bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 14506: Re-Evaluating Clinically Relevant Genes in Conotruncal Cardiac Defects by Burden Analyses of Rare and Ultra-Rare Protein-Altering Variants
Authors: Chui Martin Man Chun , Mak Christopher C.Y. , Yu Mullin , Chau Fong Ting Jeffrey , Lun K.S. , Yung T.C. , Kwong Anna K.Y. , Chow Pak-cheong , Chung Brian H.Y.
Published: June 2023

Conotruncal cardiac defects (CTD) is a group of congenital heart diseases (CHD) involving malformation of outflow tract, with an estimated prevalence of 11.6 per 10,000 births. Currently, a robust consensus on causative genes for nonsyndromic CTD remains to be elucidated. To prioritize clinically relevant genes in whole exome sequencing (WES), we performed gene burden analysis on rare (gnomAD exome allele frequency < 0.01%) protein-altering variants in a cohort of nonsyndromic CTD (n = 245) comparing with ethnicity and location matched controls (n = 853); and expanded to a combined analysis of damaging ultra-rare (CADD ≥ 20 and absent in gnomAD exome) variants involving four CTD cohorts (n = 1451; 391 Chinese and 1060 Europeans) and ethnicity matched gnomAD exome singletons as controls. Gene burden analysis on variants identified within a high-confidence list of 132 CHD genes showed significant (Bonferroni corrected p-value < 0.05) excess of rare protein-altering variants in two well-established genes (
GATA6
,
NOTCH1
) and four potentially relevant genes for CTD (
ANKRD11
,
DOCK6
,
NPHP4
,
STRA6
). Furthermore, burden analysis of ultra-rare variants in the combined cohorts identified three genes robustly (Bonferroni corrected p-value < 0.05) associated with CTD (
FLT4
,
NOTCH1
,
TBX1
). Predominantly more
FLT4
loss-of-function variants were reported in Europeans than in Chinese, while
GATA6
was the only gene with robust burden in Chinese but was not identified in Europeans, suggesting potential differences in the genetic landscape of CTD disease etiology among different ethnicities. Our results provided evidence of aggregate variant excess for nonsyndromic CTD in case-control comparisons and shortlisted significant genes with potential clinical relevance for further systematic curation, to guide appropriate genetic diagnosis for CTD with the application of WES.
Abstract 14520: Paradoxical Increase in Myeloperoxidase Inhibitory Capacity Associated With Poorer Outcomes in Acute Cardio-Renal Syndrome
Authors: Mauch Joseph , Engelman Timothy , Tang Wai Hong W
Published: June 2023

Introduction:
While implicated in both cardiac and renal dysfunction, it remains unclear if myeloperoxidase (MPO) plays a role in the development of acute cardiorenal syndrome (CRS). We developed an assay to quantify MPO inhibitory capacity (MIC) to assess a plasma sample’s capacity to inhibit MPO activity.

Hypothesis:
We hypothesized that unopposed MPO activity (less inhibition) contributes to development of acute CRS and greater MPO inhibition leads to improved clinical outcomes.

Methods:
90 paired samples of acute heart failure (AHF) patients were collected at enrollment and between 24-96 hours follow-up. Diluted samples were supplemented with 100 ng/mL exogenous MPO and allowed to equilibrate for 1 hour at room temperature. Equal parts sample and Amplex UltraRed Reagent were incubated for 30 minutes, and fluorescence was read. 59 patients had long-term follow-up data for time to readmission survival analysis, censored for loss to follow up, death, or transplantation.

Results:
Patients with CRS have higher rather than lower MIC compared to that in uncomplicated patients (50% vs 34%, p=0.048). Serial MIC measurements during hospitalization revealed that patients with persistently low MIC experienced better outcomes (median time to readmission 575 days vs 104 days, p=0.023, Figure).

Conclusions:
Contrary to our original hypothesis, we observed acute CRS patients had higher rather than lower MIC, and that persistently low MIC experienced better long-term outcomes. These results imply that in patients experiencing acute CRS, there is a circulating MPO inhibitory component that has not been previously accounted for, and that unopposed MPO activity was not associated with CRS or poor outcomes.
Abstract 14532: Myocardial Blood Flow in Patients Recovered From COVID-19 Infection Using Stress Cardiac Magnetic Resonance
Authors: Wang Shuo , Karagodin Ilya , Wang Haonan , Singh Amita , Gutbrod Joseph , Landeras Luis , Patel Hena , Alvi Nazia , Tang Maxine , Benovoy Mitchel , Janich Martin A , Benjamin Holly J. , Chung Jonathan H. , Patel Amit
Published: June 2023

Introduction:
Severe COVID-19 infection is known to alter myocardial perfusion through its effects on the endothelium and microvasculature. However, a significant proportion of the world population suffered from only mild COVID-19 symptoms, and it is unknown if their myocardial perfusion is altered following their recovery.

Hypothesis:
In this study, we aimed to determine if there are detectable abnormalities to myocardial perfusion using cardiac magnetic resonance (CMR) in individuals who have recovered from mild COVID-19 infection.

Methods:
We conducted a prospective, comparative study of individuals who have recovered from COVID-19 infection (n=33) and risk-factor matched controls (n=27) using regadenoson stress CMR by a 1.5T MR scanner (GE Signa Artist) (figure). Quantitative stress perfusion images were acquired using the dual sequence technique. MBF was measured during rest (rMBF) and stress (sMBF) using Cvi42 software(figure). Myocardial perfusion reserve (MPR) was calculated as sMBF/rMBF. Unpaired
t
test or the Mann-Whitney U test was used to test differences between the two groups.

Results:
The median time interval between COVID-19 infection and CMR was 6 (4, 9) months. 31/33 (94%) patients in COVID-19 infection were not hospitalized. Symptoms including chest pain, shortness of breath, syncope, and palpitations were greater in COVID-19 group than in the matched controls (19/33 (58%) vs 2/27 (7%), p<0.001). No differences in rMBF (1.50 ± 0.47 vs 1.36 ± 0.45ml/g/min, p=0.21), sMBF (2.84 ± 0.56 vs 2.75 ± 0.64ml/g/min, p=0.56), or MPR (1.94 (1.48-2.75) vs 2.0 (1.59-3.05), p=0.34) were observed between the groups(figure).

Conclusions:
No significant abnormalities in myocardial perfusion during rest or stress conditions were seen in individuals who had recovered from mild COVID-19 infection suggesting that microvascular dysfunction is unlikely to be a common sequela in this patient population.
Abstract 14533: Molecular Imaging of Fibroblast Activity in Pressure Overload Heart Failure
Authors: Wang Guokun , Yang Qinqin , Wu Shengyong , Xu Xudong , Cheng Chao , liu suxuan
Published: June 2023

Introduction:
Cardiac fibrosis, mediated by the activation of cardiac fibroblasts, is critical in pressure overload-induced heart failure. Fibroblast activation protein (FAP), specifically expressed by activated fibroblasts, can be visualized by radiolabeled FAP inhibitors (FAPI) PET/CT.

Hypothesis:
To evaluate whether 68Ga-FAPI-04 could characterize the early stages of cardiac fibrosis in pressure overload heart failure.

Methods:
Sprague-Dawley rats underwent abdominal aortic constriction (AAC) (n = 12) and sham surgery (n = 10). All rats were scanned with
68
Ga-FAPI-04 PET/CT at 2, 4, and 8 weeks after surgery. Cardiac function was measured by echocardiography. The expression of FAP in the myocardium was detected by immunohistochemistry.

Results:
Compared with the sham group, the AAC group presented with decreased ejection fraction (EF) and fractional shortening (FS) and increased left ventricular internal dimensions in diastole (LVIDd) and systole (LVIDs) at 4 and 8 weeks (all p < 0.01). The AAC group showed higher
68
Ga-FAPI-04 accumulation in the heart than the sham group at 2, 4, and 8 weeks, respectively (all p < 0.001), and FAPI increased significantly from 2 to 8 weeks. Immunohistochemistry confirmed the higher density of the FAP
+
area in the AAC group. The intensity of the
68
Ga-FAPI-04 PET signal correlated with the density of the FAP
+
area on histology (p < 0.001). The expression of the
68
Ga-FAPI-04 at 4 weeks correlated with the deterioration of cardiac function at 8 weeks (EF: R = -0.87; FS: R = -0.72; LVIDd: R = 0.77; LVIDs: R= 0.79; all p < 0.001). The AAC group also showed an increased
68
Ga-FAPI-04 signal in the liver, peaking at 4 weeks and then declining. Cardiac and liver PET signals directly correlated at 4 weeks in the AAC group (R = 0.69, p = 0.0010). A combination of the FAPI intensity in the heart and liver at 4 weeks better predicted the deterioration of cardiac function at 8 weeks.

Conclusion:
The activated fibroblasts in the heart and liver after pressure overload can be monitored by
68
Ga-FAPI-04 PET/CT. This imaging technique reveals an early fibrotic link in cardio-liver interactions and could better predict nonischemic heart failure prognosis.
Abstract 14550: A Decade Trend, Sex, Racial and Socioeconomic Disparities Amongst Patients Hospitalized for Premature Myocardial Infarction in the United States
Authors: ASEMOTA IRIAGBONSE , Akuna Emmanuel , Sharma Bharosa , Hammo Hasan , Sana Muhammad Khawar , Almani Muhammad Usman , Deangelo San , Yilmaz Mahir
Published: June 2023

Introduction:
Acute myocardial infarction (AMI) is the leading cause of premature morbidity and premature death worldwide. Premature myocardial Infarction (MI) defined as AMI in men < 55 or women < 65 still maintains high incidence compared to the known decrease in AMI in the elderly over the year.

Hypothesis:
Our study sought to assess the trend of premature MI using a nationally representative sample

Methods:
This was a trend study of the National Inpatient database (NIS) from 2010 to 2019. We searched for premature MI as the reason for hospitalization using the ICD codes for AMI in females and males less than 65 and 55 respectively. We estimated trends, inpatient mortality, mean length of hospital stay (LOS) and mean total hospital charges (THC) over the studied period. We performed a stratified analysis in categories: sex (male and female), race (Hispanics, Blacks and Caucasians), and median household income for patient's zip code (low-income quartile [LIQ] : 1-$49,999 vs high-income quartile [HIQ]: >$86,000) to assess disparities in outcomes. Multivariable regression analysis adjusted for age and sex was used to obtain trend statistics on outcomes

Results:
There was a total of 637,173 hospitalizations for premature MI with 58.6% of a them being females. The proportion of females rose by 4.2% in 2010 compared to 2019. Premature MI proportion increased by 43% in Hispanics, 16.4% in Blacks and 4.6% among Caucasians. LIQ had a 8.9% increase in Premature MI while the HIQ had a 10% reduction. There was no significant increase in incidence of premature MI over the time period. Average mortality in female was 2.1% compared to 1.5% in males. Average mortality rate for the time period under study was 1.82% with a 13.7% decrease in mortality over the studied decade. Mortality decreased by 15.2% and 13.6% among females and males respectively. Mortality among Caucasian was 1.72% and decreased by 233.8%, while mortality following premature MI was 1.9% in blacks and decreased by 22.6%. There was trend towards decreasing mean LOS with a 33.2% increase in THC.

Conclusions:
There appears to be an increased incidence of Premature MI amongst women and LIQ households. Also, among the three studied races, the Hispanic race had the highest rise in the incidence of premature MI.
Abstract 14553: Clonal Hematopoiesis of Indeterminate Potential is Associated With Atrial Fibrillation in Patients With Early Coronary Artery Disease
Authors: Akhiyat Nadia , Lasho Terra , Ganji Morsaleh , Corban Michel T , Ahmad Ali , Lerman Lilach O , Patnaik Mrinal , Lerman Amir
Published: June 2023

Introduction:
The mechanistic link between early coronary artery disease (CAD) and atrial fibrillation (AF) continues to be explored. Clonal hematopoiesis of indeterminate potential (CHIP) is increasingly recognized as a risk factor for cardiovascular disease. We hypothesize CHIP further increases the risk for AF in early CAD.

Methods:
184 participants underwent invasive coronary angiogram with endothelial function testing. Buffy coat was used for whole exosome sequencing to identify CHIP (variant allele frequency > 2% and minor allele frequency ≤ 0.1%). Early CAD was defined by the presence of coronary endothelial dysfunction (CED) in the absence of obstructive CAD. Invasive coronary angiography with endothelial function testing characterized CED as ≥ 20% increase in coronary artery diameter or ≤ 50% increase in coronary blood flow in response to acetylcholine. AF was identified by ICD-10 code or patient survey and confirmed by an independent investigator by chart review. Cox proportional hazard regression was adjusted for age, sex, and conventional cardiovascular comorbidities (hypertension, diabetes, and total cholesterol).

Results:
Of the 184 participants, we identified 23 cases with both early CAD and CHIP and 62 normal controls without CHIP or CAD. Case patients were significantly older (mean 60 ±9 vs 52 ±10 years, p = 0.004 years) and predominantly female (74% vs 81%, p = 0.506). AF was more likely among case participants when compared to normal controls (29% vs 10%, p = 0.036). Mean time to AF or last follow-up was 11 ±7 years. Case patients with both early CAD and CHIP were nearly 10 times more likely to develop AF when compared to normal controls in a Cox regression model adjusted for age, sex, and conventional cardiovascular comorbidities (HR 9.52, 95% CI 1.93 - 47.02, p = 0.006). The risk for AF was not significant if we defined cases by only the presence of CHIP (n = 30) or early CAD (n = 122).

Conclusions:
Patients with both CHIP and early CAD may have greater risk for developing AF beyond the presence of CHIP or CAD alone. Our findings suggest an added mechanistic role of CHIP that further increases the risk for AF in early CAD.
Abstract 14557: Prognostic Role of Pathogenic Mutations in Brugada Syndrome: Results From Wide Gene Testing
Authors: Pannone Luigi , Bisignani Antonio , Osei Randy , GAUTHEY Anais , Sorgente Antonio , Vergara Pasquale , Monaco Cinzia , Della Rocca Domenico , Overeinder Ingrid , Bala Gezim , Almorad Alexandre , Ströker Erwin , Sieira Juan , de Ravel Thomy , BRUGADA Pedro , La Meir Mark , Chierchia Gian Battista , Van Dooren Sonia , de Asmundis Carlo
Published: June 2023

Introduction:
A pathogenic/likely pathogenic (P/LP) mutation can be found in 20-25% of patients with Brugada syndrome (BrS) and a P/LP mutation in SCN5A is associated with a worse prognosis. However, the prognosis of non SCN5A genes mutations is unclear.

Methods:
All BrS patients, were prospectively enrolled in the UZB registry between 1992 and 2022. Inclusion criteria for this study were: 1) BrS diagnosis; 2) Genetic analysis performed with a wide gene panel; 3) Classification of variants following ACMG guidelines. Patients with a P/LP variant in SCN5A were defined as (P+/SCN5A+); patients with a P/LP variant in a gene different from SCN5A were defined as (P+/SCN5A-). All other patients were classified as (P-).

Results:
A total of 452 BrS patients were analyzed. Any P/LP mutation was found in 108 (23.9%) patients, 94 (20.8%) patients P+/SCN5A+ and 14 (3.1%) patients P+/SCN5A-. Compared with P- patients, P+ patients were younger, more frequently had a spontaneous BrS type I ECG, sinus node dysfunction, aborted sudden cardiac death history and longer PQ interval, Table 1. After a mean follow-up of 116.7 months, 47 patients (10.4%) experienced a ventricular arrhythmia (VA). At survival analysis, P- patients had higher VA free survival, compared with P+/SCN5A+ (93% vs 81.9%, p=0.023) and with P+/SCN5A- (93% vs 57.1%, p<0.001). Among P+ patients, P+/SCN5A+ patients had higher VA free survival compared with P+/SCN5A- (81.9% vs 57.1%, p=0.023), Figure 2. At Cox multivariate analysis, P+ was an independent predictor of VA occurrence (HR= 2.23, CI 95% 1.10-4.58, p=0.027).

Conclusions:
In a large BrS cohort, the diagnostic yield for P/LP mutations is 23.9%. P+ is an independent predictor of VA.
Abstract 14566: The Role of Eosinophils in Pulmonary Hypertension
Authors: Shu Ting , Zhang Jiawei , Chen Zhihua , Zhou Yitian , Xing Yanjiang , Wang Jing , Wang Chen
Published: June 2023

Introduction:
Pulmonary hypertension (PH) is a severe life-threatening disease with insidious onset and high mortality, featured by pulmonary vascular remodeling and perivascular inflammatory cell infiltration. However, the precise immune mechanisms underlying PH remain unclear. Although an enhanced Th2 immune response in PH has been reported for years, the role of eosinophils (EOS), one of the Th2 effector cells, in PH is seldom reported. Investigating the roles and molecular mechanisms of EOS may present a novel paradigm of PH development.

Hypothesis:
EOS protect against PH through lipid metabolites.

Methods:
EOS infiltration and chemotaxis were investigated in peripheral blood and lung tissues from PH patients and sugen/hypoxia-induced PH mice. ΔdblGATA mice and anti-IL5 antibody (TRFK5)-treated mice were applied to investigate the role of EOS in PH development. Flow cytometry-based assays were used to quantify infiltration of different immune cells. The culture supernatants and lysates of EOS were collected to explore the mechanisms in co-culture cell experiments.

Results:
EOS accumulated in lung tissues from PH patients and mice, and the infiltration of EOS into pulmonary tissues during PH may be promoted by fibroblast-derived CCL11. Furthermore, EOS deficiency increased neutrophil (p=0.0038) and monocyte/macrophage (p=0.0344) infiltration and promoted pulmonary arterial smooth muscle cell proliferation, leading to aggravated PH in mice. Mechanistically, arachidonate 15-lipoxygenase (ALOX15), which catalyzes the production of pro-resolving lipid mediators, is specifically expressed by EOS.

Conclusions:
EOS play a beneficial role during PH development via ALOX15 and its downstream lipid mediators, suppressing perivascular inflammation and maintaining smooth muscle cell homeostasis.
Abstract 14568: Recognition of Cardiovascular Disease Related Risk Factors, Eligibility and Completion of Recommended Health Checks Among Australian Adults
Authors: Nijam Lucy C
Published: June 2023

Introduction:
Cardiovascular disease (CVD) is a leading cause of death in women globally. Risk factors include hypertension (HTN), hyperlipidaemia, high body mass index (BMI), diabetes, poor mental health and health literacy. Early identification and management of risk factors is imperative, given that CVD in women is often under-recognised.

Methods:
Using selected social media platforms a survey was conducted among adult Australians (>18yrs) in 2019, evaluating knowledge of risk factors for CVD, eligibility and completion of Australian Guideline recommended health checks.

Results:
Amongst 229 respondents 77% (177/229) were women. 62% of women (111/177) and 71% of men (37/52) were under the age of 44 years.

Women reported a mean of 5/12 risk factors and men reported a mean of 7/12 risk factors for CVD. Women were more likely to report family history compared to men (29.3%, 52/177; vs 9.61%, 5/52; p=0.001), hyperlipidaemia (29.3%, 52/177; vs 11.5%, 6/52; p=0.004), high BMI (37.85%, 67/177 vs 23%, 12/52 p=0.002), HTN (18%, 32/177; vs 5.76%, 3/52; p=0.015) and an unhealthy diet (35%, 62/177; vs 27%, 14/52; p=0.1382). Women were less likely to report inactivity (33% 59/177, vs 36.5%, 19.52; p=0.334). Smoking was the most frequently reported risk factor by both sexes (40.3%, 74/177 and 41.8%, 21/52; p=0.427).

Fewer women were aware of eligibility for a blood pressure check (9.6%, 17/177; vs 11.5%, 6/52; p=0.341), cholesterol (13%, 9/66; vs 33%, 5/15; p=0.034) and weight check (0%, 0/177; vs 2%, 1/52; p=0.033).

Awareness of eligibility for a diabetes check was similar between the sexes (12%, 8/66 in women vs 11%, 1/15 in men; p=0.272). More women had completed a blood pressure (71%, 126/177; vs 65%, 32/52; p=0.093) and weight check (34%, 61/177; vs 32%, 17/52; p=0.406) than men however less women had completed a cholesterol (52%, 34/66; vs 60%, 9/15; p=0.276) and diabetes check (21%, 14/66; vs 33%, 5/15; p=0.159).

Conclusion:
This pilot study found that knowledge of CVD risk factors and eligibility for health checks was low & risk factor profiles differed significantly between the sexes. Future studies evaluating a larger cohort are needed to further assess the significance of sex-based differences in awareness to risk factors, eligibility and completion of health checks.
Abstract 14572: Exposure to Multiple Size Fractions of Particulate Matter Air Pollution and Sudden Cardiac Death
Authors: Borchert William , Hart Jaime E , Nethery Rachel , Albert Christine M , Laden Francine
Published: June 2023

Introduction:
Recent literature has suggested an association between short-term exposures to air pollution and sudden cardiac death (SCD). There is little known on the relationship between medium- and long-term exposure to particulate matter air pollution (PM) and SCD. Moreover, most studies focus on PM less than 2.5μm in diameter (PM
2.5
) and have not considered larger coarse particles (PM
2.5-10
) or the effect of combined exposures.

Methods:
117,358 women in the Nurses’ Health Study, a nationwide prospective cohort, returned biannual questionnaires to update health status and risk factors. Suspected and definite SCD cases from 1988 to 2013 were identified by medical records and next of kin reports. Spatiotemporal models estimated the monthly exposures to PM at each residence. We calculated time-varying 12 month moving averages as a measure of long-term exposure and the difference between 12- and 3-month moving average and the difference between 3-month and 1-month moving averages as measures of medium-term exposure for both PM
2.5
and PM
2.5-10
. Time-varying Cox proportional hazard models were used to examine the association between all size fractions and time windows and SCD, and to calculate hazard ratios with corresponding 95% confidence intervals. The basic model was adjusted for age, year, season, and region, and a full model also considered demographics, medication use, health history, and socioeconomic status.

Results:
During 2,070,408 person-years of follow-up, there were total 351 definite and probable SCDs. Medium term exposures to both PM
2.5
and PM
2.5-10
were associated with risk of SCD, although the specific time windows of greatest risk varied (
Table 1
). Notably, in our full model, exposure to PM
2.5-10
was associated with SCD (Hazard Ratio: 1.07; 95% Confidence Interval: 1.02, 1.13).

Conclusions:
PM air pollution in the past month or season may be an important contributor to the population level risk of SCD.
Abstract 14583: Large-Scale Real-World Experience of Cardiovascular and Renal Outcomes Among Hypotensive HFrEF Patients Treated With Angiotensin Receptor-Neprilysin Inhibitor
Authors: Hsu Chien-Yi , Chang Hung-Yu , Chung Fa-Po , Hung Chung-Lieh
Published: June 2023

Background:
Hypotension remains a major clinical scenario limiting the use of
novel a
ngiotensin receptor-neprilysin inhibitors (ARNi) treatment for heart failure with reduced ejection fraction (HFrEF).

Hypothesis:
To explore the mid- to long-term cardiovascular and renal outcomes of ARNi treatment in HFrEF patients from a large-scale real-world setting.

Methods:
In a multi-center survey, we categorized totally 7,772 HFrEF patients (≥20 years, baseline renal replacement excluded) according to blood pressure (hypotensive status as systolic blood pressure <100mmHg) and ARNi use: Group1: Hypotensive/Non-ARNi users (n=488), Group 2: Hypotensive/ARNi users (n=311), Group 3: Normotensive/Non-ARNi users (n=4,700), and Group 4: Normotensive/ARNi users (n=2,273).

Results:
Hypotensive/Non-ARNi (Group 1) had smallest body mass and less likely to have baseline co-morbidity albeit higher prior myocardial infarction compared to other groups. Group 2 had slight yet significantly lower initiation dose of ARNi versus Group 4 (103.5±64.0 vs. 129.1±65.8 mg/daily, p<0.001). During a median 1.82-year follow-up, both Group 2/Group 4 HFrEF patients had significantly lower all-cause mortality and cardiovascular (CV) death, and a composite of HF hospitalization/CV death in a fully adjusted model, with Group 3 had lower all-cause and CV death (Group 1 as reference) (Table 1). There were fewer though non-significant adjusted incident new onset renal replacement therapy (HD) for Group 2, 3 and 4 compared to Group 1. Kaplan-Meier survival curves showed significant survival differences among 4 groups for all cardiovascular/mortality endpoints (all log-rank p: <0.001; worst in Group 1 vs. best survival in Group 4) except new onset HD (log-rank p: 0.29).

Conclusion:
Our current large-scale demonstrated that HFrEF patients with hypotension may still benefit from ARNi treatment. Hypotensive HFrEF patients should not be routinely excluded from ARNi use in a real-world setting.
Abstract 14584: Successful Cardiac Targeting of a Superoxide Dismutase-Loaded Nanoparticle in a Rodent Ischemia-Reperfusion Model
Authors: Herbst David A , Guevara-Plunkett Sara , Chhay Bonirath , Dominic Jessica , Iyengar Amit , Weingarten Noah , Meldrum Danika , Helmers Mark R , Tsourkas Andrew , cheng zhiliang , Atluri Pavan
Published: June 2023

Introduction:
Encapsulating superoxide dismutase (SOD) in a semi-porous nanoparticle (NP) preserves myocardial function in rats following ischemia-reperfusion (I/R) injury. Cardiac targeting maximizes enzyme efficacy by enhancing retention. This study describes the formulation, characterization, and functional analysis of cardiac myosin (CM) targeted SOD NP.

Method
Targeted SOD NP with anti-CM antibody was developed in three steps and characterized with dynamic light scattering (DLS), colorimetric SOD assay, and in vitro imaging with isolated mature rat cardiomyocytes. In vivo function was assessed with a rat model of cardiac I/R injury in which the LAD was occluded for 60 minutes, ligation was released, and treatments were injected in the myocardium. Animals were recovered for 28 days and terminal pressure-volume (PV) loop analysis was performed.

Result
Anti-CM SOD NP was formulated by first encapsulating SOD in a polymersome containing an azide functional group. Second, a photoreactive antibody-binding domain was bonded to the azide. Third, covalent bonding of the NP to anti-CM antibody was performed with UV-light activation (Fig 1A). Consistent size was confirmed by DLS during formulation (Fig 1B). In vitro visualization of rhodamine-tagged anti-CM NP bound to mature cardiomyocytes confirmed antibody conjugation (Fig 1C). SOD activity was preserved during formulation and after degradation with Triton X, confirming conjugation did not affect porosity (Fig 1D). 53 rats underwent I/R injury and were randomized to 4 treatment groups of which 44 survived to terminal analysis (Fig 1E). Rats injected with anti-CM SOD NP had preserved EF (med 57%) and significant improvement in EF compared to PBS (med 40%, p=0.04).

Conclusion
Cardiac targeting of SOD NP with anti-CM antibody was successful and preserved EF in a rat I/R model. Ongoing future steps include correlation of scar volume with PV loop data, myocardial retention analysis and biodistribution of anti-CM NP.
Abstract 14605: Deleterious Effects of Type 2 Diabetes on the Myocardium of Patients With Aortic Stenosis
Authors: CHERPAZ Maelle , SEILLIER Gaultier , Bergerot Cyrille , Pozzi Matteo , Pierrard Romain , Chanon StÃ©phanie , Brun Camille , Chalabreysse Lara , May Chloe , Givre Lucas , Farhat Fadi , Vola Marco , Obadia Jean François , Amaz Camille , Paillard Melanie , Thibault Helene
Published: June 2023

Introduction:
Type 2 diabetes (T2D) may induce myocardial alterations and is associated with an increased risk of heart failure. T2D is often associated to LV pressure overload, as encountered in aortic stenosis (AS).

Hypothesis:
We hypothesized that T2D has deleterious effects on LV remodelling and function in patients with severe AS and we explored some underlying mechanisms.

Methods:
Non diabetic and T2D patients with severe AS, referred for aortic valve replacement, were included. Patients with atrial fibrillation, LV ejection fraction (LVEF) <50%, significant coronaropathy or other valvulopathy were excluded. Before surgery, patients underwent blood tests and a complete echocardiography. During surgery, a LV myocardium biopsy was obtained for histological analysis.

Results:
We included 82 patients, including 33 T2D. Hypertension and dyslipidaemia were more frequent in T2D patients. Severity of the AS was similar between the two groups. Echocardiography revealed that T2D was associated with a more pronounced LV hypertrophy (mass LV 3D/hight
2.7
; p=0.03) and systolic dysfunction (Global Longitudinal Strain (GLS) 15±3 vs 18±2 %; p<0.01). In addition, LV ventricular filling pressure was more often increased in T2D patients (50% of T2D vs 26% of non-diabetics; p=0.03). Circulating levels of leptin and endothelin 1 were significantly higher in T2D. Interestingly leptin level correlates with diastolic function (left atrial strain; r=-0.25, p=0.01) and Endothelin 1 with LV mass (r=0.27, p<0.001) and GLS. Histologic analysis revealed an enhanced cardiomyocyte hypertrophy in T2D biopsies but similar degrees of fibrosis. Proximity ligation assay displayed a significant decreased proximity between the IP3-receptor and the mitochondrial porin VDAC in T2D hearts suggesting a reduced reticulum-mitochondria Ca
2+
transfer.

Conclusions:
T2D is associated with an increased LV remodelling and dysfunction in patients with a severe AS as well as an increased circulating level of leptin and endothelin-1. Our results also suggest a potential role of reticulum-mitochondria Ca
2+
uncoupling.
Abstract 14610: Geographic Differences Among Patients With Acute Myocardial Infarction in the PARADISE-MI Trial
Authors: Butt Jawad H , Sim David , Claggett Brian , Jering Karola , van der meer peter , Kerkar Prafulla , Nuez Llota Julio E , Cadena Alberto , Ntsekhe Mpiko , Zhou Yinong , Kober Lars , McMurray John J , Pfeffer Marc A
Published: June 2023

Introduction:
The globalization of clinical trials has highlighted geographic differences in patient characteristics, treatments and outcomes, but there are few data on those with high-risk acute MI. We examined these differences in PARADISE-MI, the most globally representative trial in high-risk MI patients to date

Methods:
PARADISE-MI enrolled 5661 patients with an acute MI complicated by left ventricular dysfunction and/or pulmonary congestion; 23.0% were randomized in Eastern Europe/Russia (EER), 17.5% Western Europe, 12.2% Southern Europe, 10.1% Northern Europe (NE), 12.0% Latin America (LA), 9.3% North America (NA), 10.0% East/South-East Asia, 5.8% South Asia (SA)

Results:
Those from Asia, particularly SA, were notably different from patients enrolled in the other regions - they were younger, thinner and had a different pattern of comorbidities (high prevalence of diabetes despite lower BMI, and very low prevalence of AF), type of MI (more often STEMI) and treatment (low rate of primary PCI). By contrast, the characteristics of patients from LA did not differ meaningfully from those in Europe or NA. Use of ACEi/ARB (34.8%) and beta-blockers (65.5%) was remarkably low in SA, whereas MRA use was lowest in NA (21.8%) compared with the highest rate (53.0%) in EER. Rates of the primary composite outcome of cardiovascular death or incident HF varied two-fold among regions with the lowest rate in SA (4.6 / 100 person-years [PY]) and the highest in LA (9.2 / 100 PY). Strikingly, rates of incident HF varied almost six-fold among regions with the lowest rate in SA (1.0 /100 PY) and the highest in NE (5.9 /100 PY). Conversely, the rate of death from any cause varied about two-fold among regions (Figure) with the lowest rate in NA (2.4 /100 PY) and the highest in LA (5.3 / 100 PY) although the rate in the other six regions differed little (range 3.9 to 4.7 / 100 PY)

Conclusion:
In PARADISE-MI, there were substantial regional differences in patient characteristics, treatments and outcomes
Abstract 14629: Predictive Model Testing for Life-Sustaining Treatment Decisions at the End-of-Life: Applying Machine Learning Methods
Authors: An Minjeong , Lim Hoi-Jeong , Heo Seongkum , Kim Jongho , Kim JinShil
Published: June 2023

Introduction:
Predictive models of factors affecting decisions about life-sustaining treatments (LSTs) have been frequently examined, but the accuracy and precision of those models remain elusive. Machine learning algorithms (MLAs) may help identify the best model in terms of its performance measures.

Objectives:
To determine the best MLA to predict LST preferences (cardiopulmonary resuscitation [CPR], ventilation support, and hemodialysis, and hospice care).

Methods:
In this secondary analysis, three MLA-based prediction models of LST preferences, including seven known predictors, were developed based on random forest (RF), logistics regression (LR), and linear support vector machine (SVM), and were evaluated by a five-fold validation set comprising accuracy, precision, area under the receiver operating characteristic curve, recall, and F1 score.

Results:
Among 375 adults with malignancy or non-malignancy diseases or healthy adults, 23.2% preferred CPR, 17.9% ventilation support, 19.2% hemodialysis, and 60.8% hospice care. Compared to RF and LR, SVM was the most accurate and precise model to predict each preference of CPR (0.78 vs. 0.85; 0.15-0.44 vs. 0.75, respectively), ventilation support (0.84 vs. 0.88; 0.00-0.10 vs. 0.89, respectively), hemodialysis (0.82 vs. 0.84; 0.33-0.54 vs. 0.69, respectively), and hospice care (0.64-0.68 vs. 0.85; 0.65-0.70 vs. 0.84, respectively). In the models, age, attitudes toward advance directives, and susceptibility to end-of-life care were reported as common predictors with relatively high importance on LST preferences (Table 1).

Conclusions:
SVM was the best model in identifying predictors of LST preferences in people with or without chronic diseases. In addition, the findings suggest important targets of interventions, including attitudes toward advance directives, and susceptibility to end-of-life care, to assist people to make the best decisions for their future medical care.
Abstract 14630: Cigarette Smoking and Risk of Carotid Atherosclerotic Lesions Among Chinese Adults With or Without Cardiometabolic Disorders: A Longitudinal Study
Authors: Song Mingyu , Liu Jieyu , Xiao Meng , Wang Yueqing , Yang Haiming , Zhao Yuxuan , Yu Canqing , Ma Yuan , Lv Jun , Li Liming , Wang Bo , Sun Dianjianyi
Published: June 2023

Backgroud:
Cigarette smoking is closely associated with the presence of carotid atherosclerotic lesions (CAL); however, whether such association differs in participants with or without cardiometabolic disorders (CD) is largely unknown.

Methods:
A dynamic retrospective cohort study of health checkup data was used from the Beijing MJ Health Screening Centers. A total of 14 410 participants were included among those who took both routine tests and carotid ultrasonography (CU) at least twice from 2008 to 2018 and had no CAL at the first time. Information on smoking status was collected from self-reported questionnaires. CAL was defined as increased carotid intima-media thickness, carotid plaques, or carotid stenosis. CD was defined with the presence of hypertension, diabetes, and/or dyslipidemia. The associations of smoking with CAL among participants with or without CD and the joint effect of smoking and CD were estimated by logistic regression.

Results:
Among 5810 and 8600 participants with and without CD at baseline, 2016 and 1386 developed CAL during follow-up, respectively. We found the status of CD significantly modified the associations between smoking and CAL (
P
interaction
<

0.01). Among participants without CD, non-current smoking was independently associated with a decreased risk of CAL (odds ratio [OR] and 95% confidence interval [CI]: 0.80 [0.68-0.94]). Whereas, such association was not observed among CD patients. In joint analyses, compared with current smokers with CD (CD
+
&smoking
+
), the ORs (95% CIs) were 0.72 (0.61-0.84), 0.94 (0.82-1.07), and 0.56 (0.49-0.64) for participants in the CD
-
&smoking
+
, CD
+
&smoking
-
, and CD
-
&smoking
-
group, respectively.

Conclusion:
Never and former smokers without CD might have a lower risk of CAL, but not the ones prevalent with CD, highlighting the carotid atherosclerotic benefits of early smoking cessation.
Abstract 14649: Low Plasma Transthyretin is Associated With All-Cause and Cardiovascular Mortality in the General Population
Authors: Christoffersen Mette , Greve Anders M , Hornstrup Louise S , Nordestgaard Borge G , Tybjaerg-hansen Anne
Published: June 2023

Introduction:
Transthyretin tetramer destabilization is the rate-limiting step in transthyretin cardiac amyloidosis, which is an underrecognized contributor to heart failure and mortality in older adults. Evidence suggests that low plasma transthyretin is an
in vivo
marker of transthyretin tetramer instability.

Hypothesis:
We tested the hypothesis that low plasma transthyretin genetically and observationally associates with all-cause and cardiovascular mortality.

Methods:
We genotyped 102,204 individuals and measured plasma transthyretin concentrations in 19,619 individuals from two studies of the Danish general population, the Copenhagen City Heart Study and the Copenhagen General Population Study. We first tested whether genetic variants in
TTR
, which associated with increasing transthyretin tetramer instability, also associated with lower plasma transthyretin and higher risk of all-cause and cardiovascular mortality. Second, we tested whether low plasma transthyretin associated with higher risk of all-cause and cardiovascular mortality.

Results:
Compared to p.T139M, a well-known transthyretin stabilizing mutation,
TTR
genotype was associated with stepwise lower transthyretin concentrations of -20% for wild-type and -30% for heterozygotes for “Other mutations” (p.V142I, p.H110N, p.D119N). The corresponding hazard ratios (HR) for all-cause and cardiovascular mortality were 1.37(95% CI: 1.06-1.77) and 1.63(0.92-2.89) in wild-types, and 1.66(0.95-2.88) and 2.23(0.78-6.34) in carriers of “Other mutations”, respectively (Figure). In adjusted observational analysis individuals with plasma transthyretin ≤5
th
percentile (<19.1 mg/dL) versus 6-95
th
percentile (reference) had HRs of 1.39(1.17-1.64) and 1.66(1.17-2.38) for all-cause and cardiovascular mortality.

Conclusions:
Genetically and observationally low transthyretin concentrations are associated with higher risk of all-cause and cardiovascular mortality.
Abstract 14672: Regulation of Succinate Signaling and Immunometabolism in Diabetes-Associated Atherosclerosis by Microrna-369-3p
Authors: Rawal Shruti , Rizvi Syed Husain M , Wara Akm , Sachan Madhur , Randhawa Vinay , Weisbrod Robert M , Asara John , Hamburg Naomi M , Feinberg Mark W
Published: June 2023

Introduction:
The risk of atherosclerotic cardiovascular disease (ASCVD) is increased in people with diabetes. Diabetes (D) is associated with impaired metabolism and functionality of macrophages (Mps), resulting in chronic inflammation. Identifying factors to combat metabolic alterations and promote resolution of inflammation remains an unmet goal. microRNAs (miRs) orchestrate multiple signaling events in Mps and regulate inflammation.

Hypothesis:
miR-369-3p regulates metabolic reprogramming in Mps during diabetes-associated atherosclerosis (D-AS).

Methods and Results:
miRNA-seq profiling from aortic intimal lesions of LDLR-/- mice on a high-fat sucrose containing (HFSC) diet revealed miR-369-3p downregulation with D-AS progression. miR-369-3p was also downregulated in PBMCs derived from D and D-associated ASCVD patients. Cell-type profiling showed miR-369-3p enrichment in mouse bone marrow derived Mps (BMDMs). oxLDL-stimulated BMDMs (foam cells, FCs) resulted in marked downregulation of miR-369-3p, increased secretion of IL1-β, and metabolic shift of oxidative phosphorylation (OXPHOS) to glycolysis, while miR-369-3p overexpression (miR-369-3p O/E) favored OXPHOS over glycolysis and reduced IL1-β secretion. Metabolomics revealed succinate, a key immunometabolite was profoundly elevated extracellularly from FCs, while miR-369-3p O/E reversed this phenotype. Extracellular succinate activates its receptor, GPR91. Indeed, GPR91 was upregulated in FCs while miR-369-3p O/E significantly repressed GPR91. 3’UTR luciferase reporter assay confirmed GPR91 as a miR-369-3p target. miR-369-3p O/E dampened GPR91-mediated inflammasome activation and mitochondrial dysfunction in FCs by decreasing p-ERK, p-DRP1, and NLRP3. Therapeutic delivery of miR-369-3p in LDLR-/- mice fed HFSC diet for 12 weeks reduced plaque size by ORO staining and plasma IL1-β. Flow cytometry of aortic Mps revealed that miR-369-3p decreased GPR91 expression by ~50%, along with a decrease in M1 and increase in M2-like-Mps.

Conclusions:
miR-369-3p confers a pro-resolving role in regulating lipid-driven inflammation and metabolic rewiring in Mps via targeting GPR91 and preventing D-AS plaque progression.
Abstract 14675: High-Throughput CRISPR Screening Links CAD Loci to Endothelial Cell Programs and Causal Pathways
Authors: Gupta Rajat M , Schnitzler Gavin R , Kang Helen , Ma Rosa R , Lee-Kim Vivian , Zeng Anthony , Zhou Ronghao , Vellarikkal Shamsudheen K , Sias Oscar , Munson Glen , Guo Katherine , Cleary Brian , Lander Eric , Engreitz Jesse M
Published: June 2023

Introduction:
Genome-wide association studies (GWAS) have discovered >300 associations for CAD. Few loci are functionally characterized and may represent new mechanisms of disease.

Hypothesis:
Can a high-throughput, unbiased transcriptional screen for all candidate GWAS genes identify the causal genes and biological pathways at CAD GWAS loci in endothelial cells (ECs)?

Methods:
We applied CRISPRi-Perturb-seq to knock down the expression of all genes within 500 Kb of coronary artery disease GWAS loci (2,300 genes in total) and measure their effects on the transcriptome using single-cell RNA-seq.

Results:
We identified 60 programs of co-expressed genes, which represent core cellular pathways (i.e. ribosome biogenesis) and EC-specific pathways such as flow response and angiogenesis. The EC-specific programs show the greatest contribution to CAD heritability. 6 EC-specific programs have the greatest number of CAD GWAS candidate genes. One of the EC-specific programs had genes regulated by
KLF
-transcription factors and was enriched for shear-stress response genes. The novel CAD candidate genes in this program included multiple known mediators of the cerebral cavernous malformation (CCM)-signaling complex. 9 known members of the CCM-signaling cascade and several potentially novel mediators of CAD clustered together in the
KLF
Perturb-seq topic. These included genetic variants in the
CCM2
,
KLF4
,
RAC1
, and
HEG1
loci as well as genes will a similar transcriptional profile but no prior connection to the CCM-signaling complex.

Conclusions:
High-throughput functional analysis of 2,300 genes proximal to CAD GWAS loci prioritized pathways—such as angiogenesis and EC migration—that are regulated by multiple risk SNPs. Our study identifies new genes that likely influence risk for CAD, identifies convergence of CAD genes into certain pathways in endothelial cells, and demonstrates a generalizable strategy to connect disease variants to functions.
Abstract 14681: Quantitative Whole Blood Platelet Aggregation Predicts Occurrence of Subacute Thrombosis in Patients After Percutaneous Coronary or Peripheral Intervention
Authors: Funabashi Nobusada , Misumi Kazuo
Published: June 2023

Introduction:
The risk of subacute thrombosis (SAT) after percutaneous coronary intervention (PCI) or percutaneous peripheral intervention (PPI) is high if patients show high whole blood platelet aggregation.

Hypothesis:
For such high-risk patients, even though dual antiplatelet therapy is performed, whole platelet aggregation should be quantitated and if high, the indication for additional antiplatelet therapy determined.

Methods:
This is a retrospective analysis of 12095 stents from 12095 patients (9173 males; mean age 69±11 years; 9470 PCI, 2625 PPI). The whole blood platelet aggregatory threshold index (PATI; WBA-Neo; ISK, Osaka, Japan) was calculated. PATI was used to determine the minimum concentration of adenosine 5'-diphosphate causing a non-reversible aggregation of platelets and indicated platelet aggregation (range 0-8 μM). The higher the PATI, the lower the platelet aggregation. All patients received single or double antiplatelet drug therapy according to physician choice.

Results:
SAT occurred in 18 (0.19%) of 9470 patients after PCI and in 9 patients (0.34%) of 2625 patients after PPI. Of 9470 patients after PCI, total blood PATI was 4.40 in 18 patients with SAT and 7.00 in 9452 patients without SAT (P<0.001). Of 2625 patients after PPI, the total blood PATI was 4.97 in nine patients with SAT and 6.39 in 2616 patients without SAT; the former was significantly lower than the latter (P<0.001). We combined patients with PCI and PPI. PATI was divided into nine grades: 0-0.99, 1-1.99, 2-2.99. 3-3.99, 4-4.99. 5-5.99, 6-6.99, 7-7.99, and >7.99. Of 12095 patients, if PATI was 0-0.99, the incidence of SAT was greatest at 1.89%. If PATI was >7.99, the incidence of SAT was lowest at 0.09%. We divided 12095 patients into two groups: PATI of 0-4.99 (N=2229) and PATI of >4.99(N=9866); the incidence of SAT was greater in the former (0.72%) than latter (0.11%; P<0.001). No significant differences existed in the percentage of each coronary risk factor between patients with and without SAT after PCI, PPI, and PCI or PPI.

Conclusions:
In patients after PCI and/or PPI, despite single or double antiplatelet drug therapy, the whole blood platelet aggregation should be checked, and if PATI is 0-4.99 the indication for additional antiplatelet therapy should be considered.
Abstract 14689: Evaluation of Left Myocardial Mechanics in Pediatric Heart Transplant Patients by Speckle Tracking Echocardiography
Authors: Xie Yuji , Zhu Shuangshuang , Zhang Yiwei , Wu Anjun , Sun Chenchen , Xie Mingxing , Zhang Li
Published: June 2023

Objective:
The aim of this study was to evaluate the left myocardial mechanics in pediatric heart transplant (PHT) patients after heart transplantation by three- dimensional speckle tracking echocardiography (3D-STE).

Method:
We retrospectively analyzed thirty-eight pediatric patient who underwent orthotopic heart transplantation from January, 2015 to December, 2021 at Union Hospital, Tongji Medical College, Huazhong University of Science and Technology. Clinical characteristics and conventional echocardiographic indices were described. 3D-STE were used to analyze myocardial mechanics in thirty-eight PHT patients. Left ventricular strain and rotational indices at 6 month and 1 year after heart transplant were obtained. Differences between left ventricular myocardial mechanic indices at 6 months and 1 year after heart transplant were analyzed and compared with normal reference range.

Results:
There were no statistically significant difference of LVGLS, LVGCS, LVGRS, 3D-apical peak rotation, 3D-basal peak rotation, 3D-peak twist, and 3D-peak torsion in PHT patients between 6 months and 1 year after heart transplantation(
P
>0.05). Compared with 3D strain normal reference, 3D-LVGLS decreased and 3D-LVGCS increased in PHT patients at 6 months after transplantation(
P
<0.05). Compared with 3D rotational normal reference, 3D-peak twist and 3D-peak torsion increased at 6 months after transplantation(
P
<0.05).

Conclusion:
Compared with normal reference range, strain parameters were decreased and rotational parameters were increased. The study provided evidence for further investigations in establishing normal reference range of left ventricular myocardial mechanics in PHT patients and post-transplantation management of PHT patients.