bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 10931: Impact of Atrial Fibrillation Type (paroxysmal vs. Non-paroxysmal) on Long-Term Clinical Outcomes: The Raffine Registry Subanalysis
Authors: Wada Hideki , MIYAUCHI Katsumi , SUWA Satoru , Miyazaki Sakiko , Hayashi Hidenori , MIYAZAKI Tadashi , Sumiyoshi Masataka , NAKAZATO YUJI , Minamino Tohru , Daida Hiroyuki
Published: June 2023

Background:
Type of atrial fibrillation (AF) (paroxysmal or non-paroxysmal) is important for determining the therapeutic management. However, prognostic impact of AF type on incidence of cardiovascular events remains uncertain.

Methods:
We investigated patients with AF who were selected from an observational, multicenter, prospective registry (RAFFINE) comprising 4 university hospitals and 50 general hospital / clinics in Japan between 2013 and 2015. In this subanalysis of the RAFFINE trial, patients were divided into 2 groups according to their AF pattern at the time of enrollment. The primary outcome was composite of all-cause death, ischemic stroke, and heart failure related hospitalization.

Results:
Among 3,845 patients, 1,472 (38.3%) and 2,373 (61.7%) were paroxysmal and non-paroxysmal AF, respectively. Patients with non-paroxysmal AF were older, higher CHADS
2
score and had higher prevalence of comorbidities compared with those with paroxysmal AF. During a median follow-up of 3.7 years, 681 (17.7%) primary endpoints were identified. Cumulative incidences of primary endpoint were significantly higher in non-paroxysmal AF group (log-rank p<0.0001,
Figure
), however, rates of bleeding events were not significantly different between groups. Multivariate cox hazard analysis showed that non-paroxysmal AF had significantly higher risk of cardiovascular events compared with paroxysmal AF (adjusted hazard ratio: 1.38, 95% confidence interval 1.17-1.64, p = 0.0002).

Conclusions:
In the RAFFINE registry, non-paroxysmal AF was significantly associated with worse clinical outcomes among AF patients. Long-term clinical outcomes might be improved if the transition paroxysmal to non-paroxysmal AF can be prevented.
Abstract 11027: SGK1 Inhibition and Attenuation of the Action Potential Duration in Re-Engineered Heart Cell Models of Drug-Induced QT Prolongation
Authors: Tester David J , Sager Philip T , Kim Maengjo , Pradhananga Sabindra , Hamrick Samantha K , Srinivasan Dinesh , Das Saumya , Ackerman Michael J
Published: June 2023

Background:
Drug-induced QT prolongation (DI-QTP) is a clinical entity in which administration of a HERG/I
Kr
blocker such as dofetilide prolongs the cardiac action potential duration (APD) at the cellular level and the QT interval clinically, and increases the risk for a potentially lethal, QT-triggered ventricular arrhythmia. There may be a role for inhibition of I
NaL
to counter DI-QTP. Recently, we have shown that inhibition of serum and glucocorticoid regulated kinase-1 (SGK1) reduces the APD90 in induced pluripotent stem cell derived cardiomyocytes (iPSC-CM) from patients with LQT3 and ameliorates increases in I
NaL
.

Objective:
To test the efficacy of novel SGK1 inhibitors (SGK-I) in re-engineered cardiomyocyte models of dofetilide-induced APD prolongation.

Methods:
Normal iPSC-CMs were treated with dofetilide [5 nM] to produce a DI-QTP iPSC-CM model. The SGK1-I’s therapeutic efficacy for shortening the dofetilide-induced APD90 prolongation was compared to mexiletine. The APD90 values were recorded 4 hours after treatment using FluoVolt, a voltage-sensitive fluorescent dye.

Results:
The APD90 was significantly prolonged in normal iPSC-CMs treated with dofetilide (673 ± 8 ms with dofetilide vs 436 ± 4 ms with DMSO, p<0.0001). While 10 μM mexiletine shortened the average APD90 of dofetilide-treated normal iPSC-CMs from 673 ± 4 ms to 563 ± 8 ms (46% attenuation, p<0.0001), 30 nM of SGK-I shortened the APD90 from 673 ± 4 ms to 478 ± 10 ms (82% attenuation, p<0.0001).

Conclusions:
Therapeutically inhibiting SGK1 effectively shortens the cardiomyocyte APD in a human heart cell model of DI-QTP. The novel SGK1 inhibitor normalized the pathological APD prolongation almost fully (> 80%) in the iPSC-CM model treated with dofetilide. This pre-clinical data supports further development of this therapeutic strategy to counter and neutralize the threat of DI-QTP.
Abstract 11029: Bioenergetic Independent Stress Signaling in the Heart Due to Mitochondrial Protein Import Stress
Authors: Rana Arnav , Wang Xiaowen , Chen Xin Jie
Published: June 2023

Mitochondrial diseases are some of the most common genetically inherited disorders, yet the prognosis for affected patients has not drastically improved in recent years. Most therapies are supportive as the underlying biochemical derangements in these diseases are incompletely understood. Mitochondrial functions rely on the import of nuclear-encoded proteins, and it has recently been appreciated that defective import of mitochondrial proteins can result in the cytosolic accumulation of these preproteins. The accumulation of these preproteins results in cellular toxicity independently of any changes to the mitochondrial bioenergetic function, raising the possibility that mitochondrial protein import stress may be a yet uncharacterized pathway that links mitochondrial dysfunction with pathology. Here, we model this cytosolic mitochondrial precursor overaccumulation stress (mPOS) in mice through overexpression of the inner mitochondrial membrane protein Adenine Nucleotide Translocase 1 (ANT1). The goal of this study is to determine whether ANT1 can induce mPOS and tissue remodeling prior to the onset of cardiac bioenergetic defects. Using isolated cardiac mitochondria from these mice, we detected a moderate decrease in the levels of Complex I, II ,and IV. By measuring oxygen consumption in these mitochondria from 2-month-old animals, we found only a mild reduction in complex II based state 3 and 4 respirations. No change in complex I-based state 3 and 4 respirations was observed. Using RNAseq and western blot analysis, we find the robust activation of the integrated stress response (ISR). Transcriptomic data further demonstrates a strong upregulation of transcripts involved with 1-carbon metabolism, the amino acid starvation response, and proteolysis. Using echocardiographic evaluation of heart function on anesthetized mice at 6 months old, we find no significant alteration in systolic function. Together these data support the idea that mPOS may be a potent trigger of the ISR in a bioenergetics-independent manner. Whether activation of the ISR can alter cardiac function later in life is being evaluated.
Abstract 11817: Induced Pluripotent Stem Cell-Derived Cardiac Disease Modeling for Studying Mitogenic Cardiomyopathy in Alström Syndrome
Authors: Duelen Robin , Costamagna Domiziana , Chai Yoke Chin , Caluwe Ellen , Gillijns Hilde , Jacobs Johanna , Wu Ming , Malgrange Brigitte , devriendt koenraad , Sampaolesi Maurilio , Janssens Stefan P
Published: June 2023

Introduction:
Cardiomyopathies are a prominent cause of heart failure and affect millions of people worldwide. We reported two case studies describing siblings with a mutation in the
Alström 1 (ALMS1)
gene causing Alström syndrome (ALMS), who developed mitogenic cardiomyopathy, characterized by delayed postnatal cardiomyocyte (CM) cell cycle arrest resulting in neonatal heart failure and death in early infancy.

OBJECTIVES
: To generate induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) from ALMS patients and investigate molecular mechanisms of persistent CM proliferation in co-culture with ALMS1 fibroblasts.
METHODS
: We reprogrammed somatic cells from ALMS patients with mitogenic cardiomyopathy into iPSCs using Sendai virus technology and generated ALMS-specific iPSC-CMs using established
in vitro
differentiation protocols. We analyzed cell cycle progression by determining CM percentages in the G0/G1, S and G2/M phase using flow cytometry, and measured expression and secretion of periostin (POSTN) and collagens from ALMS1 fibroblasts in the extracellular matrix (ECM) using RT-QPCR and western blot. Finally, we investigated Hippo signaling by measuring expression and nuclear translocation of its downstream effectors YAP/TAZ using western blot and immunostaining.

RESULTS
: iPSC-CMs were successfully generated from ALMS patients and controls. ALMS1-deficient iPSC-CMs exhibited impaired ability to undergo cell cycle arrest, evidenced by a higher cell percentage in the G2/M phase. Furthermore, increased ECM levels of POSTN, a potent regulator of CM proliferation, were observed in co-cultures of ALMS1-deficient iPSC-CMs and ALMS1 fibroblasts. Finally, we found preliminary evidence of dysregulation of the Hippo pathway with altered cellular localization of YAP, and dysregulated total YAP and phosphorylated YAP.

CONCLUSION
: ALMS1-deficient iPSC-CMs recapitulate persistent postnatal proliferation observed in ALMS patients with mitogenic cardiomyopathy. Increased POSTN in the ECM and altered downstream Hippo signaling contribute to the mitogenic phenotype and suggest critical cues for future therapies aiming at stimulating CM turnover, a much-sought objective in cardiac repair to improve contractile function.
Abstract 12023: The Serum ACE2 Molecule in SARS-CoV2 / COVID-19 Infection and Its Potential Prognostic and Therapeutic Role (ACCEPT Study)
Authors: Fioretti Francesco , Sammartino Antonio Maria , Ravasio Francesco , Praderio Angelica , Inama Lorenza , Pagnesi Matteo , Pallotti Francesco , Nodari Savina
Published: June 2023

BACKGROUND:
It is well known that the entry of the SARS- CoV-2 into cells is mediated by the binding between the virus Spike-glycoprotein (S) and the membrane ACE2-receptor (ACE2R). When SARS-CoV-2 binds to ACE2R, a down-regulation of ACE2R occurs, playing a crucial role in the inflammatory response. Also ACE2 deficiency is thought to play an important role in the pathogenesis of SARS-CoV-2 infection, and could be particularly harmful in subjects with pre-existing ACE2 deficiency, for example due to advanced age, the presence of DM, arterial hypertension or pre-existing heart disease, including HF.
AIM OF THE STUDY:
we aimed to identify predicting factors of a higher risk in terms of severity of the clinical course and worse prognosis in the population of the Brescia area, affected by a large number of cases in the first period of COVID-19 outbreak. In particular, we aimed to verify whether there is correlation between levels of serum ACE2 (sACE2) and the risk of SARS-CoV-2 infection, as well as between sACE2 and the different severity of the clinical manifestations of COVID-19 in pts with and without CV diseases.

Methods:
we enrolled subjects with previous documented SARS-CoV-2 infection and divided they into three groups: pts with asymptomatic course; pts with symptomatic course but without the need for hospitalization for COVID-19; pts with severe symptomatic course requiring hospitalization in ICU. Blood samples were taken for sACE2 dosage. We compared the concentrations of sACE2 in these groups in relation to the age, clinical course, comorbidities, and ongoing therapies.

Results:
at March 2022, we enrolled 178 pts, 51 (28%) were hospitalized for COVID-19, whereas 78 (44%) had symptomatic course without hospitalization and 49 (28%) were completely pauci-asymptomatic. Only 6 pts (4%) had myocarditis or pericarditis SARS-CoV-2-related. Between hospitalized pts, male sex (67%), older age and higher BMI were most frequent. Moreover, chronic heart failure (20%), a diagnosis of cardiopathy (29%) and AF or atrial flutter (22%) were most frequent.
PERSPECTIVES:
ACCEPT study will help to clarify the relationship between ACE2 molecule, the risk of SARS-CoV2 infection and the severity of clinical presentation of COVID-19 in pts with or without CV diseases.
Abstract 12093: Inter-Reader Reliability of Coronary Calcium Estimation From Non-Gated Chest Computed Tomography Scans Using a Semi-Quantitative Scoring Method
Authors: Dhaduk Nehal , Choi Daniel , Maidman Samuel , Hayes Dena , Smilowitz Nathaniel , Donnino Robert
Published: June 2023

Introduction:
Coronary artery calcium (CAC) is strongly associated with cardiovascular risk. CAC burden can be qualitatively estimated from non-gated chest computed tomography (CT) imaging and may be used to predict future cardiovascular outcomes. We evaluated whether resident physician trainees can reliably estimate CAC burden from existing non-gated chest CTs using a semi-quantitative scoring method.

Methods:
A group of 4 resident physicians without formal training in CT image interpretation underwent a training session to qualitatively estimate CAC burden from non-gated, contrast and non-contrast CT scans. CAC was estimated for each coronary artery as absent, mild (1-24% vessel length), moderate (25-49% vessel length) and severe (>50% vessel length). All Chest CTs were reviewed by two physicians, each blinded to the interpretations of the other reviewer, to assess (a) the presence or absence of CAC, (b) the presence or absence of moderate-severe CAC, and (c) a semi-quantitative CAC index, at a per-patient level and by vessel. Inter-reader reliability (IRR) was assessed by percent agreement, Cohen's kappa coefficient, and the intraclass correlation coefficient (ICC).

Results:
Using a semi-quantitative scoring system to estimate an index of overall CAC burden, the ICC was 0.96 (CI 0.94-0.98). The percent agreement for the presence of any CAC was 74% (kappa 0.82) and 89% for moderate-to-severe CAC (kappa 0.85). The IRR stratified for each coronary vessel is shown in
Table 1.
CAC estimated from both contrast and non-contrast scans was associated with substantial agreement between readers (
Table 1
).

Conclusions:
With a single training session, resident physicians can quickly and reliably estimate CAC burden from non-gated chest CT imaging. This may facilitate cardiovascular risk stratification in patients without dedicated cardiac testing.

1b
Abstract 12263: Lack of Diversity in Aortic Stenosis Progression Cohorts: A Systematic Review
Authors: Man Joshua J , Trinquart Ludovic , Mohanty Sharanya , Wessler Benjamin S
Published: June 2023

Introduction:
Aortic stenosis (AS) is characterized by highly variable progression rates. Differential rates of AS progression have been proposed to explain apparent disparities in the treatment of severe AS. However, the evidence supporting this claim is uncertain.

Methods:
We conducted a systematic review of MEDLINE and EMBASE from 1989 to 2022 to identify prospective cohort studies of AS hemodynamic progression. We evaluated the pooled patient demographics, AS severity, baseline and mean annual changes in echocardiographic markers, and prognostic factors.

Results:
We identified 32 prospective cohort studies. Overall, 11,432 patients were followed for 27 +/- 15 months on average. The average age was 67 +/- 8 years. The average percent female was 36 +/- 14%. Race was reported in only 4 (13%) cohorts; the average proportion of white patients was 93.9 +/- 6.1%. The average baseline hemodynamic severity was consistent with aortic sclerosis, mild AS, moderate AS, and severe AS in 3 (9.4%), 8 (25.0%), 19 (59.3%), and 2 (6.3%) studies, respectively. Overall, average baseline and annual changes in echocardiographic values were: peak aortic jet velocity (Vmax) 3.21 +/- 0.61 m/s (0.20 +/- 0.09 m/s/yr); aortic valve area (AVA) 1.23 +/- 0.31 cm2 (-0.09 +/- 0.05 cm2/yr); and mean aortic valve gradient (MG) 26.2 +/- 7.6 mmHg (3.9 +/- 1.6 mmHg/yr). Age, sex, coronary artery disease, hypertension, diabetes, hyperlipidemia, and smoking were not associated with AS progression in >75% cohorts. Baseline Vmax and MG were associated with greater AS progression in 6 cohorts (75%). Baseline aortic valve calcification (AVC) and AVA were consistently associated with greater AS progression in 9 cohorts (100%). One cohort found that women have a greater ΔMG for a given level of AVC. A univariate analysis of race in one cohort showed that African American ethnicity was associated with lower risk of progression from normal aortic valves to incident AS.

Conclusion:
There is limited representation of women and ethnic minorities in prospective AS progression cohorts. Active recruitment of diverse populations in these cohorts is needed. The available clinical evidence provides limited support for claims of differential progression as the cause of racial disparities in AS treatment.
Abstract 12375: Gender-Related Differences in the Prognostic Value of Biomarkers in Patients With Acute Chest Pain Without Myocardial Infarction
Authors: Myrmel Gard M , Steiro Ole-Thomas , Tjora Hilde L , Langorgen Jorund , Bjorneklett Rune O , Skadberg Oyvind , Bonarjee Vernon , Mjelva Øistein , Vikenes Kjell , Omland Torbjorn , Aakre Kristin Moberg
Published: June 2023

Introduction:
Patients presenting with acute chest pain may carry an increased risk of cardiovascular events even though myocardial infarction (MI) is excluded. Whether there are gender-related differences in the prognostic value of biomarkers in this patient population is unclear.

Methods:
We performed a post hoc analysis of the WESTCOR trial that included 1319 patients (779 male and 540 female) admitted with acute chest pain without MI. Biomarkers included peak high sensitivity cardiac troponin T (hs-cTnT), peak high sensitivity cardiac troponin I (hs-cTnI), N-terminal proB-type natriuretic peptide (NT-proBNP), growth differentiation factor 15 (GDF-15) and C-reactive protein (CRP), all from Roche Diagnostics. Cox regression analysis was performed for ln-transformed biomarkers in unadjusted models and models adjusting for age, hypercholesterolemia, current smoking, diabetes, hypertension, previous MI and eGFR <60 ml/min/1.73m2 in predicting a combined endpoint of all-cause mortality, future MI and hospitalization for acute heart failure. Gender differences in C-statistics were also estimated.

Results:
During a median follow-up of 1545 days (range 4 - 2208), the endpoint occurred in 11% of females and 13% of males (p = 0.212). Peak biomarker levels are shown in
Table
1a.
In the unadjusted and adjusted Cox regression analysis, increasing levels of all biomarkers were associated with a higher risk of death and cardiovascular events in women, but the interaction by gender was only significant for NT-proBNP and GDF-15 (
Table 1b
). The C-statistic for prediction of the endpoint was significantly higher for hs-cTnI and GDF-15 in women than in men (
Table 1c
). For hs-cTnT, NT-proBNP and CRP the difference in C-statistic between genders was non-significant.

Conclusion:
Circulating concentrations of cardiac troponins, GDF-15 and NT-proBNP seem to be associated with a higher risk of death and cardiovascular events in women compared to men.
Abstract 12453: Tricuspid Regurgitation After ICD Implantation is Rather Due to the Transvenous Lead Than Natural Progression
Authors: Breeman Karel T , Peijster Annelot J , de Bruin-bon rianne A , Pepplinkhuizen Shari , Van Der Stuijt Willeke , De Veld Jolien A , Beurskens Niek E , Stuiver Martijn M , Wilde Arthur A , Tjong Fleur V , Knops Reinoud E
Published: June 2023

Introduction:
Transvenous implantable cardioverter-defibrillators (TV-ICDs) are associated with greater tricuspid regurgitation (TR) severity, which leads to increased mortality. The pathophysiology is often assumed to be lead-related, hence, treatment includes lead extraction and alternative defibrillation strategies. However, TR may also be naturally occurring in the ICD population with a high risk of secondary TR, or may be caused by right ventricular pacing.

Purpose:
We aimed to evaluate the effect of ICD type (with or without lead) and pacing percentage on post-implantation TR severity.

Methods:
In this retrospective cohort study, we included consecutive patients with a first S-ICD or TV-ICD implantation between December 2009 until December 2019 and who underwent an echocardiography study ≤3 months before and ≤3 years post-implantation. TR severity at follow-up was adjusted for potential confounders using ordinal regression analysis.

Results:
118 patients were included (mean age 52±21; 29% female), of whom 31 (26%) with an S-ICD and 87 (74%) with a TV-ICD. Follow-up echocardiography was performed median 20 months (IQR 14-29 months) after implantation. Worsening TR between pre- and post-implantation echocardiography was found in 11/31 (34%) patients with an S-ICD and 45/87 (52%) patients with a TV-ICD (p=0.15). Adjusted for age, atrial fibrillation, baseline TR and mitral regurgitation, ventricular pacing percentage and time since ICD implantation, TV-ICDs were significantly associated with greater TR severity at follow-up (OR 8.38, p=0.002). Ventricular pacing percentage was very low (5/118 [4%] were paced >10%), and not significantly associated with greater TR severity (OR 0.97, p=0.123).

Conclusions:
Our results suggest that greater TR severity in ICD patients is mainly caused by the transvenous lead, rather than natural progression in the ICD population.
Abstract 13084: Clinical Outcomes and Factors for Adverse Events in Patients With Severe Coronary Calcification Assessed by Optical Coherence Tomography
Authors: Nagata Takako , Minami Yoshiyasu , Katsura Aritomo , Asakura Kiyoshi , Katamine Masahiro , Muramatsu Yusuke , Fujiyoshi Kazuhiro , Kinoshita Daisuke , Ako Junya
Published: June 2023

Introduction:
Severe coronary calcification is a known factor for worse clinical and angiographic outcomes after percutaneous coronary intervention (PCI). However, the association between lesion characteristics and post-stent findings and worse clinical outcomes in patients with severely calcified lesions remains to be elucidated.

Hypothesis:
Among patients with severely calcified lesions, pre and post stent findings assessed by optical coherence tomography (OCT) are associated with future adverse events.

Methods:
A total of 241 consecutive patients with severely calcified lesions, who underwent OCT imaging of the culprit lesion were included. Severely calcified lesion was defined as a lesion with a maximum calcium angle >180°, maximum thickness >0.5 mm and calcium length >5 mm, which were assessed by OCT. The device-oriented clinical endpoint (DoCE) was defined as a composite of cardiac death, target vessel-related myocardial infarction, ischemia-driven target lesion revascularization, and stent thrombosis.

Results:
The presence of eruptive calcified nodule (eCN) (41% vs. 18%,
p
=0.003) in the culprit lesion and medial dissection with calcified flaps (59% vs. 26%,
p
<0.001) after stenting was significantly higher in patients with DoCE than in those without. Among the four groups classified by the presence of eCN and medial dissection with calcified flap, incidence of DoCE was the highest in lesions with both eCN and medial dissection with calcified flap (
p
<0.001) (Figure).

Conclusions:
An increased incidence of DoCE was demonstrated in lesions with the combined presence of eCN and medial dissection with calcified flap. The present results may explain the importance of the careful assessment of severely calcified lesions using OCT for the risk stratification of future adverse events.
Abstract 13138: Dissection of Cardiomyocyte versus Fibroblast Effects of Interleukin-11 in Heart Failure
Authors: Sweeney Mark , O'Fee Katie , Villanueva-Hayes Chelsie , Vanezis Konstantinos , Rahman Ekhlas , Widjaja Anissa , Hausenloy Derek , Barton Paul J , Cook Stuart A
Published: June 2023

Introduction:
Interleukin-11 (IL-11) is a cytokine produced in response to tissue damage and cellular stress and is secreted from and acts on both parenchymal and stromal cells across tissues. The relative contributions of IL-11 to cardiomyocyte dysfunction and fibroblast activation in heart failure pathologies are ill-defined.

Hypothesis:
IL-11 causes both cardiomyocyte dysfunction and fibroblast activation that leads to distinct pathologies common to heart failure syndromes.

Methods:
Cardiomyocytes were isolated from adult C57BL/6 mice and treated with recombinant mouse IL-11 (rmIL-11) or control for 2 hours. Cardiomyocytes were then incubated with a calcium indicator (Fluo-4AM) and stimulated at 1Hz to allow recordings of contractility and calcium transients. In vivo studies were performed using C57BL/6 mice which were injected with rmIL-11 2 hours prior to echocardiography under isoflurane anaesthesia. HFpEF was induced in C57BL/6 mice with diet containing 60% fat and drinking water containing the nitric oxide inhibitor L-NAME. IL-11 was conditionally overexpressed in cardiomyocytes of C57BL/6 mice using a Myh6 dependent cre-loxp system. Ventricular function was measured by echocardiography and molecular analysis was performed 6 weeks following induction of overexpression.

Results:
Acute treatment for 2 hours with rmIL-11 impaired contractility at both a cellular level in isolated cardiomyocytes and of the whole heart in vivo, as measured by echocardiography. The impairment in systolic function was associated with reduced calcium uptake in cardiomyocytes, an effect which was rapidly reversible. In a mouse model of HFpEF, IL-11 was elevated in the ventricle of treated mice as compared to controls with an associated increase in IL-11 dependent profibrotic gene expression. IL-11 expression in cardiomyocytes results in extensive fibrotic changes in the myocardium, notably peri-vascularly, and significantly reduces systolic function, as compared to control animals.

Conclusions:
IL-11 is increased in a mouse model of HFpEF, is negatively inotropic in vitro and in vivo and induces fibrosis when secreted from cardiomyocytes. Hence, IL-11 contributes to heart failure pathologies across cellular compartments in the failing heart.
Abstract 13188: Co-Translational Profiling in the Cardiac Endothelium During the Development of Sepsis
Authors: Goldspink Paul , Warren Chad M , Swaminathan Bhairavi , Langa Paulina , Niemczyk Stephanie , Wolska Beata M , Kitajewski Jan , deTombe Pieter , Solaro R John
Published: June 2023

Introduction:
The production of functional proteins is a multistep process whereby key maturation and regulatory processes occur co-translationally by coupling mRNA translation and nascent polypeptide chain maturation on the ribosome. However, limited data exist regarding co-translational regulation in the cells of the intact cardiovascular system. To overcome this limitation, we adapted the translating ribosome affinity purification (TRAP) approach using the HA-tagged ribosomal protein L22 reporter mouse (RiboTag) crossed with an inducible endothelial-specific
Cdh5creERT2
mouse (

RiboTag
EC

).

Hypothesis:
We hypothesized this model would permit the simultaneous immunoprecipitation (IP) of mRNA and nascent proteins for RNAseq and proteomic analysis from the coronary endothelium.

Methods:
Mice were injected with E.
coli
lipopolysaccharide (LPS) (6mg/Kg, i.p. 12 hours) to induce sepsis and perturb endothelial cell function. Hearts were homogenized, a small amount (~10%) was used for RNA-Seq and proteomics input controls (IN), and the remainder was used to IP ribosomal bound polyA+ mRNA and nascent proteins. Eluted proteins were digested, labeled with isobaric tags for quantification, and analyzed by MS3 with a Thermo Scientific Fusion Lumos Orbitrap.

Results:
Principal components analysis of the RNAseq data showed clear separation of the IP (endothelial cells) and IN (whole heart) transcriptomes between control and LPS groups. Transcripts characteristic of endothelial cells (EC) were enriched, whereas markers characteristic of cardiomyocytes, fibroblasts, and smooth muscle cells were depleted. Overall, >7000 proteins were identified, and initial analysis showed similar depletion and enrichment of proteins in the control and LPS hearts. Alignment of transcript and protein datasets was used for bioinformatic analysis. A hierarchical view of one of the top networks in which concordant expression of both EC transcripts and proteins identified interferon-gamma (IFNG) as an upstream signal in the pathogenesis of sepsis.

Conclusions:
Our “functional translatome” approach is a new discovery platform for a deeper predictive analysis of functionally relevant signaling networks and disease pathways in the intact cardiovascular system.
Abstract 13199: Transcatheter Valve Implantation in Reversed Potts Shunt in Pulmonary Arterial Hypertension: Keeping the Shunt Reversed
Authors: Goldar Ghazaleh , Ghobrial Joanna
Published: June 2023

Case description:
19-year-old female with idiopathic PAH diagnosed at the age of 4 with surgical valved reversed Potts shunt (rPS), from the left pulmonary artery (LPA) to the descending aorta (DsAo), at the age of 16. In her case, the valved rPS was fashioned using a 10 mm Fusion graft (Getinge
®
, Getinge, Sweden), and a 12 mm valved Contegra conduit (Medtronic
®
, MN, USA) that was trimmed at a shorter length than the graft and positioned in the middle of it, leaving the distal edges of the graft intact at the smaller diameter. She presented in 2021 with decompensated right-sided heart failure requiring continuous oxygen supplementation and pressor and ionotropic support.

Investigation:
Echocardiography showed normal LV size and function, severe RV dilation and dysfunction with RVSP of 102 mmHg (SBP: 119 mmHg). New bidirectional flow across the valve within the rPS was noted.

Management:
Patient taken to the cardiac catheterization lab for valve implantation within the rPS. Her RA pressure was 11, RV 90/16, PA 90/45 (64) with a simultaneous aortic pressure of 90/56 (71), PCWP of 14, PA saturation of 60%, AsAo saturation of 84%, and DsAo saturation of 84%. Angiography showed bidirectional shunting and an incompetent deteriorated rPS valve. We modified the 18mm Ensemble
®
transcatheter valve delivery system to fit a 20 mm Melody
®
(Medtronic, MN, USA) valve, by removing the 18 mm balloon and using a15 mm balloon instead, maintaining the external sheath of the delivery system. Once the valve was crimped onto the balloon, we advanced it with the tip of the balloon slightly inflated over a stiff wire. After valve deployment, angiography demonstrated resolution of left to right shunting. Post valve deployment, her hemodynamics were stable as prior except for a drop in her PA saturation to 49%, and DsAo saturation to 80%.

Discussion:
rPS is designed to offload the RV in severe PAH. The bovine jugular valve in this case prevented left to right flow across rPS and thus pulmonary overcirculation, functioning as it was originally intended: a valved unidirectional rPS. This valve, while originally intended to be deployed to 18-22 mm in diameter in the pulmonary position, can be functional at diameters as narrow as 12-16 mm.
Abstract 13208: Pathways Linking Posttraumatic Stress Disorder to Ischemic Heart Disease in Women Veterans
Authors: Ebrahimi Ramin , dennis paul , Alvarez Carlos , Perkins Aaron , Yang Hui , Shroyer Annie L , beckham jean , Sumner Jennifer
Published: June 2023

Introduction:
Posttraumatic stress disorder (PTSD) is associated with increased risk of ischemic heart disease (IHD). It is unclear if this excess risk is entirely mediated through traditional IHD risk factors (hyperlipidemia, hypertension, diabetes, and smoking). We examined 13 potential mediators of the PTSD-IHD association in a large cohort of women veterans: traditional risk factors, other conditions (obesity, chronic kidney disease, neuroendocrine disorders), women-specific risk factors (e.g., gestational diabetes and hypertension, pre-eclampsia), and psychiatric disorders (depression, anxiety, psychotic disorders, alcohol dependence, and drug dependence).

Methods:
The study cohort included women veterans ≥18 years of age who were enrolled in Veterans Health Administration care between 1/1/2000 to12/31/2017. Diagnosis of each risk factor and disorder was based on administrative billing codes (International Classification of Disease versions 9 and 10). The final study cohorts included 1:2 propensity-score matched group of patients with and without PTSD respectively. The cohorts were matched for age, number of prior visits, and presence of the above risk factors. Cox regression examined associations of PTSD with time to development of the above 13 risk factors. Cox regression with time-varying covariates was used to model time to development of IHD as a function of PTSD and each of above 13 risk factors as time-varying predictors in separate models.

Results:
The cohorts included 132,293 patients with, and 265,846 patients without PTSD. PTSD was positively associated with each of the 13 risk factors. Results are tabulated in the table below.Conclusion: Traditional risk factors cumulatively accounted for just one third of the risk of IHD posed by PTSD, and all examined risk factors accounted for less than half of the increased risk associated with PTSD. More research is needed to identify pathways by which PTSD accelerates cardiovascular risk.
Abstract 13239: Variation in Cost by HEART Score in Patients With Suspected Acute Coronary Syndrome
Authors: Kawatkar Aniket A , Sharp Adam , Baecker Aileen , Redberg Rita F , Lee Mingsum , Ferencik Maros , Goodacre Steve , Thokala Praveen , Wu Yi-Lin , Shen Ernest , zheng chengyi , Musigdilok Visanee , Sun Benjamin
Published: June 2023

Introduction:
The variation in medical cost by risk stratification using history, electrocardiogram, age, risk factors and troponin (HEART), after an emergency department (ED) evaluation for suspected acute coronary syndrome (ACS), is not well understood.

Hypothesis:
We hypothesized that annual total all cause cost will increase significantly with increasing HEART score and the primary driver of the total cost will be cardiovascular disease (CVD) related care.

Methods:
This was a retrospective cohort study of adults (age ≥18) with chest pain and complete data for HEART score, presenting at EDs within the Kaiser Permanente Southern California health system from 1/2016-12/2018. We analyzed direct medical cost associated with medical office visits, hospital facility and ED visits, pharmacy utilization, hospice stays, skilled nursing stays, home health, dialysis, laboratory, and radiology utilization during the 1-year following the index ED visit. Stratified by HEART score categories, we used one part and two part generalized linear models (log link & gamma family distribution) adjusted for socio-demographics, cardiovascular disease (CVD) history and treatment and non-CVD comorbidities, to estimate average adjusted total all cause expenditure as well as subgroups of utilization.

Results:
The cohort included 33,990 patients (60% Low risk; 37% intermediate risk and 3% high risk). The adjusted annual total cost varied from $6,544 (95% CI $6,228 to $6,860) in the low risk to $21,210 ($19,458 to $22,962) in the high-risk group (Table 1). In each group, the primary driver of total cost was CVD related care accounting for 41% to 46% of total cost. CVD care provided in a hospital setting accounted for 44%-76% of CVD total cost.

Conclusions:
Increased follow-up medical office visits, improved medications and lifestyle management may reduce the near exponential increase in cost driven by catastrophic hospital utilization, in higher HEART risk stratified patients.
Abstract 13272: Diabetic Cardiomyopathy as a Coronary Artery Disease Mimic: A Case Report
Authors: Chander Yogesh , Duggal Bhanu , L Narayan M , P Pradeep
Published: June 2023

A 49-year-old female presented with complaints of angina and dyspnea on exertion for last 4 months, which caused significant limitation of ordinary physical activity. She had poorly controlled diabetes mellitus type 2 with HbA1C of 10.3%. EKG showed complete LBBB with QRS duration of 180 milliseconds. Echocardiogram was consistent with dilated left ventricle and global hypokinesia of left ventricle with ejection fraction of 25-30%. There was marked reduction in GLS (GLPS average of -7.0%). She underwent coronary angiogram which revealed normal epicardial coronary arteries.
99m
Tc-sestamibi SPECT myocardial perfusion imaging (MPI) at rest, demonstrated moderate to severe ischemia involving apical, antero-septal, adjacent anterior wall and adjacent basal 2/3
rd
of inferior wall segments of LV myocardium (involving approx.~73% of RCA territory and 57% of LAD territory at 50% uptake threshold). There was wall motion abnormality in above mentioned segments on ECG gated SPECT and estimated LVEF with QGS was ~29±5%. She has been started on anti-ischemic measures, guideline directed therapy for HFrEF and comprehensive diabetes care. Diabetic cardiomyopathy is myocardial dysfunction with normal epicardial coronary arteries and absence of other cardiovascular diseases. It is characterized by myocardial fibrosis and associated systolic dysfunction preceded by diastolic dysfunction. Cardiac insulin resistance leads to advanced glycation end products, microvascular dysfunction etc. Perfusion defects observed during MPI in patients with LBBB may be due to CAD, microvascular dysfunction, or artifacts. In the setting of LBBB, isolated anteroseptal defect has low probability of CAD but presence of perfusion defects in RCA territory and apical region increases probability of ischemic events.In this case, there was ischemia with systolic dysfunction in the absence of any overt clinical coronary artery disease and no other identifiable cause.
Abstract 13296: The Internal Jugular Vein for Leadless Pacemaker Implantation in Patients Under 30 Kg
Authors: Salameh Souleiman , Cortez Daniel
Published: June 2023

Pacemaker placement in pediatrics involves consideration for potential complications with leads, pocket erosion and infection. Pacemaker generators also carry their own complications such as hematoma formation and additional infection. This is why a reliable leadless pacemaker implantation technique is desired. In this dual center, single operator, retrospective study we demonstrate the feasibility of leadless pacemaker implantation via internal jugular vein in patients under 30 kg. This technique does not require surgical cut-down and preserves the patency of the involved vessels. Procedures were conducted by an electrophysiologist at the University of Minnesota and UC Davis Medical Center and University of Minnesota Medical Center from 2018-2021 with the Micra (Medtronic, Minneapolis, MN, USA). Vascular access in the largest diameter internal jugular vein was obtained in the right or left internal jugular veins via the Seldinger technique with serial dilation from 5 or 8 French size to 27 French. Results showed that in eight patients under 30kg, leadless pacemaker can implanted via the internal jugular vein with no need for surgical cut down due to having good short-term and mid-term vein patency. Seven out of eight patients were discharged the next day after the procedure. No venous complications related to access were noted. All patients met an indication for pacemaker implantation with ventricular-only pacing needed or had prophylactic leadless pacemaker placed or was the patient and cardiology team preference after multi-disciplinary discussion. We recommend echocardiographic guidance to minimize perforation risk.
Abstract 13312: Can the Extent of Late Gadolinium Enhancement on Cardiac Magnetic Resonance Be Predicted by the 12-Lead Electrocardiogram?
Authors: Bao Chen , Madias Christopher , Studley Rachael , Bokhari Nadia , Quintana Erick , Maron Barry , Maron Martin S , Maron Martin , Rowin Ethan J
Published: June 2023

Background:
In hypertrophic cardiomyopathy (HCM), late gadolinium enhancement (LGE) on cardiac magnetic resonance imaging (CMR) is an in vivo marker of replacement fibrosis with a continuous relationship between amount of LGE and both risk for sudden death and development of endstage disease. Cost and accessibility can limit routine utilization of CMR. In contrast, electrocardiogram (ECG) is an inexpensive readily available test and identifies patients with myocardial scarring in ischemic heart disease. Its ability to identify presence and extent of LGE in HCM is unknown.

Methods:
1983 consecutive HCM patients were included; 62% male, average wall thickness 18 ± 3mm, and 36% with resting LV outflow tract obstruction ≥ 30mmHg. ECGs were analyzed for LV hypertrophy, T wave abnormalities, ST-segment depression or elevations, abnormal Q waves, conduction disease, atrial enlargement and QTc prolongation. Extent of LGE was quantified and expressed as a proportion of total LV myocardium.

Results:
822 (41%) had no LGE, while 1161 (59%) had LGE, including 687 (35%) with <5%, 299 (15%) with 5-9%, 92 (5%) with 10-14%, and 83 (4%) with ≥ 15%. Compared to no LGE, Patients with LGE were more likely to have pathologic T wave inversions (55% vs. 36%, p<0.01), positive T waves in aVR (34% vs. 20%, p<0.01), and ST-depressions (29% vs. 21%, p<0.01), with no difference in LV hypertrophy, bundle branch block, pathologic Q waves, first degree AV block, QTc prolongation ≥ 480ms, or ST-elevations (p>0.05). Notably, as extent of LGE increased there was a corresponding progressive increase in the prevalence of both positive T waves in aVR (20% in no LGE to 42% in ≥ 15% LGE, p<0.01) and pathologic T wave inversions (36% in no LGE to 61% in ≥ 15% LGE, p<0.01) but with no incremental differences in ST depressions (p>0.05). In contrast, 43% of patients with LGE did not have either positive T waves in aVR or pathologic T wave inversions, including 34% with ≥ 15% LGE.

Conclusion:
Most ECG findings including pathologic Q waves have no relation to presence or extent of LGE. While positive T waves in aVR and pathologic T wave inversions are associated with LGE, they have limited sensitivity. These finding support that routinely evaluated ECG abnormalities do not predict presence or extent of scarring in HCM.
Abstract 13383: Is Genotype Negative Hypertrophic Cardiomyopathy Really Benign? The Increased Risk of Sudden Death and Advanced Heart Failure in the Absence of Pathogenic Sarcomere Mutations
Authors: Bonaventura Jiri , Chin Michael T , Maron Barry J , Maron Martin S , Rowin Ethan J
Published: June 2023

Introduction:
The genetic basis of hypertrophic cardiomyopathy (HCM) is complex, and the genotype-phenotype correlations have not been completely resolved. Patients lacking a pathogenic variant are presumed to have a better prognosis than patients with sarcomeric pathogenic mutations.

Aim:
We sought to assess the relationship between the genotype status and the adverse clinical events.

Methods:
Consecutive patients with HCM underwent genetic testing focused on HCM-related genes. Patients with pathogenic or likely pathogenic variants were considered genotype positive (G+), and those without definite disease-causing mutation were considered genotype negative (G-). Patients were followed for 5.2 ±4.9 years for outcomes. Sudden death (SD) events included out-of-hospital cardiac arrests, appropriate ICD interventions, and HCM-related death.

Results:
Of 988 HCM patients, 212 (21%) were G+, while 776 (79%) were G -. As compared to G-, G+ HCM patients were younger (45 ± 14 vs. 53 ± 13 years), had more extensive LV hypertrophy (maximum wall thickness: 19.6 ± 5 mm vs. 18.4 ± 4 mm, p<0.001), and with no difference in the presence of LVOT obstruction (59% vs. 66%, p=0.06). Despite G- status, 3% of G- patients had extensive scarring on cardiac MRI (≥15% of LV mass; no different from G+, p=0.54). Over follow-up, 66 patients had SD events. While SD events were more common in G+ patients (11.3% vs. 5.4%, p=0.002), the majority of SD events occurred in G- patients (64%). Similarly, end-stage HCM developed 54 patients, more commonly in G+ (9.0% vs. 4.5%, p=0.01), but with majority of events in G- patients (65%).

Conclusion:
Contrary to certain prevailing views, in this large consecutive genotyped HCM cohort, sarcomere genotype-negative patients (representing a distinctive majority) did not express an entirely benign prognosis. In fact, nearly two-thirds of SD events and end-stage HF progression occurred in G- HCM patients, albeit at somewhat lower rates than in G+ patients. These data do not support that genotype should not be included as a risk marker of adverse arrhythmic and advanced heart failure events.
Abstract 13393: Equity Model Evaluation of a Predictive Cardiac Positron-Emission Tomography (PET) Risk Score for 90-Day and One-Year Major Adverse Cardiac Events and Revascularization
Authors: McCubrey Raymond O , Mason Steve M , Le Viet T , Bride Daniel L , Horne Benjamin D , Meredith Kent G , Sekaran Nishant K , Anderson Jeffrey L , Knowlton Kirk U , Min David B , Knight Stacey
Published: June 2023

Introduction:
Artificial Intelligence (AI) algorithms should be evaluated to discern differences in prediction amongst population groups. The Intermountain data science group has developed a software package iEAI, which performs a model evaluation (ME) analysis to detect such meaningful prediction differences. Here we apply this software package to a recently developed cardiac PET/CT stress test-based risk score that predicts 90-day and one-year major adverse cardiac events (including death and myocardial infarction) and revascularization (MACE-Revasc). The results of these analyses will reveal any discrepancies in prediction and help with equity.

Methods:
5049 patients who had a clinically indicated PET/CT study from January 1, 2018, to December 31, 2018, were considered. The ME analyses were done for gender, age, and race. Precision (or positive predictive value) and recall (or sensitivity) were measured and meaningful differences were those that were statistically significant and had a ratio < 0.85 or >1.25 in magnitude than the reference category (e.g., the largest category).

Results:
The ME analysis of the PET/CT risk score for MACE-Revasc are shown in the table. For the 90-day PET/CT risk score a recall bias existed for females compared to males (0.49 vs 0.62). There was also bias with improved recall for Native-Hawaiian/ Pacific Islanders compared to Whites (0.87 vs 0.58). For the one-year PET/CT risk score, recall (0.38 vs 0.52) and precision (0.34 vs 0.47) biases were found for females compared to males, and recall biases were found for those aged 50-59 compared to 60-69 (0.34 vs 0.50).

Conclusion:
Meaningful biases were found in both the PET/CT risk scores for 90-day and One-year MACE-Revasc. As the application of AI in healthcare grows, evaluations like the above should be carried out. Then any detected inequalities could be addressed by refining or redeveloping the risk score models to eliminate biases.