bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 9546: Effects of Endogenous Hydrogen Sulfide on Differentiation of Cardiac Stem Cells
Authors: Li Qianhong , Luo Li , Chen Ning , Ou Qinghui , O'Brien Erin M , Yuan Fangping , Hunt Gregory N , O'Toole Timothy , Guo Yiru , Bolli Roberto
Published: April 2024

Although hydrogen sulfide (H
2
S) has recently emerged as a novel gaseous transmitter with important cardioprotective properties, nothing is known regarding the role of endogenous H
2
S in modulating cardiac stem cells (CSCs). To clarify this issue, murine lin
(-)
c-kit
(+)
CSCs were pretreated with NaHS (an H
2
S donor) at a physiological concentration of 100 uM or β-cyano-L-alanine (BCA, 2 mM) and DL-propargylglycine (PAG, 2 mM; two inhibitors of H
2
S biosynthesis), for 24 h in culture media (CM) for flow cytometric analysis, or continually exposed to the same for 72 h in differentiation media (DM) for determining cardiac protein expression. After 72 h of differentiation, the levels of three major markers, von Willebrand factor (VWF) for endothelial cell (EC), α-smooth muscle actin (α-SMA) for smooth muscle cell (SMC), and α-sarcomeric actin (α-Src) for myocytes, did not change in NaHS treated-differentiated CSCs but were significantly increased in BCA or PAG treated-differentiated CSCs as compared with the differentiated control CSCs (n=4,
P
<0.05, Fig. A). Furthermore, at 24 h of treatment in the culture media, flow cytometric analysis revealed that NaHS treatment did not change the transcription factors expressed early in the cardiac lineages (Ets-1 for EC; GATA-6 for SMC; GATA-4, MEF-2C and Nkx-2.5 for myocytes), whereas BCA or PAG resulted in markedly elevated expression of Ets-1, MEF-2C, and Nkx-2.5 in CSCs (n=5,
P
<0.05, Fig. B). These data demonstrate, for the first time, that endogenous H
2
S is involved in the lineage specification of adult cardiac stem cells and that it negatively modulates cardiac transcription factors Ets-1, MEF-2C, and Nkx-2.5, thereby providing insights into myogenesis.
Abstract 9556: Role of Telomere in Endothelial Dysfunction in Type 2 Diabetic Mice
Authors: Zhang Hanrui , Wu Junxi , Cui Jian , Zhang Cuihua
Published: April 2024

Type 2 diabetes (T2D) is characterized by shorter telomeres in peripheral blood cells. We examined telomere morphology and confirmed they are also shortened in the T2D vasculature and proceeded to investigate whether telomere shortening acts as a mechanism contributing to vascular complications under metabolic disorders. We hypothesized that vascular telomere dysfunction accelerates early vascular aging and leads to endothelial dysfunction in T2D. To test this, we examined the aortic endothelial function, the expression of telomere-associated proteins, telomerase activity, telomere length, and vascular apoptosis in the aortas of control mice (m Lepr
db
) and T2D mice (Lepr
db
) at 3 and 10 months of age (n=6 mice). The expression of telomere-associated protein TRF2 and telomerase activity were reduced, and telomeres were shortened in the aortas of 3-month and 10-month Lepr
db
vs. 3-month control mice. However, TRF2 expression, telomerase activity and telomere length were not altered in 10-month control mice. The aortic expression of apoptosis regulator Chk2, caspase 3/7 activity and apoptotic cell numbers were elevated in 3-month and 10-month Lepr
db
, but not in 10-month control mice. Acetylcholine-induced endothelium-dependent vasorelaxation of aortas was impaired in 3-month and 10-month Lepr
db
, but was normal in 10-month control mice. The aortic endothelial function, telomerase activity and telomere length were not statistically different between 3-month and 10-month Lepr
db
, suggesting an early vascular aging in type 2 diabetic mice. In cultured mouse coronary artery endothelial cells, incubation at high glucose concentration (30 mmol/L) for 48 hours significantly reduced the mRNA expression of telomerase reverse transcriptase (TERT), supporting the potential role of hyperglycemia in telomere malfunction. We postulated that decreased telomere-associated protein expression and reduced telomerase activity lead to telomere shortening, which is a marker of telomere malfunction. Telomere malfunction contributes to the vascular apoptosis and impairs vasodilatory response in type 2 diabetic mice. In conclusion, telomere dysfunction plays an important role in diabetes-associated early vascular aging and endothelial dysfunction.
Abstract 9558: Overnight Use of Adaptive Servo Ventilation Reduces Cardiac Overload and Improves Renal Function in Patients with Chronic Heart Failure and Cheyne-Stokes Respiration
Authors: Yoshihsa Akiomi , Suzuki Satoshi , Miyata Makiko , Sato Takamasa , Yamaki Takayoshi , Sugimoto Koichi , Kunii Hiroyuki , Nakazato Kazuhiko , Suzuki Hitoshi , Saitho Shu-ichi , Takeishi Yasuchika
Published: April 2024

Background:
Cheyne-Stokes respiration associated with central sleep apnea (CSR-CSA) deteriorates the prognosis of patients with chronic heart failure (CHF). Adaptive servo ventilation (ASV) is a new therapeutic modality to treat CSR-CSA. Renal function plays critical roles in the progression of CHF and is a strong predictor of clinical outcomes. Cystatin C is a more sensitive marker of renal function than creatinine. The purpose of the present study was to examine whether ASV is effective for cardiac overload and renal dysfunction in CHF with CSR-CSA.

Methods and Results:
Forty two patients with CHF and CSR-CSA (mean age 62.0 ± 11.8, male 37, New York Heart Association functional class 2.5 ± 0.6, mean left ventricular ejection fraction 34.6 ± 12.6%) were examined. We performed polysomnography for consecutive two days (baseline and on ASV), and measured levels of plasma N terminal pro B-type natriuretic peptide (NT-pro BNP), cystatin C, and estimated glomerular filtration rate (eGFR) by the MDRD formula. ASV significantly imporved apnea hypopnea index (39.0 ± 17.3 to 9.9 ± 7.9 /h, P<0.01), central apnea index (17.6 ± 14.2 to 1.1 ± 1.6 /h, P<0.01), arousal index (25.9 ± 9.0 to 16.7 ± 7.5 /h, P<0.01), mean SPO
2
(94.7 ± 2.8 to 96.7 ± 1.6%, P<0.01), and lowest SPO
2
(79.1 ± 8.9 to 89.2 ± 5.8%, P<0.01) compared to baseline. ASV reduced mean heart rate (72.1 ± 10.8 to 67.4 ± 9.8 bpm, P<0.01). ASV decreased levels of log NT-pro BNP (3.032 ± 0.725 to 2.955 ± 0.714, P<0.01) and cystatin C (1.337 ± 0.546 to 1.284 ± 0.471 mg/l, P<0.05), and improved eGFR (67.1 ± 32.4 to 70.4 ± 36.2 ml/min/1.73cm
2
, P<0.01).

Conclusions:
ASV improved CSR-CSA, reduced cardiac overload, and protected renal function in chronic heart failure patients with Cheyne-Stokes respiration. ASV has short-term (overnight) beneficial effects on not only CSR-CSA but also renal function. ASV might be a promising useful tool for chronic heart failure as an important non-pharmacotherapy.
Abstract 9601: A Statin-Loaded Nanotherapy Increases Anti-Inflammatory Effects of Statin on Atherosclerosis
Authors: Tang Jun , Duivenvoorden Raphael , Izquierdo-Garcia David , Cormode David P , Stroes Erik S , Lobatto Mark E , Kuan Emma L , Randolph Gwendalyn L , Fuster Valentin , Fisher Edward A , Mulder Willem J
Published: April 2024

Introduction:
Statins have a potent cholesterol lowering capability and have shown anti-inflammatory effects, but these effects are limited. We hypothesize that statin-loaded reconstituted high-density lipoprotein nanoparticles ([s]-rHDL) exhibit improved anti-inflammatory effects on atherosclerotic plaques.

Methods & Results:
First, we evaluated the targeting of [s]-rHDL in ApoE KO mice with MRI, NIRF imaging, fluorescence microscopy and flow cytometry (n=9). Second, we evaluated the capability of [s]-rHDL to inhibit the progression of atherosclerosis. ApoE KO mice (n=62) were put on a high fat diet and received placebo (n=15), oral Simvastatin (10 mg/kg/day; n=15), intravenous rHDL (10 mg/kg ApoAI twice/week; n=16), or intravenous [s]-rHDL (15 mg/kg Simvastatin, 10 mg/kg ApoAI twice/week; n=16) for 12 weeks. To quantitatively analyze histological sections (n≈4000), an automated procedure was built. Histology results at termination showed that plaque size (hematoxylin phloxine saffron staining) in the [s]-rHDL treated group was significantly reduced compared to rHDL and placebo groups (a). Importantly, the macrophage positive area (anti-CD68 immunostaining) in the [s]-rHDL treated group was profoundly reduced compared to all other groups (b). Third, we assessed the capability of [s]-rHDL to induce rapid regression of atherosclerosis. Mice (n=43) with advanced atherosclerotic plaques were intravenously administered with high dose [s]-rHDL (60 mg/kg Simvastatin, 40 mg/kg ApoAI), low dose [s]-rHDL (15 mg/kg Simvastatin, 10 mg/kg ApoAI), high dose rHDL (60mg/kg ApoAI), or placebo 4 times in one week. One week high dose [s]-rHDL treatment decreased plaque size (c) and almost entirely depleted macrophages in atherosclerotic plaques (d).

Conclusion:
[s]-rHDL efficiently targets plaques, thereby improves the anti-inflammatory effects of statins, and can be applied to inhibit plaque progression and induce plaque regression.
Abstract 9624: Suppressive Effects of Irbesartan on Inflammation and Apoptosis in Atherosclerotic Plaques of Apoe
-/-
Mice: Molecular Imaging with
14
C-FDG and
99m
Tc-annexin A5
Authors: Zhao Yan , Zhao Songji , Kuge Yuji , Watanabe Ayahisa , Fukao Keita , Tanaka Yoshikazu , Nakano Toru , Takemoto Hiroshi , Tamaki Nagara
Published: April 2024

Background:
Although irbesartan, an angiotensin II subtype 1 receptor blocker, reportedly can suppress the progression of atherosclerosis, the mechanisms of the therapeutic effects remain unclear. FDG and annexin A5 are two promising molecular probes that can be used to image inflammation and apoptosis, respectively.

Objectives:
To clarify the relationship between the therapeutic effects of irbesartan and the inflammatory and apoptotic reactions in atherosclerotic plaques, using FDG and annexin A5.

Methods:
Female apoE
−/−
mice were administered a diet containing irbesartan (50 mg/kg/day) for 12 weeks. After 1 week of discontinuation of the treatment, the mice (n=11) were coinjected with
14
C-FDG and
99m
Tc-annexin A5, and the cryostat sections of aortic root were prepared 2 h after the injection. The sections were used for dual-tracer autoradiography, and the uptake levels of
14
C-FDG and
99m
Tc-annexin A5 in the plaques were evaluated (%ID×kg). Histological examination was performed with Mac-2 (macrophage infiltration), TUNEL (apoptosis), Movat's pentachrome (plaque size), and Oil Red O (lipid deposition) staining methods on serial sections. The same experiments were performed as control with age-matched mice on irbesartan-free diet (n=11).

Results:
Irbesartan treatment significantly (
p
<0.05) reduced the
14
C-FDG and
99m
Tc-annexin A5 uptake levels in the plaque to 43.0% ± 18.6% and 45.9% ± 16.8% that of control, respectively. Histological examinations showed a significant reduction (
p
<0.05) of the intraplaque macrophage infiltration levels (61.9% ± 20.8% of control), number of apoptotic cells (14.5% ± 16.6%), and lipid deposition levels (53.6% ± 20.2%), as well as the plaque size (56.4% ± 11.1%). Positive correlations were observed between the
14
C-FDG uptake and macrophage infiltration levels (r=0.69,
p
<0.001), and between the
99m
Tc-annexin A5 uptake level and number of apoptotic cells (r=0.69,
p
<0.001).

Conclusions:
Remissions of inflammation and apoptosis as the potential therapeutic effects of irbesartan on atherosclerosis were identified by histological examinations and molecular imaging with
14
C-FDG and
99m
Tc-annexin A5. The accuracy and usefulness of molecular imaging for monitoring therapeutic effects are also suggested.
Abstract 9651: The Role of Instruction for Use in Endovascular Aneurysm Repair for Abdominal Aortic Aneurysm: Report From National Hospital Organization Network Study in Japan
Authors: Handa Nobuhiro , Onohara Toshihiro , Okamoto Minoru , Yamamoto Tsuyoshi , Shimoe Yasushi , Okada Masahiro , Takahashi Toshiki , Yamashita Masafumi , Ishibashi Yoshimitsu , Nakai Mikizou , Suhara Hitoshi , Kasashima Fuminari , Endo Masamitsu , Nishina Takeshi , Furuyama Tadashi , Kei Jyunichi , Mizuno Akihiro , Ueno Yoichirou
Published: April 2024

Recent reports regarding a high incidence of aneurysm sac enlargement after endovascular aneurysm repair (EVAR) for abdominal aortic aneurysm focused on if strict adhesion to instruction for use (IFU) is essential. A total of 277 consecutive pts (male gender 84%, age: 77±7) who had EVAR with commercial devices at 10 national medical centers in Japan between July 2007 and September 2010 were retrospectively analyzed. Three devices were used (Zenith n=139, Excluder n=118. Powerlink n=19). Groups consisted of within IFU (WIFU) in 185 pts and beyond it (BIFU) in 92 pts. Mean age was similar between groups (77±7 vs 78±7). Female gender and hostile abdomen was more common and Physiological status of American Society of Anesthesiology was more advanced in BIFU. Anatomical feature in BIFU included angulated neck (n=23), short distal landing zone (n=20), short neck (n=13) bilateral iliac aneurysm (n=12) and access problem (n=10). No cases with proximal neck diameter more than 28mm were treated.

Results:
In-hospital mortality was one case in each group. Patients in BIFU required longer procedure time and more blood transfusion than in WIFU. Endoleaks were observed in 72 patients (type I: WIFU vs BIFU =4 vs 5, type II: 37 vs 16, type III, 0 vs 4, type IV: 5 vs 1). Early morbidity included delayed wound healing or infection (n=8: 5 vs 3), deterioration of renal dysfunction (n=7: 5 vs 2), and stroke (n=3: 1 vs 2). Endoleaks, either type I or III was increased in BIFU, compared with WIFU. Fifteen late deaths during total follow-up term of 305 patient-year included two unknown causes and seven cardiovascular deaths. The survival rates freedom from all cause death at one year were 94.9±1.9% for WIFU and 94.8±2.6% for BIFU (P=0.318). The survival rates freedom from cardiovascular death and from aneurysm related death at one year were 97.8±1.3% and 94.8±2.6% (P=0.039), and 98.8±0.9% and 97.2±2.0%, (P=0.117) respectively. Of 13 endoleaks of either type I or III, eleven endoleaks were disappeared within 6 months, and two cases required re-intervention.

Conclusion:
In the Japanese multicenter study, the early outcomes of EVAR in BIFU were satisfactory. It may be explained by the two reasons that recent generation of devices was used in all cases and that the proximal neck size in IFU was kept strictly.
Abstract 9653: Crucial Role of SmgGDS in the Molecular Mechanisms of the Pleiotropic Effects of HMG-CoA Reductase Inhibitors
Authors: Tanaka Shin-ichi , Nochioka Kotaro , Fukumoto Yoshihiro , Shiba Nobuyuki , Miyoshi Jun , Williams Carol L , Liao James K , Shimokawa Hiroaki
Published: April 2024

Background:
The
pleiotropic effects of HMG-CoA reductase inhibitors (statins) independent of cholesterol-lowering effects are thought to be mediated through inhibition of the Rho/Rho-kinase pathway. We have previously demonstrated that the pleiotropic effects of low-dose statins are mediated mainly through inhibition of the Rac1 signaling pathway rather than the Rho/Rho-kinase pathway. However, the molecular mechanisms of the selective inhibition of the Rac1 signaling pathway by low-dose statins remain to be elucidated.

Methods and Results:
We tested our hypothesis that the small GTP-binding protein dissociation stimulator (SmgGDS) plays an important role in this mechanism. In cultured human umbilical venous endothelial cells (HUVEC), statins (atorvastatin, 10 to 30 μ mol/L and pitavastatin, 1 to 10 μ mol/L) concentration-dependently increased SmgGDS expression and decreased nuclear Rac1 after 24h treatment (both P<0.05, n=3 each). Intranuclear degradation of Rac1 was reduced by the proteasome inhibitor, MG-132 (P<0.01, n=3). When SmgGDS was knockdown by its siRNA in HUVEC, statins were no longer able to induce Rac1 degradation (P<0.01, n=3) or to inhibit angiotensin II-induced production of reactive oxygen species (ROS) (P<0.01, n=8). In littermate mice, the protective effects of statins (atorvastatin, 10 mg/kg/day for 2 weeks and pravastatin, 50 mg/kg/day for 2 weeks) against AngII-induced cardiovascular hypertrophy and diastolic dysfunction were noted (AngII group vs. statin groups, P<0.01, n=10), whereas in SmgGDS-deficient mice, the protective effects of statins were absent (n=10). Finally, in normal healthy volunteers, a low-dose statin (pravastatin; 10 mg/day for 4 weeks) significantly increased SmgGDS expression (P<0.01, n=19). A significant negative correlation was noted between the extent of SmgGDS expression and oxidative stress markers (MDA-LDL-cholesterol, R=0.45; 8-OHdG, R=0.40), whereas no significant correlation was noted with total or LDL-cholesterol.

Conclusions:
These results provide the first direct evidence that SmgGDS plays a crucial role in the molecular mechanisms of the pleiotropic effects of statins through enhancement of intranuclear Rac1 degradation in animals and humans.
Abstract 9675: Ultrasound and Microbubble-Targeted Delivery of Small Interfering RNA into Primary Endothelial Cells Is More Effective than Delivery of Plasmid DNA
Authors: Juffermans Lynda J , Meijering Bernadet D , Henning Robert H , Deelman Leo E
Published: April 2024

Introduction
Ultrasound and microbubble-targeted delivery (UMTD) is a promising non-viral technique for genetic-based therapy. Recently, we demonstrated that with UMTD employing low-intensity ultrasound small dextran molecules enter endothelial cells through transient pores, while the entry of larger dextrans was dependent upon endocytosis. Extrapolating these findings to UMTD of therapeutic compounds for effective genetic-based therapy, we hypothesized that UMTD employing low-intensity ultrasound is more effective when delivering small interfering RNA (siRNA) than plasmid DNA (pDNA).

Methods
Red fluorescently-labeled siRNA against housekeeping gene GAPDH, pDNA encoding GAPDH, and red fluorescently-labeled pDNA encoding green fluorescent protein (GFP) were delivered into primary bovine aortic endothelial cells using ultrasound (1 MHz, 0.22 MPa) and SonoVue microbubbles. Cellular localization and GFP expression were determined using fluorescent microscopy. The effect of siRNA and pDNA delivery on GAPDH protein levels was determined by western blotting.

Results
UMTD of siRNA transfected 97.9±1.5% of the cells, with labeled siRNA localized homogenously in the cytoplasm directly after ultrasound exposure. Whereas UMTD of pDNA resulted in only 43.0±4.2% transfected cells, with localization mainly in vesicular structures, co-localizing with endocytosis markers clathrin and caveolin. Delivery of siRNA decreased GAPDH protein levels to 24.3±7.9% of non-treated controls (p<0.01, n=5). In contrast, 24h after delivery of pDNA no increase in GAPDH protein levels could be detected. Transfection efficiency, verified with red fluorescently-labeled pDNA encoding GFP, showed that of the transfected cells only 2.0=0.7% expressed the transgene.

Conclusions
The localization of small RNA and large DNA molecules after UMTD employing low-intensity ultrasound is an important determinant for the effectiveness of these two genetic-based technologies, as the target for siRNA is located in the cytosol, but for pDNA to be transcribed it needs be in the nucleus. In conclusion, this compartmentalization of therapeutic compounds should be taken into account when designing new genetic-based therapies with UMTD.
Abstract 9687: Vagal Reflexes as a Simple Clinical Tool to Stratify Risk Among LQT1 Patients
Authors: Crotti Lia , Spazzolini Carla , Porretta Alessandra , Vanoli Emilio , Goosen Althea , Heradien Marshall , Brink Paul A , George Alfred L , Schwartz Peter J
Published: April 2024

Background
We demonstrated that lower baroreflex sensitivity (BRS) values can identify Long QT Syndrome 1(LQT1) patients at lower risk for life-threatening arrhythmias, suggesting a protective role of “blunted” autonomic responses. However, the complexities of the phenylephrine method to assess BRS have limited its use for risk stratification in clinical practice.

Objectives
To identify an easily quantifiable marker of reflex vagal activation that might perform as well as BRS in predicting a differential risk for life-threatening arrhythmias in LQT1 patients. Specifically, to test the predictive value of heart rate (HR) recovery during the first minute after cessation of an exercise stress test.

Methods
In a South African LQT1 founder population segregating KCNQ1-A341V, 44 mutation carriers (MCs) underwent an exercise stress test and a phenylephrine test off-β-blockers. The HR decrease during the first minute of recovery from the peak of exercise (Δ
1min-rec
) was measured and subsequently correlated with BRS values among symptomatic (syncope, cardiac arrest, sudden death) and asymptomatic patients.

Results
Asymptomatic MCs had a smaller decrease in HR during the first minute of recovery from peak exercise (Δ
1min-rec
) than symptomatic MCs (13±5 vs 19±7 bpm, p< 0.05). A Δ
1min-rec
<15 bpm, which corresponds to the first tertile of its distribution, predicted a much lower probability of being symptomatic (OR 0.13, 95%CI 0.028-0.63, p<0.05). The Δ
1min-rec
values were significantly correlated with BRS values (r=0.64, p=0.001). Both tests performed similarly and quite accurately in discriminating between MCs with or without cardiac events (AUC 0.77 and 0.80).

Conclusions
LQT1 patients are at risk for life-threatening arrhythmias especially in association with rapid HR changes in either direction. Blunted autonomic responses, identified by lower values of BRS and - as vagal reflexes are concerned - by smaller HR reductions at the end of exercise, can usefully contribute to their risk stratification in a novel, simple, and inexpensive way.
Abstract 97: Intra-arrest Induction of Therapeutic Hypothermia via Large-Volume, Ice-Cold Saline Infusion Results in Improved Outcomes Among Out-of-Hospital Cardiac Arrests of Cardiac Etiology
Authors:   NYC Project Hypothermia Working Group, Freese John
Published: April 2024

Background:
New York City Project Hypothermia is a collaborative effort involving the Fire Department of New York (FDNY), Greater New York Hospital Association, Health and Hospitals Corporation, the Regional Emergency Medical Advisory Committee, and the New York State Department of Health. As part of this effort, the FDNY implemented a new pilot protocol in the New York City 9-1-1 System that introduced the induction of therapeutic hypothermia during initial resuscitation efforts via large-volume ice-cold saline infusion.

Purpose:
We sought to assess the effects of this protocol on immediate survival end-points following out-of-hospital cardiac arrest (OOHCA) of cardiac etiology.

Methods:
OOHCA data was analyzed for the following periods: August 1, 2009 - May 31, 2010 (historicalcontrol group) and August 1, 2010 - May 31, 2011 (study group). Except for the intra-arrest induction of hypothermia, no other aspect of the regional resuscitation protocols differed between the two periods. Standard Utstein definitions were utilized. Fisher's exact test was utilized, and a p <0.05 was considered significant.

Results:
4,459 / 5,582 (79.9%) of resuscitations during the control period and 3,581 / 4,727 (75.8%) of resuscitations during the study period were of cardiac etiology. The groups did not differ with respect to age, gender, race, response time, bystander witnessed status, or frequency of bystander CPR. Patients in the study period were less likely to have an EMS-witnessed arrest (6.5% vs 7.8%, p=0.03). Return of spontaneous circulation (ROSC) and sustained ROSC were improved in the study group as compared to the control group: 31.1% vs 26.8% (p<0.0001) and 23.6% vs 19.9% (p<0.0001), respectively.

Conclusion:
The initiation of therapeutic hypothermia via large volume, ice-cold saline infusion improves immediate survival for non-traumatic out-of-hospital cardiac arrest of cardiac etiology. Further study is required to identify specific populations for whom this therapy is most appropriate.
Abstract 9708: Strain Rate of Mitral Papillary Muscles: a New Imaging Prognostic Tool for Mitral Valve Repair
Authors: Grapsa Julia , Dawson David , Jakaj Gentaj , Punjabi Prakash P , Nihoyannopoulos Petros
Published: April 2024

Purpose:
New imaging modalities have been employed for the accurate anatomical mapping of the mitral apparatus. The aim of the study was to assess strain of mitral apparatus (papillary muscles and chordae) with a computational speckle tracking model and to associate strain with residual regurgitation post mitral valve surgical repair.

Methods:
50 patients with posterior mitral leaflet prolapse underwent mitral valve repair. The left ventricular ejection fraction (LVEF), mitral regurgitant volume (Mvol), the longitudinal strain of the anterolateral papillary muscle (AL), posteromedial papillary muscle (PM) and their chordae (CAL, CPM) were calculated before and 6 months after the repair.Speckle tracking was performed with Toshiba Artida, from apical 2 chamber view and on the same timepoint of the cardiac cycle for all measurements. The groups (pre and post surgical repair) were compared and the strain on papillary muscles was associated with the recurrence of mitral regurgitation post-repair.The global strain of mitral apparatus (Σstrain ) was calculated as: Σstrain= (AL + CAL) - (PM + CPM).

Results:
Six patients (15%) had residual mitral regurgitation of grade II and III. LVEF before and after the operation did not differ (pre: 69 ± 5%, post: 68.2 ± 3%, p<0.01). PM had significantly higher strain when compared to AL (PM pre: (-18.9) ± (-3)% compared to AL pre: (-4) ± (-1.1) %, p<0.01), while post repair the strain between PM and AL was similar. Patients with residual mitral regurgitation had residual high PM longitudinal strain ((-15.3) ± (-1.4) %). Σstrain overall was significantly reduced post repair (Σstrain pre : (-19.2) ± (-3) % , Σstrain post: (-2.2) ± (-0.6) %, p<0.01).

Conclusions:
Longitudinal strain of mitral valve apparatus by utilising speckle tracking can be a useful prognostic tool for post repair mitral regurgitation. It seems that a global strain of papillary muscles and chordate (Σstrain) almost equal to zero is associated with trivial regurgitation.
Abstract 9712: Lack of Association Between Common p.T111I Variant in the Endothelial Lipase Gene and the Risk for Coronary Artery Disease in Familial Hypercholesterolemia: Insights From the Modulation of Phospholipids in the HDL Particles
Authors: Tada Hayato , Kawashiri Masa-aki , Nakanishi Chiaki , Tsubokawa Toshinari , Konno Tetsuo , Hayashi Kenshi , Uchiyama Katsuharu , Nohara Atsushi , Fujino Noboru , Ino Hidekazu , Inazu Akihiro , Kobayashi Junji , Mabuchi Hiroshi , Yamagishi Masakazu
Published: April 2024

Background:
endothelial lipase (EL) is a major determinant of high-density lipoprotein cholesterol (HDL-C) metabolism through the lipolysis of the phospholipids (PL) in the HDL particles (HDL-PL). Several studies indicated that common p.T111I variant in EL gene (LIPG: rs2000813) is negatively associated with the risk of coronary artery disease (CAD) independent of HDL-C levels. However, few data exist regarding the influence of this variant on the content of HDL-PL in terms of the association with CAD, especially in familial hypercholesterolemia (FH) subjects. The aim of our study is to elucidate the clinical impact of common p.T111I variant in the EL gene on the content of HDL-PL, and whether this variant could be useful predictor of the risk of CAD in FH subjects, which always exhibit low HDL-C levels.

Methods:
The p.T111I variant was genotyped in our heterozygous FH subjects (n=80, male=56, mean age=64±18yr, mean TC=340±64mg/dl). All those subjects' plasma lipoproteins were investigated by ultracentrifugation method. Overall HDL-C level, HDL-PL level, and the existence of CAD were investigated for each group (TT group vs. TI and II group).

Results:
The minor allele frequency in the combined pools of subjects was 0.25. There was no significant association between this variant with overall HDL-C level (42±14 vs. 43±17mg/dl, p=NS) nor with HDL-PL level (86±24 vs. 88±27mg/dl, p=NS). In addition, multiple logistic regression analysis revealed no association between this variant and CAD (odds ratio 0.96, 95%CI:0.88-1.04, p=NS) although significant associations between several coronary risk factors and CAD were observed (figure).

Conclusions:
These data suggest that common p.T111I variant in LIPG neither plays a role in determining HDL-C as well as HDL-PL levels nor is a useful predictor of the risk of CAD in genetically determined heterozygous FH subjects.
Abstract 9726: Cigarette Smoking: Association Between Inflammation, Subclinical Atherosclerosis and Cardiovascular Events. The Multi-Ethnic Study of Atherosclerosis (MESA)
Authors: Mcevoy John W , Blaha Michael J , Lima Joao A , Bluemke David A , Hundley Gregory , Min James K , Shaw Leslee J , Lloyd-Jones Donald M , Barr Graham , Budoff Matthew J , Blumenthal Roger S , Nasir Khurram
Published: April 2024

Background:
Cigarette smoking is known to increase cardiovascular event risk. Whether smoking continues to be associated with adverse events after taking into account the burden of subclinical atherosclerosis and vascular inflammation is unclear.

Methods:
MESA is a population-based study of 6815 adults free of baseline cardiovascular disease. We stratified participants based on smoking status into 3 groups: Never (NS), Former (FS), and Current Smokers (CS). FS and CS were further stratified into quartiles of pack-year history of tobacco exposure (PYH). We excluded 28 participants with missing information on smoking (n=23) or follow-up events (n=5). We analyzed the association of smoking status with CHD (coronary heart disease) and CVD (cardiovascular disease) events after taking into account traditional risk factors, CRP, as well as burden of CAC.

Results:
A total of 6787 participants were followed for median 5.8 years. CS comprised 887 (13%, mean age 58yrs), FS 2484 (37%, 63yrs) and NS 3416 (50%, 62yrs). Significantly more CS suffered both CHD and CVD events than NS (4.5% vs 3.3% [p=0.003] and 6.5% vs 4.9% [p=0.019], respectively). Multivariable HRs of 1.8 (CHD, p=0.004) and 1.9 (CVD, p<0.001) were found in CS, compared to NS. These findings were increased with higher PYH, suggesting a dose-response effect of smoking on events. Incremental reductions in these HRs were found on addition of CRP (e.g. CVD HR=1.8, p<0.001) and then CAC (e.g. CVD HR=1.5, p=0.012) to the multivariable adjusted regression model. No differences in event HRs were found between FS and NS.

Conclusions:
CS, but not FS, was strongly associated with events. This association weakened slightly with the inclusion of CRP, and more significantly with the inclusion of CAC. However, the persistent association of smoking with events even after accounting for the burden of inflammation and CAC confirms the importance of additional pathways contributing to the cardiovascular risk associated with smoking.
Abstract 9736: Identification of Phenotypes at Risk of Transition from Systo-Diastolic Hypertension to Isolated Systolic Hypertension
Authors: Izzo Raffaele , De Simone Giovanni , De Marco Marina , Giudice Renata , Migliore Teresa , Trimarco Valentina , Iovino Gianni Luigi , Trimarco Bruno , De Luca Nicola
Published: April 2024

Background:
Isolated Systolic Hypertension (ISH) is the most frequent subtype of uncontrolled hypertension in elderly patients and is associated with high cardiovascular (CV) risk. Little is known about the natural evolution towards this type of hypertension and the CV phenotype associated with its appearance. Aim of the present study was to detect predictors of evolution towards ISH in subjects with initial systo-diastolic hypertension (SDH).

Methods:
6,027 individuals with SDH (age 53±11 years, 57% men, systolic blood pressure [SBP] 159±21, diastolic blood pressure [DBP] 99±10), without prevalent CV disease, MDRD-estimated glomerular filtrate ratio (eGFR)>30mL/mmHg/1.73 m2 , and with at least 6 month-follow up were selected from the CampaniaSalute registry. Echocardiography and carotid ultrasound were performed. The diagnosis of ISH was made at the end of follow up according to the ESH/ESC and JNCVII Guidelines (SBP ≥140 mmHg with DBP<90 mmHg).

Results:
After a mean follow up period of 55±44 months, 19% of the study population exhibited ISH (n=1122). Patients with ISH were older, more often women and more often diabetic, and exhibited higher initial SBP, HDL-cholesterol, left ventricular (LV) mass, relative wall thickness, pulse pressure/stroke index ratio (PP/SVi), more severe carotid atherosclerosis and lower values of eGFR (all p<0.001). These differences were studied using a multivariate proportional hazard model (Cox) including all variables that were found different at the descriptive analysis. Presence of ISH at follow up was independently predicted by older age (p<0.0001; HR=1.20/5 years; CI=1.12-1.28), female gender (p<0.004; HR=1.22; CI=1.06-1.40), baseline higher LV mass index (p=0.04;HR=1.04/5g*m-2.7; CI=1.01-1.05), higher carotid intima-media thickness (p=0.02; HR=1.12/mm; CI=1.02-1.22) and higher PP/SVi (p<0.0001;HR=1.35/Unit); CI=1.23-1.48).

Conclusion:
Factors influencing the transition from SDH to ISH are older age, female gender and signs of CV target organ damage. Thus, a prompt and aggressive therapy for arterial hypertension before the onset of target organ damage appears desirable to help lowering the prevalence of ISH especially in elderly female patients.
Abstract 9771: Reg1, a Novel RNA-Aptamer Direct Factor IXa-inhibitor (pegnivacogin) Reduces Platelet Activation in Healthy Volunteers and Residual Platelet Aggregation in Patients with ACS. A Radar Substudy
Authors: Ahrens Ingo , Putz Vera , Zelenkosfke Steven L , Moser Martin , Povsic Thomas J , Alexander John H , Becker Richard C , Rusconi Christopher P , Bode Christoph
Published: April 2024

Background and Rationale:
Residual platelet reactivity is a predictor of cardiovascular adverse events in patients with acute coronary syndromes (ACS) undergoing percutaneous coronary interventions (PCI). In addition to patient factors and antiplatelet therapy, the choice of anticoagulant determines the risk for periprocedural ischemic and bleeding events. The ideal anticoagulant would demonstrate a fast onset, effective anticoagulation, and controlable reversibility. REG1 consisting of pegnivacogin, a RNA-aptamer direct factor IXa inhibitor, and anivamersen, its specific, and titratable active control agent meets these requirements. We examined whether inhibition of factor IXa with pegnivacogin affects platelet reactivity in vitro and in vivo in healthy volunteers and in a subset of patients with ACS undergoing PCI from the phase IIb RADAR trial (
NCT00932100
).

Methods and Results:
For the in vitro study, blood from healthy volunteers was spiked with pegnivacogin (50µg/ml) and ADP-induced platelet activation was measured by flow cytometry (expression of CD62P and PAC-1 binding). Platelet aggregation was assessed by light transmission aggregometry (LTA). For the in vivo measurements, LTA was done with blood from patients with ACS enrolled in the RADAR trial. Blood samples were taken before and 20 minutes after the administration of pegnivacogin. All patients were loaded with clopidogrel (600mg) and aspirin (>325mg). In vitro pegnivacogin significantly reduced maximum ADP-induced CD62P-expression (100% vs 89.8+/- 12.1%, p=0.0035) and PAC-1 binding (100% vs 83+/-18.5%, p=0.0006). Furthermore maximum platelet aggregation was reduced by 26.3+/-16.4% (p=0.0031). In patients with ACS residual platelet aggregation (1µM ADP) was reduced from 33.3+/-4% to 14.7+/-8.1% (n=4, p=0.005) 20 minutes after intravenous pegnivacogin (1mg/kg).

Conclusion:
The novel IXa inhibitor pegnivacogin decreases ADP-induced platelet activation and aggregation in vitro and in vivo. In addition to its effect as an anticoagulant, REG1 may provide a means to overcome residual platelet reactivity in patients with ACS undergoing PCI, this may contribute to clinical outcomes and should be studied in appropriately sized phase 3 clinical trials.
Abstract 9841: Microbubble Enhanced Sonothrombolytic Therapy Facilitates Reduction of Central Venous Catheter Associated Thrombi in vivo
Authors: Kutty Shelby , Gao Shunji , Xie Feng , Drvol Lucas , Therrien Stacey L , Danford David A , Lof John , Hammel James M , Porter Thomas R
Published: April 2024

Background
We sought to investigate the therapeutic efficacy of microbubble (MB) enhanced sonothrombolysis in comparison with ultrasound (US) therapy alone for aged central venous catheter (CVC) associated thrombi
in vivo

Methods
A model of chronic indwelling CVC in the low superior vena cava with thrombus
in situ
was established after feasibility and safety testing in 7 pigs. This model was subsequently used for randomized sonothrombolytic treatments in 4 pigs. Baseline intracardiac echocardiography (ICE, 10.5F Acunav, Sequoia, Siemens), fluoroscopy and saline flushing confirmed the absence of any pre-existing CVC associated thrombus. By withdrawing 0.5-0.7 ml of blood into the CVC, a thrombus was allowed to form and age over 24 hours. The created thrombus at the distal CVC tip was localized and measured by ICE, and transthoracic guided high mechanical index (MI) two dimensional US treatments (1.6 MHz; 1.1 MI; iE33, Philips) applied intermittently whenever microbubbles were visualized near the thrombus. Total treatment time was 45 minutes. Lipid encapsulated MBs (3% MRX-801, NuvOx Pharma) were infused through both the CVC and a peripheral vein. Control pigs received transthoracic US alone. Post-treatment thrombus area determined by ICE planimetry was compared with pre-treatment measurements.

Results
Eight randomized treatments were applied for CVC thrombi- 4 US+MB (Group A) and 4 US alone (Group B). Thrombus area measurements before and after treatment were 0.25 and 0.13 cm
2
respectively in Group A; compared to 0.27 and 0.23 cm
2
in Group B (p = 0.01). The Figure shows ICE examples of CVC thrombi before and after US+MB treatment. No alterations in oxygen saturation or hemodynamics occurred with either treatment.

Conclusions
Guided high MI diagnostic US+systemic MB facilitates reduction of aged CVC associated thrombi
in vivo
. MB enhanced sonothrombolytic therapy may be a non-invasive safe alternative to thrombolytic agents in treating thrombotic CVC occlusions.
Abstract 9844: Clinical Outcomes of Saphenous Vein Graft Interventions Using Drug Eluting Stents Compared with Bare Metal Stents: A Comprehensive Meta-Analysis of All Randomized Clinical Trials
Authors: Alam Mahboob , Bandeali Salman J , Shahzad Saima A , Virani Salim S , Jneid Hani M , Ramanathan K B , Kleiman Neal S , Lakkis Nasser M
Published: April 2024

Introduction:
Clinical outcomes of PCI in patients with saphenous vein grafts (SVG) remain poor despite the use of drug eluting stents. There is disparity in clinical outcomes in SVG PCI based on various registries while randomized data remains scant.

Hypothesis:
In the setting of an earlier randomized trial showing higher mortality in patients who underwent DES implantation for SVG disease we sought to assess whether DES use in SVG interventions will improve short and intermediate-term clinical outcomes compared to BMS.

Methods:
An aggregate data meta-analysis of clinical outcomes in RCTs comparing PCI with DES vs. BMS for SVGs reporting at least 12 months of follow-up was performed. A search of Medline and conference proceedings between 01/2003 and 05/2011 identified 4 RCTs enrolling 812 patients (416 in DES and 396 in BMS arms). Summary odds ratios & 95% confidence intervals were calculated using the random-effects model. Review Manager Version 5.1 (The Cochrane Collaboration) was used for data analyses. Primary endpoint was all cause mortality. Secondary outcomes included non-fatal myocardial infarction (MI), repeat revascularization (i.e. target vessel revascularization [TVR] or target lesion revascularization [TLR]), and MACE (composite endpoint of death, MI and TLR/TVR). These outcomes were assessed in cumulative fashion at 30 days, 18 months and 36 months.

Results:
Overall, there were no inter-group differences in baseline clinical and socio-demographic characteristics. Following a median follow-up of 25 months (range 12 - 35months), patients in the DES and BMS group had similar rates of death, MI and MACE. Patients in the DES arm had significantly lower rates of repeat revascularization OR = 0.40, 95% CI 0.22 - 0.75). Table I provides details of the meta-analysis outcomes at various follow-up periods.

Conclusions:
Use of DES in SVG interventions is associated with significant reduction in rate of repeat revascularization without an excess in mortality.
Abstract 9845: Efficacy and Safety of Transcranial Ultrasound and Microbubbles in Treating Acute Ischemic Stroke Without Thrombolytic Agents
Authors: Liu Jinjin , Gao Shunji , Xie Feng , Lof John , Shi William T , Vignon Francois , Powers Jeff E , Porter Thomas R
Published: April 2024

Background.
Although transcranial ultrasound (TCUS) and microbubbles (MB) have been utilized in the emergent management of stroke, it remains unclear what TCUS parameters are required to be effective. Furthermore, it is unclear whether TCUS alone, without supplemental thrombolytic agents, could produce thrombolysis without intracranial hemmorhage (ICH). The purpose of this study was to determine whether TCUS pulse sequences which elicit predominately inertial cavitation (IC) versus stable cavitation (SC) of MB would be more effective in recanalizing the cerebral vessels in acute stroke.

Methods.
In 24 pigs, three hour old venous thrombi were embolized into the internal carotid and middle cerebral arteries. After angiographic documentation of persistent bilateral occlusion, pigs were randomized to a continuous infusion of MB using intravenous 3% Definity, during which either guided high mechanical index (MI) impulses (2.3 MI; 5 usec pulse duration) or guided intermediate MI impulses (1.7 MI, 20 usec pulse duration) were administered. The impulses were applied only when simultaneous low MI imaging detected MB within the cortex. A third control group received high MI impulses (2.3 MI) alone without MB. All pigs received aspirin. Radiofrequency (RF) data was collected from returning signals in all pigs to determine whether noise based IC or ultraharmonic based SC were created. Microscopic analysis (Hematoxylin/Eosin) was performed to analyze for ICH post-mortem.

Results.
Attenuation across the pig skull (measured ex vivo) using a calibrated hydrophone was >52% in all pigs. Recanalization rates were highest for guided high MI impulses in the presence of MB (8/8 versus 3/8 for guided intermediate MI impulses/MB and 4/8 for high MI TCUS alone; p<0.05). Although the intermediate MI impulses created both SC and IC, a more homogenous IC field was created with guided high MI impulses in the presence of MB. Microscopic analysis of ipsilateral and contralateral cortex indicated no ICH in any pig.

Conclusions.
TCUS and intravenous commercially available MB are capable of safely restoring cerebral blood flow without the need for thrombolytic agents. Achieving a dominant IC field appears critical to produce thrombolysis.
Abstract 9848: A Subgroup Analysis of Carotid Artery Stenting with Distal Protection in High Surgical Risk Patients in Routine Clinical Practice: Results of the CABANA Safety Surveillance Program
Authors: White Christopher J , Hopkins L. Nelson , Foster Malcolm , Powell Richard J , Zemel Gerald , Diaz-Cartelle Juan , Dawkins Keith D
Published: April 2024

INTRODUCTION:
The multicenter, nonrandomized CABANA Study evaluated periprocedural outcomes in high surgical risk patients with carotid artery stenosis treated with the Carotid WALLSTENT plus FilterWire EZ Embolic Protection System (Boston Scientific, Natick, MA)

HYPOTHESIS:
We assessed whether a patient's symptomatic status, high risk category and age (≤80 years vs >80 years) had an impact on the 30-day composite rate and individual event rates of major adverse events (MAE including stroke, death and myocardial infarction [MI]).

METHODS:
Of the 1,097 patients enrolled, 34.4% were at high risk for carotid endarterectomy due to prespecified anatomic criteria, while 65.6% had medical comorbidities. Approximately one-third of patients were symptomatic for carotid artery disease (≥50% carotid artery stenosis); the rest were asymptomatic (≥80% carotid stenosis). Follow-up at 30 days included clinical evaluation and independent neurologic and NIH stroke scale assessments.

RESULTS:
At 30 days postprocedure, the MAE rate in the overall population was 4.6% (47/1025). In asymptomatic and symptomatic patients, MAE rates were 4.2% (29/697) and 5.5% (18/328); respectively (
P
=0.34); in the ≤80-year and >80-year cohort, MAE rates were 4.1% (34/836) and 6.9% (13/189), respectively (
P
=0.10). Individual event rates are shown in Table 1. Patients with comorbid risk factors showed strong trends towards higher major stroke rates (2.5% vs 0.9%,
P
=0.07) versus those at anatomic high risk. No differences were seen in MAE (3.7%, anatomic vs 5.1%, comorbid, P=0.33), death, or MI rates between groups.

CONCLUSIONS:
Composite MAE and individual event rates at 30 days in all subgroups were low and similar to the outcomes in the overall CABANA dataset. A trend toward higher incidence of major stroke in the comorbid high risk group was observed. These results demonstrate the safety of the Carotid WALLSTENT plus FilterWire EZ in high surgical risk patients, regardless of their risk profile.
Abstract 9888: Is There Additional Prognostic Value of Stress Echocardiography in Patients Achieving a High Exercise Capacity (≥10 Metabolic Equivalents)?
Authors: Yao Siu-Sun , Agarwal Vikram , Chaudhry Farooq A
Published: April 2024

Background:
High exercise capacity is a predictor of favorable prognosis in patients with known or suspected coronary artery disease. The purpose of this study was to examine the prognostic value of stress echocardiography (SEcho) in patients achieving high exercise workload.

Methods:
We evaluated 970 patients (51 ± 11 years; 62% male) achieving nine minutes (≥10 metabolic equivalents) on a Bruce protocol by treadmill SEcho. Resting left ventricular ejection fraction and regional wall motion were assessed. The left ventricle was divided into 16 segments and scored on 5-point scale of wall motion. Abnormal SEcho was defined as stress-induced ischemia (wall-motion score of ≥1 grade). Followup (3.4 ± 1.5 years) for non-fatal myocardial infarction (n = 11) and cardiac death (n = 3) were obtained.

Results:
By univariate analysis, both peak wall motion score index (p=0.002) and number of new ischemic wall motion abnormalities (p<0.0001) were significant predictors of cardiac events. Cumulative survival in patients achieving nine minutes (≥10 metabolic equivalents) was signficantly worse in patients with abnormal (ischemic) vs. normal (nonischemic) SEcho (1.1%/year vs. 0.2%/year, p=0.001)(Graph). Multivariate logistic regression analysis identified number of new ischemic wall motion abnormalities as the strongest predictor of cardiac events (RR 1.27, 95% CI 1.0-1.6, p=0.01).

Conclusions:
The ability to achieve nine minutes (≥10 metabolic equivalents) by treadmill stress echocardiography confers a benign prognosis (~1.0%/year). In the setting of high achieved exercise capacity, stress echocardiography (absence or presence of ischemia) is further able to effectively risk stratify a low risk group.