1.2% vs. 5.1±0.9%, P=0.01), but similar cfPWV (7.2±0.7 vs. 7.0±0.5 m/sec, P=0.8).
Conclusions: Our results indicate
that compared to mid-life adult alcohol abstainers, binge drinkers had lower endothelial function, but similar arterial stiffness. These findings suggest that repeated binge drinking may further impair endothelial function throughout the aging process.
Abstract 12228: Development of a Novel Polygenic Risk Score to Predict Risk of Aortic Stenosis Events
Authors: Small Aeron M , Melloni Giorgio , Kamanu Frederick , Roselli Carolina , Bergmark Brian A , Bonaca Marc P , Odonoghue Michelle L , Giugliano Robert , Scirica Benjamin M , Bhatt Deepak L , Antman Elliott M , Raz Itamar , Peloso Gina , WILSON PETER , Odonnell Christopher J , Natarajan Pradeep , Braunwald Eugene , Lubitz Steven A , Ellinor Patrick T , Ruff Christian T , Sabatine Marc S , Marston Nicholas F
Published: June 2023

Introduction:
Aortic stenosis (AS) is the most common valvular heart disease. Polygenic risk scores (PRS) use common genetic variants to enhance risk prediction for disease but have not yet been applied in AS.

Methods:
We generated an AS genetic risk score using summary data from a recently performed GWAS in the Million Veteran Program and score selection performed in the UK Biobank. We analyzed investigator reported adverse events with either newly identified AS or worsening of AS (including heart failure in the setting of AS or aortic valve replacement) from 5 TIMI trials (FOURIER, PEGASUS, SAVOR, SOLID, and ENGAGE). Cox proportional hazard models (adjusted for age, sex, diabetes, BMI, hyperlipidemia, and the first 5 principal components) were used to generate adjusted hazard ratios for risk of AS evaluating normalized PRS as a continuous variable.

Results:
The best performing AS PRS used a p-value threshold of 5x10
-8
and consisted of 27 independent single nucleotide polymorphisms which together predicted AS in the UKBB with a p-value of 2.6x10
-5
. In the TIMI trials, there were a total of 52,183 individuals (median age 66 years [interquartile range 60-72], 71.7% male) with a median follow up of 2.4 years. Of these, 215 (0.4%) had an AS-related adverse event. Age was the strongest clinical risk factor for an AS-related adverse event (HR 1.08 [1.06-1.10] per 1-SD, p-value 1.8x10
-19
), followed by diabetes and BMI. After adjustment for all clinical risk factors there was a 16% increase in the risk of an AS-related adverse event with each standard deviation (SD) increase in the AS PRS (HR 1.16 [1.02-1.31] per 1-SD, p-value 0.03).

Conclusions:
We developed a novel polygenic risk score that predicts clinical risk of aortic stenosis-related adverse events in patients with cardiometabolic disease, even after adjustment for traditional risk factors.
Abstract 12241: Correlation of Breast and Coronary Artery Calcification and Associated Cardiovascular Risks
Authors: Estep Zachary J , Ameen Daniyal , Hartnett Josette , Newman Rebecca , Hsi David H
Published: June 2023

Introduction:
There is a known association between microvascular breast artery calcifications (BAC) and atherosclerotic cardiovascular disease. Similarly, coronary artery calcification (CAC) has been shown to have association with 10-year ASCVD risk. Using an investigational artificial intelligence software, we sought to determine if a relationship exists between BAC and CAC severity on CT imaging obtained for non-cardiac reasons and whether this relationship has prognostic implications for major adverse cardiac events (MACE).

Methods:
A single center retrospective pilot study of patients who underwent CT chest imaging for non-cardiac issues and had also undergone a routine screening mammogram within one year. A database created by our central imaging archives for patients with known CAC and BAC was utilized. CAC severity was scored using the semi-quantitative Weston method. BAC severity (termed Bradley score) was scored by cmAngio
R
, an automated software created by CureMetrix.

Results:
Seventy-three patients were included for BAC analysis during a median follow-up of 85 months. A mean Bradley score by cmAngio of 10.40 was significantly associated with low risk of CAC (0-2 Weston). A mean Bradley score for moderate (3-7 Weston) and high (> 7 Weston) risk of CAC was 19.70 and 42.64, respectively. The results were statistically significant (p=0.0222). A CAC total score ≥5 was previously published by us to be the optimal cutoff value for predicting MACEs.

Conclusions:
This retrospective pilot study confirms a relationship exists between patients found to have BAC as identified by an investigational artificial intelligence software on routine mammogram and CAC on CT imaging obtained for non-cardiac reasons. The addition of routine disclosure of BAC on mammographic reports may be of clinical value to capture patients who may not meet traditional guidelines for coronary atherosclerosis risk stratification and may help primary care clinicians begin discussions about lifestyle modifications and potential treatment directed towards primary prevention of MACE.
Abstract 12243: Impacts of Obesity in Clinical Outcomes in Patients Hospitalized for Atrial Flutter
Authors: Lukan Abdulkareem O , Orji Richard , Okoh Nelson , Babayale Omofolarin , Eromosele Oseiwe 'Benjamin' , Ahmad Muhammad , Nduka Tagbo C
Published: June 2023

Introduction:
Atrial Flutter is an abnormal heart rhythm affecting the heart's upper chamber. It has comparative stroke risk to atrial fibrillation but differs in the arrhythmia's origin. There is Paucity of data comparing the relationship between obesity and atrial flutter. This study aims to bridge that gap.

Methods:
We analyzed the National Inpatient Sample (NIS) database from 2016 to 2019. The NIS was searched for hospitalized adult patients with atrial flutter as a principal diagnosis with and without obesity as a secondary diagnosis using ICD-10 codes. The primary outcome was inpatient mortality. The secondary outcomes were the rate of catheter ablation, cardiogenic shock (CS), cardiac arrest (CA), total hospital charge (THC), and length of stay (LOS). Multivariate logistic and linear regression analyses were used accordingly to adjust for confounders.

Results:
About 1,891,479 patients were admitted for Atrial Flutter, 21% (398,040) had underlying Obesity. Cohorts with Obesity vs No Obesity had a mean age of 64.4 years [CI 64.3 - 64.5] vs 72.2 years [CI 72.1 - 72.3]; male (52.4% vs 50.4%), female (47.6% vs 49.6%); white (79.8% vs 82.2%), black (11.0% vs 7.8%), and Hispanic (6.2% vs 5.9%). Compared to patients without Obesity, patients admitted with coexisting Obesity had a statistically significant decrease in mortality (0.47% vs 0.95% aOR 0.72, 95% CI 0.64 - 0.81, P 0.001), CA (0.33% vs 0.42%, P=0.003), and CS (0.58% vs 0.61%, P<0.001) compared to those without obesity. The obesity cohorts also had a statistically significant increase in rates of catheter ablation (aOR 1.18, P<0.001), LOS (aIRR 1.05, P<0.001) and THC (aIRR 1.08, P<0.001).

Conclusion:
Patients admitted primarily for Atrial Flutter with co-existing Obesity had lower inpatient mortality, CA, and CS. There was a statistically significant increase in the rates of catheter ablation, LOS and THC among the obese group. Additional studies are required to elaborate on the management of this patient group.
Abstract 12249: Optimal Timing of Extracorporeal Membrane Oxygenation (ECMO) Application for the Prognosis of Patients With Acute Coronary Syndrome (ACS) Accompanying Cardiogenic Shock
Authors: Kim Dong-Gil , Kwon Sung Uk ,   RESCUE researchers
Published: June 2023

Introduction:
Advances in mechanical circulatory support (MCS) devices and several studies showing that early application of MCS devices can improve survival rates in cardogenic shock (CS) patients are increasing interest in the usefulness of MCS devices in CS patients. However, studies on the optimal use and timing of application of MCS device in CS patients are still lacking.

Methods:
The RESCUE study is multicenter, retrospective, and prospective registry of patients that presented with CS. From January 2014 to December 2018, 1247 patients with CS were enrolled from 12 major centers in Korea. Among enrolled patients, ECMO was applied to 238 of 693 patients who performed percutaneous coronary intervention (PCI) with acute coronary syndrome. The primary endpoint was a composite of in-hospital, 30-day, 6-month and 12-month mortality according to ECMO application timing.

Results:
There was no difference in the 30-day mortality in ACS patients with CS according to ECMO application timing before and after PCI. However, when stratified by time from CS recognition to ECMO application (Shock to ECMO application time, ≤100 minute vs. >100 minute), 30-day Kaplan-Meier survival curve showed differences according to ECMO application timing. When the time from CS to ECMO application less than 100 minutes, patients who applied ECMO during or after PCI had a 34% reduction in 30-mortality compared to patients who applied ECMO before PCI (HR = 0.64, 95% CI: 0.39-1.03; P = 0.07). And, when the time from CS to ECMO application exceeded 100 minute, patients who applied ECMO during or after PCI had an approximately twice the 30-day mortality compared to patients who applied ECMO before PCI (HR = 2.03, 95% CI: 1.07-3.85; P = 0.03).

Conclusions:
According to ECMO application timing, prognosis of ACS patients with cardiogenic shock was different. In case of exceed 100 minute, early initiation of ECMO application was associated with improved prognosis in 30-day mortality.
Abstract 12295: Relation Between Withdrawal of Heart Failure Therapy and Left Ventricular Function After Improvement of Cancer Therapeutics Related Cardiac Dysfunction
Authors: Lee Nuri , Kim Kye Hun , Park Hyukjin , Kim Hyung Yoon , Cho Jae Young , Yoon HyunJu
Published: June 2023

Introduction:
This study aimed to investigate withdrawal of guideline-directed medical therapy (GDMT) is associated with decline of left ventricular (LV) function after recovery from cancer therapeutics related cardiac dysfunction (CTRCD).

Methods:
From Mar 2015 to Dec 2021, 126 patients with improving CTRCD [defined as >10% point improvement in LV ejection fraction (LVEF)] were identified. They were divided into 2 groups: patients who continued GDMT (GDMT+) and withdrew GDMT (GDMT-) after improvement of CTRCD. LV functional changes within 1 year and composite clinical outcome which was defined as hospitalization due to heart failure and all-cause death were compared between 2 groups.

Results:
The most frequent primary cancer was breast cancer [94 (74.6%)], followed by lymphoma [16 (12.7%)] and multiple myeloma [7 (5.6%)]. GDMT was withdrawn in 41 (32.5%) patients after improvement of CTRCD. Mean LVEF and LV global longitudinal strain (GLS) were comparable between 2 groups at the time of CTRCD diagnosis (LVEF: 44.6±8.5% in GDMT+ vs. 45.5±7.7% in GDMT-, p=0.592, LV GLS: 13.3±2.9% in GDMT+ vs. 13.6±2.7% in GDMT-, p=0.553), and when LVEF was improved (LVEF: 57.1±8.0% vs. 58.3±7.4%, p=0.457, LV GLS: 14.1±3.2% vs. 14.6±3.1%, p=0.398). Dividing into 4 groups according to LVEF at the time of CTRCD diagnosis, patients with LVEF 45-55% showed no significant difference of LV function after withdrawal of GDMT (LVEF: 65.4±3.9% vs. 63.5±4.1%, p=0.066, LV GLS: 16.9±2.2% vs. 16.2±1.8%, p=0.205), but patients with LVEF <45% experienced significant decline of LVEF (LVEF: 52.7±6.4% vs. 48.7±7.2%, p=0.041, LV GLS: 11.8±2.7% vs. 11.2±2.4%, p=0.445). Withdrawal of GDMT was associated with poor composite clinical outcome in the multivariable-adjusted model [hazard ratio (95% CI) 1.38 (1.01 - 1.93), p=0.005].

Conclusions:
Withdrawal of GDMT was associated with poor clinical outcome and decline of LV function in patients with improving CTRCD, particularly in patients with LVEF <45%.
Abstract 12304: Right Ventricular Hemodynamics in COVID Patients With Shock
Authors: Hollenberg Steven M , Parrillo Joseph E , Klinkhammer Brent , Jamal Sameer , Landers David , Safi Lucy M , Tancredi Jana , Turi Zoltan
Published: June 2023

Introduction:
Patients with serious COVID infections frequently develop shock. Their right-sided hemodynamic profiles have not been well characterized.

Methods:
In a prospectively collected database including 1997 patients hospitalized for COVID pneumonia from March 2020 to March 2021, 368 had shock requiring vasopressors. 327 had echocardiography to assess ventricular function and stroke volume based on clinical indications. LVEF (LV ejection fraction) and RVFAC (RV fractional area change) were measured using Simpson’s rule, stroke volume (SV) by aortic Doppler, and RVSP (RV systolic pressure) from tricuspid regurgitation velocity; 187 had evaluable data on all parameters. Patients were divided into groups with low or preserved RVFAC (

RVFAC
L

or

RVFAC
P

, cutoff <e35%), and low or normal cardiac index, (CI,

CI
L

or

CI
N

,
cutoff <e2.2 L/min/m
2
).

Results:
Mean age: 65±12, LVEF 59.5±12.8, RVFAC 35.3±10.6, CI 2.41±0.89. Overall hospital mortality in this cohort with shock was 80%. Mean RVSP was 38.8±12.2, PEEP 11.0±3.7. 43% of patients had low RVFAC (<35%), and RVFAC correlated with other measures of RV function such as tricuspid annular peak systolic excursion (TAPSE) and lateral tricuspid annulus peak systolic velocity (S’). Higher RVSP correlated with lower CI (r=0.134, p= 0.016) but not with PEEP (r=0.03, p=0.70). Mortality did not differ significantly among groups, (p=0.19 by ANOVA) but was highest in the group with low RVFAC and low CI. (
Figure
)

Conclusion:
RV dysfunction is common in patients with severe COVID-19 and shock. Although RV dysfunction is probably associated with a worse prognosis, outcome in COVID may be tied to pulmonary recovery. Whether treatment targeted at RV dysfunction will improve outcome remains uncertain.
Abstract 12421: Assessment of Flow Measurements Using a Noninvasive Photoplethysmography-Based Device Compared to Invasive Pulmonary Artery Catheter
Authors: Nachman Dean , Rahamim Eldad , Ibrahimli Mahsati , Asenov Asen G , Goldstein Nir , Kolben Yotam , Huly Segev , Ben Ishay Arik , Fons Meir , Merin Roei , Eisenkraft Arik , Amir Offer , Asleh Rabea
Published: June 2023

Introduction:
Invasive monitoring is considered the gold standard of hemodynamic monitoring, yet it is associated with inherent risks. We compared advanced hemodynamic measurements taken using a noninvasive wearable photoplethysmography-based (PPG) monitor and an invasive Swan-Ganz catheter (SGC).

Methods:
Patients with a prior diagnosis of heart failure undergoing right heart catheterization as part of their clinical assessment were recruited. The noninvasive PPG monitor was applied and readings of cardiac output (CO) and stroke volume (SV) commenced in parallel to the invasive hemodynamic study. Bland-Altman plots and Pearson’s correlations were used to assess the accuracy and degree of agreement between techniques.

Results:
90 patients (19-89yo, 53 males) were recruited and included in the final analysis. The mean values of the CO measured using the indirect Fick method, the PPG device, and the thermodilution (TD) method was 5.0±1.4 L/min, 4.9±1.3 L/min, and 4.9±1.6 L/min, respectively. Bland-Altman analysis showed that the PPG had a bias of 0.1 L/m (1.7 - -1.5 L/m 95% LOA) and the TD had a bias of 0.2 L/m (2.2 - -1.8 L/m 95% LOA). The mean SV with the indirect Fick method, the PPG device, and the TD method were 63.6±20.2 mL/beat, 62.0±17.0 mL/beat, and 61.3±20.8 mL/beat, respectively. Bland-Altman analysis showed that the PPG device had a bias of 1.6 mL/beat (23.2 - -20.0 mL/beat 95% LOA) and the TD had a bias of 2.3 mL/beat (28.3 - -23.7 mL/beat 95% LOA). Correlations between the indirect Fick method and the PPG device, and between the indirect Fick method and the TD method were 82.5% and 77.7% for CO, and 83.7% and 79.6% for SV, respectively.

Conclusions:
The PPG device provides CO and SV measurements that highly correlate with the gold standard invasive indirect Fick method, similarly to the invasive thermodilution method.
Abstract 12449: Inhibition of the Sodium Potassium ATPase Alpha 3 (ATP1A3) Pump Function Alters Repolarization Time and is Proarrhythmic in Cardiac Myocytes
Authors: Zheng Scott , Bidzimou Minu-Tshyeto , Kurzlechner Leonie , ZHANG ZHUSHAN , Perelli Robin M , Moya-Mendez Mary E , Mikati Mohamad A , Landstrom Andrew P
Published: June 2023

Introduction:
Inhibition of Na
+
/K
+
-ATPase (NKA) is arrhythmogenic, but the specific effect of alpha 3 NKA isoform (ATP1A3) inhibition is unknown. Variants in human
ATP1A3
can lead to ventricular arrhythmias, yet the mechanism remains unknown.

Hypothesis:
Loss of NKA function results in shortening of QT interval and increased arrhythmia susceptibility due to intracellular Na+ and Ca2+ overload. Pharmacological inhibition of sodium-calcium exchanger (NCX) can rescue ECG parameter changes and arrhythmic phenotypes by reducing Ca2+ overload in the cell.

Methods:
Whole-cell patch clamp action potential recordings were conducted on induced pluripotent stem cell cardiomyocytes (iPSC-CMs) from an ostensibly healthy individual to measure action potential duration (APD) and presence of delayed after depolarizations (DADs). Cells were exposed to 10
-7
M ouabain and 10
-5
M ORM-10103 (a selective inhibitor of NCX). ECGs and
in vivo
intracardiac electrophysiology studies were performed in mice at 12-14 weeks of age after intraperitoneal drug administration of 5 μg/g ouabain and 10 μg/g ORM-10103.

Results:
APD recordings of iPSC-CMs demonstrated both shortening and lengthening of APD with ouabain exposure. In both models, DADs were found in 6 of 18 cells with ouabain treatment. These findings were rescued with pretreatment using ORM-10103, as 0 of 8 cells developed DADs. On mouse ECG recordings, ouabain led to QRS and QT prolongation. During programmed electrical stimulation, no arrhythmia was noted with vehicle-treated mice. Following ouabain administration, 2 in 12 mice developed induced monomorphic ventricular tachycardia. Pretreatment of ORM-10103 in mice did not rescue QRS and QT prolongation with ouabain administration.

Conclusions:
Pharmacologic inhibition of ATP1A3 variably altered cardiac repolarization time in a species-specific manner, yet was associated with a substrate for triggered arrhythmias. The arrhythmogenic phenotype was rescued with inhibition of NCX in human cardiac myocytes, suggesting that NCX plays a role in the arrhythmogenic mechanism of ATP1A3. However, these effects were not seen in murine cardiac myocytes. Exploration of specifies-specific differences in NKA isoform expression and cardiac repolarization is needed.
Abstract 12450: Identifying Differential Proteins of the Arrhythmogenic Right Ventricular Cardiomyopathy Type 5 Associated Mutation in Transmembrane Protein 43 Ser358Leu by Proteomics and Interaction Studies Using TurboID
Authors: Ratnavadivel Sandra , Klinke Nora , Bernauer Miriam , Harten Heiko , Paululat Achim , Gummert Jan , Milting Hendrik
Published: June 2023

Introduction:
Transmembrane protein 43 (TMEM43) is localized in the nuclear envelope and endoplasmic reticulum (ER).
TMEM43-
c.1073C>T, p.S358L leads to a rare fully penetrant type 5 arrhythmogenic right ventricular cardiomyopathy (ARVC5). The molecular pathomechanism of ARVC5 is not well understood.

Methods:
TurboID cloned to N- and C-terminal of TMEM43 WT and p.S358L were transfected in HEK293 cells. Biotinylation assay was performed and biotinylated proteins were immunoprecipitated using streptavidin-beads. After on beads-digestion, peptide fragments were analyzed by Orbitrap mass-spectrometry (MS). Furthermore, we cultivated primary dermal fibroblasts of three
TMEM43
p.S358L carriers. Proteins were isolated from cell cultures and analyzed by MS. Additionally, TMEM43-p.S358L and control fibroblasts were investigated by transmission electron microscopy (TEM).

Results:
TurboID proteome data shows differences in the interacting proteome of TMEM43 WT and p.S358L. VDAC2, which is involved in metabolic regulation of lipids and part of the ER-mitochondrion contact site, was one of the prominent interacting proteins less represented in TMEM43 p.S358L. The proteome of fibroblasts show 11 proteins upregulated in TMEM43-p.S358L (p<0.003). Of note, proteins involved in fatty acid metabolism, such as acyl-coenzym A thioesterase 1 encoded by the gene
ACOT1,
and Malonate-CoA ligase encoded by
ACSF3
were strongly upregulated. ACOT1 and ACSF3 regulate intracellular levels of free fatty acids and are expressed in human cardiomyocytes. TEM images of
TMEM43
p.S358L carriers show accumulation of multilamellar bodies, which may support the dysregulation of the lipid metabolism as a prominent pathomechanism.

Conclusions:
The altered interaction of TMEM43 p.S358L with VDAC2 is a plausible mechanism for miscommunication of ER and mitochondria perturbing the lipid homeostasis. Additionally, the differentially regulated proteins in dermal fibroblasts and the accumulation of multilamellar bodies also suggest a dysregulation of the lipid metabolism by TMEM43 p.S358L, which may explain the development of myocardial fibrofatty replacement contributing to ARVC5.
Abstract 12489: Reclassification of 10-Year Coronary Heart Disease Risk in 5324 Primary Prevention Patients: Ascvd, Rrs versus Mesa-Cac Scores
Authors: Hajj Ali Adel , Nakhla Michael , Cho Leslie , Seballos Raul , Lang Richard S , Feinleib Steven , Flamm Scott D , SCHOENHAGEN Paul , Wang Tom Kai Ming K , Desai Milind Y
Published: June 2023

Introduction:
Cardiovascular (CV) risk prediction score have provided physicians with powerful screening and prevention tools.

Hypothesis:
In a large screening program of asymptomatic individuals, we sought to assess the CV risk reclassification provided by comparing multiethnic study on subclinical atherosclerosis-coronary artery calcium scoring (CACS) vs American Heart Association (AHA)-American College of Cardiology (ACC)-Atherosclerotic Cardiovascular Disease (ASCVD) score and Reynolds Risk Score (RRS).

Methods:
We included all 5324 patients (age 57± 8 years, 76% male and 87% white) who underwent CACS screening in a primary prevention clinic between 3/2016 and 10/2021. 10-year ASCVD, RRS and MESA-CACS scores were calculated and categorized as 0, 1-4.99%, 5-9.99% and ≥10%.

Results:
Mean MESA-CACS, ASCVD and RRS were 4.9± 5.6%, 6.6 ± 6.2%, and 4.5 ± 4.4%. A total of 2962 (56%) had a CAC of 0 of which 481 (16%) were on statin. MESA-CAC was moderately correlated with ASCVD and RRS (R= 0.65 and 0.62 respectively, both p<0.001, Figure 1a-b). Compared to ASCVD score, using MESA-CACS resulted in a downgraded risk in 1666 (31%) subjects, while 738 (14%) had an upgrade in risk. Similarly, compared to RRS, using MESA-CAC resulted in an upgraded risk in 797 (15%) and a downgrade in 1380 (26%) subjects. Additionally, 916 subjects (421 and 495 with an ASVCD score between 5-7.5 and 7.5-20% respectively) met criteria for statin therapy, but had CACS of 0, of which 234 (26%) were on a statin.

Conclusions:
Utilization of MESA-CACS in primary prevention results insignificant reclassification of traditional CV risk scores with, RRS underestimating and ASCVD overestimating the 10 year-coronary heart disease risk. A quarter of patients with ASCVD score 5-20% who were on statins had a CACS of 0; hence CACS can potentially help refine subjects who would best benefit from statin therapy.

Fig 1
Distribution of patients with %10-year risk based on MESA CAC score vs ASCVD (A) and RRS (B)
Abstract 12514: Ceramide-Based Lipid Profiles and the Prevalence of Type 2 Diabetes Differ Between Patients With Coronary Artery Disease and Those With Peripheral Artery Disease
Authors: Leiherer Andreas , Muendlein Axel , Brandtner Eva Maria , Saely Christoph H , Vonbank Alexander , Mader Arthur , Sprenger Lukas , Maechler Maximilian , Larcher Barbara , Jylha Antti , Laaperi Mitja , Laaksonen Reijo , Maerz Winfried , Fraunberger Peter , Kleber Marcus , Drexel Heinz
Published: June 2023

Introduction:
Serum lipids and metabolic diseases, in particular type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD), predict the atherosclerotic diseases coronary artery disease (CAD) and peripheral arterial disease (PAD). However, it is not known in how far a more detailed characterization including serum lipids improves discrimination of PAD from CAD.

Hypothesis:
We hypothesize that ceramide-based lipid profiles and T2D status differ in CAD and PAD.

Methods:
A cohort of 274 statin-naïve patients with either PAD (
n
= 89) or stable CAD (
n
= 185) were referred to metabolic screening and were characterized using nuclear magnetic resonance- and liquid chromatography-tandem mass spectrometry based advanced lipid and lipoprotein analysis. Results were validated in an independent cohort of 1239 patients with PAD or CAD.

Results:
We found a significant difference in T2D prevalence and in the ceramide-based lipid profile between PAD and CAD patients. However, neither cholesterol-based markers (including LDL-C, HDL-C) and detailed lipoprotein profiles nor the NAFLD status differed significantly between PAD and CAD patients (figure). The difference between ceramide-based lipid profiles of CAD and PAD remained significant also after adjusting for body composition, smoking, inflammatory parameters, and T2D.

Conclusions:
We conclude that PAD and CAD differ in ceramide-based lipid profiles and T2D status, but not in other lipid characteristics or metabolic diseases.
Abstract 12574: Highest Post-PCI Ischemic Event Occurrences in African American Men During COVID-19 Outbreak Compared to Before COVID-19: A Community Hospital Experience
Authors: Duhan Sanchit , Ali Asgar Juzer , Kundan Parshotam , Walia Naval , Bliden Kevin , Cummings Charles , Abuzara Mohammed , Singh Arvind , Tantry Udaya , Gurbel Paul
Published: June 2023

Introduction:
African Americans (AAs) have a higher risk for post-PCI ischemic events and worse COVID-19-related events than non-AAs. Race and gender-related post-PCI events before and during the COVID-19 pandemic in a community hospital setup are unknown.

Methods:
Demographics and one-year post-PCI ischemic event occurrences were compared between AAs and non-AAs undergoing PCI immediately before (2017-2019) and during COVID-19 (2020-2022) in an urban community hospital.

Results:
In total, 291 and 292 non-AAs and 221 and 219 AAs who underwent PCI before and during the COVID-19 pandemic respectively, were included in the analysis. AAs were younger and had a higher prevalence of diabetes and ACS (p<0.01 for all). Among non-AAs, there were no differences in major demographics except a higher % of pts with prior PCI (p=0.02) before vs. during COVID-19. Platelet counts were higher in both groups during COVID-19 (p≤0.008) (Table). Among AAs, % of pts with ACS was higher during COVID-19 (p=0.003) which was mainly driven by a higher % of NSTE-ACS (p<0.001). In total, one-year recurrent ischemic events were higher during the COVID-19 pandemic compared to before (112 vs. 198, p<0.001). Among non-AAs, although the total number of events was higher during COVID-19 (p<0.001), % of pts with events were similar and all-cause death and MI were higher during the COVID-19 (p≤0.008). Among AAs, both total events and % of pts with events were higher during COVID-19 (p≥0.02). Except for all-cause death, other ischemic events were higher in AAs during COVID-19 (p≤0.02) which occurred in men (p=0.0001) but not in women (p=ns). TIMI bleeding events were numerically lower during COVID-19

Conclusions:
In our community hospital, AAs have a higher risk for post-PCI ischemic events which mainly occurred in men during COVID-19, whereas non-AAs have a similar risk before and during COVID-19. This data suggest that AA men with COVID-19 undergoing PCI should be treated with aggressive antiplatelet therapy.
Abstract 12596: Comparison of the Efficacy and Safety of Direct Oral Anticoagulants With Vitamin K Antagonists in Patients With Thrombotic Antiphospholipid Syndrome: Systematic Review and Meta-analysis of Randomized Clinical Trials
Authors: Bejjani Antoine , Khairani Candrika D , Piazza Gregory , Jimenez David , Monreal Manuel , Chatterjee Saurav , Pengo Vittorio , Woller Scott , Cortes-Hernandez Josefina , Connors Jean M , Kanthi Yogendra , Krumholz Harlan M , Middeldorp Saskia , Falanga Anna , Cushman Mary , Goldhaber Samuel Z , Garcia David , Bikdeli Behnood
Published: June 2023

Introduction:
The efficacy and safety of direct oral anticoagulants (DOACs) as treatment alternatives for patients with thrombotic antiphospholipid syndrome (APS) remain controversial.

Methods:
We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) that compared the efficacy and safety of DOACs with vitamin-K antagonists (VKAs) in patients with thrombotic APS. We searched PubMed, EMBASE and Cochrane Central Register of Controlled Trials through April 9, 2022. Main efficacy outcomes were a composite of arterial thrombotic events, and a composite of venous thromboembolic events (VTE). The main safety outcome was major bleeding according to the International Society on Thrombosis and Hemostasis (ISTH) criteria. A random effects model with inverse variance was used for the primary analysis. Risk of bias was assessed using the Cochrane Collaboration criteria.

Results:
Our search retrieved 253 studies. Four RCTs involving 474 patients were included (Figure). All four RCTs were open-label but had proper random sequence generation and adequate allocation concealment. The DOACs used were rivaroxaban (3 trials) and apixaban (1 trial). The mean percent time in therapeutic range in the warfarin arm among the four studies was 60%. Overall, use of DOACs compared with VKAs was associated with increased odds of composite of arterial thrombotic events (OR 5.64, 95% confidence interval [CI] 1.96-16.27,
p
=0.001, I
2
= 0%). The odds of subsequent VTE events (OR 1.19, 95% CI 0.31-4.53,
p
=0.80, I
2
= 0%), or major bleeding (OR 1.02, 95% CI 0.42-2.47,
p
=0.97, I
2
= 0%) were not significantly different between the two groups.

Conclusions:
Patients with thrombotic APS randomized to DOACs compared to VKAs appear to have increased risk for arterial thrombosis. No significant differences were observed between patients randomized to DOACs vs VKAs in the risk of subsequent VTE or major bleeding.
Abstract 12619: Diverse Effects of Cilostazol on Proprotein Convertase Subtilisin/Kexin Type 9, Obesity or Not
Authors: Chen Po-Wei , Tseng Shih-Ya , Chao Ting-Hsing
Published: June 2023

Introduction:
Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a key role in cholesterol homeostasis. Cilostazol exerts favorable cellular and metabolic effects; however, the effect of cilostazol on the expression of PCSK9 has not been previously reported.

Hypothesis:
Our study aimed to investigate the potential mechanisms of action of cilostazol on the expression of PCSK9 and lipid homeostasis.

Methods:
We evaluated the effects of cilostazol on the expression of PCSK9 in HepG2 cells and evaluated potential molecular mechanisms by measuring signaling molecules in the liver and serum lipid profiles in high-fat diet-induced obese mice and normal chow-fed mice. Additionally, the baseline and post-treatment serum PCSK9 levels of obese and non-obese human participants treated with cilostazol were measured.

Results:
Cilostazol treatment significantly induced the messenger RNA and protein expression of PCSK9 in HepG2 cells and enhanced PCSK9 promoter activity. Chromatin immunoprecipitation assays confirmed that cilostazol treatment enhanced PCSK9 transcription by binding to peroxisome proliferator-activated receptor-γ (PPARγ) via the PPARγ DNA response element. PPARγ knockdown attenuated the stimulatory effect of cilostazol on PCSK9. In vivo experiments revealed that cilostazol treatment increased serum levels of PCSK9 in normal mice but significantly reduced PCSK9 levels in obese mice (Figure). Clinical data showed that cilostazol treatment significantly reduced serum PCSK9 levels in patients with obesity. The expressions of relevant miRNAs also showed consistent results.

Conclusions:
The obesity-dependent effects of cilostazol on PCSK9 expression observed from bench to bedside demonstrate the therapeutic potential of cilostazol in clinical settings.