bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 9895: Metformin Attenuates Atherosclerosis and Vascular Aging Beyond Glycemic Control
Authors: Forouzandeh Farshad , Salazar Gloria , Patrushev Nikolay , Xiong Shiquin , Hilenski Lula , Alexander Robert W
Published: April 2024

Background:
Cardiovascular disease due to atherosclerosis, the main cause of morbidity and mortality in most of the world, can be exacerbated by other age-related changes in blood vessels, including arterial stiffness mediated by angiotensin II (Ang II). Thus, strategies that can target atherosclerosis and vascular aging concomitantly are of special interest. Metformin, the first line medication for type 2 diabetes, was shown to attenuate all-cause mortality and myocardial infarction compared with other standard diabetes medications, suggesting that metformin has protective effects in the cardiovascular system beyond its glucose control activities. However, the exact mechanism(s) of action for metformin that are beyond its antihyperglycemic effects are still unknown.

Methods and Results:
We found that metformin even at concentrations as low as 20 μM can decrease Ang II-induced senescence of vascular smooth muscle cells. Using the ApoE-Knockout mice, we further tested whether metformin can diminish the progression of atherosclerosis and vascular aging and in response to Ang II treatment or high fat diet (HFD). We found that both Ang II induced hypertension and vascular aging were almost completely abolished by metformin treatment. Moreover, metformin treated animals had significantly less atherosclerotic plaque area compared with control groups. Similar vasculoprotective effects were observed when metformin was given to the mice fed HFD (Fig. 1). However, the vasculoprotective findings in both models were not accompanied by significant differences in blood glucose or cholesterol levels. Based on our ongoing studies, these effects of metformin could be explained, at least in part, by its role in modulation of the mTOR pathway that plays a major role in response to nutrition status.

Conclusion:
Metformin can be useful as a primary or secondary preventive therapy for patients at risk of suffering cardiovascular disease even in the absence of diabetes.
Abstract 9912: Global Intracoronary Infusion of Allogeneic Atrial Cardiosphere-Derived Cells (CDCs) Stimulates Myocyte Regeneration and Reverses LV Remodeling in Miniature Swine With Chronic Myocardial Infarction
Authors: Suzuki Gen , Weil Brian R , Leiker Merced M , Canty John M
Published: April 2024

Background:
Intracoronary infusion of autologous CDCs (icCDCs) into the infarct-related artery using the “stop flow” technique improves regional function in patients but global function remains unchanged. We tested the hypothesis that this reflects the inability to regress cellular hypertrophy and replace myocytes lost in remote remodeled regions that can be overcome by global intracoronary infusion of CDCs.

Methods:
Miniswine (n=10) were studied 8 weeks after chronic infarction was produced by LAD microembolization (1x10
6
microspheres, 45μm diameter). Ejection fraction decreased from 63 ± 2% at baseline to 31 ± 2% four weeks after infarction (p<0.05 vs. baseline) and remained unchanged at 8 weeks (32 ± 2%, p-ns vs. 4 weeks). Allogeneic CDCs (20 x 10
6
CDCs, cyclosporine 100 mg/day) isolated from donor atrial biopsies were infused into the 3 major coronary distributions without interrupting flow. We assessed myocardial function (echo), myocyte proliferation (Ki67) and infarct size (TTC) in comparison to untreated controls. Regional myocyte regeneration was quantified by assessing myocyte nuclear density and size.

Results:
Infusing icCDCs into infarcted and remodeled remote myocardium increased regional function and ejection fraction (Table). icCDCs stimulated myocyte proliferation (Ki67) in LAD and remote regions by three-fold. As a result, myocyte number (nuclear density) increased by 35% and myocyte cell diameter decreased by 33% in both LAD and remote myocardium. The reduction in infarct volume after icCDCs was not significant.

Conclusion:
We conclude that global infusion of allogeneic icCDCs without “stop flow” 1.) stimulates myocyte proliferation throughout the LV and 2.) in a model of infarction, improves regional function with a substantial increase in left ventricular ejection fraction. Thus, allogeneic icCDCs may afford a widely available platform to reverse LV dysfunction in patients with chronic post infarction LV remodeling.
Abstract 9919: Incremental Values of Resting and Exercise Cardiac Dysfunction for Prediction of Outcome in Asymptomatic Aortic Regurgitation
Authors: Kusunose Kenya , Marwick Thomas H , Griffin Brian P , Popovic Zoran B
Published: April 2024

Background:
The role of exercise echocardiography in decision-making regarding surgical timing for aortic regurgitation (AR) remains a matter of debate, because there are limited data on its link with outcome. The aim of this study was to assess the role of echocardiographic measurements at rest and during exercise as predictors of prognosis in asymptomatic aortic regurgitation.

Methods and Results:
Comprehensive resting and exercise echocardiography was performed in 164 consecutive patients (50±15y; 78% male) with isolated moderate to severe AR and preserved left ventricular (LV) function (LV ejection fraction >50%, LV end-diastolic dimension ≤70mm, LV end-systolic dimension ≤50mm or ≤25mm/m2) in whom initial management was expectant. Echocardiographic measurements were performed at rest and during exercise. LV and right ventricular (RV) longitudinal strain was analyzed at rest using velocity vector imaging. Valve surgery was performed in 38 patients (23%) over 33±12 months. After adjustment for age and gender in a multivariable Cox proportional hazards model, exercise tricuspid annular plane systolic excursion (TAPSE) (HR=0.81, p=0.002) was associated with valve surgery-free survival, independent of resting LV strain (HR=1.16, p=0.043), exercise LV end-diastolic volume (HR=1.01, p=0.134) and resting RV strain (HR=1.17, p=0.009). In sequential Cox models, a model based on clinical data (chi-square, 25.6) was improved by resting LV strain (chi-square, 30.1, p=0.010), resting RV strain (chi-square, 46.0, p=0.001) and further increased by exercise TAPSE (chi-square, 56.7, p=0.001)(Figure).

Conclusions:
In asymptomatic AR, resting LV strain, resting RV strain and exercise TAPSE were independently associated with the need for earlier aortic surgery.
Abstract 9920: Evaluation of Global Circumferential Strain as Prognostic Marker After Administration of β-blockers for Dilated Cardiomyopathy
Authors: Tanaka Hidekazu , Mochizuki Yasuhide , Matsumoto Kensuke , Yamadori Yoshiki , Sawa Takuma , Motoji Yoshiki , Imanishi Junichi , Miyoshi Tatsuya , Fukuda Yuko , Tatsumi Kazuhiro , Onishi Tetsuari , Kawai Hiroya , Hirata Ken-ichi
Published: April 2024

Background:
The prognosis of dilated cardiomyopathy (DCM) has improved by the use of β-blockers, and the appearance of left ventricular (LV) reverse remodeling is generally thought to result in a favorable prognosis. Although there are many prognostic predictors, they are not sensitive in individual patients. It is recently reported that global circumferential strain (GCS) is a powerful predictor of cardiac events and appears to be a better parameter than LV global function in heart failure patients. Accordingly, the objective of our study was to test the hypothesis that GCS predicted LV reverse remodeling after administration of β-blockers in patients with DCM.

Methods:
Fifty patients with DCM with EF of 28±8% (all<45%) were prospectively recruited. Either carvedilol or bisoprolol was titrated to a targeting dose depending on the tolerability of each patient. Echocardiography was performed at enrollment and 8±5 months after the maintenance dose of β-blockers. LV reverse remodeling was defined as the presence of an absolute increase in EF of at least 10%. GCS was determined as the peak global speckle-tracking circumferential strain from mid-LV short-axis view. Event-free survival was tracked over 30-month.

Results:
Among all indices, GCS<-4.01% best predicted responders, with 100% sensitivity, 62% specificity, and an area under the curve of 0.796 (p= 0.0004). On multivariate Cox proportional-hazards analysis, GCS was the independent and the most powerful predictor of LV reverse remodeling (hazard ratio, 1.228; p=0.02). Furthermore, patients with GCS<-4.01% experienced fewer cardiovascular events than those with GCS≥-4.01% (log-rank p=0.023).

Conclusions:
GCS predicted LV reverse remodeling after administration with β-blockers, and was also associated with long-term outcome in patients with DCM. GCS may reflect intrinsic LV myocardial function
,
and have clinical implications for better management of such patients.
Abstract 9936: Hypoxanthine is a Biomarker of Ischemia
Authors: Gehr Lynne , Gehr Todd , Bachmann Lorin , Vetrovec George
Published: April 2024

We hypothesize that hypoxanthine (HX) is an early biomarker of ischemia. Our goal was to assess early HX values in patients presenting with acute chest pain (ACP) and late troponin elevation (n=27) compared to those with known coronary artery disease (CAD) presenting for elective CABG (n=10) and normal controls without known CAD (n=24).

Methods:
In a retrospective manner after IRB approval was obtained, we examined residual plasma for HX in 27 patients presenting to the emergency room with troponin samples requested by the clinician as per routine clinical practice. Patients with a non diagnostic troponin level for myocardial infarction (MI) at the time of presentation but who subsequently ruled in for MI (troponin of > .39 μg/L) were included in the study. Significant differences between the groups was determined using a standard t test.

Results:
Initial sample results for the ACP patient group who subsequently ruled in for MI by troponin show a mean troponin of 0.07+/-0.014(SEM)μg/L and a mean HX level of 27.38 +/- 3.53 μM compared to normal controls whose mean HX was 4.03 +/- 0.32 μM (p<.05). Ten patients without ACP presenting for elective CABG had a mean HX of 5.09+/- 0.67 μM. In the figure below, we demonstrate that HX is elevated in ACP patients who on subsequent sampling rule in by troponin criteria for MI. Reported HX levels in normal volunteers are approximately 3.5 μM consistent with our controls.

Conclusion:
HX is elevated prior to troponin elevation in patients presenting with ACP that subsequently rule in for MI by troponin criteria. These levels were elevated relative to normal control patients as well as in 10 patients with known CAD without ACP presenting for elective CABG. Therefore, HX is potentially an early maker of ischemia in the acute clinical setting.
Abstract 10034: Digital Assessment of Peripheral Vascular Endothelial Function is Useful for the Risk Stratification in Patients With Hypertension
Authors: Yamamoto Eiichiro , Sugiyama Seigo , Matsuzawa Yasushi , Hirata Yoshihiro , Akiyama Eiichi , Fujisue Koichiro , Tokitsu Takanori , Sugamura Koichi , Kaikita Koichi , Hokimoto Seiji , Ogawa Hisao
Published: April 2024

Introduction:
Hypertension (HT) is the major risk factor of coronary artery disease (CAD), however all HT patients were not equally predisposed to CAD. Endothelial dysfunction has been implicated in atherogenesis, and digital assessment by reactive hyperemia peripheral arterial tonometry (RH-PAT) is a novel examination to evaluate endothelial function.

Methods:
In 1323 stable patients with suspected CAD including 1057 HT patients, we assessed peripheral endothelial function as fingertip RH-PAT index (RHI) and examined the presence and severity of CAD by coronary angiography.

Results:
Ln-RHI was significantly attenuated in HT patients (n=215) compared to risk-factor-matched non-HT patients (n=215) (0.538±0.224 vs. 0.664±0.248, p<0.001) after matching number of patients and coronary risk factors (CRFs). In HT patients, ln-RHI was further lower in CAD (n=786) than in non-CAD (n=271) (0.514±0.185 vs. 0.634±0.219, p<0.001). By multivariate-logistic-regression analysis, ln-RHI was independently associated with the presence of CAD in HT (per 0.1; odds ratio [OR]: 6.15, 95% confidence interval [CI]: 1.87-20.3, p<0.001). CAD with high-ln-RHI was significantly associated with the complication of multi-vessel disease (MVD) and B-type natriuretic peptide (both p<0.001). In receiver-operating-characteristic analysis, ln-RHI was a significant determinant for the presence of CAD (area under curve [AUC]: 0.650, 95% CI: 0.646-0.721, p<0.001), and adding ln-RHI to CRFs improved predictive values of CAD (AUC: 0.737, 95% CI: 0.701-0.773, p<0.001). The net reclassification index was significant with the inclusion of ln-RHI (13.8%, p<0.005).

Furthermore, ln-RHI was significantly lower in CAD with MVD (n=464) than in those with single-vessel disease (n=322) (0.46 vs. 0.57, p<0.001). Multivariate-logistic-regression analysis suggested that ln-RHI was independently associated also with the presence of MVD in CAD (per 0.1; OR: 0.66, 95% CI: 0.60-0.73, p<0.001).

Conclusions:
Ln-RHI significantly correlated with the presence and severity of CAD in HT, and the combination with CRFs may be more powerful at predicting CAD. Identifying high-risk HT patients by RH-PAT might provide clinical benefits for risk stratification.
Abstract 10132: Outcomes of Peripheral Vascular Interventions for Lower Extremity Acute Limb Ischemia
Authors: Inagaki Elica , Farber Alik , Rybin Denis V , Doros Gheorghe , Kalish Jeffrey , Eslami Mohammad H , Hamburg Naomi M
Published: April 2024

Introduction:
Acute limb ischemia (ALI) is increasingly managed with peripheral vascular interventions (PVI).

Objective:
The objective of our study was to elucidate the clinical outcomes following PVI in patients with ALI.

Methods:
We identified 365 patients who underwent PVI for lower extremity ALI between 2010 and 2014 in the Vascular Study Group of New England registry. The control group included 1808 patients who underwent PVI for chronic critical limb ischemia (CLI) who were matched (5:1 to ALI) by arterial segment treated (aortoiliac, femoropopliteal, and infrapopliteal). Comparisons of in-hospital and two-year outcomes, including after adjustment for relevant clinical covariates, were made between the two groups.

Results:
Compared to CLI patients, ALI patients treated with PVI had lower prevalence of comorbidities but were more likely to have had prior ipsilateral revascularizations including PVI and/or leg bypass. ALI patients experienced lower technical success (89% vs 93%, p=0.04), higher rate of distal embolization (5% vs 2%, p=0.001), longer length of stay (6±8 days vs 4±6 days, p<0.001), and higher in-hospital mortality (4% vs 1%, p=0.001). No differences in two-year outcomes were found between the two groups with respect to rates of major amputation (6% vs 6%, p=0.9) and mortality (20% vs 21%, p=0.8). After adjustment for covariates and previous ipsilateral revascularizations, ALI continued to be associated with lower technical success (OR 0.6 [95% CI 0.4-0.8] p=0.008), higher rate of distal embolization (OR 2.7 [95% CI 1.5-4.9] p=0.001), longer length of stay (OR 1.6 [95% CI 1.4-1.8] p<0.001), and increased in-hospital mortality (OR 2.8 [95% CI 1.3-5.9] p=0.007). However, ALI was not associated with major amputation (HR 1.1 [95% CI 0.7-1.8] p=0.6) or mortality (HR 1.2 [95% CI 0.9-1.5] p=0.3) at two-year follow-up.

Conclusions:
In a large, observational cohort of patients undergoing PVI, those with ALI had more short-term adverse events compared to patients with CLI. However, two-year amputation rates and mortality were similar between ALI and CLI patients.
Abstract 10361: Prognostic Impact of Sequential Organ Failure Assessment Score in Cardiogenic Shock or Cardiac Arrest Patients With Percutaneous Veno-Arterial Extracorporeal Membrane Oxygenation
Authors: Kuroki Norihiro , Abe Daisuke , Iwama Tooru , Tateishi Kazuya , Kaneko Masakazu , Harunari Tomohiko , Yui Yoshiaki , Yuba Takao , Suzuki Kou , Sugiyama Kazuhiro , Akashi Akiko , Hamabe Yuichi , Sato Akira
Published: April 2024

Introduction:
Veno-Arterial Extracorporeal Membrane Oxygenation (VA-ECMO) has been reported to improve survival in patients with cardiogenic shock or cardiac arrest. However, the prognostic predictors were uncertain. We investigated the association between sequential organ failure assessment (SOFA) score just before implantation and clinical outcome in patients undergoing VA-ECMO due to cardiogenic shock and cardiac arrest.

Methods:
A cohort of 299 patients who underwent ECMO at our hospital was registered from January 2005 to April 2015. We excluded 72 patients caused by non-cardiogenic event. The remaining 227 patients (58±14 years old, male82%) were divided into 2 groups according to initial sequential organ failure assessment (SOFA) score . High SOFA Group: SOFA score ≥13 points (n=106); Low SOFA Group: SOFA score <13 (n=121). Clinical outcome was all -cause death at 30 days.

Results:
The 87% of patients received VA-ECMO due to cardiac arrest(81 out-of-hospital cardiac arrest, 116 in-hospital cardiac arrest). In baseline characteristics, Low SOFA group was significantly shorter time from collapse to ECMO (35.1 vs. 40.7 min), higher Hb (13.1 vs. 11.6 g/dl), and lower BUN (18.1 vs. 24.4 mEq/l, all p<0.05) than High SOFA group. Incidence of death at 30days was significantly lower in Low SOFA group than in High SOFA group (Low SOFA vs. High SOFA; 56.2% vs. 76.4%: p= 0.0014) . Kaplan-Meier curve showed Low SOFA group was better outcome compared with High group (p<0.001, log-rank test) (Figure). SOFA score was an independent predictor of mortality after adjustment of multiple cofounders (SOFA Score per increase, OR: 1.18, 95% confidence interval: 1.00-1.39, p=0.047). Positive independent predictors of mortality were age (per increase OR: 1.04, 95% CI: 1.01-1.07, p<0.01) and other factors.

Conclusions:
Initial high SOFA score just before implantation provides worse clinical outcome in patients with VA-ECMO due to cardiogenic shock and cardiac arrest.
Abstract 10369: Safety of Anatomic versus Functional Diagnostic Testing: Insights From the PROMISE Trial (PROspective Multicenter Imaging Study for Evaluation of Chest Pain)
Authors: Lu Michael T , Douglas Pamela S , Udelson James E , Adami Elizabeth C , Ghoshhajra Brian B , Picard Michael H , Roberts Rhonda , Lee Kerry L , Einstein Andrew J , Mark Daniel B , Velazquez Eric J , Carter William , Ridner Michael , Al-Khalidi Hussein R , Hoffmann Udo
Published: April 2024

Introduction:
Suspected coronary artery disease (CAD) is a common indication for diagnostic testing. However, a comprehensive, randomized comparison of test safety, including radiation dose, incidental findings, and test complications, of coronary computed tomography angiography (CTA) and functional tests has not been performed.

Methods:
All PROMISE patients completing a diagnostic test were analyzed as tested for differences between CTA vs functional tests in A) 90 day cumulative radiation dose in milliSieverts (mSv), B) index test and cumulative dose for those whose physicians intended referral for nuclear stress before randomization, C) incidental findings (all and prespecified as potentially clinically significant) and D) index test complications.

Results:
Of 9470 eligible patients (mean age 61, 53% women), 4633 had CTA and 4837 had functional testing (3263 nuclear stress, 1083 stress echo and 491 exercise ECG).

As a strategy comparison, CTA had lower median but higher mean cumulative radiation dose than functional testing (median: 10.3 vs 11.5 mSv, p<0.001, mean: 12.5 vs 10.6, p<0.001). In a test to test comparison in 6349 intended for nuclear stress before randomization, CTA had lower index test (mean: 10.5 vs 14.1, p<0.001) and cumulative (mean: 12.4 vs 15.2, p<0.001) dose than nuclear stress.

Incidental findings were more common on CTA than functional tests (43% vs 2%, p<0.001). CTA found more potentially clinically significant incidentals (19% vs 0.7%, p<0.001), including valvular disease (echo), breast uptake (nuclear), and lung nodules, pneumonia or pulmonary embolism (CT).

There were no major index test complications. Minor complications occurred in 0.8% of CTAs and 0.4% of functional tests (p<0.01). In those intended for nuclear stress, complications occurred in 0.8% of CTAs and 0.5% of nuclear stress tests (p=0.17), including hypotension (nuclear) and mild contrast reaction or extravasation (CT). No CTA and 5 functional test complications led to hospitalization.

Conclusions:
CTA had lower median but higher mean radiation dose compared to all functional testing, but lower dose than nuclear stress. CTA had more potentially clinically meaningful incidental findings, and despite very low overall rates, more minor complications.
Abstract 10420: Utilization of Cardiac Resynchronization Therapy in Patients Hospitalized With Heart Failure: Has it Changed and is it Associated With Patient Outcomes?
Authors: Randolph Tiffany C , Hellkamp Anne S , Zeitler Emily P , Shulte Phillip J , Fonarow Gregg C , Hernandez Adrian F , Yancy Clyde W , Peterson Eric J , Al-Khatib Sana M
Published: April 2024

Background:
Prior work has demonstrated that cardiac resynchronization therapy (CRT) reduces heart failure hospitalization (HFH) and mortality particularly in patients who are female, have non-ischemic disease, low ejection fraction and wide QRS. However, patterns of use in clinical practice remain largely unknown. We investigated temporal trends in the utilization of CRT among patients hospitalized for HF and assessed whether CRT use was associated with differences in all-cause mortality.

Methods:
We included 72,008 patients with EF ≤35% admitted for HFH at 388 sites in the Get With the Guidelines-Heart Failure (GWTG-HF) registry from 2005 - 2014. Using logistic regression we evaluated the association of race, gender, and time with CRT use. Among 15,619 patients linked to Medicare inpatient data 2005 - 2012, Cox proportional hazards models assessed association between CRT and mortality.

Results:
The majority of patients were men (60.0%), white (61.9%), and had ischemic heart disease (59.3%). CRT had already been in place, was implanted during admission, or prescribed at discharge in 26.3% of patients. Women were less likely to have CRT than men over time, and black patients were consistently less likely than white patients to receive CRT. (Figure) CRT was associated with reduced mortality during the study period (hazard ratio [95% confidence interval]) (HR [CI]) (0.90 [0.84, 0.96]), p=0.002, and there was a trend towards increased benefit in more recent years (p-interaction=0.06, (2011-2012) (HR [CI]) (0.82 [0.73 - 0.92]).

Conclusions:
CRT use has increased, but it continues to be underutilized in many HF patients. A new gender disparity has developed despite evidence that women are more likely than men to benefit from CRT. There is an association between CRT and reduced mortality that has strengthened over time. Future initiatives should address the disparity in CRT utilization among women and black patients to help them derive mortality benefit from this therapy.
Abstract 10460: Completeness of Revascularization and its Impact on the Outcomes of a Staged Approach of Percutaneous Coronary Intervention Followed by Minimally Invasive Valve Surgery for Patients With Concomitant Coronary Artery and Valvular Heart Disease
Authors: Pineda Andres M , Chandra Ramesh , Gowani Saqib A , Mihos Christos G , Santana Orlando , Kirtana Ajay J , Stone Gregg W , Kurlansky Paul , Smith Craig R , Beohar Nirat
Published: April 2024

Introduction:
A staged approach of percutaneous coronary intervention (PCI) followed by minimally invasive valve surgery (MIVS) is an alternative to the conventional combined coronary artery bypass and valve surgery for patients with concomitant coronary artery and valve disease.

Hypothesis:
Incomplete revascularization may negatively affect clinical outcomes amongst patients with severe coronary artery and valve disease undergoing a staged approach of PCI followed by MIVS.

Methods:
A total of 138 patients, who underwent a staged approach between January 2009 and June 2013, were retrospectively evaluated. Coronary angiograms were reviewed by 2 cardiologists blinded to outcomes and were then categorized into 2 groups: complete or incomplete revascularization, which was defined as ≥1 major epicardial coronary arteries of at least 2.0 mm diameter with ≥70% untreated obstruction after the index percutaneous coronary intervention and before minimally invasive valve surgery.

Results:
Complete and incomplete revascularization was achieved in 105 (76%) and 33 (24%) patients, respectively (Table). The patients with incomplete revascularization had a lower ejection fraction, a higher STS score, and more prior myocardial infarctions and multi-vessel coronary artery disease. There were no differences in the post-operative complications, 30-day mortality, or 3-year survival (84 vs. 83%, p=0.68). After a median follow up of 29 months, incompletely revascularized patients had a higher incidence of acute coronary syndrome (2.9 vs. 12.9%, p=0.05).

Conclusions:
In patients undergoing a staged approach of percutaneous coronary intervention followed by minimally invasive valve surgery, incomplete revascularization did not significantly impact the short or mid-term survival, but was associated with an increased incidence of acute coronary syndrome at follow up.
Abstract 10467: Inflammation may be Involved in Ischemic Preconditioning in Rat Model of CPR
Authors: Zhao Shen , Wang Jiangang , Yin Lu , Tang Ziren , Sun Peng , Kline Jena , Wu Xiaobo , Tang Wanchun
Published: April 2024

Background:
Ischemia preconditioning (IPC) is a potent strategy that minimizes post-resuscitation cardiac and neurological dysfunction via a K
ATP
channel-dependent mechanism. Inhibition of inflammation is also related to ischemic tolerance. In this study, we investigate the relation between the two intrinsic mechanisms in a rat model of cardiac arrest and CPR.

Hypothesis:
Activation of K
ATP
channels and anti-inflammatory response are two independent mechanisms of IPC to improve post-CPR myocardial and cerebral function.

Methods:
A total of 24 Sprague-Dawley rats (450-550g) were randomized into three groups (n=8 for each group): 1) control, 8 minutes of untreated ventricular fibrillation (VF) followed by 8 minutes of cardiopulmonary resuscitation and defibrillation; 2) IPC, remote IPC initiated 55 minutes before the induction of VF; 3) IPC+GLIB, glibenclamide (0.3 mg/kg, i.v.) was administered 45 minutes before remote IPC, and rest of protocol was the same as the IPC group. Doppler echocardiography, neurologic deficit score (NDS) scale, and the duration of survival were monitored in all animals. The level of NF-κB, IL-1β, IL-10 were evaluated using the enzyme-linked immunosorbent assay (ELISA).

Results:
Compared with the control groups, significantly greater CO and EF, lower MPI, improved NDS, and increased duration of survival were observed in both the IPC and IPC+GLIB group during post-resuscitation (
p
< 0.05 or 0.01 versus control group). Glibenclamide partly reversed the improvement induced by ischemic preconditioning (
p
< 0.05 or 0.01 versus IPC group) (Fig. 1). However, there were no significant differences in biomarkers between the IPC and IPC+GLIB group (Fig. 2).

Conclusions:
In a rat cardiac arrest model, anti-inflammatory response attenuated the myocardial and neurological dysfunction during the post-resuscitation via a non-K
ATP
channel-dependent mechanism.
Abstract 10763: Electrocardiographic Markers of Myocardial Infarction Size
Authors: Lee Daniel C , Albert Christine M , Narula Dhiraj , Kadish Alan H , Wu Edwin , Panicker Gopi , Goldberger Jeffrey J
Published: April 2024

Background:
Myocardial infarction
(MI)
size is an important determinant of mortality in post-MI patients, but the current gold standard test, cardiovascular magnetic resonance imaging
(CMR)
, is expensive and not widely available. We sought to determine whether information from a readily available standard 12-lead electrocardiogram
(ECG)
could be utilized to estimate infarct size on CMR.

Methods:
Patients with a clinical history of MI enrolled in the DETERMINE Trial and Registry who had CMR and ECG performed were included. Patients with left bundle branch block were excluded. Candidate ECGs markers, which may signify the presence of MI [Q waves
(Qw),
fragmented QRS
(fQRS),
and T wave inversion
(TWI)
] were examined for correlations with MI as a percent of LV
(MI%)
quantified by late gadolinium enhanced CMR. Contiguous Qw
(cQw MI)
and TWI
(cTWI)
in a coronary distribution and Qw and TWI in individual leads were examined separately in linear regression models.

Results:
Of the 540 patients (mean age 62±11 years, 78% men, and mean LVEF=40±11%) included in the analysis, 334 had cQw MI, 225 had fQRS, 235 had cTWI, and 92 had none of these ECG markers. Patients without any of these ECG markers had an infarct size of 9.2±6.5% as compared to 14.6±7.6%, 18.6±9.1%, and 20.3±9.5% for those with one (n=175), two (n= 200), or all three (n= 73) ECG markers (P<0.001). By multivariate linear regression, the presence of cQwMI, fQRS, and cTWI were independently associated with an increase in MI% by 6.7%, 3.4%, and 4.9%, respectively. On per lead analysis, multivariate linear regression demonstrated a significant continuous relationship between MI% and the number of leads affected by Qw, fQRS, and TWI. MI% was 8.8% when all leads were free of candidate ECG markers and increased by 1.6%, 0.6%, and 0.6% for each lead affected by Qw, fQRS, and TWI, respectively (see table).

Conclusion:
In patients with prior MI, Qw, fQRS, and TWI on ECG are independently associated with an increase in MI% measured by CMR.
Abstract 10765: Dilated and Tilted Mitral Annulus by Left Atrial Dilation May Cause Mitral Regurgitation in Nonvalvular Atrial Fibrillation
Authors: Kono Tatsuji , Otsuka Kaoru , Soyama Akiko , Matsuoka Tomohiro , Murakami Shogo , Tsuda Eimei
Published: April 2024

Background:
Although mitral annular dilation has been considered to be the primary mechanism of mitral regurgitation (MR) in patients with nonvalvular atrial fibrillation (AF), whether a stretched mitral annulus is sufficient to cause significant MR remains controversial. The aim of this study was to clarify it.

Methods:
The presence of MR and left atrial dimension (LAD) were evaluated by echocardiography. Cardiac magnetic resonance imaging was performed in patients with AF and MR (AF-MR; n=23) or without MR (AF-noMR; n=56) and in controls with normal sinus rhythm (n=130). Using 4-chamber view, we quantified the end-systolic septolateral mitral annular diameter (MAD), angle (Angle) between the mitral annulus and the perpendicular line of the long axis of the left ventricle passing through the base of the anterior leaflet (Line), and the distance (Distance) between the mitral leaflets coaptation point and the Line (Figure).

Results:
LAD was significantly increased in AF-MR compared to AF-noMR and controls (50±9 mm, 41±7 mm, 36±5 mm, respectively, AF-MR vs. AF-noMR, P<0.001, AF-MR vs. controls, P<0.001). MAD, Angle and Distance were significantly increased in AF-MR compared to AF-noMR and controls (Figure). CONCLUSIONS: In concert with mitral annular dilation, tilted mitral annulus by left atrial dilatation may cause incomplete coaptation of the mitral leaflets resulting in the development of MR in nonvalvular AF.
Abstract 10766: What is an Optimal Setting of Continuous-flow Left Ventricular Assist Device for Severe Mitral Regurgitation?
Authors: Naito Noritsugu , Nishimura Takashi , Kishimoto Satoru , Takewa Yoshiaki , Ono Minoru , Tatsumi Eisuke
Published: April 2024

Introduction:
Excessive volume unloading of the left ventricle (LV) affects the right ventricular (RV) function by causing shift of the ventricular septum during left ventricular assist device (LVAD) support in patients with mitral regurgitation (MR). Optimal settings of LVAD that control MR without RV dysfunction are required. We developed a novel cardiac-cycle synchronized rotational speed (RS) modulation system for a continuous-flow LVAD and assessed the system in a goat model of MR.

Methods:
We implanted EVAHEART (Sun Medical Technology Research Corp.) through left thoracotomy in six adult goats weighing 66.4 ± 10.7 kg. After implantation of the device, severe MR was induced with inflation of a temporary inferior vena cava filter that was placed in the mitral valve. The severity of MR was defined by left ventriculography and echocardiography. We evaluated total flow (TF: the sum of aortic flow and pump flow), RV fractional area change (RVFAC) calculated by echocardiography, left atrial pressure (LAP), LV end-diastolic pressure (LVEDP), LV end-diastolic volume (LVEDV), and LV stroke work (LVSW) with a bypass rate (pump flow divided by TF) of 100% under four conditions: circuit-clamp, continuous mode, co-pulse mode (increase RS in systole) and counter-pulse mode (increase RS in diastole).

Results:
TF tended to be higher in counter-pulse mode (3.27 ± 1.09, 3.51 ± 2.14, 3.45 ± 2.58, and 3.75 ± 2.39 L/min, in circuit-clamp, continuous mode, co-pulse mode, and counter-pulse mode, respectively; p > 0.05). RVFAC was significantly higher in counter-pulse mode than in co-pulse mode (0.68 ± 0.05 vs 0.51 ± 0.08 , p < 0.05). LAP was significantly lower in all the driving modes than in circuit-clamp. LVEDP, LVEDV and LVSW, shown as percentages of those in circuit-clamp (= 100%), were significantly lower in counter-pulse mode than in circuit-clamp (54.43 ± 32.05, 89.6 0 ± 4.23, and 60.30 ± 28.41 %, respectively; p < 0.05).

Conclusions:
Good control of MR in counter-pulse mode could be achieved with enough LV volume unloading during diastole not to leave blood that regurgitates during systole. Given higher TF and RVFAC in counter-pulse mode, the mode has less adverse effects on the RV function. In conclusion, the mode may offer a favorable control of MR with minimizing RV dysfunction.
Abstract 10818: Lomitapide Observational Worldwide Evaluation Registry (LOWER): One-Year Data
Authors: Blom Dirk , Kastelein John J , Larrey Dominique , Makris Lukas , Schwamlein Charles , Phillips Helen , Bloedon LeAnne , Underberg James
Published: April 2024

Introduction:
Lomitapide is a microsomal triglyceride transfer protein inhibitor indicated as an adjunctive therapy for adults with homozygous familial hypercholesterolemia (HoFH). LOWER is a global, long-term, prospective, observational registry of the long-term safety and effectiveness of lomitapide in clinical practice. At least 300 adult HoFH patients will be followed for a minimum of 10 years. Enrollment opened in March 2014 for adult HoFH patients with less than 15 months of lomitapide exposure. We present data from the first year of the registry.

Results:
As of March 1, 2015, 84 patients with mean age 55.4 (SD 11.5) years, were enrolled in LOWER; 6 (7%) have since discontinued. Exposure duration was up to 26 months, with 60% of patients receiving the drug for ≥12 months. Lomitapide dose ranged from 5 to 40 mg; dose increased over time to a median of 13.0 mg (mean 14.4 mg) after 2 years’ exposure. Mean LDL-C at baseline was 216.3 (SD 76.9) mg/dL which decreased by 42% at Month 4 and was maintained throughout the reporting period. Fifty-one (61%) and 30 (36%) respectively achieved an LDL-C value <100 mg/dL or <70 mg/dL, at least once while receiving lomitapide. Events of special interest (ESI) include: 1 major adverse cardiovascular event (MACE) resulting in death; 11 hepatic events; and 6 gastrointestinal events. No tumors, pregnancies, or coagulopathy events were reported. Elevated aminotransferase levels ≥3x upper limit of normal (ULN) were observed in 16 patients (20%); 4 of these patients experienced elevations of ≥5x - <10x ULN. No cases of Hy’s Law were recorded. Diarrhea was the most common adverse event (AE), experienced by 24% of patients, and the only AE reported by >10% of patients. Serious AEs occurred in 6 (7%) patients. Eight (10%) patients discontinued lomitapide because of an AE.

Conclusions:
Data from the first year of the LOWER registry demonstrate both safety and efficacy that are consistent with the product labeling. There were no new safety signals. Discontinuations because of aminotransferase or gastrointestinal ESIs were low. Future data from LOWER will provide further information about the real-world, long-term safety and effectiveness of lomitapide in HoFH.
Abstract 10829: Biological and Pharmacological Properties of the Protease Proprotein Convertase Subtilisin-Like Kexin Type 9 Antagonists
(Best of Basic Science Abstract)
Authors: Elshourbagy Nabil A , Meyers Harold V , Mousa Shaker A , Abdel-Meguid Sherin S
Published: April 2024

Protease proprotein convertase subtilisin-like kexin type 9 (PCSK9) is a new important target for the treatment of hypercholesterolemia. Currently, several pharmaceutical companies are racing to develop new drugs against PCSK9, which could be the newest weapon against heart disease since the introduction of statins in the 80’s. However, those companies have focused primarily on the development of mAbs, not small molecules, as drugs. PCSK9 is a serine protease that is synthesized as a zymogen that undergoes autocatalytic processing and secretion. Secreted PCSK9 binds to the LDL-receptor (LDLR) and chaperones it to the degradation pathway. This study focused on the identification of antagonists of the PCSK9/LDLR interaction and explored their mechanism of action using a range of functional assays, as well as determined pharmacokinetic (PK) and pharmacodynamic (PD) properties of the lead compounds. Potential inhibitors of the PCSK9/LDLR interaction were identified through a virtual screen at the PCSK9 surface where the LDLR-EGF-A binds. The top hits exhibited inhibition of PCSK9/LDLR binding in the low micromolar (μM) range, a 5-fold upregulation of the LDLR at an inhibitor concentration of 1.6 μM in recombinant cell-based assays, and an increase in the fluorescently labeled DiI-LDL uptake in the nanomolar (nM) range
in situ
. Pharmacological studies revealed that subcutaneous injection of 4 mg/kg of one of these compounds resulted in a 32% reduction of the total cholesterol and 20% reduction in LDL-C levels in mice fed a high fat/high cholesterol diet. Moreover, administration of 40mg/kg of atorvastatin resulted in a 27% total cholesterol reduction and 20% reduction in LDL-C level. Additional studies were performed to evaluate the effect of the combination of our PCSK9 inhibitor with atorvastatin. Administration of the PCSK9 inhibitor (4 mg/ kg) in combination with atorvastatin (40 mg/kg) resulted in more than a 40% reduction in LDL-C in mice fed a high fat/high cholesterol diet.
In vivo
PK and PD evaluation of our lead PCSK9 inhibitor demonstrated that it was efficacious and exhibited 13% oral bioavailability. To our knowledge, no small molecule orally bioavailable antagonist against PCSK9 has been reported, only mAbs.
Abstract 10859: Preventive Effects of Neopterin on Atherosclerosis
Authors: Shirai Remina , Sato Kengo , Watanabe Kaho , Watanabe Rena , Matsuyama Taka-aki , Koba Shinji , Hirano Tsutomu , Watanabe Takuya
Published: April 2024

Introduction:
Neopterin, a GTP metabolite produced by activated macrophages after stimulation by interferon-γ released by T cells, is expressed at high levels in the carotid atherosclerotic lesions in patients with angina pectoris. However, the modulatory effect of neopterin on atherogenesis has not yet been reported.

Objective and Methods:
We aimed to clarify the effects of neopterin on atherogenesis. We investigated the atheroprotective effects of neopterin on human umbilical vein endothelial cells (HUVECs), human monocyte-derived macrophages, human aortic smooth muscle cells (HASMCs)
in vitro
, and aortic lesions in ApoE
-/-
mice
in vivo
. Plasma neopterin levels were compared between 25 patients with acute coronary syndrome (ACS) and 15 healthy volunteers.

Results:
Neopterin attenuated TNF-α-mediated monocyte adhesion to HUVECs. Neopterin suppressed TNF-α-induced upregulation of MCP-1, ICAM-1, and VCAM-1 in HUVECs. Neopterin shifted the phenotype overwhelmingly to anti-inflammatory M2 rather than inflammatory M1
via
NF-κB downregulation during differentiation of human monocytes into macrophages. Neoptein significantly suppressed oxidized LDL-induced foam cell formation associated with reduced CD36 expression and increased both expressions and activities of ABCA1 and ABCG1 in human monocyte-derived macrophages. Neopterin significantly suppressed angiotensin II-induced migration of HASMCs, but increased fibronectin and MMP2 expressions accompanied with enhanced MMP2 activity in HASMCs. Four-week-infusion of neopterin into ApoE
-/-
mice significantly retarded the development of aortic atherosclerotic lesions with reduced monocyte/macrophage infiltration and lowered plasma levels of total cholesterol. In addition, plasma neopterin levels were markedly increased in ACS patients than healthy volunteers, suggesting that neopterin increased to counteract the formation of atherothrombosis.

Conclusions:
Our results indicate that neopterin prevents atherogenesis by suppressing monocyte adhesion to endothelial cells, macrophage foam cell formation, and VSMC migration. Thus, neopterin could serve as a novel therapeutic target and potential biomarker for atherosclerotic cardiovascular diseases.
Abstract 10860: Association Between Fractional Flow Reserve and Coronary Plaque Characteristics Assessed by Optical Coherence Tomography
Authors: Lee Seung-Yul , Hong Myeong-Ki
Published: April 2024

Introduction:
The assessment of fractional flow reserve (FFR) in coronary lesions determines the strategy of percutaneous coronary intervention. However, the association between FFR and characteristics of underlying coronary plaque has not been sufficiently investigated.

Methods:
A total of 110 coronary lesions in 106 patients were evaluated using both FFR and optical coherence tomography (OCT). Coronary plaque was classified into fibrous, fibrocalcific, or fibroatheroma according to OCT evaluation at the site of minimal lumen area. Plaque microstructures such as cap thickness, macrophage accumulation, intimal vasculature, or cholesterol crystal were also evaluated.

Results:
Compared to lesions with FFR >0.8, those with FFR ≤0.8 showed a higher frequency of fibroatheroma, macrophage accumulation, and cholesterol crystal. However, multiple linear regression analysis revealed that any morphological characteristics of plaques assessed by OCT were not independently associated with FFR. Minimal lumen area (coefficient, 0.036; 95% confidence interval [CI], 0.022-0.049; p<0.001) and area stenosis (coefficient, - 0.003; 95% CI, -0.005--0.001; p<0.001) assessed by OCT significantly correlated with FFR. Thin-cap fibroatheroma was identified in 12 (10.9%) of all 110 lesions. There were no significant differences of minimal lumen area, area stenosis, or FFR between lesions with and without thin-cap fibroatheroma.

Conclusions:
Morphological characteristics of coronary plaque are not directly related to FFR. Conversely, the extent of functional or anatomical stenosis cannot identify the lesion with thin-cap fibroatheroma.
Abstract 10871: Changes in Lipid Profile of Obese Patients Following Contemporary Bariatric Surgery: A Meta-Analysis
Authors: Heffron Sean P , Parikh Amar , Volodarskiy Alexandar , Ren-Fielding Christine , Schwartzbard Arthur , Nicholson Joseph , Bangalore Sripal
Published: April 2024

Background:
Dyslipidemia drives the development of atherosclerosis and obese individuals frequently manifest dyslipidemia. Although metabolic surgery was originally performed to treat hypercholesterolemia, the effect of contemporary bariatric surgery on serum lipids has not been systematically characterized.

Methods:
We queried MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials from inception through the second week of May, 2015 for studies with at least 20 obese adults who underwent Roux-en-Y Gastric Bypass (RYGBP), Adjustable Gastric Banding, Bilio-Pancreatic Diversion (BPD), or Sleeve Gastrectomy reporting lipid data at baseline and at least one year following surgery. Primary outcome measures were change in total cholesterol (TC), LDL-cholesterol (LDL-C), HDL-cholesterol (HDL-C), and triglyceride values from baseline to 1-year follow-up after bariatric surgery.

Results:
There were 180 articles eligible for inclusion with 25,189 obese subjects (mean body mass index 45.1±4.8 kg/m2) and over 47,800 patient-years follow-up. In patients who underwent surgery, compared to baseline, there were significant reductions in TC, LDL-C, triglycerides and a significant increase in HDL-C (P<0.00001 for all), although the magnitude of change varied with surgical type (Pinteraction <0.05; Figure). The magnitude of the change in lipid parameters with surgery (overall) was significantly greater than the change in lipid parameters among patients who did not undergo surgery (Figure). Results were similar beyond one year.

Conclusions:
Contemporary bariatric surgical techniques produce significant improvements in lipid parameters at one year following surgery, which are greater in magnitude than those in patients not undergoing surgery. However, the magnitude of change in lipid parameters varies widely with surgical type, indicating that these differences may be relevant in deciding the most appropriate technique for a given patient.
Abstract 10874: O-Linked β-N-acetylglucosamine Modification is Increased in Freshly Isolated Human Endothelial Cells in Type 2 Diabetes
Authors: Masaki Nobuyuki , Bihua Feng , Breton-Romero Rosa , Fetterman Jessica L , Inagaki Elica , Berk Brittany D , Linder Erika A , Weisbrod Robert M , Holbrook Monika , Hamburg Naomi M
Published: April 2024

Background:
Diabetes mellitus (DM) is characterized by hyperglycemia that may contribute to abnormal vascular function. High glucose levels upregulate the hexosamine biosynthesis pathway leading to protein glycosylation with O-linked N-acetylglucosamine (O-GlcNAc). We sought to investigate the functional relevance of O-GlcNAc modification to endothelial dysfunction in DM.

Method and Results:
Freshly isolated endothelial cells obtained by J-wire biopsy from patients with DM had impaired insulin-mediated eNOS phosphorylation at Ser1177 compared to controls. Incubation in normal glucose conditions (5mM, 24hours) restored insulin-mediated eNOS phosphorylation in endothelial cells from patients with DM whereas insulin resistance persisted in high glucose conditions (30mM), suggesting a link between glucose levels and endothelial insulin resistance. Endothelial O-GlcNAc level was higher in diabetes patients compared to healthy controls (22±8 vs 12±5%, N=18/10, P=0.003, Figure A). Higher endothelial O-GlcNAc levels correlated with higher body mass index (P= 0.03), fasting blood glucose (P=0.01), HbA1C (P=0.02), and triglycerides (P=0.01). Normal glucose conditions lowered O-GlcNAc levels in endothelial cells isolated from patients with DM (P=0.028, Figure B). Ongoing studies are evaluating the effect of agents that reducing O-GlcNAc on insulin-mediated eNOS phosphorylation.

Conclusion:
Our results provide evidence that O-GlcNAc is more abundant in the endothelium of diabetic patients and glucose normalization reduces O-GlcNAc and improves reaction to insulin. Further work is needed to determine the contribution of O-GlcNAc modification to vascular disease in diabetes.