bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 12250: Prediction of Patients With Chronic Heart Failure at Risk for Sudden Cardiac Death by Combination of Cardiac I-123 Metaiodobenzylguanidine Imaging and Long Runs of Non-Sustained Ventricular Tachycardia:a Serial Evaluation Study
Authors: Ishimi Masashi , Yamada Takahisa , Morita Takashi , Furukawa Yoshio , Tamaki Shunsuke , Iwasaki Yusuke , Kawasaki Masato , Kikuchi Atsushi , Kondo Takumi , Fukunami Masatake
Published: April 2024

Background:
Identification of patients (pts) with chronic heart failure (CHF) at risk for sudden cardiac death (SCD) is an important objective. Cardiac I-123 metaiodobenzylguanidine (MIBG) imaging provides prognostic information in pts with CHF. On the other hand, long runs of non-sustained ventricular tachycardia (high-grade NSVT) has been associated with an increased risk of SCD in pts with coronary artery disease. However, there is little information available on the comparison of the prognostic significance for SCD between MIBG and high grade-NSVT in patients with CHF.

Methods and Results:
We studied 105 consecutive outpatients (NYHA class: 2.1±0.6), with LVEF 27%.High-grade NSVT was defined as consecutive 6 or more beats and more than 100 bpm. All pts underwent 24-hour ECG Holter monitoring and MIBG at the entry and every year after entry for three years. In the serial Holter monitoring, 32 pts had high-grade NSVT. At the last evaluation of MIBG study, 51 pts had abnormal WR. During the mean follow-up period of 5.1±3.5 years, 22 pts had SCD. A multivariate Cox analysis revealed that both abnormal WR and high-grade NSVT were significantly and independently associated with SCD (abnormal WR; hazard ratio 3.4 [95%CI 1.2-10.0], p = 0.025, high-grade NSVT; hazard ratio 3.3[95%Cl 1.3-8.2], p = 0.012). Pts with both abnormal WR and high-grade NSVT and those with either abnormal WR or high-grade NSVT had a significantly higher SCD risk than those with none of these parameters (47 [9/47] % vs 29 [13/45] % vs 0 [0/41] %, p<0.0001).

Conclusion:
The combination of abnormal WR and high-grade NSVT would be more strongly associated with an increased risk of SCD in CHF pts.
Abstract 12359: Clinical Impact of Left Ventricular Trabeculae in Hypertrophic Cardiomyopathy: Insights From Cardiac Magnetic Resonance Analysis
Authors: Yasuda Masakazu , Iwanaga Yoshitaka , Kawamura Takayuki , Miyaji Yuki , Nakamura Takashi , Miyazaki Shunichi
Published: April 2024

Introduction:
Hypertrabeculation has been associated with adverse events in patients with left ventricular (LV) non-compaction. However, the clinical significance remains unclear in patients with other cardiomyopathies.

Hypothesis:
LV trabeculae analyzed by cardiac magnetic resonance (CMR) may have a pathophysiological significance and clinical impact in patients with HCM.

Methods:
102 HCM patients receiving regular outpatient treatment underwent CMR. LV volume and mass were analyzed from short-axis cine images using a steady-state free precession sequence and LV fibrosis mass were obtained from late gadolinium enhancement imaging. Individual trabeculae and papillary muscles (TPM) and papillary muscles (PM) were manually planimetered separately on each end-diastolic frame in every slice. Trabeculae (T) was calculated by subtraction of PM from TPM. The data were compared with those of 22 normal control subjects (Cont).

Results:
In total HCM patients, LV mass index (compacted muscle excluding TPM) was 83.5 ± 23.6 g/m2. TPM mass index were greater in patients with HCM compared with Cont (21.7 ± 7.3 vs 12.4 ± 2.5 g/m2, p < 0.001), and T mass index were also greater (16.8 ± 6.6 vs 9.2 ± 2.2 g/m2, p <0.001). Greater TPM and T masses were associated with more substantial LV mass (r = 0.662 and 0.572, both p <0.001). By multivariate analysis, increased T mass index was independently associated with LV outflow-tract obstruction, increased LV end-diastolic volume index, and LV fibrosis mass index. Kaplan-Meier analysis showed that baseline TPM or T mass index was not associated with cardiovascular outcomes during 14.7 months follow-up. However, baseline T mass / LV mass ratio was significantly associated with the clinical outcomes (p = 0.0124).

Conclusions:
Alterations of LV trabeculae in HCM may be associated with LV hemodynamic stress and LV remodeling. Furthermore, trabeculae mass to LV compacted mass ratio may be a useful marker for the prognosis in patients with HCM.
Abstract 12423: Rapid And Robust Reprogramming Of Fibroblasts Into Integration-free Functional Cardiomyocytes With Sendai Viral Vectors
Authors: Miyamoto Kazutaka , Y amakawa Hiroyuki , Muraoka Naoto , Sadahiro Taketaro , Kojima Hidenori , Haginiwa Sho , Isomi Mari , Kuishi Yuki , Ninomiya Shintaro , Fukuda Keiichi , Ieda Masaki
Published: April 2024

Rationale:
Direct reprogramming of fibroblasts into functional cardiomyocytes (iCMs) holds great potentials for disease modeling and regenerative purposes, but the technique thus far has been slow and inefficient. Moreover, integration of viral transgenes into host genome may hinder clinical applications of this strategy.

Objective:
The aim of this study is to develop new Sendai viral vectors (SeVs) which overexpress reprogramming factors without genomic integration, and to determine the efficiency and safety of cardiac reprograming with SeVs.

Methods and Results:
We generated separate Gata4 (G), Mef2c (M), and Tbx5 (T) SeVs, and a polycistronic SeV containing GMT in a single transgene (SeV-GMT). Transduction of separate G, M, T SeVs did not induce cardiac reprogramming in mouse fibroblasts. In contrast, the polycistronic SeV-GMT greatly promoted cardiac reprogramming and induced spontaneously beating iCMs up to 40% of the starting fibroblasts, which was 100-fold greater than the retroviral-mediated reprogramming. Moreover, SeV-GMT shortened the duration to induce beating cells from 30 to 10 days, compared to retrovirus-GMT, demonstrating rapid and robust cardiac induction with SeV-GMT. FACS analyses demonstrated that the number of cardiac troponin T (cTnT) + cells and the intensity of cTnT expression were strongly increased with SeV-GMT compared with retrovirus-GMT. EdU incorporation assays and sequential gene expression profiles revealed that the increase in beating iCMs with SeV-GMT was not due to cell proliferation or conversion to multipotent cardiac progenitor cells. SeV-GMT transduction resulted in lower expression of Tbx5 compared to separate G, M, T SeV transduction or retroviral-GMT transduction. Supplementation of Tbx5 in SeV-GMT-transduced cells greatly reduced cardiac reprogramming, suggesting stoichiometry of transcription factors might be optimal in SeV-GMT. Genomic DNA analyses revealed that the SeV transgenes were not integrated into the host genome, and no tumors were detected in culture after 2 months of SeV-GMT transduction.

Conclusions:
We developed a highly efficient and safe direct cardiac reprogramming platform with SeV-GMT.
Abstract 12433: Cardiac Sympathetic Nerve Activity Predicts Ventricular Tachyarrhythmia After Implantable Cardioverter Defibrillator Implantation
Authors: Anjo Naofumi , Taguchi Isao , Hori Yuichi , Nakahara Shiro , Chida Ryuji , Hisauchi Itaru , Nakagawa Ayako , Nishiyama Naoki , Yamada Kohta , Higashi Akihiro , Nakamura Hidehiko , Fujikake Akinori , Kuroyanagi Takanori , Hayashi Akiko , Komatsu Takaaki , Sakai Yoshihiko
Published: April 2024

Introduction:
In patients with implantable cardioverter defibrillators (ICDs), increased sympathetic tone is associated with sudden death.

Hypothesis:
We assumed that cardiac sympathetic nerve activity (CSNA)is associated with Ventricular arrhythmia(VT).

Methods:
To evaluate whether CSNA estimated by the heart to mediastinum ratio (H/M) of I-123 MIBG imaging can predict the occurrence of VT after ICD implantation, 56 consecutive patients (43 males/13 females, 61±13 y.o.) who received ICD implantation were enrolled. The endpoint was defined as the occurrence of VT that required antitachycardia pacing (ATP) and/or shock therapy by the device. Receiver-operating characteristic curve analysis was used to obtain the cut-off value of the delayed H/M ratio required to predict VT. The patients were divided into two groups based on this cut-off value: a higher H/M (≥1.92) group (H-H/M, n=31), and a lower H/M (<1.92) group (L-H/M, n=25). The average follow-up was 10.7 ± 6.4 months.

Results:
One or more VT episodes occurred in 11 patients (ATP:4, shocks:7). The VT event rate in the L-H/M group was significant higher than that in the H-H/M group (40% (10/25) vs. 3.2% (1/31), p=0.0013). The Kaplan-Meier VT event-free curve showed a worse outcome in the L-H/M group than in the H-H/M group (p=0.00044 by the log-rank test, Fig.1).

Conclusions:
CSNA estimated by the H/M ratio of I-123 MIBG imaging might predict the occurrence of VT after ICD implantation.
Abstract 12451: Pulmonary Artery Stiffness is an Independent Predictor of Right Ventricular Mass and Function
Authors: Dawes Timothy , Gandhi Ajay , de Marvao Antonio S , Buzaco Rui , Tokarczuk Pawel , Quinlan Marina , Durighel Giuliana , Diamond Tamara , Monje-Garcia Laura , De Cesare Alain , Cook Stuart , O’Regan Declan
Published: April 2024

Background:
Right ventricular (RV) mass is independently associated with cardiovascular risk in the general population, but the underlying causes are not known.

Objectives:
We used cardiac magnetic resonance (CMR) imaging to determine if there was a relationship between pulmonary (PA) stiffness and measures of RV function and mass.

Methods:
156 healthy volunteers underwent 1.5T cardiovascular magnetic resonance imaging. Pulmonary pulse wave velocity (PWV), derived from phase-contrast imaging, was used to assess vascular stiffness. RV performance was assessed using feature-tracking to derive peak systolic strain and strain rate, as well as peak early-diastolic strain rate (PEDSR). RV volumes, ejection fraction (RVEF) and mass (RVM) were measured from the cine images. The association of pulmonary PWV with RV function and mass was quantified by univariate linear regression.

Results:
Pulmonary PWV and RV ejection fraction (RVEF) both increased with age (R = +0.32, p < 0.001; R = +0.17, p = 0.04 respectively). Adjusting for the effects of age, body surface area and gender, pulmonary PWV showed an independent association with increased RVEF (R = +0.17, p = 0.03), RVM (R = +0.26, p=0.001), RV radial strain (R = +0.36, p = 0.005) and strain rate (R = +0.38, p < 0.001) and reductions in radial (R = -0.45, p = 0.002), longitudinal (R = -0.42, p = 0.008) and circumferential (R = -0.45, p = 0.003) PEDSR.

Conclusions:
In subjects with no known cardiovascular disease, PA stiffness increases with age and is independently associated with both RV mass and diastolic dysfunction. These findings suggest that prognostically adverse changes in RV function and morphology are associated with age-related changes in PA stiffness.
Abstract 12495: Enhanced Thrombin Activity in Biglycan-deficient Mice Promotes Vascular Inflammation in Murine Atherosclerosis
Authors: Grandoch Maria , Melchior-Becker Ariane , Feldmann Kathrin , Müller Julia , Klatt Christina , Homann Susanne , Dick Lena-Sophia , Nagy Nadine , Schäfer Liliana , Skroblin Philipp , Yin Xiaoke , Mayr Manuel , Tannock Lisa , Fischer Jens W
Published: April 2024

Introduction:
Thrombin signalling initiates inflammatory events directly and through activation of platelets. Endogenous and pharmacologic inhibitors of thrombin are therefore of relevance during atheroprogression and for therapeutic intervention. The small leucine-rich proteoglycan biglycan (BGN) is thought to inhibit thrombin activity by activation of heparin cofactor II. Hypothesis: Genetic deletion of BGN affects thrombin activity, inflammation and atherosclerosis. Methods:Male mice deficient in apolipoprotein E and BGN (ApoE-/-/Bgn-/0) were compared with their ApoE-/- littermates.

Results:
In ApoE-/- mice BGN was detected in the plasma and subendothelial matrix of capillaries, arterioles and in atherosclerotic plaques. In line with a role of BGN in balancing thrombin activity, ApoE-/-/Bgn-/0 mice exhibited higher activity of circulating thrombin and greater platelet activation than did ApoE-/- mice. Furthermore, higher concentrations of circulating cytokines in ApoE-/-/Bgn-/0 mice suggested a proinflammatory phenotype. Accordingly, isolated peritoneal macrophages released elevated concentrations of proinflammatory cytokines in response to Toll-like receptor stimulation. Immunohistochemistry and FACS analysis of the aorta demonstrated increased macrophage content in atherosclerotic lesions. Furthermore, ApoE-/-/Bgn-/0 mice exhibited higher aortic plaque burden and larger atherosclerotic lesions at the aortic root. Treatment with the thrombin inhibitor argatroban reversed platelet activation and aortic macrophage accumulation in ApoE-/-/Bgn-/0 mice. Finally, ApoE-/-/Bgn-/0 mice exhibited progressive dilation of the aortic arch, a pathological finding corroborated by markedly reduced collagen fibril density.

Conclusions:
The present results indicate that BGN plays a previously unappreciated protective role during progression of atherosclerosis by inhibiting thrombin activity and platelet activation, and ultimately macrophage-mediated plaque inflammation.
Abstract 12503: Liver Injury is Associated With Total Cardiovascular Disease, Heart Failure, Stroke, Coronary Heart Disease and Acute Myocardial Infarction Including Among Those Without Viral Hepatitis (B Or C), Hiv, Alcohol Abuse and Obesity
Authors: So-Armah Kaku , Tate Janet , Lim Joseph , Lo Re Vincent , Marconi Vincent , Samet Jeffrey , Gibert Cynthia , Leaf David , Butt Adeel , Goetz Matthew , Rimland David , Rodriguez-Barradas Maria , Budoff Matthew , Chang Chung-Chou , Justice Amy , Freiberg Matthew
Published: April 2024

Introduction:
Hepatitis C and human immunodeficiency virus (HCV, HIV) are associated with cardiovascular disease (CVD). Liver injury is common in HIV and HCV and is associated with pro-atherosclerotic conditions e.g. altered coagulation. We assessed whether liver injury independently predicts CVD risk including among participants without major liver-related co-morbidities.

Methods:
Participants from the Veterans Aging Cohort Study Virtual Cohort (VACS VC), without CVD at baseline (first clinical visit after 4/1/2003) were included. Liver injury was defined by liver fibrosis index 4 at baseline (FIB4 calculated using age, liver transaminases and platelets) and ICD-9 codes for cirrhosis and hepatic decompensation. Total fatal and non-fatal CVD were assessed using 1) National Death Index cause of death data; 2) VA; 3) VA Fee For Service; and 4) Medicare ICD-9 and procedure codes for acute myocardial infarction, heart failure (HF), coronary heart disease (CHD) and stroke. Follow-up ended after a CVD event, or death, or on 9/30/2012. Cox regression analyses were used to estimate the risk of total CVD, HF, stroke, CHD and AMI by liver injury.

Results:
Mean (SD) age was 49.6 (9.5) years in this cohort (N=104731, 90% male) followed for a median (IQR) of 7 (3, 9) years. LDL cholesterol and BMI decreased with increasing FIB4 while age increased. African American race, HIV, HCV, HBV, current smoking, type 2 diabetes, alcohol abuse, cocaine use and anemia were more common among participants with FIB4 >1.45 compared to those with FIB4 <1.45. Incident CVD rates increased with increasing FIB4. FIB4 >3.25 or a clinical diagnosis of cirrhosis or hepatic decompensation was independently associated with significantly elevated CVD risk. This association persisted in Veterans without HCV, HBV, HIV, alcohol use disorder and BMI >30 kg/m2.

Conclusions:
Liver injury is associated with increased risk of CVD. Future studies should assess whether FIB4 improves CVD risk prediction algorithms.
Abstract 12532: Cellular and Cardiac Microtissue Assays of iPSC-derived Myocytes With the Hypertrophic Cardiomyopathy Mutation in MYH7-Val606Met
Authors: Sheng Calvin C , Hinson John T , Chopra Anant , Chen Christopher S , Seidman Jonathan , Seidman Christine
Published: April 2024

Introduction:
Hypertrophic cardiomyopathy (HCM) is the most common inherited heart disease affecting 1 in 500 people and is the leading cause of sudden cardiac death in young adults. Mutations in β-myosin heavy chain (
MYH7
) account for one-third of cases, but the underlying pathogenesis remains unclear. In this study, we investigated myocytes derived from CRISPR-Cas9-engineered isogenic induced pluripotent stem cell cardiomyocytes (iPSC-CMs) with a missense mutation Val606Met by single-cell and microtissue functional assays.

Hypothesis:
We hypothesize that iPSC-CMs with Val606Met will recapitulate features of HCM in single cell and microtissue assays, such as changes in contractile function and hypertrophic signaling.

Methods & Results:
Val606Met mutations in
MYH7
(VM/+, VM/VM) were introduced by targeting an iPSC line using CRISPR-Cas9. Transfected iPSCs were isolated by FACS to detect green fluorescent protein, clones were expanded, and mutational events were confirmed by Sanger sequencing. Mutant iPSCs, like isogenic wildtype control iPSCs, were differentiated into cardiomyocytes with >90% efficiency. Microtissue studies of mutant iPSC-CMs exhibited increases in contractility (WT=2.96±0.23μN, VM/+ = 3.51±0.34μN, VM/VM = 4.63±0.51; R
2
= 0.963). Mutant iPSC-CMs also showed evidence of altered signaling by increases in spontaneous beating rate (WT < VM/+ < VM/VM; R
2
=0.946), cell size (compared to WT, ~20% increases in both VM/+, p=0.04 and VM/VM, p=0.038), and sarcomere content (compared to WT, ~20% increases in both VM/+, p=4e-06 and VM/VM, p=0.11). These changes are supported by activated expression in myocytes of hypertrophic genes such as
NPPA
,
NPPB
, and
ACTA2
as well as transcriptional up-regulation of TGF-β.

Conclusions:
Isogenic iPSC-CMs with
MYH7
variant Val606Met created by CRISPR-Cas9 recapitulate features of HCM
in vitro
. Our data confirms Val606Met as a pathogenic mutation that causes increased contractility in cardiac microtissues and myocyte hypertrophy. We speculate that increased myocyte-derived TGF-β signaling may contribute to the HCM phenotype. This approach could also be used for better understanding of genotype-phenotype correlations in HCM.
Abstract 12577: The Efficacy and Safety of Third Generation P2Y12 Inhibitors in Women versus Men: A Sex-Specific Meta-Analysis
Authors: Lau Emily S , Braunwald Eugene , Murphy Sabina A , Wiviott Stephen D , Bhatt Deepak L , Harrington Robert A , Bonaca Marc P , Sabatine Marc S , O’Donoghue Michelle L
Published: April 2024

Introduction:
Sex-specific differences in the response to antiplatelet therapies have been described. Whether women and men derive comparable efficacy and safety from intensification of antiplatelet therapy with 3rd generation P2Y12 inhibitors is uncertain.

Methods:
A sex-specific meta-analysis was conducted of phase III or IV randomized trials that examined the efficacy and safety of 3
rd
generation P2Y12 inhibitors in patients with CAD, including prasugrel, ticagrelor, and cangrelor. Five trials were included that enrolled a total of 19,536 women and 52,043 men based on published data. MACE was defined as the primary endpoint for each trial (components included CV death and MI for all trials). The safety endpoint was defined as non-CABG major bleeding for each trial. Data used for analyses were obtained from published reports.

Results:
Administration of a 3
rd
generation P2Y12 inhibitor significantly reduced the risk of MACE by 14% in women (HR 0.86, 95% CI 0.77-0.95) and by 17% in men (HR 0.83, 95% CI 0.79-0.88) with no heterogeneity in the magnitude of effect (P interaction =0.66; Figure). The 3
rd
generation P2Y12 inhibitors increased the risk of non-CABG major bleeding by 38% in women (HR 1.38, 95% CI 1.05-1.81) and by 50% in men (HR 1.50, 95% CI 1.09-2.07), again without heterogeneity (P interaction = 0.88).

Conclusions:
In randomized trials, the efficacy and safety of the 3
rd
generation P2Y12 inhibitors were comparable between men and women. Since women remain undertreated with guideline-recommended therapies, these data support the administration of 3
rd
generation P2Y12 inhibitors in women with appropriate indications for use.
Abstract 12617: Decreased Mitral Valve Area During Exercise After Restrictive Mitral Annuloplasty in Functional Mitral Regurgitation is Associated With Absence of Left Ventricular Reverse Remodeling and Subsequent Worse Clinical Outcome
Authors: Petrus Annelieke H , Braun Jerry , Tops Laurens F , Holman Eduard R , Marsan Nina A , Versteegh Michel I , Schalij Martin J , Bax Jeroen J , Klautz Robert J
Published: April 2024

Introduction:
Restrictive mitral annuloplasty (RMA) can provide a durable solution for functional mitral regurgitation (MR). Implantation of a downsized annuloplasty ring might however induce mitral stenosis at rest or, more pronounced, during exercise, with potential clinical impact.

Hypothesis:
We evaluated the hypothesis that RMA does not induce a clinically relevant functional mitral stenosis during exercise.

Methods:
Semi-supine bicycle exercise echocardiography was performed in 32 patients after RMA (ring sizes 24 or 26) for functional MR. Left ventricular volumes and ejection fraction, transmitral gradients and mitral valve area (MVA by VTI) were assessed at rest and during peak exercise and compared with preoperative echocardiographic data. Clinical events (all-cause mortality and hospital readmission for heart failure) were prospectively collected from the study visit until May 2015.

Results:
Exercise echocardiography was performed 77 ± 35 months after RMA. In 25 patients MVA significantly increased during exercise (1.6 ± 0.4 to 2.0 ± 0.6 cm2, p <0.001), whereas MVA decreased in 7 patients (1.8 ± 0.5 to 1.5 ± 0.4 cm2, p <0.05). In patients with increased exercise MVA, LV end diastolic volumes at rest were reduced compared to preoperative echocardiographic data (190 ± 72 ml vs 144 ± 62 ml, p <0.01) with improved ejection fraction (36 ± 11 vs 40 ± 10 %, p <0.05). In contrast, in patients with decreased exercise MVA, LV reverse remodeling was absent (LVEDV 174 ± 54 ml preoperatively vs 189 ± 80 ml at rest; NS) and ejection fraction unchanged (37 ± 8 vs 33 ± 9 %, respectively; NS). Patients with decreased exercise MVA had worse event-free survival at 22 ± 6 months after the study visit (92 vs 57 %, p <0.05).

Conclusions:
Hemodynamically significant mitral stenosis was not observed at rest nor during peak exercise after RMA. A decrease in MVA during exercise was related to absence of LV reverse remodeling between surgery and exercise echocardiography examination. Event-free survival was significantly worse in patients with decreased exercise MVA. In conclusion, not the insertion of a downsized mitral annuloplasty ring, but the absence of LV reverse remodeling is associated with the occurrence of decreased MVA during exercise and subsequent worse clinical outcome.
Abstract 12624: Therapeutic Lymphangiogenesis Improves Diastolic Function by Limiting Cardiac Edema and Fibrosis After Myocardial Infarction
Authors: Henri Orianne , Houssari Mahmoud , Pouehe Chris , Galas Ludovic , Nicol Lionel , Edwards-Lévy Florence , Henry Jean-Paul , Dumesnil Anais , Schapman Damien , Thuillez Christian , Richard Vincent , Mulder Paul , Brakenhielm Ebba
Published: April 2024

Little knowledge exists on how cardiac lymphatics respond to myocardial infarction (MI). We investigated the impact of MI on cardiac lymphatic structure and function during the development of chronic heart failure (CHF).

We hypothesized that 1) insufficient cardiac lymph drainage may contribute to the deleterious cardiac remodeling post-MI; and 2) therapeutic stimulation of lymphatic growth, or lymphangiogenesis, may reduce chronic myocardial edema and inflammation in this setting.

MI was modeled in Wistar rats by coronary occlusion (45 min) followed by reperfusion. Lymphangiogenesis-selective VEGF-C was delivered intramyocardially using slow-release albumin-alginate microparticles. Animals were divided into: sham (n=19), control MI (n=64), and treated MI, receiving low (1.5 μg; n= 54) or high (5 μg; n=26) dose of VEGF-C upon reperfusion. Cardiac function, lymphatics, edema, and levels of infiltrating immune cells were evaluated at 3 and 8 weeks post-MI.

We found that control rats displayed lymphatic remodeling with increased lymphatic capillary density but rarefaction of epicardial pre-collector and collector vessels, leading to cardiac lymphatic dysfunction. In accordance with insufficient lymph drainage, chronic myocardial edema and low grade inflammation were found at both 3 and 8 weeks post-MI as determined by gravimetry, MRI T2 imaging, and immunohistochemistry, respectively. VEGF-C treatment led to a dose-dependent increase in lymphatic capillary density (sham, 255±16; con, 267±25; VEGF-C, 362±22 lymphatics/mm
2
; p<0.05) and reduced rarefaction of pre-collectors and collector vessels. As a consequence, myocardial edema (sham, 75.5±0.1; con, 77.9±0.2; VEGF-C, 77.3±0.1% water content; p<0.05) and macrophage infiltration levels were both significantly reduced. Further, cardiac interstitial fibrosis was completely prevented by 8 weeks, even by low dose VEGF-C (con, 6.0±0.6; VEGF-C, 3.3±0.1% fibrosis; p<0.001), leading to reduced diastolic dysfunction (LVDPVR, LV end-diastolic pressure-volume relation: sham, 0.8±0.1; con, 2.0±0.2; VEGF-C, 1.1±0.1; p<0.001).

In conclusion, our data suggest that therapeutic lymphangiogenesis may represent a new therapeutic target in CHF.
Abstract 12626: Predictors of Initial Revascularization versus Medical Therapy in Patients With Non-ST Segment Elevation Acute Coronary Syndrome Undergoing an Invasive Strategy
Authors: Wijeysundera Harindra C , Sidhu Mandeep S , Bennell Maria C , Qiu Feng , Knudston Merril , Tu Jack V , Ko Dennis T , Boden William E
Published: April 2024

Background:
Although an invasive strategy is a Class I clinical practice guideline for non-ST-segment elevation acute coronary syndromes (NSTE-ACS), there is wide variation in the proportion of such patients who undergo revascularization despite early angiography. We sought to identify the predictors of early revascularization versus medical therapy alone in NSTE-ACS patients undergoing an invasive strategy and contrast their clinical outcomes.

Methods:
We assessed revascularization status (PCI or CABG within 7 days of the index angiogram) in all NSTE-ACS patients treated with an invasive strategy at 18 hospitals in Ontario, Canada from October 1st 2008 to October 31st, 2013, using the Cardiac Care Network registry. Follow-up was until December 31st, 2014. The primary outcome was death. Multivariable, hierarchical logistic models were used to identify predictors of revascularization. Multivariable Cox models with treatment strategy as a 3-level time-varying covariate were developed to understand the relationship between revascularization status and clinical outcomes.

Results:
We identified 50,302 NSTE-ACS patients of whom 34,288 (68.2%) underwent early revascularization (28,011 by PCI; 6,277 by CABG). There was a twofold variation in revascularization rates (Figure). High risk based on the TIMI/GRACE score was a significant predictor of revascularization (OR 1.26; 95% CI 1.18-1.35) as was having the angiogram by an interventional cardiologist (OR 1.76, 95% CI 1.57-1.98) or at a diagnostic only hospital (OR 1.22, 95% CI 1.01-1.48). Compared to patients treated medically, those who were revascularized with either PCI (HR 0.64, 95% CI 0.60-0.69) or CABG (HR 0.53, 95% CI 0.47-0.60) had improved survival.

Conclusions:
While more than 2/3rds of NSTE-ACS patients who underwent an early invasive approach did receive revascularization, there was wide variation. Those who underwent revascularization had significantly improved clinical outcomes.
Abstract 12719: Expression of DHRS7c, A Novel Cardiomyocyte-expressed Gene Affected by Adrenergic Stimulation, is Strongly Associated With Ventricular Reverse-remodeling in Dilated Cardiomyopathy
Authors: Kao David P , Lowes Brian D , Gilbert Edward M , Minobe Wayne , Meyer Leslie K , Quaife Robert A , Bristow Michael R
Published: April 2024

Background:
The molecular mechanisms by which β-blockers produce ventricular reverse-remodeling in nonischemic dilated cardiomyopathy (NDCM) are incompletely understood.
DHRS7C
is a short chain dehydrogenase/reductase of uncertain functional significance expressed preferentially in the myocardium and down-regulated in heart failure or with α- and β-adrenergic stimulation. The objective of this study was to determine the association of
DHRS7C
with DCM and reverse-remodeling in heart failure patients taking β-blockers.

Methods and Results:
Forty-seven NDCM patients were randomized to metoprolol succinate, metoprolol + doxazosin, or carvedilol for 18 months. Ejection fractions (EFs) were measured by radionuclide ventriculography, and myocardial biopsy was performed at baseline, 3, and 12 months. Transcriptome-wide myocardial mRNA expression was measured using the Affymetrix HGU133 plus 2.0 GeneChip.
DHRS7C
expression was significantly reduced in DCM patients compared with 4 non-failing controls (7.3±0.2 vs. 9.0±0.7, p=0.03). Thirty-one (66%) patients had a reverse-remodeling response defined as improvement of 8 LVEF units at 12 months or if not available, 5 LVEF units at 3 months.
DHRS7C
was significantly more up-regulated in responders vs. non-responders (4.1±0.6 vs. 2.2±0.7 fold change, p=0.03). Change in gene expression was significantly correlated with change in LVEF (r=0.52, p<0.001), RVEF (r=0.40, p<0.001), and heart rate (r=-0.38, p<0.01). These correlations were comparable to other genes associated with reverse-remodeling.

Conclusions:
Myocardial expression of
DHRS7C
is significantly down-regulated in human NDCM. As expected, expression increases in response to β-AR blockade and is strongly correlated with both EF and heart rate response to beta-blockers comparable to
MYH6
and
ADRB1/2
. Although its function is unclear,
DHRS7C
may be an important biomarker or mechanistically important for ventricular reverse-remodeling.
Abstract 12822: Continuous Smoking Promotes Neoatherosclerosis Formation in Stent Restenotic Neointimal Tissue After Drug-Eluting Stent Implantation
Authors: Uchida Yasuhiro , Ichimiya Satoshi , Ishii Hideki , Mizutani Koji , Yamaguchi Ryo , Oishi Hideo , Miki Yusuke , Fujimoto Masanobu , Kawamiya Toshiki , Mihara Hirotsugu , Ichimiya Hitoshi , Hayano Shinji , Suzuki Susumu , Watanabe Junji , Kanashiro Masaaki , Amano Tetsuya , Matsubara Tatsuaki , Murohara Toyoaki
Published: April 2024

Introduction:
Despite the advance of drug-eluting stents (DES), late adverse events such as very late stent thrombosis (VLST) and late target lesion revascularization are of concern. Although continuous smoking is an independent risk factor of VLST, the pathogenic impact on in-stent restenotic neointimal tissue components after DES implantation remains unclear.

Hypothesis:
We assessed the hypothesis that continuous smoking after DES implantation might promote neoatherosclerosis formation in restenosis lesions.

Methods:
We enrolled 47 consecutive patients with in-stent restenosis requiring revascularization after DES implantation between January 2008 and March 2015. In advance, we excluded the patients with recurrent restenosis, thrombotic lesions, and total occlusion. For evaluation of in-stent tissue components, integrated backscatter intravascular ultrasound (IB-IVUS) was performed. Patients were divided into current smokers and nonsmokers including both previous smokers and never-smokers.

Results:
Of these patients, 12 (25.5%) were current smokers. On volumetric IB-IVUS analyses, current smokers had a significantly higher percentage of lipid tissue volume within the neointima and a significantly lower percentage of fibrous tissue volume than nonsmokers (42.9 ± 19.4 vs. 26.3 ± 12.8%; p = 0.03, and 55.1 ± 19.2 vs. 70.9 ± 11.9%; p = 0.04, respectively). Moreover, continuous smoking was positively correlated with the percentage of lipid volume on multiple linear regression analysis after adjustment for confounding factors (β = 0.35, p = 0.03). Interval from stent implantation was similar between current smokers and nonsmokers (44.6 ± 38.2 vs. 37.5 ± 29.1 months; p = 0.58).

Conclusions:
Continuous smoking was associated with larger lipid tissue volume within the neointima after DES placement, suggesting the development of neoatherosclerosis and vulnerable neointima. Thus continuous smoking might lead to future adverse coronary events.
Abstract 12914: The Effect of Isosorbidemononitrate on Myocardium in a Swine Model of Cardiac Arrest
Authors: Tang Ziren , Wang Tao , Hang Chenchen , Wu Caijun , Shao Rui , Fang Yingying , Zhao Shen , Tang Wanchun
Published: April 2024

Introduction:
To investigate the protective effect of isosorbidemononitrate (IM) on myocardial injury after the return of spontaneous circulation (ROSC) in a swine model of ventricular fibrillation cardiac arrest (VFCA).

Methods:
Ventricular fibrillation was induced and untreated for 8 minutes in twenty domestic pigs. Defibrillation was attempted after 2 minutes of CPR. The animals were randomized into two groups: IM group (n=10) and saline control group (SA group, n=10). IM (2μg/kg/min) or the same volume of saline was administered for 6 hrs post-resuscitation. Post resuscitation myocardial function was evaluated using pulse-induced contour cardiac output (PiCCO) at 1, 6 and 24 hrs after ROSC. Serum troponin I was tested using the enzyme-linked immunosorbent assay (ELISA) at the same time points during 24 hours post-resuscitation. Echocardiography and transmission electron microscopy were performed at 72 hrs after ROSC. The duration of survival was monitored in all animals.

Results:
Significantly greater ejection fraction (EF) and cardiac output (CO) in the IM group at 1, 6 and 24 hrs after ROSC (Fig.1). Troponin I in the IM group was significantly lower than that in the SA group at 6 and 24 hrs after ROSC. Better cardiac function (Table 1) and less ultrastructural deterioration were observed in the MI group at 72 hrs after resuscitation. However, there is no significant difference in the duration of survival between the two groups.

Conclusions:
In a swine model of cardiac arrest, isosorbidemononitrate attenuated post-resuscitation myocardial dysfunction.
Abstract 13035: Impact of Ezetimibe on Hospitalization-Related Costs Among Patients With a Recent Acute Coronary Syndrome: Results From the IMPROVE-IT Trial
Authors: Magnuson Elizabeth A , Chinnakondepalli Khaja , Vilain Katherine , Mark Daniel B , Davies Glenn , Giugliano Robert P , Braunwald Eugene , Cannon Christopher P , Cohen David J
Published: April 2024

Impact of Ezetimibe on Hospitalization Costs among Patients with a Recent Acute Coronary Syndrome: Results from the IMPROVE-IT Trial

Objectives:
The IMPROVE-IT Trial demonstrated that in patients with a recent acute coronary syndrome, the combination of ezetimibe 10 mg and simvastatin 40 mg (E+S) significantly reduced the rate of major cardiovascular events relative to simvastatin 40 mg (S) alone. We used patient-level resource data to compare costs associated with hospitalizations (hosps) between E+S and S over the course of the trial (median follow-up 6 years; mean 5.4 years).

Methods:
Details regarding hosps for all patients (n=18,144) were collected prospectively. MS-DRGs were assigned to all cardiovascular (CV) hosps, to which average 2013 Medicare reimbursement rates were applied. Physician costs associated with hosps were estimated as a % of hospital costs. Hosp rates/costs per patient were compared using Poisson regression/bootstrapping.

Results:
Over the follow-up period, there were 8612 and 9105 CV hosps for E+S and S, respectively (p=0.03). Treatment with E+S led to a $459/patient reduction in hospitalization-related costs (95% CI -$885 to -$42; p=0.02). Lower costs associated with coronary revascularization accounted for the majority ($392/patient) of the lower hosp costs for E+S. Forty percent of hosps for an adjudicated MI (1106/2769) involved a revascularization procedure and hosp costs for revascularization procedures in the setting of an MI were $314/patient lower with E+S. Lower costs associated with hosp for angina, stroke, and acute MI not requiring revascularization also contributed to the lower costs with E+S vs. S.

Conclusions:
Over a mean 5.4 year follow-up period, E+S was associated with lower rates of CV hospitalization and associated hospitalization costs compared with S. The extent to which these lower hospitalization costs offset the higher drug costs is expected to be more favorable when ezetimibe becomes generic in 2016.
Abstract 13142: Characteristics of Decremental Accessory Pathways in Children
Authors: Hill Allison , Silka Michael , Bar-Cohen Yaniv
Published: April 2024

Introduction:
While decremental retrograde accessory pathways (DAPs) classically present clinically as permanent junctional reciprocating tachycardia (PJRT), they may be diagnosed unexpectedly during electrophysiology study (EPS). Although DAPs associated with PJRT have been studied, information about other variants of DAPs in children is limited.

Methods:
We retrospectively studied patients 0 - 21 years of age with retrograde DAPs who underwent EPS between 2005 and 2014. Decrement was defined as rate-dependent prolongation of the local ventriculo-atrial (VA) time by > 30 ms during ventricular extrastimulus or rapid ventricular pacing. Clinical presentation, electrophysiologic properties and ablation outcomes of patients with DAPs were compared to an age-matched cohort of patients with non-decremental accessory pathways. In addition, a sub-analysis examined patients with DAPs depending on whether clinical PJRT was diagnosed prior to the EPS.

Results:
A total of 29 patients with DAPs and 83 controls were included [mean age at time of EPS 10.3 ± 5.7 years and 10.7 ± 5.2 years, respectively (p = NS)]. Compared to controls, DAPs were more likely to be associated with syncope [6/29 (21%) vs 3/83 (4%), p = 0.01], ventricular dysfunction [6/29 (21%) vs 4/83 (5%), p = 0.04], and treatment with antiarrhythmic medications [20/29 (69%) vs 39/83 (47%) p = 0.04]. In addition, DAPs were more likely to be right-sided [20/29 (69%) vs. 24/83 (29%), p < 0.01] and septal [19/29 (66%) vs 17/83 (21%), p < 0.01]. DAPs and their age-matched controls had similar rates of acute ablation success [26/29 (90%) vs 77/83 (93%), p = NS] and recurrence [2/29 (7%) vs 4/83 (5%), p = NS]. There were no major procedural complications in either group. Of the patients with DAPs, only 12 (41%) had clinical PJRT, and these patients had more syncope [6/12 (50%) vs 0/17 (0%), p < 0.01], slower ORT (mean cycle length 383 ± 89 ms vs 323 ± 60 ms, p = 0.04), and longer maximum VA times (mean 283 ± 116 ms vs 208 ± 42 ms, p = 0.01) compared to those with DAPs without clinical PJRT.

Conclusions:
The majority of pediatric patients with DAPs do not present with clinical PJRT. DAPs in general are typically associated with more severe symptoms, but ablation outcomes are similar to age-matched controls with non-decremental pathways.
Abstract 13219: Dll4-Notch Signaling Mediates Vascular Inflammation and Calcification in Chronic Kidney Disease: A Novel Mechanism
Authors: Nakano Toshiaki , Kum Angelo S , Kuromoto Rodrigo K , Iwata Hiroshi , Aikawa Elena , Aikawa Masanori
Published: April 2024

Background:
Chronic kidney disease (CKD) increases cardiovascular risk. However, the underlying mechanisms remain obscure and current therapies, including statins, cannot prevent CKD-associated cardiovascular events. We previously demonstrated that the Notch signaling ligand Delta-like 4 (Dll4) promotes macrophage activation. To identify a new mechanism and therapeutic target, we investigated the causal role of the Dll4-Notch pathway in vascular inflammation in CKD.

Methods & Results:
[In vitro] Indoxyl sulfate, a major uremic toxin, is an independent risk predictor in CKD. Clinically relevant concentrations (0.5-1.0 mM) of indoxyl sulfate increased the expression of proinflammatory molecules (e.g., IL-1β, TNFα, MCP-1), and Notch signaling components (e.g., Dll4, Notch3) in human primary macrophages derived from peripheral blood mononuclear cells. Notch inhibition with the γ-Secretase inhibitor DAPT suppressed indoxyl sulfate-triggered induction of proinflammatory molecules (e.g., MCP-1, Figure A) in macrophages. [In vivo] In LDL receptor-deficient (Ldlr-/-) mice, an established model of atherosclerosis, 5/6 nephrectomy induced renal dysfunction assessed by elevated creatinine (0.56 ± 0.05 mg/dl) and BUN (128.0 ± 1.9 mg/dl), CKD accelerated the expression of IL-1β, IL-6, TNFα, and MCP-1 in splenic macrophages, and aortic atherosclerosis and calcification in Ldlr-/- mice Suppression of Notch signaling by Dll4 antibody reduced the size of atherosclerotic lesions of the aorta (p<0.05) and luminal stenosis in the brachiocephalic arteries (p<0.05) in the CKD cohort as compared to mice treated by control IgG (n=14/13 per group). Dll4 antibody also decreased macrophage accumulation and early calcification (alkaline phosphatase activity) in the aorta (Figure B).

Conclusion:
The present study suggests that Dll4 serves as a new therapeutic target for atherosclerotic plaque inflammation and calcification in CKD.
Abstract 13244: Is Early Statin Treatment Justified Before Formation of Atherosclerotic Plaques?
Authors: Li Yuxin , Onishi Akira , Sudo Mitsumasa , Haruta Hironori , Lin Qing-Fei , Takayama Tadateru , Suzuki Shunichi , Fuchimoto Daiichiro , Sembon Shoichiro , Iwamoto Masaki , Hashimoto Michiko , Yoda Shunichi , Kunimoto Satoshi , Hiro Takafumi , Matsumoto Taro , Mitsumata Masako , Sugitani Masahiko , Saito Satoshi , Hirayama Atsushi
Published: April 2024

Objective:
Although statin is recommended for secondary prevention of acute coronary syndrome regardless of the baseline LDL-cholesterol level, statin administration in the pre-intervention phase has not been established as a routine strategy because of lack of sufficient evidence. We conducted an animal study comparing the results of early statin administration vs. no such administration in pigs susceptible to atherosclerosis.

Methods and Results:
Three-month-old LDL receptor knockout (LDLR-/-) pigs with no atherosclerosis were divided into two groups: those fed an atherosclerotic diet consisting of 15% fat and 1.5% cholesterol for 4 months (control group) and those fed the same diet but given oral pitavastatin (40 mg/day) (early treatment group). Human-like unstable plaques developed in the coronary arteries of the control pigs. After in vivo intravascular ultrasound (IVUS) examination, pigs’ coronary arteries were harvested and cut into 1-cm sections for pathological analyses. Blood cholesterol levels (mg/dL) did not differ significantly between the control group and early treatment group: total cholesterol, 931±45 vs 881±81; VLDL, 539±26 vs 514±59; LDL, 277±35 vs 245±36; HDL, 89±3 vs 95 ± 6, respectively). IVUS and pathological examination revealed similar lumen areas but a significant reduction in plaque and vessel volume in the early treatment group. The proportion of atherosclerotic lesions was 80% in the control group and 67% in the early treatment group (P=0.01). Most lesions (87%) in the early treatment group were early-stage lesions (Stary types I-III), whereas 45% of lesions in the control group were early-stage lesions (P<0.01). Only 1% of lesions were considered unstable plaques (Stary type VI lesions) in the early treatment group (vs 10% in the control group) (P<0.01). With respect to instability, thin-cap fibroatheroma was 40% in the control group vs. 8% in the early treatment group (P<0.01), intraplaque hemorrhage was 11% vs 1% (P<0.01), and calcification was 22% vs 1% (P<0.01).

Conclusions:
Our large-animal experiment provides support for early statin treatment before occurrence of atherosclerosis. Early statin treatment appears to retard development of coronary artery atherosclerosis and maintain lesion stability.
Abstract 13263: Risk of Heart Failure in Children and Young Adults Born Preterm- A National Cohort Study
Authors: Carr Hanna , Cnattingius Sven , Ludvigsson Jonas F , Bonamy Anna-Karin E
Published: April 2024

Introduction:
An increasing number of infants survive preterm birth. Previous studies have found that preterm birth is associated with increased risks of hypertension, stroke and cardiovascular mortality later in life. We hypothesized that preterm birth would be associated with an increased risk of later heart failure. Aim: To investigate the association between preterm birth and incident heart failure children and young adults without previous ischemic heart disease.

Material and Methods:
This registry-based cohort included 2.5 million individuals born in Sweden between 1987 and 2010. Subjects were followed from one year of age to end of study in December 2011. Event definition was a diagnosis of or death from heart failure in the Swedish National Patient Register or Cause of Death Register. We used Cox proportional hazards regression to estimate the association between preterm birth (categorized as extremely preterm, <28 weeks of gestation; very preterm, <28-31 weeks of gestation; and moderately preterm, 32-36 weeks of gestation) and heart failure.

Results:
During 29.2 million years of follow-up time we found 373 cases of heart failure (1.3/100 000 person-years). Preterm birth was associated with an increased risk of heart failure across all categories of prematurity, also after exclusion of children with major malformations and adjustment for birth weight, maternal and paternal cardiovascular disease, and other potential confounders. Risk elevation was most pronounced in subjects born <28 weeks, with an adjusted hazard ratio of 19.5 (95% CI, 7.89-48.23). Corresponding hazard ratios for very and moderately preterm birth were 3.11 (1.12-8.62) and 1.76 (1.10-2.81), compared to subjects born at term.

Conclusions:
This study found a strong association between preterm birth and risk of incident heart failure in children and young adults. Risk elevation was inversely related to gestational age at birth. Although the absolute risk of heart failure is low at this young age, our findings may indicate a future health problem among the new generations of survivors after preterm birth.
Abstract 13333: Restrictive Lung Function is Related to Sympathetic Hyperactivity in Patients With Chronic Heart Failure
Authors: Joho Shuji , Ushijima Ryuichi , Akabane Takashi , Hirai Tadakazu , Inoue Hiroshi
Published: April 2024

Introduction:
Sympathoexcitation and impaired lung function are common characteristics of patients with severe heart failure (HF). However, whether impaired lung function is associated with sympathoexcitation independently of HF severity remains unknown.

Hypothesis:
We postulated that impaired lung function itself is associated with sympathetic overactivation independently of HF severity.

Methods:
Muscle sympathetic nerve activity and clinical variables were determined in 83 HF patients with left ventricular ejection fraction (LVEF) < 0.45. Abnormal spirometric findings with restrictive and obstructive changes were defined as reduced forced vital capacity (%FVC) < 80% and a ratio of forced expiratory volume in the first second to FVC (FEV1.0%) < 70%, respectively.

Results:
Restrictive and obstructive changes were identified in 17 and 21 patients, respectively. Muscle sympathetic nerve activity was higher in patients with, than without restrictive changes (p<0.01), but comparable in those with or without obstructive changes. Univariate analyses showed that %FVC, glomerular filtration rate, specific activity scale, brain natriuretic peptide level, LVEF, age and use of aldosterone receptor blockers were significant predictors of burst incidence. Multivariate analysis revealed that %FVC, LVEF and glomerular filtration rate were common independent factors of increased burst rate and burst incidence. Changes in %FVC during follow-up negatively correlated with changes in burst rate (n=11, p<0.01).

Conclusions:
Restrictive lung function is associated with increased sympathetic nerve activity independently of HF severity.