bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 8543: Ectopic Fat Mobilization Following a Bariatric Surgery-Induced Weight Loss; Association with Insulin Resistance
Authors: Auclair Audrey , Martin Julie , Bastien Marjorie , Bonneville Nadine , Hould Frédéric-Simon , Marceau Simon , Poirier Paul
Published: April 2024

Severe obesity is associated with increased cardiovascular morbidity and mortality and is increasing in prevalence. The purpose of the study was to measure the impact of weight loss and changes in insulin resistance following biliopancreatic diversion with duodenal switch (BPD-DS) procedure on adiposity and skeletal muscle. Anthropometric measures, mid-thigh computed tomography (CT) and fasting plasma glucose and insulin were measured at baseline, at 6 and 12 months in severely obese subjects who underwent BPD-DS (n=43) and in a severely obese control group (n=24). At baseline, the two groups were similar for age, sex, weight (128.3±23.3 vs. 117.6±19.1 kg; p=0.059, BPD-DS vs. control respectively) and mid-thigh CT composition but not for body mass index (BMI) (47.6±5.9 vs. 43.5±4.8 kg/m2; p=0.004). At 6 months, in the BPD-DS group, there were a significant decrement in weight (-26.7±7.4%), BMI (-26.7±5.6%), as well as in mid-thigh CT composition: total adipose tissue (-34.7±10.5%), deep adipose tissue (-36.1±15.4%), subcutaneous adipose tissue (-34.7±10.5%), total skeletal muscle (-19.2±8.8%), fat infiltrated muscle (-54.4±29.4%) and non-fat infiltrated muscle (-17.7±11.4%); all p<0.001. Between month 6 and 12, in the BDP-DS group, weight, BMI, total, deep and subcutaneous adipose tissue decrease significantly but to a lesser degree compared to the first 6 month; all p≤0.001. There was no change regarding total skeletal muscle, but a significant increment in non-fat infiltrated muscle (5.3±7.8%) and decrement in fat infiltrated muscle (-11.8±10.8%); all p≤0.001. A decreased in insulin resistance at 6 and 12 months was associated with a reduction of thigh deep adipose tissue (r=0.469, r=0.692, 6 and 12 months respectively) and fat infiltrated muscle (r=0.469, r=0.526); all p≤0.001. There were no changes, in all these parameters in the control group. BPD-DS surgery-induced weight loss had major impact on muscle and fat mass. Mobilization of thigh ectopic fat; thigh deep adipose tissue and fat-infiltrated muscle, may be one mechanism that improves insulin resistance. Muscle regain at 12 months suggests that BPD-DS exerts a physiologic effect beyond that of nutrient restriction on the regulation of energy metabolism.
Abstract 8547: Patient-Specific Cellular Therapy (Ixmyelocel-T) is Safe and Improves Time to Treatment Failure in Patients with Critical Limb Ischemia and No Revascularization Options
Authors: Marston William , Powell Richard , Dall'Olmo Carlo , Guzman Raul , Berceli Scott , Moore Colleen J , Martinez Jeff , Halloran Brian , Henke Peter , Stiff Patrick , Comerota Anthony , Velazquez Omaida , Tzeng Edith , Mendelsohn Farrell , Henry Tim , Bohannon W T , Saucedo Jorge , Bartel Ronnda , Longcore Amy , Stern Theresa , Watling Sharon
Published: April 2024

Background:
Critical limb ischemia (CLI) represents the most severe degree of peripheral arterial disease and is associated with significant morbidity and mortality. Cellular therapy offers the potential to promote tissue remodeling, immuno-modulation, and angiogenesis. This Phase 2 study assessed the safety and efficacy of patient-specific, expanded bone marrow cells (ixmyelocel-T) in a no-option CLI population followed for 12 months.

Methods:
This randomized (2:1), double-blind, placebo-controlled, multicenter study compared one-time treatment of ixmyelocel-T with placebo, administered via 20 IM lower extremity injections. Bone marrow aspirates from patients in the ixmyelocel-T group were processed over 12 days to generate ixmyelocel-T mixed cell product. The primary objective was safety. A composite treatment failure efficacy endpoint (major amputation on treated limb, death, doubling of wound size from baseline, or de novo gangrene) and amputation-free survival (major amputation or death) were also evaluated.

Results:
Of the 72 patients who received injections (mean age 69 years, 67% male, 50% diabetic, 84% current or past smokers, 63% with baseline wounds), 48 received ixmyelocel-T and 24 placebo. No major safety concerns were evident (Table 1). The time to first occurrence of treatment failure was significantly longer in ixmyelocel-T-treated patients compared with placebo-treated patients (Figure 1, logrank test, p = 0.0032). Amputation-free survival showed a clinically meaningful 32% reduction in event rate but did not reach statistical significance (p = 0.3880).

Conclusions:
Ixmyelocel-T was safe and increased time to treatment failure.
Abstract 8681: The Cardioprotective Role of Renin-Angiotensin System Antagonism in the Prevention of Doxorubicin and Trastuzumab Mediated Cardiac Dysfunction
Authors: Bhullar Navdeep , Kotrec Marian , Zeglinski Matthew , Golian Mehrdad , daSilva Megan , Lytwyn Matthew , Bohonis Sheena , Fang Tielan , Oomah Sacha , Nepomuceno Roman , Du Xiaozhou , Karlstedt Erin , Sharma Anita , Garber Philip , Singal Pawan , Jassal Davinder
Published: April 2024

Background:
In breast cancer patients, the administration of chemotherapeutic based agents, in particular Doxorubicin (Dox), is associated with an increased risk of cardiotoxicity. The introduction of novel monoclonal antibodies in breast cancer therapy, specifically Trastuzumab (Trz), further compounds this issue of drug induced cardiac dysfunction. Little is known about the use of renin-angiotensin system (RAS) antagonists in the prevention of Dox and Trz mediated cardiac dysfunction.

Objective:
To evaluate the cardioprotective effects of RAS antagonism in the prevention of Dox and Trz mediated cardiomyopathy in a chronic murine model.

Methods:
A total of 120 C57Bl/6 mice were randomized to three arms: (A) Trz; (B) Dox; or (C) Dox+Trz. The mice in each arm were further randomized to receive prophylactic treatment daily in their drinking water with either placebo, direct renin inhibitor (DRI), angiotensin converting enzyme inhibitor (ACEI), or angiotensin receptor blocker (ARB). Serial murine echocardiography was performed weekly for 13 weeks, after which the hearts were removed for histopathologic analyses.

Results:
In arm A (Trz), there was no evidence of cardiotoxicity at week 13. In arms B (Dox) and C (Dox+Trz), prophylactic treatment with either RAS antagonist was partially cardioprotective. In arm C (Dox+Trz), mice prophylactic treated with either placebo, DRI, ACEI or ARB demonstrated a decrease in fractional shortening from 51±2% at baseline to 26±2%, 40±2%, 32±2% and 34±2% (p<0.05), at week 13, respectively. Survival analyses of each arm corroborated the echocardiographic findings (Figure 1). There was a decrease in histologic evidence of cardiac damage due to Dox+Trz pretreated with either RAS antagonist.

Conclusion:
Prophylactic administration of RAS antagonists is partially cardioprotective in a chronic murine model of chemotherapy induced cardiac dysfunction.
Figure 1:
Abstract 8688: Incident Stroke and Mortality Associated with First-detected Atrial Fibrillation in Patients Hospitalized with Severe Sepsis
Authors: Walkey Allan J , Wiener Renda S , Ghobrial Joanna M , Curtis Lesley H , Benjamin Emelia J
Published: April 2024

Introduction:
First-detected fibrillation (AF) has been reported in 6-20% of patients with severe sepsis. Whereas chronic AF is a known risk factor for stroke and death, the clinical significance of first-detected AF in the setting of sepsis is uncertain. Our objective was to determine the in-hospital stroke and in-hospital mortality risks associated with first-detected AF in patients with severe sepsis.

Hypothesis:
First-detected AF during severe sepsis is associated with increased risk for in-hospital stroke and in-hospital mortality.

Methods:
Retrospective population-based cohort derived from 2007 California State Inpatient Database administrative claims data. Data was available from 3,147,787 hospitalized adults. Severe sepsis [N=49,082 (1.56%)] was defined by validated
ICD-9-CM
code 995.92. First-detected AF was defined as AF that occurred during the hospital stay, after excluding AF cases present at admission.
A priori
outcome measures were in-hospital ischemic stroke (
ICD-9-CM
433, 434, or 436) and mortality. Analyses of stroke and mortality outcomes were adjusted for demographics, comorbidities, and acute factors.

Results:
Patients with severe sepsis were 69±16 years old and 48% were women. First-detected atrial fibrillation occurred in 5.9% of patients with severe sepsis versus 0.6% of patients without severe sepsis [multivariable-adjusted odds ratio (OR), 6.82; 95% confidence interval (CI), 6.54-7.11;
P
<0.001]. Severe sepsis was present in 14% of all first-detected AF in hospitalized adults. Participants with severe sepsis and first-detected AF had in-hospital ischemic stroke at a rate of 34.5 (95% CI, 27.2-43.3) strokes/100 patient-years. Compared with severe sepsis patients without first-detected AF, patients with first-detected AF during sepsis had greater risks of in-hospital stroke (0.6% vs. 2.6%, adjusted OR 2.70; 95% CI, 2.05-3.57;
P
<0.0001) and in-hospital mortality (39% vs. 56%, adjusted relative risk, 1.07; 95% CI, 1.04-1.11;
P
<0.0001).

Conclusion:
First-detected AF during severe sepsis is associated with clinically significant adverse outcomes including higher risk of stroke and death. Investigation of strategies to decrease risks associated with incident AF during severe sepsis are warranted.
Abstract 8697: Left Atrial Appendage Function Assessed by Speckle Tracking Echocardiography as a Predictor of Thrombus in Patients with Permanent Atrial Fibrillation
Authors: Fujii Tomoko , Kawasaki Masanori , Tanaka Ryuhei , Ono Koji , Watanabe Takatomo , Nagaya Maki , Onishi Noriyuki , Tokoro Fumitaka , Matsuoka Reiko , Abe Shintaro , Goto Yoshiaki , Yoshizane Takashi , Kato Takashi , Warita Syunichiro , Kojima Tai , Iwama Makoto , Hirose Takeshi , Tanihata Shintaro , Noda Toshiyuki , Iida Mami , Watanabe Sachiro , Minatoguchi Shinya
Published: April 2024

Background:
Left atrial appendage (LAA) thrombus is a high risk factor of thromboembolism in patients with atrial fibrillation (AF). Spontaneous echo contrast (SEC) and LAA emptying velocity are echocardiographic predictors of LAA thrombus and CHADS2 score is used as a risk stratification of thrombus. However, LAA contractile function may be an important determinant of thrombus. Thus, we assessed the hypothesis that LAA emptying function (EF) would be more useful to predict LAA thrombus in AF.

Methods:
Using speckle tracking echocardiography (STE) (ACUSON sequoia 512, Siemens), time-LAA or LA volume curve can be automatically provided. LAAEF and LAEF were measured by STE and compared with manual tracing method using transesophageal (TEE) and transthoracic echocardiography in consecutive 142 patients with AF and treated with warfarin. They were grouped according to the presence of thrombus; AF with thrombus (n=38, age 69±10, 30 men) and AF without thrombus (n=104, age 65±12, 80 men). LAAEF and LAEF were defined as (maximum - minimum volume) / maximum volume x 100% during a cardiac cycle. SEC score, LAA peak and mean velocity, left ventricular ejection fraction and LA dimension were also measured. Average values of 3 cardiac cycles were analyzed.

Results:
LAAEF and LAEF by STE correlated with manual tracing method (r=0.98, r=0.95, respectively, p<0.001). Patients with AF and thrombus were older and had more prior strokes, longer AF duration and reduced LAAEF (Table). Using 20% of LAAEF as a cutoff value, sensitivity was 92% and specificity was 88% for thrombus. In multivariate analysis, LAAEF and age were independent predictors of LAA thrombus.

Conclusion:
LAA thrombi appeared to exist in elderly patients with AF and more reduced LAAEF compared to AF with preserved LAAEF despite no difference in PT-INR, suggesting that LAA thrombus formation depends on LAA contractility. LAAEF by STE using TEE may be a useful predictor of LAA thrombus in patients with AF and warfarin therapy.
Abstract 8699: Validation of Speckle Tracking Echocardiography in Assessment of Left Atrial Volume and Function: a Comparative Study with Three-dimensional Computed Tomography
Authors: Matsuoka Reiko , Tanaka Ryuhei , Hirose Takeshi , Watanabe Takatomo , Chikamatsu Kaoru , Kako Nobuo , Nagaya Maki , Onishi Noriyuki , Sato Noriaki , Fujii Tomoko , Iwama Makoto , Ono Koji , Tanihata Shintaro , Noda Toshiyuki , Watanabe Sachiro , Kawasaki Masanori , Minatoguchi Shinya
Published: April 2024

Background:
Noninvasive assessment of left atrial (LA) function was limited by a lack of a suitable method and automated LA border detection with acoustic quantification was expected to facilitate the assessment of LA volume and function. Speckle tracking echocardiography (STE) (ACUSON sequoia 512, Siemens) which can detect LA border and provide time-LA volume curve automatically has been recently used to assess LA function. Thus, the aim of this study was to validate STE in assessment of LA volume (LAV) and function compared with 3-dimensional computed tomography (CT).

Methods
: Maximum (max.) and minimum (min.) LAV measured using Simpson's rule in apical 4-chamber view and LA total emptying function (EF) were compared to manual tracing method in 66 subjects in a blind way and were compared to CT with 64 rows in 20 subjects undergoing catheter ablation. Interobserver variability of max. LAV and min. LAV and LA total EF by STE in 66 subjects was determined by 2 observers in a blind way. Intraobserver variability of those parameters by STE in 66 subjects was determined by one observer with 7 days interval. LA total EF was defined as (max. LAV - min. LAV) / max. LAV.

Results
: LAV and LA total EF were easily and quickly obtained by STE. There was a good correlation between STE and manual tracing method in max. LAV, min. LAV and LA total EF (r=0.98, r=0.98 and r=0.95, respectively, p<0.001). There was also a good correlation between STE and CT in those parameters (r=0.95, r=0.96 and r=0.97, respectively, p<0.001). Bland-Altman analysis between STE and CT in those parameters revealed an excellent correlation. The interobserver correlation coefficient and relative differences in max. and min. LAV and LA total EF by STE were 0.98 and 0.94±6.8%, 0.99 and 8.0±11% and 0.99 and 2.2±15.9%, respectively. The intraobserver correlation coefficient and relative differences in those were 0.98 and 2.6±6.2%, 0.98 and 8.1±11.6% and 0.90 and 4.0±12.4%, respectively.

Conclusion:
Max. LAV, min. LAV and LA total EF determined from time-LA volume curve by STE exhibited a good agreement with those determined by the manual and CT method. STE had an excellent feasibility as a noninvasive estimation of LA and may be no less useful in the routine clinical setting for the evaluation of LA volume and function than CT.
Abstract 8712: Anticoagulation-Associated Adverse Drug Events
Authors: Piazza Gregory , Nguyen Thanh N , Cios Deborah , Labreche Matthew , Hohlfelder Benjamin , Fanikos John , Fiumara Karen , Goldhaber Samuel Z
Published: April 2024

Introduction:
Anticoagulant drugs are among the most common medications that cause adverse drug events (ADEs) in hospitalized patients.

Hypothesis:
We assessed the hypothesis that anticoagulant-associated ADEs are preventable sources of morbidity, mortality, and increased hospitalization costs.

Methods:
We reviewed all inpatient anticoagulant-associated ADEs, including adverse drug reactions (ADRs) and medication errors (MEs), reported at Brigham and Women's Hospital through the Safety Reporting System from May 2004 to May 2009. We also collected data regarding the cost associated with hospitalizations in which ADRs occurred.

Results:
Of 463 anticoagulant-associated ADEs, 226 were MEs (48.8%), 141 were ADRs (30.5%), and 96 (20.7%) involved both an ME and ADR. Patients who suffered anticoagulant-associated ADEs had a median length of stay of 13 days and a high rate of re-hospitalization within 30 days of the ADE (17.5%). Seventy percent of anticoagulant-associated ADEs were preventable. Transcription errors (48%) were the most frequent root cause of anticoagulant-associated MEs, while MEs were the most common root cause of anticoagulant-associated ADRs (40%). Death within 30 days of anticoagulant-associated ADEs occurred in 11% of patients. After an anticoagulant-associated ADR, most hospitalization expenditures were attributable to nursing costs (mean $33,189 per ADR) followed by pharmacy costs (mean $7,451 per ADR).

Conclusion:
Most anticoagulant-associated ADEs among inpatients are due to MEs and are therefore preventable. We observed an increased 30-day mortality rate among patients who suffered an anticoagulant-associated ADE and high hospitalization costs following ADRs. Further Quality Improvement efforts to reduce anticoagulant-associated MEs are warranted to improve patient safety and decrease health care expenditures.
Abstract 8768: Involvement of Rho-Kinase Activation in the Pathogenesis of Coronary Hyperconstricting Responses Induced by Drug-Eluting Stents in Patients with Coronary Artery Disease
Authors: Aizawa Kentaro , Yasuda Satoshi , Takahashi Jun , Takii Toru , Kikuchi Yoku , Tsuburaya Ryuji , Ito Yoshitaka , Ito Kenta , Nakayama Masaharu , Takeda Morihiko , Shimokawa Hiroaki
Published: April 2024

Background:
We have previously demonstrated that activation of Rho-kinase, the effector of the small GTP-binding protein Rho, plays a central role in the pathogenesis of coronary vasospasm in pigs and humans and coronary hyperconstricting responses following drug-eluting stent (DES) implantation in pigs. In this study, we further examined whether Rho-kinase activation is also involved in the DES-induced coronary hyperconstricting responses in humans.

Methods:
We examined 25 patients with coronary artery disease who underwent coronary intervention with either DES (n=16, sirolimus/paclitaxel 15/1, M/F 10/6, 69 ± 11[SD] years) or bare-metal stents (BMS, n=9, M/F 7/2, 70 ± 8 years). We examined coronary vasoconstricting responses to intracoronary (IC) acetylcholoine (ACh) before and after the intracoronary treatment with a Rho-kinase inhibitor, fasudil (300 μ g/min for 15 min). We evaluated coronary vasomotor responses by quantitative coronary angiography (QCA) and coronary vascular structure by optical coherence tomography (OCT).

Results:
QCA showed that the coronary vasoconstricing responses to ACh were significantly enhanced in the DES group compared with the BMS group at both the proximal (BMS -13.0 ± 10.7% vs. DES -24.7 ± 14.2[SD] %, P<0.05) and the distal segments (BMS -24.4 ± 12.2%, DES -42.8 ± 14.8%, P<0.01). Importantly, fasudil markedly attenuated the enhanced vasoconstricting responses to ACh in the DES group (proximal -10.2 ± 11.3%, distal -14.2 ± 10.2% vs. before fasudil, both P<0.01). In contrast, coronary vasodilator responses to intracoronary isosorbide dinitrate were comparable between the 2 groups. Although OCT showed a variable degree of intimal thickening at the segments adjacent to DES, there was no significant correlation between intimal thickness and coronary vasoconstriction to ACh.

Conclusion:
These results indicate that Rho-kinase activation is substantially involved in the pathogenesis of the DES-induced coronary hyperconstricting responses in patients with CAD as well, suggesting the therapeutic importance of Rho-kinase pathway.
Abstract 8783: Methylation of
FOXP3
In Regulatory T Cells is Related to the Severity of Coronary Atherosclerosis
Authors: Jia Lei , Wang Jizheng , Wang Xiaojian , Chen Jingzhou , Zhang Channa , Hui Rutai
Published: April 2024

Objective:
Regulatory T (Treg) cells play a protective role in experimental atherosclerosis. However, the role of Treg in the development of human coronary artery disease (CAD) is inconsistent. Demethylation in the DNA that encodes
transcription factor forkhead box P3
(
FOXP3
) is a prerequisite for the stable maintenance of suppressive properties in Tregs, which is also identified as the most specific marker for human Tregs. We aim to evaluate Treg levels in CAD patients by a novel method based on Treg-specific DNA demethylation within
FOXP3
gene.

Methods and Results:
We included patients with acute myocardial infarction (AMI) and unstable angina (UA), and control subjects with normal coronary artery on angiography (NCA) in our study. Peripheral blood mononuclear cells were collected to determine Treg levels by both flow cytometry and PCR based DNA methylation analysis. We found that Treg levels that were quantified by the demethylation rate of Treg-specific demethylated region in
FOXP3
gene, but not by flow cytometry, were univocally decreased in UA and AMI patients (NCA 4.22% ± 1.92%; UA 3.29% ± 1.45%; AMI 2.86% ± 1.26%). This decline was inversely related to the severity of CAD (
r
=−0.308,
P
<0.05). After adjustment for traditional risk factors, the association was still significant (
β
=−0.336,
P
<0.05). Furthermore, we detected the expression of DNA methyltransferases in CD4
+
CD25
+
Tregs sorted from included subjects. A significant increase of DNA methyltransferase3b was observed in CAD patients compared with normal controls. Treatment of CD4
+
CD25
+
Tregs with ox-LDL induced a 41% increase in the methylation of
FOXP3
, accompanied with a more than 3-fold reduction of FOXP3 mRNA expression and increases in the expressions of DNA methyltransferase 3a and 3b. Moreover, the effect of ox-LDL on FOXP3 can be reversed by methyltransferase inhibitor (-)-epigallocatechin-3-gallate.

Conclusion:
Our data demonstrate that Treg cells are decreased in CAD patients and its reduction are associated with the severity of atherosclerosis. Ox-LDL decreases the expression of FOXP3 by DNA methylation. Thus, we confirm the important role of Treg cells in human CAD and suggest potential epigenetic regulation in the progression of atherosclerosis.
Abstract 8796: Comparison of Coronary Flow Velocity Reserve Measurement by Transthoracic Doppler Echocardiography with 320-Row Multidetector Computed Tomography Coronary Angiography for Predicting Coronary Artery Stenosis in Calcified Lesions in the Three Major Coronary Arteries
Authors: Kakuta Kentaro , Dohi Kaoru , Yamanaka Takashi , Kawamura Masaki , Sugimoto Tadafumi , Nakajima Hiroshi , Nakamori Shiro , Tanigawa Takashi , Yamada Norikazu , Nakamura Mashio , Ito Masaaki
Published: April 2024

Objectives:
This study examined the diagnostic accuracy of coronary flow velocity reserve (CFR) measurement using transthoracic Doppler echocardiography (TTDE) by comparing 320-row multidetector computed tomography coronary angiography (CTCA) for predicting coronary artery stenosis in calcified lesions in the 3 major coronary arteries.

Methods and Results:
Invasive coronary angiography (ICA), CTCA, and CFR measurement were performed in 101 patients. The presence of stenosis ≥50% was considered significant stenosis by ICA. By CTCA, the degree of coronary artery calcification was assessed using the Agatston calcium score (CS) method. Prospectively electrocardiographically-gated CTCA was performed with the use of test-injection method for the assessment of coronary artery stenosis. Coronary flow velocity was recorded in each target coronary artery by TTDE at rest and during hyperemia induced by intravenous infusion of adenosine triphosphate. CFR <2, calculated as the ratio of hyperemic to basal peak and mean diastolic velocity, was considered ≥50% stenosis.

Results:
A significant coronary stenosis by ICA was found in 60 vessels. Coronary artery legions were successfully assessed in 91% and 95% of all vessels by CTCA and TTDE, respectively. CTCA had a sensitivity of 92%, a specificity of 93%, a positive predictive value (PPV) of 73%, and a negative predictive value (NPV) of 98% in patients with 0-299 CS, and had a sensitivity of 89%, a specificity of 67%, a PPV of 47%, and an NPV of 95% in patients with 300-599 CS for predicting coronary artery stenosis. In patients with ≥ 600 CS, 73% of vessels were unassessable. CFR<2.0 had a sensitivity of 90%, a specificity of 90%, a PPV of 71%, and an NPV of 97% in patients with 0-299 CS, had a sensitivity of 92%, a specificity of 89%, a PPV of 79%, and an NPV of 96% in patients with 300-599 CS, and had a sensitivity of 100%, a specificity of 85%, a PPV of 77%, and an NPV of 100 % in patients with ≥ 600 CS for predicting coronary artery stenosis.

Conclusions:
CFR measurement accurately predicts significant coronary artery stenosis irrespectively of the degree of coronary artery calcification whereas progression of coronary calcification negatively influences diagnostic accuracy of CTCA-based assessment of coronary artery stenosis.
Abstract 8817: Niacin Promotes Macrophage Reverse Cholesterol Transport in Hypercholesterolemic Mice In a CETP-Dependent Manner
Authors: Nakaya Kazuhiro , Komaru Yohei , Tohyama Junichiro , Millar John S , Billheimer Jeffrey T , Rader Daniel J
Published: April 2024

Background-
Niacin is the most effective drug currently available to increase HDL-cholesterol. The aim of the present study was to examine the effect of niacin on macrophage reverse cholesterol transport (RCT), a primary atheroprotective property of HDL, and to determine the mechanisms by which this occurs.

Methods and Results-
Niacin increased HDL-cholesterol in homozygous LDL receptor-deficient (
Ldlr
-/-
) mice expressing human cholesterol ester transfer protein (CETP) (
Ldlr
-/-
.
CETP
), but not in the mice without CETP. Niacin promoted macrophage RCT in the mice in a CETP-dependent manner. Treatment of
Ldlr
-/-
.
CETP
mice with niacin decreased plasma CETP activity
ex vivo
, without the alteration of hepatic CETP expression or plasma CETP mass. Niacin also promoted macrophage RCT by reducing CETP activity even in the setting of partial lack of LDL receptor with CETP expression (
Ldlr
+/-
.
CETP
mice).
Ldlr
-/-
.
CETP
mice and
Ldlr
+/-
.
CETP
mice with niacin had the enhanced plasma capacity to promote macrophage cholesterol efflux. Moreover, niacin attenuated the transfer of cholesteryl esters from HDL to VLDL/LDL fractions
in vivo
, consistent with its inhibitory effect on CETP activity. Kinetic studies showed that niacin increased fecal excretion of HDL-derived cholesteryl esters in
Ldlr
-/-
.
CETP
, but not in
Ldlr
-/-
mice.

Conclusions-
Our observations demonstrate that niacin promotes macrophage RCT
in vivo
by decreasing plasma CETP activity in the setting of both complete and partial lack of LDL receptor. Niacin-mediated reduction in CETP activity leads to the enhanced direct pathway of RCT from HDL fractions into feces with the promotion of plasma efflux capacity from macrophages in the mice.
Abstract 8847: Racial Differences in Competing Risks for First Cardiovascular Events and Non-Cardiovascular Death in Middle-Aged and Older Adults
Authors: Feinstein Matthew J , Ning Hongyan , Kang Joseph , Bertoni Alain , Carnethon Mercedes , Lloyd-Jones Donald M
Published: April 2024

Background:
Standard survival models may over-estimate risks of incident cardiovascular disease (CVD) if they do not account for the competing risk of non-CVD death. No studies to date have compared first CVD events and non-CVD death between races in a competing risks framework.

Methods:
Using data from 2 multi-center, NHLBI-sponsored cohorts (ARIC and CHS), we used competing Cox models to estimate hazards for first CVD events and non-CVD death within and between races.

Results:
Of 14569 ARIC study participants (ppts) aged 45-64y with mean follow up of 10.5y, 11.6% had CVD and 5.0% had non-CVD death as a first event; among 4237 CHS study ppts aged 65-84y and followed for 8.5y, these figures were 43.2% and 15.7%, respectively. Figures 1 and 2 show competing cumulative incidence curves for ARIC men for specific event types. CVD events were significantly more likely to occur first rather than non-CVD death in all sex-race groups. Compared with whites, middle-aged blacks were 1.4-2.1 times more likely to have non-CVD death or CVD as first events; these disparities disappeared by older adulthood. After adjustment for CVD risk factors (RFs), however, middle-aged black men were less likely than whites to experience a first CVD event. Most likely first CVD events were CHD in white men and heart failure in black men and all women.

Conclusions:
Our finding that CVD events are more likely than non-CVD death to occur first in all sex-race groups re-affirms the importance of broadly applied CVD prevention programs. CVD affects blacks at a younger age than whites; the earlier burden of CVD among black men may be due to elevated CVD RF levels. Racial disparities in first CVD incidence disappear by older adulthood.
Abstract 8889: Isovolumic Acceleration Correlates with Single Ventricle Pre or Post Fontan Ventricular End Diastolic Pressure, Not E/e′
Authors: Khoo Nee Scze , Smallhorn Jeffrey F , Kaneko Sachie , Kutty Shelby , Hornberger Lisa , Coe James , Tham Edythe B
Published: April 2024

Background:
Estimation of diastolic function in single ventricle (SV) hearts with varied ventricular loading from staged palliative surgery is particularly challenging. To define the best non-invasive correlate of diastolic function in SV, we studied the relationship between echocardiography function parameters, and invasively measured end diastolic pressure (EDP) of the dominant ventricle in SV patients.

Methods and Results:
Thirty SV patients, mean age 41±11 months, with cardiac catheterization pre (n=20) or post Fontan (n=10), had their most closely associated echocardiogram (median 3.5, 0.6 to 9.9 months), assessed using conventional and color tissue Doppler imaging (TDI) parameters for systolic and diastolic function. Echocardiogram parameters and catheter-derived data were explored for linear correlations with p<0.05 being significant. The EDP and mean pulmonary artery (PAP) pressures were 6.5±3.5 and 9.6±3.4 mmHg respectively. No significant correlation was found between echocardiography diastolic parameters, early and late peak inflow velocities (E, A and E/A), TDI annular velocities (e′, a′ and E/e′), pulmonary venous Doppler spectra, isovolumic relaxation time, atrial size and function, and invasively measured EDP or PAP. Systolic parameters, ventricular annular excursion, TDI (s′ and Tei index), ventricular size and function, had no significant correlation with EDP or PAP. Only isovolumic acceleration (IVA), a mostly load independent non-invasive measure of myocardial contractility, held a highly significant negative correlation with EDP (Figure).

Conclusions:
Decreased IVA, a marker of reduced myocardial contractility, has the best non-invasive correlate with invasively measured EDP in SV. In contrast E/e′ and other parameters of diastolic function do not. Current echocardiographic diastolic parameters established in adults with heart failure may not be useful in SV.
Abstract 8918: Diagnostic Criteria for Ultrasound Diagnosis of Internal Carotid Artery Stenosis Vary Widely Among Accredited Vascular Laboratories. A Survey from the Intersocietal Commission for the Accreditation of Vascular Laboratories (ICAVL)
Authors: Gornik Heather L , Hutchisson Marge , Khan Mariam , Benenati James F , Jaff Michael R , Katanick Sandra , Needleman Laurence
Published: April 2024

Background:
Carotid duplex ultrasound (DUS) is widely used for diagnosis of internal carotid artery (ICA) stenosis and therapeutic decisions are often on the basis of DUS findings. There are no universal standard DUS criteria to grade the severity of ICA stenosis. A 2003 publication from the Society for Radiologists in Ultrasound (SRU) provided consensus criteria for grading ICA stenosis, but their integration into clinical practice is unknown.

Methods:
Random sample of 10% of vascular laboratories accredited in extracranial carotid testing. Data were abstracted from the ICAVL database, including most recent accreditation application. A single reviewer (HLG) compared laboratory diagnostic criteria to published references.

Results:
152 vascular laboratories were sampled, 57.2% of which were outpatient based. Mean annual carotid volume 1,330 + 124.1 studies (range 100-9,858). There were 17 diagnostic criteria in use among 117 labs with the remaining facilities utilizing locally developed (6 labs) or unreferenced or hybrid criteria (29 labs). Mean number of categories of ICA stenosis was 5.80 + .084 (range 3-12). Cut-points for the mildest disease stratum ranged from 0 to 0-60% with normal or 0% most commonly reported (67.1% of labs). The cut-point for most severe (non-occlusive) stenosis ranged from 70 to 91% with 80% most commonly reported (64.5% of labs). SRU consensus-based criteria were used in only 27.0% of laboratories, although there was a statistically significant increase in SRU utilization among labs accredited after versus before 2005 (50.0% vs. 18.8%, P <0.001). Despite divergent diagnostic criteria and severity cut-points, self-reported accuracy of DUS for diagnosis of ICA stenosis from correlation studies was high (mean 85.8 + 0.65%).

Conclusion:
Diagnostic criteria and cut-points for grading severity of ICA stenosis using DUS vary widely in accredited vascular laboratories. Despite this, diagnostic accuracy is acceptable. Uptake of SRU consensus criteria has been limited, but is more common among recently accredited facilities. Health care providers must be aware of the lab-to-lab variation in reporting of ICA stenosis while further efforts to achieve consensus reporting are considered by professional societies.
Abstract 8963: Role of Caveolin-Centered Adiponectin Signalsome and Neutral Ceramidase in Adiponectin's Anti-Inflammatory, Anti-Oxidative and Anti-Nitrative Signaling
Authors: Wang Yajing , Wang Xiaoliang , Lau Wayne Bond , Yuan Yuexing , Yi Wei , Sun Yang , Su Hui , Lopez Bernard , Christopher Theodore , Ma Xin-Liang
Published: April 2024

Endothelial and vascular protective actions of adiponectin (APN) are well-recognized, but its underlying transmembrane and intracellular signaling remain largely unknown. Recently, we demonstrated that caveolin plays an essential role in the formation of a membrane-situated APN signalsome containing adiponectin receptor (AdipoR), APPL1, and adenylate cyclase (AC). However, the significance of this signalsome in APN vascular biology has not been investigated. Moreover, a very recent study suggested that AdipoR may function as a neutral ceramidase. However, the pathological importance of APN-activated ceramidase in APN’s vascular protective action remains completely unknown. Our current study investigated the relationship between caveolin-1 (Cav1) and ceramidase in APN’s anti-inflammatory, anti-oxidative, and anti-nitrative actions. Pre-treatment of HUVECs with APN (2 µg/ml) significantly increased ceramidase activity (3.7-fold, P<0.01), and decreased TNFα-induced ICAM-1 expression (P<0.05), iNOS/NADPH oxidase expression (P<0.01), and NO/superoxide/peroxynitrite overproduction (P<0.01). These indicators of APN biological function were either markedly reduced (P<0.001) or completely lost in Cav1 knockdown cells. Neutral ceramidase knockdown virtually abolished the effect of APN upon TNFα-induced ICAM-1 expression, but only modestly inhibited the effect of APN upon TNFα-induced iNOS/NADPH oxidase expression or NO/superoxide/peroxynitrite overproduction. In contrast to APPL1 and AC, no Cav1/ceramidase interaction was detected during basal conditions, indicating the absence of ceramidase from the APN signalsome. However, Cav1/ceramidase complex was clearly detected when HUVECs were stimulated with APN. Finally, knockdown of AdipoR1 or both AdipoR1/R2 respectively markedly and completely abolished APN activation of ceramidase. These results demonstrate for the first time that the Cav1-centered APN signalsome plays an essential role in mediating APN’s vascular biological actions. Moreover, these results support that APN-induced Cav1-dependent recruitment of ceramidase to the APN signalsome is responsible for APN’s anti-inflammatory effects.
Abstract 8966: C1q/TNF-Related Proteins (CTRPs), a Family of Novel Adipokines, Induce Vascular Relaxation through the Adiponectin Receptor-1/AMPK/eNOS/Nitric Oxide Signaling Pathway
Authors: Zheng Qijung , Yuan Yuexing , Su Hui , Yi Wei , Lau Wayne Bond , Wang Yajing , Wang Xiaoliang , Sun Yang , Lopez Bernard , Christopher Theodore , Peterson Jonathan M , Peterson Jonathan M , Wong G William , Yu Shiqiang , Yi Dinghua , Ma Xin-Liang
Published: April 2024

Reduced plasma adiponectin (APN) in diabetic patients is associated with endothelial dysfunction and vascular injury. However, APN knockout animals manifest only modest systemic dysfunction unless metabolically challenged. The CTRP (C1q/TNF-related proteins) family has recently been identified as APN paralogs. Some CTRP members share APN’s metabolic regulatory function. However, the vascular biology of CTRPs remains completely unknown. This study assessed the vasoactivity of currently identified murine CTRP members utilizing in vitro and in vivo experimental models, and elucidated underlying molecular mechanisms in HUVECs. Of eight CTRPs investigated, three CTRPs (3, 5, and 9) caused significant vasorelaxation in concentration-dependent fashion, while the remaining CTRPs neither constricted nor dilated aortic segments. The vasodilatory potency of CTRP9 exceeded that of APN (3-fold), is endothelium-dependent, and mediated by nitric oxide (NO). Plasma CTRP9 levels were markedly increased in APN knockout mice, and significantly reduced in high-fat-diet induced obesity/diabetic mice (P<0.05). One week of in vivo CTRP9 administration initiated after 3 weeks high-fat-diet, at a dose restoring physiological CTRP9 levels, significantly improved vascular endothelial function (P<0.01). Mechanistically, CTRP9 increased AMPK/Akt/eNOS phosphorylation and increased endothelial NO production. AMPK knockdown completely blocked CTRP9-induced Akt/eNOS phosphorylation and NO production. Akt knockdown had no significant effect upon CTRP9-induced AMPK phosphorylation, but blocked eNOS phosphorylation and NO production. Adiponectin receptor 1 (AdipoR1), but not receptor 2 (AdipoR2), knockdown blocked CTRP9-induced AMPK/Akt/eNOS phosphorylation and NO production. Finally, pre-incubating vascular rings with an AMPK-inhibitor abolished CTRP9-induced vasodilatory effects. Collectively, we have provided the first evidence that CTRP9 is a novel vasodilatory/vasculoprotective adipokine, potentially compensatory for APN’s vascular effects in APN knockout animals. Moreover, we have demonstrated that CTRP9 exerts its vascular biological effects via the AdipoR1/AMPK/eNOS dependent/NO mediated signaling pathway.
Abstract 8980: Effective Cardiac Resynchronization Therapy May Normalize Longitudinal Dyssynchrony Evaluated by 3-Dimentional Speckle Tracking Imaging
Authors: Lee Yasuharu , Nishino Masami , Yoshimura Takahiro , Nakamura Daisuke , Taniike Masayuki , Makino Nobuhiko , Katou Hiroyasu , Egami Yasuyuki , Shutta Ryu , Tanouchi Jun , Yamada Yoshio
Published: April 2024

Background:
Cardiac resynchronization therapy (CRT) becomes standard therapy for severe heart failure and its indication is now spreading to mild to moderate heart failure. However there remains approximately 30% non-responders and the mechanism of reverse remodeling induced by CRT is still unclear. Thereby we investigated which kind of dyssynchrony parameter, existing during own beat, was improved by CRT-on.

Methods:
We investigated 43 patients by 3-dimentional speckle tracking imaging (3DSTI) (ARTIDA, TOSHIBA Medical System): 12 CRT responders, defined as left ventricular end-systolic volume reduction >15% at 6 months after CRT, 14 CRT non-responders and age matched 17 healthy normal controls. Radial strain, longitudinal strain and circumferential strain were investigated and we calculated the following 3DSTI parameter: strain delay index (SDI) which was defined as the sum of the difference between peak and end-systolic each parameter across 16 segments. 3DSTI was investigated at >6months after CRT implantation and evaluated during CRT-off as own beat and CRT-on for responders and non-responders and during sinus rhythm for normal controls to estimate CRT effect at chronic phase.

Results:
During CRT-off, radial and longitudinal SDI were significantly higher in responders than non-responders, but circumferential SDI was not significantly different. After turning CRT-on, radial and longitudinal SDI were improved to lose significant difference, but circumferential SDI showed significant difference. Turning CRT-on, longitudinal SDI of responders had no more significant difference with normal controls (figure).

Conclusions:
Effective CRT pacing at chronic phase improves radial and longitudinal dyssynchrony, especially longitudinal SDI tend to be normalized. Reverse remodeling after CRT might be induced by improvement of longitudinal dyssynchrony.
Abstract 8984: A New Therapeutic Modality for Ischemia-Reperfusion Injury: Nanoparticle-Mediated Delivery of Pitavastatin into Reperfused Myocardium Reduces Myocardial Ischemia/Reperfusion Injury in Rats
Authors: Nagaoka Kazuhiro , Matoba Tetsuya , Nakano Kaku , Sunagawa Kenji , Egashira Kensuke
Published: April 2024

Background:
In ST-elevation acute myocardial infarction (STEMI), early reperfusion is the most effective therapeutic strategy. Reperfusion, however, induces ischemia-reperfusion (I/R) injury that can paradoxically cancel the beneficial impacts of reperfusion. Pretreatment with statins at high doses before the occurrence of ischemia is known to reduce I/R injury by activating reperfusion injury salvage kinase (RISK) pathway, whereas treatment with statins at the time of reperfusion is reported to elicit no therapeutic effects. Nanoparticle (NP)-mediated drug delivery system may be promising for targeting reperfused myocardium where vascular permeability is enhanced. Hence we tested the hypothesis that NP-mediated site-specific delivery of pitavastatin into ischemic myocardium ameliorates I/R injury through activation of RISK pathway.

Methods and Results:
In the rodent model of 30-min myocardial ischemia and subsequent reperfusion, we intravenously (IV) injected NP containing 0.1 mg FITC or 0.1 mg FITC solution at the time of reperfusion. Three hours after reperfusion, we found, in the NP group, significant FITC fluorescence in viable cardiomyocytes within the area at risk (Figure A, B), while did not find in the FITC solution group (Figure B). IV treatment of pitavastatin-NP containing 1.0 mg/kg pitavastatin, but not pitavastatin solution (1.0, 10 mg/kg), reduced infarct size 24-hours after reperfusion (Figure C). Pitavastatin-NP activated RISK pathway such as Akt signals (enhanced phosphorylation at Thr 308) in the reperfused myocardium. Pretreatment of wortmannin, a PI3K inhibitor, blunted the therapeutic effects of pitavastatin-NP (Figure C).

Conclusions:
NP-mediated delivery of pitavastatin into ischemic myocardium at the time of reperfusion reduced myocardial infarct size by activating RISK pathway in rodent I/R model. This study may provide an innovative medical approach that complement current reperfusion therapy for STEMI.
Abstract 9204: High Plasma Estradiol Level as an Independent Risk Factor for Ischemic Arterial Disease Among Postmenopausal Women. A Population-Based Study (the Three-City Cohort Study)
Authors: Canonico Marianne , Scarabin Valérie , Brailly-Tabard Sylvie , Setiao Julie , Trabado Severine , Tzourio Christophe , Ritchie Karen , Dartigues Jean-François , Guiochon-Mantel Anne , Scarabin Pierre-Yves
Published: April 2024

Background
: Hormone therapy may increase the risk of coronary heart disease and stroke among postmenopausal women. However, the impact of endogenous steroid sex hormones (SSH) on ischemic arterial disease (IAD) has been poorly investigated.

Objectives.
To investigate the association of SSH with the risk of IAD among postmenopausal women.

Methods
: In the French prospective Three-City cohort study including subjects over 65 years, we investigated the association of bioavailable 17β-estradiol and total Testosterone with the 4-year incidence of IAD (coronary heart disease and ischemic stroke) among postmenopausal women who did not use any hormone therapy. Biological measurements were performed for all cases (n=106) and a random sample of controls (n=522) using a case/cohort study design. Hazards ratios (HR) and 95% Confidence Interval (95% CI) were estimated by weighted Cox proportional models.

Results.
In univariate analysis, subjects in the third tertile of bioavailable 17β-estradiol had an increased risk of IAD as compared with those in the first tertile (HR=1.80; 95%CI: 1.05-3.08, p for linear trend=0.03). Adjustment for traditional cardiovascular risk factors including obesity and diabetes did not substantially change the strength of this association (comparison of third tertile versus first tertile: HR=1.73; 95%CI: 1.01-3.05, p for linear trend=0.04). With respect to total testosterone, both univariate and multivariate analysis showed no significant association with the risk of IAD.

Conclusion.
Elevated plasma levels of bioavailable 17β-estradiol emerge as a significant and independent risk factor for IAD among postmenopausal women. These data are consistent with the findings of Women's Health Initiative trials and suggest deleterious effects of estradiol on cardiovascular disease in elderly women.
Abstract 9243: Comparison of the 2006 and 2010 Appropriate Use Criteria for CT Coronary Angiography in an Academic Medical Center
Authors: Cullen Ethany , Aggarwal Shivani , Goss Brian , Araoz Philip , Gibbons Raymond
Published: April 2024

Purpose:
We previously analyzed the 2006 appropriateness criteria for cardiac computed tomography (CT) and found 42% of our patients were not classifiable, suggesting the criteria were difficult to apply clinically. These criteria were revised in 2010. The purpose of our study is to compare the new 2010 appropriate use criteria to the original 2006 criteria to determine if the 2010 criteria were more applicable.

Materials and Methods:
In a previous study we applied the 2006 appropriateness criteria to 251 patients that underwent cardiac CT from June 1 to December 31, 2007. Each patient was assigned an indication from the 2006 appropriate use criteria by two observers, classifying patients as appropriate, inappropriate, uncertain, or nonclassifiable. A third observer settled disagreements. This process was applied to the same 251 patients using the 2010 criteria. The data from the previous study using the 2006 criteria was compared to the data obtained using the 2010 criteria to determine changes in the number of nonclassifiable, appropriate, inappropriate, and uncertain exams. These results were then analyzed using Bowker's test of symmetry. Observer agreement was calculated using the kappa statistic.

Results:
115 patients (46%) were not classifiable using the 2006 criteria. When the 2010 criteria were applied, the number of not classifiable patients decreased to 40 (16%), with the plurality, 41 (16%), of the not classifiable patients moving to inappropriate. In 2006, 69 (27%) were classified as appropriate, 25 (10%) were uncertain, 42 (17%) inappropriate. In 2010, the appropriate increased to 84 (33%), uncertain increased to 40 (16%), and inappropriate increased to 87 (35%). Bowker's test of symmetry demonstrated a statistically significant change with a p<0.001. Agreement between the two observers assigning patients to classification groups also improved with a kappa of 0.55 using the 2010 criteria compared to kappa of 0.31 in 2006.

Conclusion:
The number of not classifiable patients decreased using the 2010 criteria and the interobserver agreement improved, suggesting they are more applicable and complete than the 2006 criteria. This decrease in not classifiable patients came primarily from an increase in the number of inappropriate indications.