bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 12799: Hospitalizations and Emergency Consultations Following Generic Antihypertensive Drugs Commercialization in Quebec
Authors: Leclerc Jacinthe , Blais Claudia , Rochette Louis , Hamel Denis , Guénette Line , Poirier Paul
Published: April 2024

Introduction:
Once patent of a brand-name drug expires, generic drugs are commercialized and substitution may occur. Few studies have assessed clinical impacts of generic drugs commercialization at a population level.

Objective:
We evaluated the impact for three generic versions of antihypertensive drugs on adverse events: hospitalizations and emergency room consultations.

Methods:
This is an interrupted time series analysis using the Quebec Integrated Chronic Disease Surveillance System. The rate of adverse events for losartan (brand-name and 8 generics), valsartan (brand-name and 5 generics) and candesartan (brand-name and 3 generics) users aged ≥ 66 years (all: N=121 185 citizens) were calculated monthly, 12 months before and 12 months after generics commercialization. Periods before and after generics commercialization were compared with negative binomial segmented regression models for all users with a specific variable for generic and brand-name users.

Results:
There was an approximated monthly mean rate of 100 adverse events for 1000 exposed person-months to losartan, valsartan and candesartan. Monthly trend of adverse events was affected by generics commercialization. Generic users of losartan, valsartan and candesartan showed increased rate of adverse events of 11% (p=0.0034), 9% (p=0.0024) and 13% (p=0.0008) respectively right after generics commercialization (Figure 1) which was always higher compared to brand-name users (p<0.05). The monthly trend of hospitalizations was affected for losartan users up to 1 year after generics commercialization (generics: +1.2%, brand-name: -2.2, p=0.0094).

Conclusion:
Generics commercialization impacted population rates of adverse events. A significant adverse events increase was observed right after generics commercialization for all antihypertensive drugs studied, among generic users. More studies are required to identify differences in drugs or users, which could explain this increase.
Abstract 12834: Increased Plasma Serotonin and Circulating microRNA-1914 Reflect Oxidative Stress and Play Crucial Roles in Atherosclerosis
Authors: Sugiura Tomonori , Dohi Yasuaki , Hirowatari Yuji , Fujii Satoshi , Ohte Nobuyuki
Published: April 2024

Introduction:
Serotonin, synthesized from enterochromaffin cells, modulates vascular tonus and thrombus formation, and mediates development of atherosclerotic plaque. Oxidative stress is involved in vascular inflammation and progression of atherosclerosis.

Hypothesis:
We hypothesized that plasma serotonin plays a crucial role in increasing oxidative stress and aimed to identify the circulating microRNA(s) associated with serotonin ratio for coronary artery disease (CAD).

Methods:
Blood was sampled from 120 outpatients with cardiovascular risk factors but without a history of previous cardiovascular events. Serotonin levels both in platelet poor plasma (PPP) and whole blood (WB) were measured with HPLC, and the ratio of serotonin in PPP to that in WB (PPP/WB) was used as an index of platelet activation. For assessment of oxidative stress, serum levels of derivative reactive oxygen metabolites (d-ROM) were measured. Total RNA was isolated from subjects who were scheduled for coronary angiography with suspicion of CAD and a microRNA array analysis was performed. The expression levels of microRNAs were scaled by global normalization.

Results:
Serotonin levels in both PPP and PPP/WB ratio were significantly correlated with the d-ROM levels. Among enrolled patients, 25 subjects were diagnosed as having CAD. The levels of the PPP/WB ratio of serotonin, d-ROM, and CRP were significantly higher in subjects with CAD than in those without CAD. Logistic regression analysis performed with endpoint of having CAD revealed that the PPP/WB ratio of serotonin was independently associated with CAD. In subjects with CAD, 5 increased microRNAs and 30 decreased microRNAs were identified among more than 2000 microRNAs as compared to those without CAD. Among candidate microRNAs, expression of microRNA-1914 showed significant inverse correlation with PPP/WB ratio (r=-0.61, P<0.05) and d-ROM levels (r=-0.63, P<0.05).

Conclusions:
A significant association among platelet activation assessed by PPP and PPP/WB ratio and oxidative stress assessed by d-ROM, was detected in individuals with cardiovascular risk factors. Targeting serotonin-oxidative stress axis, and circulating microRNA-1914 may serve as novel strategy for diagnosis of atherosclerotic CAD.
Abstract 12836: Usefulness of Serum Levels of Adipocytokines and Estimated Δ-5 Desaturase Activity as Biomarkers Predicting Hepatic Steatosis in Patients With Coronary Artery Disease on Statin Therapy
Authors: Matsuda Morihiro , Tamura Ritsu
Published: April 2024

Introduction:
Nonalcoholic fatty liver disease (NAFLD) is closely linked to obesity or type 2 diabetes mellitus, which are risk factors for coronary artery disease (CAD), and also includes non-alcoholic steatohepatitis that often develops life-threatening liver cirrhosis. Imaging tests for NAFLD are more sensitive than liver biochemistries, but expensive and cumbersome as screening tests. An establishment of biomarkers for NAFLD is important for prevention of fatal liver diseases in CAD patients.

Hypothesis:
Serum levels of adipocytokines/adipokines and estimated Δ-5 desaturase (D5D) activity may be useful biomarkers predicting NAFLD in patients with CAD.

Methods:
A cross-sectional study was conducted on 127 patients with CAD on statin therapy. Dihomo-γ-linolenic acid (DGLA) and arachidonic acid (AA) in serum total lipids were measured by gas chromatography, and D5D activity was estimated by AA to DGLA ratio. Serum levels of adiponectin (Apn), leptin, resistin, visfatin and plasminogen activator inhibitor (PAI)-1, were determined by the respective ELISA. Abdominal computed tomography (CT) measured CT attenuation for liver (L-CTA) to estimate lipid content, and subjects with L-CTA <50 HU were defined as NAFLD.

Results:
Simple linear regressions revealed that L-CTA was significantly correlated with serum levels of Apn, leptin and D5D activity (p < 0.01, p = 0.03 and p < 0.001, respectively), but not with those of resistin, visfatin or PAI-1. In multivariate logistic analysis among three factors consisting of a low Apn level: < 6.8 μg/mL, a high leptin level: ≥ 3.4 ng/mL and a low D5D activity: ≤ 5.2 (the cutoff points were defined via ROC analysis against NAFLD), NAFLD was significantly associated with a high leptin level and a low D5D activity (adjusted odds ratio [OR]: 4.9, 95% confidence interval [CI]: 1.5-20) and OR: 15.6, 95%CI: 2.9-290, respectively), but weakly with a low Apn level (OR: 1.9, 95%CI: 0.6-6.5). A combination of these factors showed a strong association with NAFLD (area under the ROC curve: 0.84, p < 0.0001).

Conclusions:
Serum levels of Apn, leptin and estimated D5D activity were significantly correlated with hepatic lipid content, and incrementally predict the presence of NAFLD in patients with CAD on statin therapy.
Abstract 12843: Impact of Age on Optimal Cardiopulmonary Resuscitation Duration to Achieve Favorable Neurological Outcomes After Out-of-hospital Cardiac Arrest: Evidence From a Large-scale Registry in Japan
Authors: Funada Akira , Goto Yoshikazu , Maeda Tetsuo , Tada Hayato , Teramoto Ryota , Shimojima Masaya , Hayashi Kenshi , Yamagishi Masakazu
Published: April 2024

Introduction:
The optimal duration of cardiopulmonary resuscitation (CPR) for patients with out-of-hospital cardiac arrest (OHCA) before cessation of CPR is unclear and could differ according to age.

Hypothesis:
We determined the relationship between the duration of prehospital CPR performed by emergency medical service (EMS) personnel and survival with favorable neurological outcome (cerebral performance category scale, category 1 or 2; CPC 1-2) after OHCA by age.

Methods:
We analyzed the records of 17,238 OHCA patients (age ≥18 years) who achieved return of spontaneous circulation (ROSC) before arrival at the hospital. Data were obtained from a prospectively recorded Japanese national Utstein-style database for 2 years (2011-2012). The time from initiation of CPR by EMS personnel to prehospital ROSC (CPR duration) was calculated. The primary end point was 1-month CPC 1-2.

Results:
The rate of 1-month CPC 1-2 was 21.9% (3771 of 17238) for whole OHCA. The CPR duration was independently associated with a decreased rate of 1-month CPC 1-2 (adjusted odds ratio 0.94; 95% confidence interval 0.94-0.95). The CPR duration at which the probability of 1-month CPC 1-2 decreased to <1% was 24 min for whole OHCA. The minimum CPR duration to achieve a cumulative proportion >99% for 1-month CPC 1-2 was 35 min for whole OHCA. When sorted by age, the rates of 1-month CPC 1-2 were 36.3% (1822 of 5018), 25.0% (926 of 3697), 14.2% (688 of 4847), 9.7% (314 of 3243), and 4.8% (21 of 433), for 18-64, 65-74, 75-84, 85-94, and ≥95 years, respectively. The CPR duration at which the probability of 1-month CPC 1-2 decreased to <1% were 28, 24, 22, 21, and 19 min, for 18-64, 65-74, 75-84, 85-94, and ≥95 years, respectively. The minimum CPR duration to achieve a cumulative proportion >99% for 1-month CPC 1-2 were 34, 34, 35, 39, and 36 min for 18-64, 65-74, 75-84, 85-94, and ≥95 years, respectively.

Conclusions:
These results demonstrate that elderly OHCA patients had worse outcome. The more elderly the OHCA patients were, the earlier the probability of 1-month CPC 1-2 decreased to <1%; however, to achieve a cumulative proportion of >99% for 1-month CPC 1-2, a longer CPR duration was required. When considering cessation of CPR, the difference of optimal CPR duration by age should be taken into consideration.
Abstract 12860: Enhanced Expression and PKCδ-mediated Hyperphosphorylation Underlie the Proarrhythmic Increase in Na
+
-Ca
2+
Exchanger Activity in Patients With Chronic Atrial Fibrillation
Authors: Ghezelbash Shokoufeh , Espinosa Molina Cristina , Badimon Lina , Kamler Markus , Heijman Jordi , Dobrev Dobromir
Published: April 2024

Background:
Enhanced Na
+
-Ca
2+
exchanger type-1 (NCX1) function is implicated in triggering and maintaining atrial fibrillation (AF), but the molecular mechanisms of dysfunctional NCX in AF patients are unknown and were the main subject of this study.

Methods:
We used perforated patch-clamp technique to measure transient inward currents (I
ti
) in atrial cardiomyocytes from sinus rhythm (Ctl) and chronic AF (cAF) patients. Co-immunoprecipitation (co-IP) and Western blot in atrial tissue lysates and membrane fractions and in-cell co-IP (DuoLink
®
) in human atrial cardiomyocytes were employed to identify regulatory partners of NCX1 and potential differences in their expression in Ctl
versus
cAF patients.

Results:
Frequency of spontaneous NCX-mediated I
ti
and amplitude of caffeine-induced peak I
ti
were higher in cAF than Ctl patients, with no change in SR Ca
2+
content (Fig A), validating the increased NCX function in cAF. Expression of the functional 160 kDa full-length NCX1 protein was strongly increased in cAF membrane fractions and was responsible for more than 90% of total membranous NCX1 (Fig B). Co-IPs followed by immunoblotting identified two protein kinase-C isoforms (PKCα and PKCδ), protein phosphatase-type-1α (PP1α), phospholemman (PLM) and AMP-activated protein kinase-α (AMPKα) as parts of the NCX1 complex, whereas calcineurin-Aβ (CnAβ) and protein phosphatase type-2A (PP2A) were absent (Fig C). Although expression levels of PKCδ were 50% lower in cAF lysates, attachment of PKCδ to NCX1 was 875% higher in cAF
vs.
Ctl (Fig D). The positive interaction between NCX1 and PKCδ in the plasma membrane of human atrial cardiomyocytes was shown using Duolink (red dots in Fig E), but was absent in fibroblasts.

Conclusions:
We identified PKCα, PKCδ, PP1α, PLM and AMPKα as part of the human atrial NCX1 protein complex. Increased membranous NCX1 protein and a stronger PKCδ-mediated NCX1 phosphorylation (Fig F) may underlie the proarrhythmic NCX dysfunction in cAF.
Abstract 12896: ApoC3-Gln38Lys Variant is a Gain-of-function Mutation Associated With Human Hypertriglyceridemia
Authors: Yao Zemin , Sundaram Meenakshi , Curtis Kaitlin R , Alipour Mohsen A , Parks Robin J , McIntyre Adam D , Hegele Robert A
Published: April 2024

Introduction:
Cell culture and animal studies have suggested that expression of human apoC3 in liver cells can exert an intracellular role in promoting production of triglyceride (TG)-rich VLDL (VLDL1) under lipid-rich conditions. Previously, hypotriglyceridemia in human subjects have been linked to several loss-of-function apoC3 mutations, namely Ala23Thr and Lys58Glu. Conversely, hypertriglyceridemia has also been linked to an apoC3 variant. For example, the Gln38Lys variant was originally identified in human subjects of Mexican origin; heterozugous carriers of Gln38Lys exhibited moderate hypertriglyceridemia.

Hypothesis:
We hypothesized that the Gln38Lys variant is a gain-of-function mutation that promotes hepatic VLDL assembly/secretion.

Methods:
The recombinant Gln38Lys variant was either expressed in McA-RH7777 cells devoid of endogenous apoC3, or else expressed in apoc3-null mice using adenovirus-mediated gene transfer. The effect of Gln38Lys expression on hepatic lipogenesis, VLDL1 production, and glucose homeostasis was contrasted with that of wildtype apoC3.

Results:
Gln38Lys expression in McA-RH7777 cells and apoc3-null mice resulted in increased VLDL1-TG secretion, which was accompanied with increased
de novo
lipogenesis, increased adipogenesis, and severe hepatic steatosis (i.e. accumulation of TG and cholesteryl esters). Gln38Lys expression also increased glucose uptake and hepatic glycogen content, suggesting that apoC3 may play a role in hepatic glucose homeostasis. Live cell imaging revealed prominent association of apoC3 with endosomes, and the Gln38Lys-associated endosomes exhibited robust trafficking between Golgi apparatus and the cell periphery. Next generation sequencing of 1557 DNA samples from patients (of European, Chinese, African, and South Asian origins) with dyslipidemia (including hypertriglyceridemia, hypercholesterolemia and combined hyperlipidemia) did not detect Gln38Lys variant, nor was the Gln38Lys variant found in the ExAC databases containing 60,706 individuals.

Conclusions:
Gln38Lys is a rare, gain-of-function variant that may stimulate TG-rich VLDL1 production under lipid-rich conditions, contributing to hypertriglyceridemia..
Abstract 12903: Low-molecular Weight Heparin Improves Endothelial Function in Pregnant Women at High-risk of Preeclampsia
Authors: McLaughlin Kelsey , Baczyk Dora , Potts Audrey , Hladunewich Michelle , Parker John , Kingdom John
Published: April 2024

Introduction:
Women who develop preeclampsia (PE) demonstrate cardiovascular abnormalities during pregnancy and postpartum. Low-molecular weight heparin (LMWH) significantly reduces the incidence of PE, although the mechanisms of action are unknown.

Hypothesis:
LMWH improves cardiovascular function in pregnant women at high-risk of PE.

Methods:
Pregnant women at high-risk of PE (n=25) and low-risk pregnant controls (n=20) at 22-26 weeks’ gestation underwent cardiovascular assessments. High-risk women were then randomized to LMWH or saline placebo (30mg IV bolus and 1mg/kg subcutaneous dose). Cardiovascular function was assessed 1 and 3 hours post-randomization. The in vitro endothelial effects of patient serum and LMWH on human umbilical venous endothelial cells (HUVEC) were determined through angiogenesis assays, gene expression and protein secretion.

Results:
High-risk women demonstrated a low-volume, high resistance hemodynamic profile with significantly impaired radial artery flow-mediated dilation (FMD) when compared to low-risk controls (6.5±0.9% vs 9.7±1.0%, P=0.03). Baseline plasma and urine levels of placental growth factor (PlGF) were significantly lower in high-risk women compared with controls (P=0.003 and P=0.01, respectively). LMWH significantly increased FMD in high-risk women following randomization compared to baseline (10.8±1.0% vs 7.6±1.0%, P=0.008). LMWH also significantly increased plasma levels of PlGF, soluble fms-like tyrosine kinase-1 and myeloperoxidase (P=0.006, P=0.03 and P=0.03, respectively). Serum from high-risk women significantly impaired HUVEC angiogenesis and significantly increased PlGF-1 and PlGF-2 transcription compared to serum from controls (0.79±0.05 vs 0.99±0.05, P=0.03; P=0.03 and P=0.01, respectively). Co-exposure of high-risk serum with LMWH improved the in vitro angiogenic response such that it was equivalent to that of control serum and promoted PlGF secretion.

Conclusions:
Our data indicate that LMWH improves maternal endothelial function in pregnant women at high-risk of developing PE, possibly mediated through increased PlGF bioavailability. Future trials are needed to assess the effectiveness of LMWH for the prevention of severe PE in screen-positive women.
Abstract 12905: Initial Surgery Versus Conservative Management for Elderly Patients With Symptomatic Severe Mitral Regurgitation
Authors: Heo Ran , Kang Duk-Hyun , Lee Sahmin , Kim Dae-Hee , Song Jong-Min , Choi Kee-Joon , Song Jae-Kwan , Lee Jae-Won , Zo Joo-Hee
Published: April 2024

Background:
The benefit of surgical correction of severe mitral regurgitation (MR) may not be greater than operative risk in elderly patients without significant symptoms. This study sought to compare long-term survival between initial surgery and conservative management in elderly patients (≥ 70 years of age) with mild symptoms and severe MR.

Methods:
From 1996 to 2014, we prospectively evaluated 157 consecutive elderly patients (75 men, 74 ± 4 years of age) with severe degenerative MR who have dyspnea of NYHA functional class II. Mitral valve (MV) surgery was performed on 79 patients (OP group) within 3 months of the initial evaluation and the conservative strategy was chosen for 78 patients (conservative group). Follow-up data were obtained until April 2016, and the primary end-point was occurrence of cardiac death and the secondary end-point was death from any cause.

Methods:
In the OP group, operative mortality was 1.3%, and MV repair and replacement were performed in 64 (81%) and 15 (19%) patients, respectively, and 8 (10%) patients underwent late MV surgery in the conservative group. The risk of cardiac mortality was significantly lower in the OP group (HR 0.32; 95% CI, 0.14 to 0.75; P = 0.008), and the estimated actuarial 10-year cardiac mortality rates were 11 ± 5% in the OP group and 45 ± 8% in the conservative group (Figure). The risk of all-cause mortality was also significantly lower in the OP group (HR 0.39; 95% CI, 0.21 to 0.74; P = 0.004). Conservative strategy was independently associated with cardiac mortality (HR 0.34; 95% CI, 0.14 to 0.81; P = 0.016) and overall mortality (HR 0.41; 95% CI, 0.21 to 0.79; P = 0.008) in the Cox proportional hazards analysis adjusted for age and STS score.

Conclusions:
Compared with conservative management, initial surgical strategy for severe MR is associated with significant long-term reductions of overall mortality and cardiac mortality in elderly patients without significant symptoms.
Abstract 12913: Serotonin Regulates Qt-interval: Acceleration of Cardiac Repolarization by Enhanced Kv4.3 Membrane Trafficking
Authors: Cui Shanyu , Joung Boyoung ,   Hyewon Park;Hyelim Park;Hyo-Eun Kim,
Published: April 2024

Background:
Elevated maternal serotonin (5-hydroxytryptamine, 5-HT) production is an important determinant of normal fetal development. However, what roles the elevated serotonin plays in the electrophysiology of the mother’s heart has not been studied. In the present study, we therefore assessed the relationship between QTc duration and serotonin and studied underlying mechanisms.

Methods and results:
During pregnancy, 5-HT and tryptophan hydroxylase 1, a rate-limiting enzyme of serotonin synthesis, were markedly increased in hearts and serum. We measured QT intervals and ventricular potassium outward currents in wild-type (WT) and 5-HT3a receptor knock-out (

Htr3a
-/-

) mice at non-pregnant (NP) and late-pregnant (LP) state. The 5-HT as well as m-CPBG, an Htr3 agonist, increased
I
peak
and
I
to,f
densities with the shortening of QTc duration in WT NP, but not in WT LP and

Htr3a
-/-

mice. Additionally an Htr3a antagonist, ondansetron (5 μM) decreased
I
peak
and
I
to,f
only in WT LP, but not in WT NP mice. In contrast,
I
peak
and
I
to,f
densities were unchanged upon 5-HT and m-CPBG application in left ventricular myocytes freshly-isolated from the
Htr3a
-/-
-LP mice. Kv4.3 protein and Htr3a is co-localization in the membrane and t-tubule of cardiomyocytes. Co-immunoprecipitation showed that Kv4.3 protein directly interacts with 5-HT3a receptor. Moreover, the binding between 5-HT3a receptor and Kv4.3 was facilitated by 5-HT. This increase was mediated by 5-HT3a receptor dependent promotion of Kv4.3 channel trafficking to the cell membrane. However, these findings were not observed in WT LP mice. The heat-shock protein-90 (Hsp90) inhibitor geldanamycin abolished 5-HT-induced increase of
I
peak
and
I
to,f
densities. Finally, we evaluated and found that serotonin could shorten QTc interval by increasing potassium outward currents in rat and rabbit.

Conclusion:
Elevated 5-HT levels were associated shorter QTc intervals by acceleration of
I
peak
and
I
to,f
densities in mouse, rat and rabbit. 5-HT acts on Kv4.3 channels via enhanced 5-HT3a-receptor-medicated Hsp90 interaction, augments membrane trafficking and thereby increases repolarizing current. These results provide mechanistic insights into hormonal control of ventricular repolarization.
Abstract 12915: The Contribution of Transient Receptor Potential Vanilloid 4 (TRPV4) to Endothelium-Dependent Dilation is Enhanced by Shear Stress
Authors: Woodman Owen L , Darby William G , Potocnik Simon , McIntyre Peter
Published: April 2024

Shear stress on the endothelial surface of blood vessels influences vasodilator mechanisms. We tested the hypothesis that shear enhances the contribution of TRPV4 ion channels to vasodilation and investigated whether there was a functional interaction with the muscarinic receptor 3 (MR3). In HEK293 cells we established that the MR3 signals to and opens TRPV4. Using pressure myography, dilator responses to the TRPV4 agonist GSK1016790A and to the MR3 agonist acetylcholine (ACh) were examined in rat cremaster arterioles which had either experienced no shear stress or within 15 min of exposure to high shear stress (200 μl/min flow, 6 min, n=8-12). In control vessels GSK1016709A caused vasodilation (pEC
50
7.85 ± 0.15 M, R
max
109 ± 6 %) which was attenuated by the TRPV4 antagonist GSK2193874 (100 nM) (pEC
50
6.26 ± 0.14 M, p<0.05, R
max
84 ± 5 %) and abolished by endothelium denudation. When responses were assessed in shear treated arterioles there was an increase in sensitivity to GSK1016790A (pEC
50
8.39 ± 0.11, p<0.05, R
max
107 ± 3 %). Vasodilation to ACh (pEC
50
7.23 ± 0.06 M, R
max
99 ± 1 %) was not affected by exposure to shear forces (pEC
50
6.94 ± 0.08 M, R
max
98 ± 1 %). Dilator responses to ACh were not affected by the TRPV4 antagonist in control arterioles (pEC
50
7.24 ± 0.07 M, R
max
102 ± 2 %) but, in shear treated vessels, the ACh response was attenuated by GSK2193874 (pEC
50
6.26 ± 0.12 M, p<0.05, R
max
95 ± 3 %) indicating that shear forces stimulate a functional interaction between TRPV4 and MR3. TRPV4 antibody immunofluorescence measured in the arterioles indicated localisation of ion channels to the endothelium, but the induction of shear stress on the endothelium had no effect on the localisation of TRPV4 within endothelial cells of the intact arterioles. Expression of TRPV4 channels at the cell surface was not affected by shear forces as immunofluorescence of an antibody for the extracellular TRPV4 domain was similar in both groups of arterioles. Shear stress increases the sensitivity of endothelial TRPV4 ion channels to a selective agonist and reveals their contribution to muscarinic receptor mediated endothelium-dependent vasodilation. Investigating dilator responses in isolated arterioles without exposure to shear forces may under estimate the contribution of TRPV4.
Abstract 12959: Clinical Utility of Normal Findings on Non-Invasive Cardiac Assessment in a Population-Based Study of Older Adults
Authors: Venkatesh Sanjay , O’Neal Wesley T , Broughton Stephen T , Shah Amit J , Soliman Elsayed Z
Published: April 2024

Introduction:
The lack of abnormalities found on noninvasive cardiac testing may improve cardiovascular disease (CVD) risk stratification efforts and convey reduced risk despite the presence of traditional risk factors.

Methods:
We examined the clinical utility of normal findings on routine noninvasive cardiac assessment in 3,805 (95% white; 61% women) participants from the Cardiovascular Health Study (CHS) without baseline CVD. The combination of normal electrocardiogram (ECG) + normal echocardiogram was assessed for the development of CVD events. Normal ECG was defined as absence of major or minor Minnesota code abnormalities. Normal echocardiogram was defined as absence of contractile dysfunction, wall motion abnormalities, or abnormal left ventricular mass. Cox regression was used to compute the 10-year risk of developing coronary heart disease (CHD), stroke, and heart failure events.

Results:
There were 1,555 (41%) participants with normal ECG + normal echocardiogram at baseline. During 10 years of follow up, 783 CHD events, 414 strokes, and 576 cases of heart failure were detected. After accounting for traditional cardiovascular risk factors, a protective benefit was observed for all outcomes among participants who had normal ECG + normal echocardiogram (CHD: multivariable HR=0.56, 95%CI=0.46, 0.69; Stroke; multivariable HR=0.57, 95%CI=0.43, 0.76; Heart Failure: multivariable HR=0.36, 95%CI=0.29, 0.41). The addition of normal ECG + normal echocardiogram resulted in significant net reclassification improvement (NRI) of the Framingham risk score for heart failure (risk categories: <10%, 10-20%, >20%; NRI=0.043, 95%CI=0.010, 0.80).

Conclusions:
Normal findings on the routine ECG and transthoracic echocardiogram identify a group of individuals aged >65 years in which CVD risk is low. Our data support the existence of a low-risk noninvasive cardiac profile and further studies are needed to explore the utility of this profile regarding the decision to implement certain risk factor modification strategies, including invasive measures, to reduce CVD burden in older adults.
Abstract 12961: The Clinical Utility of Normal Findings on Noninvasive Cardiac Assessment in the Prediction of Atrial Fibrillation
Authors: Venkatesh Sanjay , O’Neal Wesley T , Broughton Stephen T , Shah Amit J , Soliman Elsayed Z
Published: April 2024

Introduction:
The absence of abnormalities found on noninvasive cardiac assessment possibly confers a reduced atrial fibrillation (AF) risk despite the presence of traditional risk factors.

Methods:
We examined the clinical utility of normal findings on routine noninvasive cardiac assessment in 5,331 (85% white; 57% women) from the Cardiovascular Health Study (CHS) who were free of baseline AF. The combination of normal electrocardiogram (ECG) + normal echocardiogram was assessed for the development of AF events. Normal ECG was defined as absence of major or minor Minnesota code abnormalities. Normal echocardiogram was defined as absence of contractile dysfunction, wall motion abnormalities, or abnormal left ventricular mass. Cox regression was used to compute the 10-year risk of developing AF.

Results:
There were 1,788 (34%) participants with normal ECG + normal echocardiogram, 2,207 (41%) with either normal ECG or a normal echocardiogram, and 1,336 (25%) with abnormal ECG + abnormal echocardiogram. During the 10-year study period, a total of 951 (18%) AF events were detected. When we examined the predictive ability of the normal ECG (multivariable HR=0.80, 95%CI=0.69, 0.92) and normal echocardiogram (multivariable HR=0.75, 95%CI=0.65, 0.87) in isolation, each marker was protective of developing AF. Compared with participants who had abnormal ECG + abnormal echocardiogram (referent), a protective benefit was observed for those with normal ECG or normal echocardiogram (multivariable HR=0.81, 95%CI=0.69, 0.95) and normal ECG + normal echocardiogram (multivariable HR=0.66, 95%CI=0.55, 0.79).

Conclusions:
Normal findings on routine noninvasive cardiac assessment identify persons in which the risk of AF is low. Further studies are needed to explore the utility of this profile regarding the decision to implement certain risk factor modification strategies in older adults to reduce the burden of AF.
Abstract 12990: Genome-wide Associations of Global Electrical Heterogeneity ECG Phenotype: The Atherosclerosis Risk in Communities (ARIC) and Cardiovascular Health (CHS) Studies
Authors: Tereshchenko Larisa G , Sotoodehnia Nona , Sitlani Colleen M , Waks Jonathan W , Kabir Muammar , Biggs Mary L , Biering-Sørensen Tor , Henrikson Charles A , Soliman Elsayed Z , Solomon Scott D , Post Wendy S , Buxton Alfred E , Siscovick David S , Josephson Mark E , Arking Dan E
Published: April 2024

Introduction:
Abnormal myocardial electrophysiological substrate quantified by global electrical heterogeneity (GEH) is independently associated with sudden cardiac death in the general population. The genetic basis of GEH has not been previously studied.

Hypothesis:
We hypothesized that a genome-wide association study (GWAS) would identify genetic loci related to GEH.

Methods:
We tested 22-26 million genotyped and imputed variants in African American (AA, N=3,378) and European American (EA, N=12,802) participants in the Atherosclerosis Risk in Communities and Cardiovascular Health Study cohorts. Five ECG markers of GEH (sum absolute QRST integral (SAI), spatial QRST angle (QRSTA), and spatial ventricular gradient (SVG) magnitude (SVGmag), elevation (SVGel), and azimuth (SVGaz)) were measured on standard 12-lead ECGs. Adjusted linear regression models were constructed with each GEH parameter as an outcome.

Results:
Ten significant susceptibility loci with 17 SNPs were identified. Multiple GEH parameters were associated with identical SNPs. A low frequency polymorphism (minor allele frequency 0.02) of
SCN5A
(rs7638275) was strongly associated with SAI (βGWAS -0.30; P=8.71x10
-11
in EA; P=3.49x10
-11
in combined EA/AA). QRSTA, SVGmag, SVGel, and SVGaz were associated with 9 loci, including transcriptional factors (
TBX3, HAND1, NFIA
), implicated in fetal gene program, facilitating molecular remodeling in response to stress. Our strongest association (rs7301677), associated with QRSTA (β
GWAS
0.16; P=1.46x10
-26
in the combined EA/AA), was previously reported associated with QRS duration and PR interval, and mapped near the
TBX3
gene, which plays a critical role in cardiac conduction system development. Both SAI (P=2.21x10
-10
) and SVGmag (P=2.40x10
-09
) were associated with rs7029396 (β
GWAS
0.09 in combined EA/AA), mapped near the
NCS1
gene, which plays a role in CaMKII-dependent cardiac hypertrophy. SAI was associated with 5 loci; genes in these loci included transcription factors
ACTB, SPI-1, IGF1R, GINS3
, and
LUZP1
, implicated in cardiac hypertrophy.

Conclusions:
We identified 10 genetic loci associated with ECG manifestation of GEH. There is a strong association between GEH and genetic signals for molecular remodeling.
Abstract 13015: Inhibition of Mitochondrial Calcium Uptake in the Heart Does Not Compromise Cardiac Energetics or Function Due to a Preferential Increase in Fatty Acid Oxidation During Increased Cardiac Work
Authors: Altamimi Tariq R , Kwong Jennifer , Fukushima Arata , Molkentin Jeffery D , Lopaschuk Gary D
Published: April 2024

The mitochondrial calcium (Ca
2+
) uniporter (MCU) is primarily responsible for relaying cytosolic Ca
2+
transients to the mitochondria. Increasing cardiac workload by positive inotropes results in increased mitochondrial Ca
2+
, increasing glucose oxidation in comparison to fatty acid oxidation. This has been attributed to Ca
2+
stimulation of pyruvate dehydrogenase, the rate-limiting enzyme in glucose oxidation. We examined what effect increasing workload has on cardiac energetics and cardiac function if mitochondrial Ca
2+
levels are decreased in hearts from inducible cardio-specific deleted MCU (MCU
-/-
) mice. Hearts from MCU
-/-
and MCU
fl/fl
control mice were isolated and perfused as working hearts with 5 mM glucose, 0.8 mM palmitate, 3% albumin, ± insulin (100 μU/ml) and isoproterenol (10 nM). Surprisingly, MCU
-/-
hearts showed increased cardiac work (p<0.05 vs. MCU
fl/fl
). MCU
-/-
hearts were also not energy-starved, displaying basal rates of glucose and fatty acid oxidation comparable to controls, and even higher glucose oxidation in response to insulin (3027±213 vs. 2268±166 nmol
.
g dry wt
-1.
min
-1
in MCU
fl/fl
, p <0.05). In response to isoproterenol treatment, MCU
-/-
hearts showed a similar increase in glucose oxidation, compared to controls. However, palmitate oxidation increased to a larger extent in MCU
-/-
hearts compared to controls (793±60 vs. 558±55 nmol
.
g dry wt
-1.
min
-1
, p <0.05, respectively), resulting in a greater reliance on fatty acid oxidation for ATP production (40.1±1.9 % vs. 32.7±2.1% in MCU
fl/fl
, p <0.05). This high fatty acid oxidation supported the higher energy demand at increased workload and provided a higher energy reserve as evident by higher acetyl-CoA/ CoA ratios (0.36±0.03 vs. 0.26±0.02 in MCU
fl/fl
, p<0.05). The rise in fatty acid oxidation correlated with lower levels of malonyl CoA, an endogenous fatty acid oxidation inhibitor, (4.50±0.29 vs. 8.66±0.98 nmol
.
g dry wt
-1
in MCU
fl/fl
, p< 0.05), and to an increase in acetylation of the fatty acid oxidation enzyme 3-hydroxyacyl CoA dehydrogenase (which stimulates activity). These results suggest that low mitochondrial Ca
2+
does not compromise cardiac energetics due to a compensatory stimulation of fatty acid oxidation.
Abstract 13023: Characteristics of Treatment Failure With Rate and Rhythm Control Strategies in Patients With Atrial Fibrillation: Insights From the AFFIRM (Atrial Fibrillation Follow-up Investigation of Rhythm Management) Trial
Authors: Maan Abhishek , Qin Ziling , Wang Yanbing , Zhang Zheng , Dudley Samuel , Dabhadkar Kaustubh , Mansour Moussa , Ruskin Jeremy , Heist E. Kevin
Published: April 2024

Introduction:
In patients with atrial fibrillation (AF) both “rate control” and “rhythm control” therapies have distinct set of limitations. We sought to investigate the rates and reasons of crossover from an initially assigned rate control arm to rhythm control and from rhythm to rate control therapy in patients who were enrolled in the AFFIRM trial.

Methods:
We compared the characteristics of patients who continued in the initially assigned treatment arm versus those who crossed over to the alternative treatment strategy in both “rhythm” and “rate” control arms. Two-sample t-test and chi-squared tests were used to compare means and proportions respectively.

Results:
A total of 4,060 patients were enrolled in the AFFIRM trial and over a mean follow-up duration of 3.5 years, 842 of them underwent crossover from an initially assigned treatment arm. The rate of crossover from an initially assigned rhythm control arm (594/2033, 29.2%) was more frequent than the rate of crossover from rate control to rhythm control (248/2027, 12.2%, p < 0.0001). In the rhythm control arm, the patients who crossed over to rate control had a significantly higher incidence of prior failure of an antiarrhythmic drug (139/594, 23.4%) than in those who continued as assigned (210/1439, 14.6%, p < 0.0001). In the rate control arm, patients who crossed over to rhythm control were relatively younger (68.3 ± 8.2 vs. 69.7 ± 8.0 years in those who continued, p = 0.01). The leading reasons for crossover to rate control were failure to achieve or maintain sinus rhythm (272/594, 45.8%) and intolerable adverse effects (122/594, 20.5%). In comparison, the major reasons for crossover to rhythm control were failure to control AF symptoms (159/248, 64.1%) and intolerable adverse effects (9/248, 3.6%). The difference in crossover pattern was statistically significant (p < 0.0001).

Conclusions:
Rhythm control was abandoned more commonly than rate control in patients who were enrolled in the AFFIRM trial. Failure of antiarrhythmic drug therapy prior to randomization was a significant factor for crossover from rhythm to rate control. Patients who crossed over from rate to rhythm control were younger than those who continued. The crossover from rhythm to rate control was driven by the occurrence of adverse effects.
Abstract 13049: Serum FABP5 Concentration, a Novel Determinant of Cholesterol Efflux From Macrophages, is a Potential Biomarker for Residual Risk of Atherosclerosis
Authors: Furuhashi Masato , Ogura Masatsune , Matsumoto Megumi , Yuda Satoshi , Muranaka Atsuko , Tanaka Marenao , Moniwa Norihito , Ohnishi Hirofumi , Saitoh Shigeyuki , Harada-Shiba Mariko , Miura Tetsuji
Published: April 2024

Introduction:
Cholesterol efflux capacity (CEC) from macrophages, represents the reverse cholesterol transport pathway, is inversely associated with risk for atherosclerotic cardiovascular disease. Fatty acid-binding protein 4 (FABP4) and 5 (FABP5) are expressed in both adipocytes and macrophages and play significant roles in the development of insulin resistance and atherosclerosis. FABP4 and FABP5 have been shown to be secreted from cells, and the circulating levels are associated with insulin resistance and atherosclerosis.

Hypothesis:
Serum levels of FABP4 and FABP5 are independently associated with CEC.

Methods:
A total of 250 subjects who were not on medication were recruited from subjects of the Tanno-Sobetsu Study, a study with a population-based cohort design. Concentrations of FABP4 and FABP5 were measured using commercially available enzyme-linked immunosorbent assay kits. CEC was measured using apolipoprotein B-depleted serum and J774.1 cells, a murine macrophage cell line.

Results:
CEC was positively correlated with HDL cholesterol and was negatively correlated with concentrations of high-sensitivity C-reactive protein (hsCRP) and FABP5 (r = -0.180, P = 0.041) but not with FABP4 level. Multiple regression analysis demonstrated that FABP5 level was an independent predictor of CEC after adjustment of age, gender and levels of HDL cholesterol and hsCRP. In 129 out of 250 subjects who underwent carotid ultrasonography, mean intima-media thickness was negatively correlated with CEC (r = -0.248, P = 0.005) and was positively correlated with concentrations of FABP4 (r = 0.178, P = 0.043) and FABP5 (r = 0.194, P = 0.028).

Conclusions:
In contrast to FABP4, FABP5 is independently associated with both carotid atherosclerosis and decreased CEC, suggesting that FABP5 level is a novel regulatory factor of CEC and a potential biomarker for residual risk of atherosclerosis in relation to cholesterol efflux from macrophages.
Abstract 13053: HAS-BLED Score and Atrial Fibrillation Type as Risk Factors for Bleeding Complications Associated With Catheter Ablation of Atrial Fibrillation among Patients Receiving Direct Oral Anticoagulants
Authors: Nakamura Kohki , Naito Shigeto , Minami Kentaro , Sasaki Takehito , Kumagai Koji , Funabashi Nobusada , Kobayashi Yoshio , Oshima Shigeru
Published: April 2024

Purpose:
This study aimed to identify predictors of thromboembolic and hemorrhagic events associated with catheter ablation of atrial fibrillation (AF) among patients receiving periprocedural direct oral anticoagulants (DOACs).

Methods:
We retrospectively studied 1034 consecutive AF patients (64±11 years; 777 males) receiving dabigatran (n=208), rivaroxaban (n=465), apixaban (n=292), or edoxaban (n=69) before AF ablation. The DOACs were continued in 61 (5.9%) patients and discontinued in 973 (94.1%) on the day of the procedure. No heparin bridging was performed before the ablation. During the procedure, heparin was given to maintain an activated clotting time (ACT) of 300-350 seconds. Major bleeding was defined as cardiac tamponade or pericardial effusions requiring drainage, intracranial and gastrointestinal hemorrhages, retroperitoneal bleeding, and bleeding requiring a blood transfusion, and vascular access site complications requiring intervention. Minor bleeding was defined as bleeding other than major bleeding.

Results:
No symptomatic thromboembolisms occurred. The incidence of major and minor bleeding was 0.6% and 8.8%, respectively, and did not significantly differ among the DOACs (P=0.351 and 0.177; Figure 1). In the multivariate logistic regression analysis, the HAS-BLED score and LSP-AF were significant positive predictors of bleeding complications (odds ratios, 1.358 and 1.956; 95% CIs, 1.108-1.665 and 1.196-3.198; P=0.003 and 0.007), but the DOAC type and dose (standard/reduced), periprocedural continuation of the DOACs, total heparin dosage, and intraprocedural ACT were not significant predictors. The periprocedural bleeding risk increased with higher HAS-BLED scores (Figure 2).

Conclusions:
Periprocedural DOAC treatment with adequate intraprocedural anticoagulation was effective in preventing symptomatic thromboembolisms. A higher HAS-BLED score and LSP-AF can be high risk factors for bleeding complications.
Abstract 13080: Transition Readiness in Adolescents With Heart Disease as Perceived by Their Parents: Do Parents and Teens Agree?
Authors: Uzark Karen , Yu Sunkyung , Lowery Ray , Afton Katherine , Yetman Angela , Cramer Jonathan W , Rudd Nancy , Cohen Scott , Gongwer Russell , Gurvitz Michelle
Published: April 2024

Introduction:
Transition is defined as “the process by which adolescents and young adults with chronic childhood illnesses are prepared to take charge of their lives and their health in adulthood”. Knowledge deficits and lack of transition readiness (TR) in 13-25 year olds with congenital or acquired heart disease have been previously reported. The aim of this multicenter study was to examine agreement between parental perceptions of their adolescent’s TR (knowledge, self-efficacy, self-management behaviors) and adolescent self-reported TR.

Methods:
Adolescents (n=175), age 13-18 yrs, and their parents completed the TR Assessment utilizing an e-tablet, web-based format at a routine clinic visit. Parent responses to the survey were compared to the teens’ self-reported responses and items of greatest disagreement identified.

Results:
Median patient age was 15.7 yrs. Parents perceived knowledge deficit scores (% of items with no reported knowledge) were significantly higher than self-reported by teens, 29.2% vs 25.9% p=.01. On a 100-point scale (higher = better), the mean score for self-efficacy was significantly lower as perceived by parents than by teens, 58.6 ± 21.1 vs 68.2 ± 18.3 (p<.0001), but parent and teen reports of self-management were not significantly different, 39.5 ± 15.2 vs 41.0 ± 15.8 (p=.27). For specific knowledge deficits, overall agreement ranged from poor to fair (kappa 0.07-0.41), highest for name of heart condition/surgery (0.41), poor for exercise/sports allowed (0.10) and follow-up needs (0.10). In patients on medications (n=94), agreement was moderate for medication purpose (0.42) and refill (0.46), but poor for name (0.17). For self-efficacy and self-management, agreement also ranged from poor to fair (kappa =0.16-0.29); parents more often perceived that their teen understood what the doctor said, but overestimated how difficult it was for the teen to talk to the doctor/nurse. Teens tended to request information more often than their parents (79% vs 65%, p=.06) and information requested varied (pregnancy/contraception, communication, insurance).

Conclusion:
Parents and teens differ in their perceptions regarding TR. Routine TR assessment is important to identify transition needs for both patients and their parents.
Abstract 13086: The Impact of Glycemic Variability on Mortality in Patients With Diabetes Hospitalized With Acute Heart Failure
Authors: Trasca Livia , Rimbas Roxana Cristina , Nitu Ileana , Calin Simona Ionela , Velcea Andreea , Andronic Anca Andreea , Vinereanu Dragos
Published: April 2024

Hypothesis:
Acute heart failure (AHF) in patients with diabetes is associated with increased mortality, however the impact of glycemic variability is unclear.

Methods:
We screened our database within 1 year to identify patients with AHF and diabetes. The glucose variables of interest were: hypoglycemia (glucose blood level <70 mg/dl); glycated haemoglobin (HbA1c); admission glycemia; mean glycemia index (MGI), defined as mean of all fasting glucose blood levels measured during hospitalization; and glycemic lability index (GLI), calculated by a validated formula, using successive glucose measurements and times between measurements. All these parameters were added to conventional potential prognostic markers: left ventricular ejection fraction (LVEF), admission systolic/diastolic blood pressure (SBP/DBP) and mean of all measurements during hospitalization (SBPm/DBPm), presence of respiratory failure, mechanical ventilation, atrial arrhythmias, troponin I and NTproBNP values, admission renal function (GRF) and mean of all measurements during hospitalization (GRFm). The outcome was in-hospital mortality.

Results:
113 patients (70±10yrs, 56% men) were identified. 13 patients (12%) died. Admission glycemia (341±81 vs 228±105 mg/dl), MGI (287±108 vs 164±38 mg/dl), GLI (18161±24774 vs 6408±18108 mg/dl
2
/h) were higher in non-survivors, whereas LVEF (22±12 vs 34±12%), SBP (102±43 vs 154±43 mmHg), SBPm (92±37vs127±25 mmHg), DBPm (76±11vs.56±24), and GRFm (37±22 vs 57±27 ml/min) were lower (all p<0.01). Presence of atrial arrhythmias, respiratory failure, but not mechanical ventilation was higher in non-survivors; hypoglicemia, HbA1c, troponin I, NTproBNP, and GRF were similar. Only MGI≥188 mg/dl and LVEF≤28% were independently associated with in-hospital mortality (Figure).

Conclusions:
Parameters of glycemic variability and LVEF are associated with in-hospital mortality in patients with diabetes hospitalized with AHF.