bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 9642: Non-Invasive Magnetic Resonance Based Three-Dimensional Voltage Maps for Electrophysiology Procedure Guidance
Authors: Sasaki Takeshi , Miller Christopher F , Hansford Rozann , Zviman Menekhem M , Henrikson Charles A , Marine Joseph E , Spragg David , Cheng Alan , Tandri Harikrishna , Sinha Sunil , Kolandaivelu Aravindan , Tomaselli Gordon F , Berger Ronald D , Calkins Hugh , Bluemke David A , Nazarian Saman
Published: April 2024

Introduction:
The association of scar on late-gadolinium enhancement cardiac magnetic resonance (LGE-CMR) with electrograms on electroanatomic map (EAM) has been investigated. We sought to quantify these associations to enable the creation of non-invasive three dimensional voltage maps (3D-VMs) based on LGE-CMR. We then tested the accuracy of the non-invasive 3D-VMs.

Methods:
LGE-CMR was performed in 17 patients with ischemic cardiomyopathy before ventricular tachycardia (VT) ablation. Left ventricular wall thickness (LVWT) and scar thickness (ST) were measured in each of 20 sectors per LGE-CMR short axis plane. In the first series of 13 patients (training set), EAM points were registered to the corresponding LGE-CMR images. Multivariate linear regression analysis (MLRA) was performed to determine significant independent variables and coefficients that predict local bipolar voltage. In the remaining patients (test set), non-invasive 3D-VMs were prospectively created with the regression equations by MLRA. Invasive local bipolar voltages were then compared with the estimated bipolar voltage based on non-invasive 3D-VMs.

Results:
A total of 1293 EAM points were analyzed. MLRA revealed independent associations between local bipolar voltage and LVWT, ST and scar location (P<0.001, respectively). Prospective non-invasive 3D-VMs were then created with custom software. There was no significant difference in mean bipolar voltage on EAMs and non-invasive 3D-VMs created for the test set (1.7±1.2 vs. 1.6±1.7 mV,P=0.17). Linear regression analysis revealed a significant association between bipolar voltages on invasive EAM and noninvasive 3D-VMs (P<0.001, R=0.79).

Conclusions:
The independent associations of local bipolar voltage with LVWT, ST on LGE-CMR enable the creation of accurate non-invasive 3D-VMs based on LGE-CMR. This novel methodology may improve the safety and efficacy of catheter ablation in patients with ischemic scar-related VT.
Abstract 9710: Hydrogen Sulfide Increases Nitric Oxide Production by Calcium-Dependent Activation of Endothelial Nitric Oxide Synthase
Authors: Kida Michiya , Sugiyama Toru , Yoshimoto Takanobu , Hirata Yukio
Published: April 2024

Purpose:
Hydrogen sulfide (H
2
S), which has been regarded as a toxic gas, was recently discovered to be synthesized in mammalian tissues by several different enzymes, such as cystathionine gamma-lyase (CSE), cystathionine beta-synthase (CBS), and 3-mercaptopyruvate sulfurtransferase (3-MST). Many studies have shown that H
2
S has various physiological functions, including vasodilator and antihypertensive effects in cardiovascular system. Therefore, H
2
S is considered as one of endothelium-derived relaxing factors (EDRFs). However, intracellular mechanisms of H
2
S-induced vasodilation and its interactions between other EDRFs, such as nitric oxide (NO), still remain unclear. In the present study, we investigated whether H
2
S directly regulates endothelial NO synthase (eNOS) activity and NO production in endothelial cells.

Methods:
We treated bovine aortic endothelial cells (BAEC) with a hydrogen sulfide donor (NaHS) and determined NO production from BAEC into the culture medium by fluorometric measurement with 2,3-diaminonaphthalene. We determined the changes of intracellular calcium concentration by using Fura 2-AM, and analyzed the activity of eNOS by western blotting.

Results:
NaHS dose-dependently (12.5 - 200 µM) increased NO production from BAEC with 2.6-fold increase (n=8, p<0.01) by 200 µM. This NaHS-induced NO production was abolished by an intracellular calcium-chelator (BAPTA-AM), but was not affected by the inhibitor of phosphatidylinositol 3-kinase (wortmannin). This effect was partially blocked by a ryanodine receptor inhibitor (dantrolene) and an inositol 1,4,5-trisphosphate receptor inhibitor (xestosponginC). NaHS induced relatively slow increases in the intracellular calcium by 11.3 ± 1.1 nM after 15 minutes (n=4, p<0.01). NaHS induced phosphorylation of eNOS at the activating phosphoserine residue 1179. This effect was completely blocked by BAPTA-AM, but wasn't affected by wortmannin.

Conclusions:
H
2
S directly acts on endothelial cells to induce eNOS activation and NO production by releasing calcium from the intracellular store in endoplasmic reticulum, which may explain one of mechanisms of its vasodilator function as an EDRF.
Abstract 9717: Hypertension-Induced Atrial Remodeling Promotes Atrial Fibrillation Stabilization Upon Tachyarrhythmia Onset
Authors: Iwasaki Yuki , Naud Patrice , Shi Yanfen , Maguy Ange , Mizuno Kyoichi , Tardif Jean-Claude , Nattel Stanley
Published: April 2024

Background:
Hypertension (HT) is a major risk factor for atrial fibrillation (AF) but the underlying mechanisms are poorly understood. We hypothesized that HT produces an AF-stabilizing influence that favors faster progresion of spontaneous AF-maintenance when atrial tachyarrhythmia (AT) begins.

Methods:
HT was induced in dogs (n=6) by left nephrectomy and right renal artery constriction (1K1C). Sham operated dogs with the same surgery but no nephrectomy or artery constriction (n=5) were controls. Beginning 28 days from surgery, AT-pacing (ATP, 600 bpm) was started for 7 days. Serial atrial ERP measurement and AF induction was performed at days 7, 14, 28, 29, 30, 32 and 35 from surgery. Final open chest EPS was performed at day 36.

Results:
Systolic blood pressure (SBP) of HT dogs increased beginning at day 7 post 1K1C surgery (baseline 128±4 mm Hg; 7-d 183±6*, 28-d 176±10* mmHg; * p<0.01 vs. baseline). SBP of sham dogs remained constant (baseline 133±4 mm Hg; 7-d 128±3, 28-d 126±6 mmHg). Mean AF duration (10 Hz burst pacing induced) increased marginally in HT dogs pre-ATP (Figure), but substantially after 1 and 2 days ATP vs control. At open-chest EPS, there were no differences in AF vulnerability to premature extrastimuli (HT, 69±5% vs. Sham, 70±11%; p=NS), AF duration (HT, 1501±273 sec vs. Sham, 1458±342 sec; p=NS) or regional ERP heterogeneity. HT dogs showed increased atrial conduction heterogeneity (heterogeneity index in HT, 2.01±0.10 vs. sham, 1.50±0.08; p<0.01), associated with significant downregulation of connexin (Cx) 43 expression (by 57%
+
,
+
p<0.05) but no change in Cx40 expression. Heart to body weight ratio increased in HT (9.7±0.4 vs. 8.5±0.2
+
), reflecting LVH.

Conclusions:
HT alone produces modest AF promotion, but changes caused by HT accelerate AF stabilization once initiated, increasing vulnerability to prolonged AF. The AF-promoting effects of hypertension are related to conduction abnormalities, possibly caused by connexin downregulation.
Abstract 9728: Arterial Stiffness is Associated with Carotid Atheromatosis in Hypertensive Patients (Campania Salute Network)
Authors: Casalnuovo Giuseppina , Gerdts Eva , Izzo Raffaele , De Marco Marina , Giudice Renata , De Simone Giovanni , Trimarco Bruno , De Luca Nicola
Published: April 2024

Background:
Pulse pressure/stroke index (PP/SVi) is a validated measure of total arterial stiffness, but its relation to carotid atherosclerosis is unknown.

Methods:
Data from 6209 hypertensive patients without prevalent cardiovascular disease (coronary heart disease, stroke, heart failure) in the Campania Salute Network underwent standard transthoracic echocardiography and carotid ultrasound. SVi was obtained by echocardiographic LV volumes computation; mean and maximal (max) carotid intima-media thickness (IMT) and the presence of plaques (≥1.3 mm) in the common and internal carotid arteries were assessed. The population was stratified into thirtiles of PP/SVi and analyzed using ANOVA.

Results:
Increase from the lowest to the highest thirtiles of PP/SVi was associated with increasing age, progressively higher systolic and diastolic blood pressure (BP), higher total cholesterol and larger number of antihypertensive drugs (Table 1). The highest PP/SVi thirtile was also associated with higher max and mean IMT and higher prevalence of carotid plaques (Table1). In multivariate logistic regression analysis, compared to the lowest thirtiles, the prevalence of carotid plaque increased by 16% (95% confidence interval [CI] 1-34%, p<0.05) in the second PPSVi thirtile and by 33% (95% [CI] 15-55%, p<0.01) in the the highest PPSVi thirtile, independently of significant associations with diabetes mellitus, age, gender and total cholesterol.

Conclusion:
In treated hypertensive patients included in the CampaniaSalute Network, higher PP/SVi is associated with carotid atherosclerosis independently of others confounders.
Abstract 9743: Profibrillatory Atrial Autonomic and Cellular Electrophysiological Remodelling with Endurance Training
Authors: Guasch Eduard , Benito Begona , Qi Xiao Yan , Naud Patrice , Tadevosyan Artak , Gillis Marc-Antoine , Mont Lluis , Nattel Stanley
Published: April 2024

Background:
Endurance exercise (Ex) increases AF risk, but underlying mechanisms are unknown. Here, we studied Ex induced autonomic and cellular electrophysiological changes controlling AF risk.

Methods:
Ex rats (daily treadmill training X 16 wks) were compared to matched sedentary (Sed) controls. Parasympathetic and sympathetic tone were assessed from heart rate (HR) changes caused by atropine and propranolol respectively. Baroreflex sensitivity was studied by HR responses to phenylephrine-induced BP changes. Ion currents (I
KACh
, I
to
, I
CaL
) were measured in atrial myocytes by patch clamp. Atrial refractory period (ARP) was measured in vivo with transvenous electrode catheters. mRNA expression was quantified by qPCR.

Results:
Atrial myocytes were hypertrophied in Ex (129±8.7 pF vs 73±5 pF Sed, p<0.001). Parasympathetic tone was significantly enhanced in Ex rats by 83%, with no changes in sympathetic tone. Reflex vagal sensitivity was enhanced (60% increase in HR-reduction vs BP-increase slope with phenylephrine boluses). Post-synaptic responses were also increased, as shown by significant increases in I
KACh
induced by 100 μ M acetylcholine, ACh (Fig. A). mRNA expression of beta-adrenergic (β1, β2) and muscarinic (M2, M3) receptors and associated G proteins did not differ between groups. Regulatory G signaling proteins (RGS, Fig. B), which decrease ACh responses, were downregulated in Ex. Balanced downregulation of voltage gated K
+
and Ca
2+
current subunits (Fig. C) and currents (Fig. D) left ARP unchanged in the absence of ACh. AF inducibility was enhanced in Ex rats, an effect that was abolished by atropine.

Conclusions:
Ex promotes AF by enhancing vagal tone through pre (baroreflex) and post (RGS, I
KACh
) synaptic mechanisms. Ion channel expression changes in a balanced way, leaving repolarization unaffected in the absence of ACh.
Abstract 9867: Insulating an Open Irrigated Ablation Electrode Improves Electrode Temperature Feedback for Radiofrequency Lesion Formation and Steam Pop
Authors: Ikeda Atsushi , Nakagawa Hiroshi , Wittkampf Fred H , Paul Saurav , Hepler Eric , Marri Prathyusha , Pitha Jan V , Sharma Tushar , Lazzara Ralph , Jackman Warren M
Published: April 2024

Introduction:
Open irrigation (Irg) cools electrode and electrode-tissue interface (ETI), and prevents thrombus while producing large RF lesions. However, electrode temperature (ET) does not predict excessive tissue heating and steam pop. The purpose of this study was to compare the relationship of ET to lesion size and steam pop between a novel thermally insulated Irg electrode (Gen2, St Jude Medical) and a conventional, non-insulated 4 mm Irg electrode (St Jude Medical) using a canine thigh muscle preparation.

Methods:
In 4 dogs, the skin over the thigh muscle was incised and raised to form a cradle, which was superfused with heparinized blood at 37°C. Gen2 has a 7F, 2.5 mm tip electrode with 6 proximal and 1 distal thermally insulated Irg channels to provide only external electrode cooling (
Fig A
). Gen2 and a conventional 7F, 4mm Irg catheter were held perpendicular or parallel to thigh muscle. Catheter-tissue contact force was applied at 5, 20 or 40 g. RF was applied for 60 sec at 20 W for Gen2 (Irg 17 ml/min) and 40 W for the 4mm electrode (Irg 17 ml/min). ET, ETI, and tissue temperatures (3 and 7mm depths) were measured. Dogs were sacrificed at 2 hours after ablation and lesion size was measured.

Results:
Table
and
Fig
.

Conclusions:
Gen2 had a wider range of peak ET than 4 mm. Gen2 had better correlation between peak ET and lesion depth (R=0.71 vs. R=0.26), and between peak ET and steam pop (ET>54°C vs. ET >34°C).
Abstract 9901: Cardiac Protection From Hypoxic Injury by a Novel Synthetic Peptide Targeting the Activator of G-Protein Signaling 8-Mediated Gβγ Signal
Authors: Sato Motohiko , Hiraoka Masahiro , Yamane Yukiko , Xianfeng Feng , Ishikawa Yoshihiro
Published: April 2024

Ischemia-reperfusion injury of the heart is associated with activation of multiple signaling pathways including those of heterotrimeric G-protein. We identified an ischemia-inducible G-protein activator, activator of G-protein signaling 8 (AGS8), which interacts directly with Gβγ and regulates Gβγ signaling in cells. The knockdown of AGS8 by siRNA dramatically blocked hypoxia-induced apoptosis of cardiomyocytes, suggesting AGS8 triggered a critical cascade leading to cell death, which could be a novel therapeutic target. To investigate this possibility further, we attempted to protect cardiomyocytes from hypoxia-induced apoptosis by utilizing a synthetic peptide which disrupts AGS8-mediated Gβγ signaling. We first developed a peptide (AGS8-peptide) that blocked the association of Gβγ with AGS8 based on amino acid sequences of the Gβγ binding domain of AGS8. We then investigated the effects of the AGS8-peptide on cardiomyocytes exposed to hypoxic stress. Cultured rat neonatal cardiomyocytes were exposed to hypoxia (6 h)/reoxygenation (18 h) following transfection with AGS8-peptide. Interestingly, AGS8-peptide effectively blocked apoptosis in cardiomyocytes, as determined by DNA end-labeling (9.7±1.5% of control, p<0.05, mean±SEM) and an increase in cleaved caspase-3 (36.7±6.5% of control, p<0.05, mean±SEM). Because AGS8-mediated Gβγ signaling influenced apoptosis of cardiomyocytes via channel protein connexin 43 (CX43), the effects of AGS8-peptide on permeability/localization of CX43 were examined. The permeability of CX43 following the exposure of cells to hypoxia, as determined by a flux of fluorescence dye (Lucifer yellow), was decreased (34.1±4.3%, p<0.05 vs. normoxia control, mean±SEM). However, AGS8-peptide blocked the decrease of membrane permeability (93.0±12.3%, p<0.05 vs. control group, mean±SEM). AGS8-peptide also blocked hypoxia-induced internalization of CX43 in cardiomyocytes (8.3±1.3% of control, p<0.05, mean±SEM). These data indicate the importance of AGS8-mediated Gβγ signaling in cardiomyocytes and suggest that the targeted disruption of the AGS8 signal will provide a novel approach for protecting the myocardium against ischemic injury.
Abstract 9929: Medium-Term Repeated Administration of Miglitol Improves Vascular Endothelial Dysfunction in Diabetic Patients with Coronary Artery Disease - Evaluation Using Flow-Mediated Dilatation
Authors: Emoto Takuo
Published: April 2024

Background:
Repeated postprandial hyperglycemia may play an important role in the development of atherosclerosis by suppressing vascular endothelial function. Although miglitol suppresses the elevation of blood glucose levels shortly after a meal more than other α-glucosidase inhibitors, the effect of medium-term repeated administration of miglitol on endothelial dysfunction is unknown.

Methods:
Fifty type 2 diabetic patients with coronary artery disease (CAD) were enrolled in the present study. The patients were randomly divided into two groups: the first was treated with miglitol (M-group, 150mg/day) and the second with voglibose (V-group, 0.6mg/day) for 3 months. Blood chemistry (lipid and blood glucose profiles, hemoglobinA1c, 1,5-anhydroglucitol, serum insulin levels, and C-reactive protein) and flow-mediated dilatation (FMD), a surrogate marker of vascular endothelial function, were measured at the beginning and end of the trial period.

Results:
Patient characteristics and blood chemistry of the two groups were similar at the beginning of the trial. At the end of the trial, hemoglobinA1c decreased in both groups, but the improvement of 1,5-anhydroglucitol levels in M-group patients were significantly higher than in V-group patients(14.5 ± 8.7 μ g/ml to 21.3 ± 9.8 μ g/ml in the M-group vs. 16.2 ± 8.3 μ g/ml to 17.6 ± 8.6 μ g/ml in the V-group) .Insulin resistance index (serum insulin levels × fasting blood sugar/405), CRP and %FMD also improved in M-group but not in V-group patients (2.8±1.9% to 5.3±2.1%, P<0.0001 vs. 3.0±3.7% to 3.2±1.7%, P=0.36).

Conclusions:
Medium-term Repeated administration of miglitol improved vascular endothelial dysfunction by strongly suppressing postprandial hyperglycemia. Miglitol may have vasoprotective and anti-atherogenic effects in type 2 diabetic patients with CAD.
Abstract 9958: The Cardiovascular Risk Factor 8-iso-Prostaglandin F2alpha Independently Predicts Mortality in Pulmonary Artery Hypertension
Authors: Schwedhelm Edzard , Cracowski Jean-Luc , Kom Ghainsom D , Degano Bruno , Chabot Francois , Labarère José , Böger Rainer H , Humbert Marc
Published: April 2024

Background.
F2-isoprostanes, among them 8-iso-Prostaglandin F2alpha (8-iso-PGF2α), have emerged as cardiovascular risk factors, activating the thromboxane A2 receptor (TP) and mediating vasoconstriction, impaired angiogenesis, altered platelet activity, and smooth muscle cell proliferation. Pulmonary artery hypertension (PAH) is a rare progressive disease with a 3-year mortality rate of 30-50 %. To date, new therapeutic options in PAH are sparse.

Methods.
We therefore investigated the prognostic value of 8-iso-PGF2α in a cohort of 110 newly diagnosed, treatment naïve, PAH patients. Eligible patients from 6 centers of the French Network on Pulmonary Hypertension were screened and patients were followed for 3 years. Urinary 8-iso-PGF2α determined by gas chromatography-mass spectrometry (GC-MS), along with other clinical and biochemical characteristics was evaluated at the time of diagnosis, i.e. right heart catheterisation.

Results.
Among 110 enrolled patients, 11 underwent heart and/or lung transplantation and 27 died during follow-up. Plasma big endothelin-1 (hazard ration [HR] per 1 standard deviation [SD] increase, 1.48, 95 % confidence interval [CI] 1.14 - 1.92), serum troponin T >0.01 mg/L (HR: 2.35, CI: 1.05 - 5.3], and urinary 8-iso-PGF2α (HR: 1.76, CI: 1.31 - 2.36) were associated with unadjusted risk. In multivariate Cox proportional hazard models, adjusting for variables with p<0.1, only 8-iso-PGF2α was independently associated with mortality (HR:1.82, CI:1.28 - 2.60).

Conclusions.
The endogenous TP agonist 8-iso-PGF2α independently predicts mortality in newly diagnosed PAH patients. Pharmacological inhibition of the TP in these selected patients may be a new valuable option additive to standard treatment.
Abstract 9990: Regulation of miR132 in Cardiac Fibroblasts After Ischemia Enhances Angiogenesis and Reduction of Apoptosis by Targeting Sonic Hedgehog
Authors: Huang Wei , Liang Jialiang , Ashraf Atif , Xu Meifeng , Millard Ronald W , Ashraf Muhammad , Wang Yigang
Published: April 2024

Background:
Synthesis of growth factors by cardiac fibroblasts (CF) during myocardiac ischemia plays an important role in maintaining cardiac structure and function. However, the dominant paracrine mediator and it's molecular mechanism in fibroblasts are not clear.

Methods and Results:
In vitro
, qPCR analysis identified miR-132 which was significantly down-regulated miRNA in infarcted heart and highly expressed in CF. Sonic hedgehog (Shh), as the predicted targeting gene of miR-132, was specifically expressed in CF and markedly increased during ischemia. To analyze the paracrine effect of Shh on angiogenesis, GFP transfected HUVEC were co-cultured with CF. Knock-down of miR-132 (anti-132) in fibroblasts significantly increased Shh, VEGF, MMP-9 and IGF-1 synthesis, concomitant with increased tube formation in comparison with the null vector transfected CF (CON) and miR-132 overexpressing groups (miR-132). Furthermore, 5 days after MI, TUNNEL staining of infarcted heart revealed an anti-apoptosis effect of anti-132 on cardiomyocytes. Mechanisms contributing to the beneficial effect of miR132 knockdown involve activation of smoothened (Smo), the non-canonical signaling pathway. Administration of miR132 antagomir
in vivo
after MI significantly enhanced angiogenesis, reduced infarction size, and cardiac remodeling in comparison with miR-132 plasmid and CON group (Fig. 1).

Conclusion:
Regulation of miR-132 in CF plays an important role in angiogenesis, anti-apoptosis and reduction of cardiac remodeling by targeting Shh.
Abstract 18281: Soluble Form of Membrane Attack Complex Independently Predicts Mortality and Cardiovascular Events in Patients with ST-segment Elevation Myocardial Infarction
Authors: Lindberg Søren , Pedersen Sune , Møgelvang Rasmus , Galatius Søren , Flyvbjerg Allan , Jensen Jan S , Bjerre Mette
Published: April 2024

Background:
The complement system is an important mediator of inflammation, which plays a pivotal role in atherosclerosis and acute myocardial infarction (AMI). Animal studies suggest that activation of the complement cascade resulting in the formation of sMAC, contributes to both atherosclerosis and plaque rupture and may be the direct cause of tissue damage related to ischemia/reperfusion injury. However clinical data of sMAC during an AMI is sparse. Accordingly the aim was to investigate the prognostic role of soluble membrane attack complex (sMAC) in patients with ST-segment elevation myocardial infarction (STEMI).

Methods:
We included 725 STEMI-patients admitted to a single, high-volume invasive heart centre, treated with primary percutaneous coronary intervention (PCI), from September 2006 to December 2008. Blood samples were drawn immediately before PCI. Plasma sMAC was measured using an in-house immunoassay. Endpoints were all-cause mortality (n=62) and the combined endpoint (n=122) of major cardiovascular events (MACE) defined as cardiovascular mortality and admission due recurrent AMI or heart failure. Follow-up time was 12 months.

Results:
Patients with high sMAC (>75
th
percentile) had increased risk of all-cause mortality and MACE. Even after adjustment for confounding risk factors by Cox-regression analyses, high levels of sMAC remained an independent predictor of all-cause mortality (hazard ratio 1.81 (95% CI 1.06-3.06; p=0.029)) and MACE (hazard ratio 1.70 (95% CI 1.16-2.48; p=0.006)).

Conclusions:
High plasma sMAC independently predicts all-cause mortality and MACE in STEMI-patients treated with PCI.
Abstract 18297: Peri-stent Contrast Staining After Drug-eluting Balloon Angioplasty for Treatment of Coronary In-stent Restenosis
Authors: Otsuji Hideaki , Kadota Kazushige , Goto Tsuyoshi , Kato Harumi , Yamamoto Hiroyuki , Oka Naoki , Fuku Yasushi , Tanaka Hiroyuki , Tada Tsuyoshi , Habara Seiji , Shigemoto Yoshikazu , Hasegawa Daiji , Ootsuru Suguru , Saito Naoki , Hayakawa Yuki , Miyake Kohshi , Yusuke Hyodo , Ozaki Masatomo , Kubo Shunsuke , Ichinohe Tahei , Mitsudo Kazuaki
Published: April 2024

Background: Peri-stent contrast staining (PSS) induced by sirolimus-eluting stent (SES) implantation has been reported and the PSS rate was about 2%. It is said that PSS is an abnormal vessel reaction and is related to stent thrombosis. However, it remains unknown whether PSS arises after drug-eluting balloon (DEB) angioplasty. We report on PSS which arose after DEB angioplasty in the in-stent restenosis (ISR) lesion in relation to previously deployed stents.

Methods: From September 2008 to October 2011, 378 consecutive patients with 453 lesions (42 de novo and 411 ISR) underwent DEB angioplasty in our hospital. The 411 ISR lesions were classified according to the previously deployed stent: SES, 182; paclitaxel-eluting stent (PES), 61; zotarolimus-eluting stent (ZES), 54; everolimus-eluting stent (EES), 34; biolimus-eluting stent (BES), 16; bare metal stent (BMS), 64. All patients underwent midterm follow-up coronary angiography (f/u CAG) at 6 months after DEB angioplasty, and those without restenosis underwent late f/u CAG at 12 months after midterm f/u.

Results: The PSS rates were as follows: overall 3.3% (15/153); de novo, 0% (0/42); SES, 4.40% (8/182); PES, 6.56% (4/61); ZES, 1.85% (1/54); EES, 0% (0/34); BES, 0% (0/16); BMS, 3.13% (2/64). There were no significant differences between each PSS lesion, between first (SES and PES) and second (ZES, EES, and BES) generation drug-eluting stents, and between de novo lesions and each generation group of drug-eluting stent. Stent thrombosis has not occurred.

Conclusion: PSS can arise after DEB angioplasty for ISR. Compared with the previous report on PSS after SES implantation, PSS occurred more frequently after DEB angioplasty than after SES implantation. With respect to stent thrombosis, long-term follow-up of patients with PSS after DEB angioplasty is necessary.
Abstract 18379: Impact of Gender on Adverse Cardiovascular Events Following Percutaneous Coronary Intervention: Pooled Analysis from the SPIRIT II, III and IV trials
Authors: Baber Usman , Kini Annapoorna S , Gukathasan Nilusha , Mehran Roxana
Published: April 2024

Background:
Female gender is a consistent and strong correlate of increased cardiovascular risk following percutaneous coronary intervention (PCI). Emerging data suggest that 2
nd
generation drug-eluting stents (DES) may improve event-free survival compared to 1
st
generation DES. Whether or not this applies to both sexes is unknown.

Methods:
The SPIRIT II, III and IV randomized controlled trials compared the second-generation everolimus-eluting stent (EES) to the first-generation paclitaxel-eluting stent (PES). Summary-level data from the latest follow-up year of each study was pooled using meta-analytic techniques. We evaluated the overall and differential impact of gender on adverse events stratified by DES type. Relative risks and 95% confidence intervals were calculated for the following outcomes: definite or probable stent thrombosis (ST), target lesion revascularization (TLR), myocardial infarction (MI), major adverse cardiovascular events (MACE) and cardiac death.

Results:
Women (n=1583, 31.7%), were older, more often diabetic and less likely to have multivessel disease compared to men (n=3405, 68.3%). After a weighted mean follow-up of 2.3 years, among patients receiving PES, the incidence of MACE (13.3% vs. 10.1%, p=0.04) was significantly higher while rates of MI (5.3% vs. 4.0%, p=0.19) and TLR (8.4% vs. 6.6%, p=0.17) were modestly higher among women compared to men. In contrast, MACE rates were lower with EES than PES in both men and women, and outcomes were similar in men and women receiving EES (Table). Rates of ST (0.5% vs. 0.7%, p=0.65) and cardiac death (0.9% vs. 1.0%, p=0.95) in EES-treated patients did not differ in women vs. men, respectively.

Conclusions:
In this pooled analysis of RCT, adverse cardiovascular events were modestly higher among women compared to men treated with PES. In contrast, outcomes were improved with EES in both men and women such that female sex was no longer associated greater MACE.
Abstract 18444: Constitutive Expression of a Dominant Negative TGF-β Type II Receptor in the Posterior Left Atrium Interrupts Heart Failure Induced Conduction Changes, with a Resulting Decrease in Atrial Fibrillation
Authors: Ng Jason , Al-Angari Haitham M , Gordon David , Aistrup Gary L , Browne Suzanne , Kunamalla Aaron , Sahakian Alan V , Knight Bradley P , Passman Rod S , Kadish Alan H , Goldberger Jeffrey J , Arora Rishi
Published: April 2024

Introduction:
Fibrosis is thought to be a key contributor to the conduction slowing and heterogeneity seen in the heart failure (HF) atrium, providing a substrate for atrial fibrillation (AF). Hypothesis: Since the TGF-β pathway contributes to the creation of atrial fibrosis, we hypothesized that decreasing TGF-β signaling in the HF posterior left atrium (PLA) by expressing a dominant-negative TGF-β type II receptor (TGF-β-II-DN) will, by attenuating formation of fibrosis, decrease conduction slowing and in-homogeneity and thereby decrease AF.

Methods:
17 dogs underwent injection+electroporation in the PLA of either an HA-tagged plasmid expressing TGF-β-II-DN (pUBc-TGFβdnRII) (Group A, N=8) or control vector (pUBc-LacZ) (Group B, N=7), followed by 3-4 weeks of right ventricular tachypacing (240 bpm) to induce HF. The following were assessed both at baseline and the terminal study: left atrial effective refractory periods (ERPs), high density activation maps of the PLA, and the number of AF episodes >30s by burst pacing. Total activation time and a conduction in-homogeneity index were determined from the activation maps. Tissue was assayed for gene expression and fibrosis (Trichrome staining).

Results:
RT-PCR and western blotting showed robust gene expression in the PLA. Group A developed significantly less fibrosis as a percentage of the PLA than group B (41.6±5.6 vs. 56.4±4.5%, p=0.05). ERP increases after ventricular tachypacing were equal in both groups (32 vs. 34.5 ms, p=NS). Ventricular tachypacing significantly increased the PLA activation time in Group B (from 22.8±2.9 to 43.3±8.6 ms, p<0.002), but not in Group A (from 25.3±5.2 to 28.7±11.3, p=0.6). The in-homogeneity index was also significantly increased in Group B (from 1.9±0.9 to 4.4±1.9, p=0.05) but not in Group A (p=0.12). This was accompanied by a lower number of sustained AF episodes in Group A compared to Group B (0.33±0.21 vs. 3±1.1, p<0.05).

Conclusions:
Targeted non-viral gene-therapy aimed at reducing TGF-β signaling - and consequent development of fibrosis - in the PLA interrupts the development of conduction slowing and in-homogeneity in the HF atrium, with a significant decrease in AF. Further optimization of this gene therapy approach may translate into effective AF therapies.
Abstract 18454: Calcium Calmodulin Dependent Protein Kinase II delta Modulates Cardiomyocytes Passive Stiffness by Phosphorylating Titin Spring Elements
Authors: Hamdani Nazha , Krysiak Judith , Kreusser Michael M , Franzel Benjamin , Wolters Dirk A , Maier Lars S , Krúger Markus , Backs Johannes , Linke Wolfgang A
Published: April 2024

Background:
High diastolic stiffness of the failing heart can result from altered cardiomyocyte mechanical properties. Cardiomyocyte passive force (F
passive
) is attributed mainly to the mechanical properties of titin, particularly isoform composition and phosphorylation. Titin can be phosphorylated by protein kinase(PK)A or PKG at the N2-Bus, which decreases F
passive
. However, PKCα phosphorylates titin's PEVK-region, which increases F
passive
. Whether other kinases relevant for cardiomyocyte function phosphorylate the titin springs has been unknown.

Aim:
To investigate whether Ca
2+
/calmodulin dependent protein kinase IIδ (CaMKIIδ) phosphorylates cardiac titin and affects cardiomyocyte F
passive
.

Methods:
Cardiac titin phosphorylation was assessed in CaMKIIδ/γ double knockout (DKO; n=8) and transgenic CaMKIIδC overexpressing mice (TG; n=6). A SILAC-DKO mouse was generated for quantitative proteomics
in vivo
. Cardiac titin separated by titin gel electrophoresis was also studied for phosphorylation sites using MudPIT mass spectrometry. Recombinant wildtype (WT) and mutant fragments of human cardiac titin were expressed and phosphorylated
in vitro
by CaMKIIδ. F
passive
of permeabilized isolated WT, DKO and TG mouse cardiomyocytes was recorded between 1.8 and 2.4 µm sarcomere length before and after CaMKIIδ administration.

Results:
Total titin phosphorylation was reduced in DKO and elevated in TG compared to WT hearts. CaMKIIδ treatment of cardiac tissue
ex vivo
increased titin phosphorylation. A CaMKII-dependent phosphosite was identified within the N2-Bus (S4062) by MudPIT and two phosphosites within the PEVK-region (
T12007
and
S12022
) by SILAC. Western blotting using phosphospecific antibodies against these sites in cardiac tissues or recombinant WT/mutant titin constructs confirmed that CaMKIIδ indeed phosphorylates these 3 sites. F
passive
was elevated in DKO and lowered in TG, compared to WT cardiomyocytes. Administering CaMKIIδ
ex vivo
lowered F
passive
in DKO but did not affect TG cardiomyocytes.

Conclusion:
CaMKIIδ phosphorylates the titin springs
,
thereby lowering F
passive
. Reducing titin-based stiffness through CaMKIIδ-dependent phosphorylation of titin N2-Bus and PEVK may benefit diastolic function.
Abstract 18502: Bleeding Post PCI: Predictors of “ANY” Bleeds: Six Month Results from the PARIS (Patterns of Non-Adherence to Antiplatelet Regimens in Stented Patients) Registry
Authors: Yu Jennifer , Weisz Giora , Witzenbichler Bernhard , Henry Timothy D , Kini Annapoorna S , Stuckey Thomas , Cohen David J , Berger Peter B , Colombo Antonio , Shawl Fayaz , Steg Philippe Gabriel , Moliterno David , Hermiller James , Xistris Sylvia , Kakoulides Socrates , Cashy Catherine , Kulina Robert , Krucoff Mitchell , Vlachojannis Georgios , Sartori Samantha , mehran Roxana
Published: April 2024

Introduction.
While recent studies have highlighted the clinical importance of minor, or “nuisance” bleeding, the predictors of all bleeding complications including minor bleeding events have not been examined in detail.

Methods.
The PARIS registry was a multicenter, international, all-comers registry of patients who had undergone successful PCI in 2009-2010 for stable angina, acute coronary syndrome (ACS) or documented silent ischemia. All bleeding events were adjudicated by a Clinical Events Committee according to the Bleeding Academic Research Consortium (BARC) criteria from source documents. We compared baseline clinical and treatment variables in patients who had any versus no bleeding at 6-months.

Results.
Of 5,033 patients, 235 (4.7%) had a bleeding event in the first 6-months. Of these, 27.7% had BARC type 1 bleeding, 40.4% had BARC type 2 bleeding, 30.2% had type 3, 0.4% had type 4 (CABG-related), and 1.3% had type 5 (fatal) bleeding. Compared to patients with no bleeding, patients who had bleeding were more likely to be older, female, non-smokers, and to be prescribed on warfarin on discharge (Table). After multivariable analysis, independent predictors of 6-month bleeding were age (OR 1.02, 95% CI 1.002 - 1.03), female gender (OR 1.9, 95% CI 1.3 - 2.9), and warfarin therapy (OR 2.6, 95% CI 1.7 - 3.7, all p<0.05), whereas hypertension was associated with reduced risk of bleeding (OR 0.7, 95% CI 0.52 - 0.98, p=0.04). Treatment with prasugrel (vs. clopidogrel) was not a predictor.

Conclusion.
In this real world, contemporary PCI registry with close evaluation of bleeding events, the 6-month rate of any bleeding was 4.7%. Almost 70% of these bleeding incidents were BARC type 1 and 2, which may be classified as minor or “nuisance” bleeds. Age, female gender, and warfarin were independent predictors of bleeding events. Table.
Abstract 18563: Pulmonary Artery Pressure Response Pattern in Heart Failure with Preserved Ejection Fraction
Authors: Dhakal Bishnu P , Murphy Ryan M , Chatterjee Neal A , Semigran Marc J , Lewis Gregory D
Published: April 2024

Background:
Inefficient ventilation during exercise, defined by steep relationship between ventilation and carbon dioxide output (VE/VCO
2
) purports a poor prognosis in heart failure (HF) patients regardless of ejection fraction (EF). However the extent to which VE/VCO
2
slope reflects hemodynamic impairment during exercise in HFpEF is unknown. We therefore investigated hemodynamic response patterns in relation to exercise gas exchange parameters in HFpEF compared to normal controls.

Methods/Results:
We studied consecutive patients referred for cardiopulmonary exercise testing with hemodynamic monitoring who had RER >1.05 and either resting supine pulmonary capillary wedge pressure (PCWP) >15 or exercise PCWP >20 mmHg and LVEF >0.50 (HFpEF, N=54, Age 62±11, Male 54%) and normal controls (N=16, Age 47±16, Male 37%). We measured simultaneous cardiac filling pressures, VO
2
and arterial and mixed venous blood gases (to determine Fick cardiac outputs [CO]) during every minute throughout incremental upright cycle ergometry CPET. HFpEF patients had higher VE/VCO2 slope than controls (36±7 vs. 31±7) and steeper, linear increments in PAP and PCWP relative to CO (3.6 and 2.7 mmHg/L min
-1
compared to 1.6, and 1.1 mmHg/L min
-1
respectively, all p<0.05,
Figure
).Upon stratification of the HFpEF patients by median VE/VCO2 (36) we found that higher VE/VCO2 was associated with steeper PAP slope (4.3 vs. 3.1 mmHg/L, p=0.02) and PCWP slope (3.6 vs. 2.5 mmHg/L, p=0.04) despite no difference between the two HFpEF sub-groups in resting upright PAP or PCWP.

Conclusion
s: We observed a linear increment in PAP and PCWP in HFpEF and controls during incremental cycle ergometry exercise. Ventilatory inefficiency is an easily measured, non-invasive variable that reflects impaired pressure-flow response patterns to exercise in patients with HFpEF.
Abstract 18701: Activation of PPAR Delta Signaling Corrects Impaired Skeletal Muscle Oxidative Metabolism in Heart Failure
Authors: Zizola Cynthia , Akashi Hirokazu , Ji Ruiping , Yu Shuiquin , Schulze Paul Christian
Published: April 2024

Background
Exercise intolerance in heart failure (HF) has been linked to impaired skeletal muscle oxidative capacity. PPARδ signaling regulates oxidative metabolism and exercise capacity. We hypothesized that decreased skeletal muscle oxidative capacity in HF can be reverted by PPARδ agonists.

Methods
Left ventricular (LV) dysfunction was induced in C57BL/6 mice by left coronary artery ligature and confirmed by echocardiography. At 11 weeks post-MI, mice received the PPARδ agonist
GW501516
(5 mg/kg body weight per day for 14 days, n=6) or vehicle (con, n=6). Exercise function was tested by swimming tests. Following sacrifice, skeletal muscle was harvested for RT-PCR, fatty acid (FA) and glucose oxidation assays, and ATP tissue content analysis. Cell culture analysis of signaling pathways was performed in C2C12 myotubes.

Results
Cardiac function decreased following MI (fractional shortening: 15.9±6.% vs 29.9±6.6% in sham; p<0.001). FA oxidation was reduced in quadriceps muscle in MI mice (2.5±1.0 vs 4.0±0.8 pmol/mg tissue in sham; p=0.04) with a trend in glucose oxidation (-27%; p=0.07). Muscle ATP content decreased following MI (3.3±1.7 vs 6.1±1.1 uM ATP/ug protein in sham; p<0.01). Expression of metabolic marker genes CPT1 (-86%), PDK4 (72%) and PGC1a (-94%) decreased in muscle post-MI (all p<0.05). 2 weeks
GW501516
administration increased muscle FA oxidation in animals with LV dysfunction (3.9±1.6 vs 1.8±0.4 pmol oleic acid/mg tissue in con; p=0.04) and also increased CPT1 expression by 309±175% (p<0.001). There was a non-significant increase (+11%) in swimming duration in the
GW501516
group. Treatment of C2C12 myotubes with 5 µM
GW501516
protected from TNFα (25 ng/ml)-dependent decrease in FA oxidation (129.2±2.5 vs 237.8±6.8 pmol oleic acid/mg protein in TNFα+
GW501516
; p<0.001) Further,
GW501516
prevented TNFα -dependent decrease in CPT1 expression (255±39 vs 58±5 % in TNFα alone, p<0.01).

Conclusion
Treatment with the PPARδ agonist
GW501516
corrects the impaired skeletal muscle oxidative capacity and metabolism in mice with ischemic LV dysfunction. Pharmacologic activation of PPARδ signaling could be an attractive intervention to counteract the progressive skeletal muscle dysfunction in HF.
Abstract 18716: Survival for Infants with Critical Congenital Heart Defects in Atlanta, Georgia, 1979-2005: Temporal Trends and Prognostic Factors
Authors: Oster Matthew E , Lee Kyung A , Honein Margaret A , Colarusso Tiffany , Shin Mikyong , Correa Adolfo
Published: April 2024

Introduction:
Pulse oximetry screening for critical congenital heart defects (CCHD) was added to the Recommended Uniform Screening Panel for newborns in 2011. However, benchmark population-based data on trends in survival and prognostic factors for infants born with CCHD in the United States are limited.

Methods:
We performed a retrospective cohort study of infants born with structural congenital heart defects (CHD) between 1979 and 2005 and ascertained by the Metropolitan Atlanta Congenital Defects Program. Infants with non-cardiac defects or chromosomal disorders were excluded. After determining survival through 2006 via linkage with state vital records and the National Death Index, we estimated Kaplan-Meier survival probabilities for 12 CCHD phenotypes (7 primary and 5 secondary targets of screening) by birth era and timing of diagnosis. We then used stratified Cox proportional hazards models to assess potential prognostic factors, including birth era, timing of diagnosis, maternal age, birth weight, race/ethnicity, sex, and socioeconomic status.

Results:
One-year survival was 75.2% for those with CCHD (n=1336) vs. 97.1% for those with other CHD (n=3530; p<0.0001), with a survival to 18 years of age of 68.8% for those with CCHD vs. 95.4% for those with other CHD (p<0.0001). One-year survival for infants with CCHD improved from 67.4% for the 1979-1993 birth era to 82.5% for the 1994-2005 era (p<0.0001). One-year survival was 71.7% for infants with CCHD diagnosed at ≤1 day of age (n=890) vs. 82.5% for those diagnosed at >1 day of age (n=405; p<0.0001). There was a significantly higher risk of one-year mortality for infants with earlier birth era, earlier diagnosis, maternal age <30, and low birth weight (Table).

Conclusions:
One-year survival for infants with CCHD has been improving over time, yet mortality remains high. These benchmark data and identified prognostic factors may aid future evaluations of the impact of pulse oximetry screening on survival from CCHD.
Abstract 18797: Clinical Impact of High on-Prasugrel Platelet Reactivity in an Acute Coronary Syndrome Population
Authors: O'Connor Stephen A , Kerneis Mathieu , Martin Rejane , Abtan Jeremie , Cayla Guillaume , Brugier Delphine , Barthélémy Olivier , Silvain Johanne , Vignalou Jean-Baptiste , Beygui Farzin , Collet Jean-Philippe , Montalescot Gilles
Published: April 2024

OBJECTIVE:
The aim of this study was to examine the pharmacodynamic and clinical outcome of patients with high on-prasugrel platelet reactivity (HPR).

METHODS:
Patients with HPR were identified from a group of 388 consecutive patients treated with prasugrel 10mg after PCI for an Acute Coronary Syndrome that had at least 2 different platelet function techniques performed simultaneously. Patients that had one or more technique demonstrating HPR according to the prespecified definitions {VASP≥50% by flow cytometry, P2Y
12
reaction units (PRU) ≥235 using the VerifyNowP2Y
12
assay, residual platelet aggregation (RPA) ≥46.2% using light transmission aggregometry} were included. Data on compliance, therapeutic action, ischemic and bleeding events at one month follow up were collected.

RESULTS:
Among the 388 patients treated with prasugrel 10 mg, a total of 33 (8.5%) patients with HPR were identified (87.8% male, mean age 60.5±12.5 yrs). The majority of patients had only one of the three techniques performed demonstrating HPR (23/33) (69.7%) and one third of patients (10/33) had at least two different platelet function techniques concordantly demonstrating HPR. Factors associated with HPR were increased BMI (p=0.03), acute stent thrombosis presentation (p<0.0001) and testing in the acute phase (<15 days) (p<0.0001). No therapeutic action was taken in 29/33 cases. A repeat loading dose was administered in 4 cases with HPR defined by at least 2 tests; 3 became responders and 1 patient required 3 loading doses over 3 days to respond. When compared with normal responders (n=355), there was as stepwise increase in ischemic cardiovascular events at 1 month follow up in patients with only 1 test versus patients with at least 2 concordant tests demonstrating HPR (0.8 vs 8.7 vs 30%, p<0.0001) (Figure)

CONCLUSIONS:
HPR on prasugrel is infrequent and may vary according to the test used. It can be overcome by reloading, but may be associated with an increased ischemic risk at 1 month follow up.
Abstract 18803: Myeloid Derived S100/calgranulins Promotes Visceral Obesity, Diabetes and Calcific Aortic Valve Disease in Transgenic Mice
Authors: Yan Ling , Earley Judy , Gardner Brandon , Ye Honggang , Hofmann Bowman Marion
Published: April 2024

Circulating serum levels of human S100/calgranulins have been associated with diabetes, coronary artery disease and increased cardiovascular mortality in clinical studies. To test whether S100/calgranulins are biomarker of inflammation or directly mediate disease, we generated a novel humanized mouse with transgenic expression of human S100/calgranulin by expression of a bacterial artificial chromosome of the human S100/calgranulin gene cluster containing genes and regulatory elements for S100A8/9 and S100A12 (60kb) in C57BL6 mice. F3 animals of the hBAC-S100 mice their wild type (WT) control littermate mice on regular rodent chow diet or on high fat diet (HFD) were studied.

Results:
hBac-100 mice express human S100A12 in circulating myeloid cells and S100A12 was present in the serum of hBAC-S100 mice (25 ng/ml serum), but was not detected in WT mice. Moreover, serum IL-6 was elevated in hBAC-S100 mice at age 3 and 12 month. hBAC-S100 mice developed increased visceral adiposity after 12 months on regular chow diet (25% vs 12% body fat upon DEXA scanning, p<0.05), or after 3 months on HFD. White adipose tissue (WAT) of lean hBAC-S100 age 4 weeks showed increased expression of T- and B cell marker and no macrophage marker compared to WT, followed by increase in gene expression for F4/80, CD68 and MCP-1 in obese hBAC-S100. Importantly, impaired oral glucose tolerance and hyperinsulinemia preceded the onset of adiposity in hBAC-S100 mice. Metabolic cage studies indicate reduced oxygen consumption and CO2 production as one mechanism leading to adiposity. This phenotype was attenuated in hBAC-S100 mice lacking RAGE. Moreover, 12-months old hBAC-S100 mice develop calcification of the aortic valve leafleat with presence of osteoblast-like cells in the ascending aortic media upon staining with Alizarin Red S. In vivo ECHO showed abnormal mitral valve doppler flow with reduced ratio of early (E) to atrial (A) filling (E/A ratio 0.85 and 1.22, p=0.03) indicative of diastolic dysfunction.

Conclusion:
Circulating myeloid derived human S100/calgranulin is sufficient to induce a sustained inflammatory state and is associated with the development of hyperinsulinemia, impaired glucose tolerance, adiposity and aortic valve calcification.