bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 18112: Low-Energy Shock Wave Treatment Induces Angiogenesis in Ischemic Muscle by Stimulation of Toll-Like Receptor 3 Signaling
Authors: Holfeld Johannes , Tepeköylü Can , Kozaryn Radoslaw , Albrecht-Schgoer Karin , Krapf Christoph , Kirchmair Rudolf , Bernhard David , Zacharowski Kai , Urbschat Anja , Grimm Michael , Paulus Patrick
Published: April 2024

Introduction:
Low energy shock waves (SW) have been shown to induce angiogenesis in ischemic myocardium. The mechanism translating the physical stimulus to a biological signal is unknown. Toll-like receptor (TLR)-3 is activated by RNA binding. It plays a key role in inflammation and angiogenesis.

Hypothesis:
SW cause cellular cavitation, thus liberating cytoplasmic mRNA that activates TLR-3 as does the specific agonist Poly I:C. Effects are suppressed in TLR-3 silenced cells and in TLR-3 knock out mice.

Methods:
The effect of SW was tested in human umbilical vein endothelial cells (HUVECs): untreated (control) vs. SW treated (SW group) vs. treated with 200 μg/ml Poly I:C (agonist). TLR-3 gene silencing was done with siRNA. Hind limb ischemia was performed in wild type and TLR-3 kock-out mice. Expression of mRNA and proteins of the TLR-3 signaling pathway as well as typical angiogenic genes and proteins were measured. Laser doppler perfusion imaging and necrosis score were assessed for clinical outcome evaluation (n=6).

Results:
Shock wave treatment of HUVECs shows increase of mRNA expression (% of control) as does Poly I:C after 2 hours: TLR-3 (SW group 123.8 ± 8.0 and agonist group 237.7 ± 14.1, p<0.0001), Tie-2 (SW group 154.3 ± 20.0 and agonist 125.7 ± 12.3, p<0.008).

TLR-3 gene silencing in SW treated HUVECs causes loss of response for TLR-3 mRNA (107.0 ± 13.3) as compared to SW group (378.3 ± 14.2) or agonist (1261 ± 72.1), both p<0.0001.

SW treated TLR-3 knock-out mice showed no improvement of perfusion ratio 4 weeks after hind limb ischemia (0.52 ± 0.07 vs. 0.53 ± 0.02 controls, p>0.05), whereas SW treated wild type animals improved significantly (0.78 ± 0.03 vs. 0.48 ± 0.08 controls, p=0.015). Pro-angiogenic genes and proteins were up-regulated significantly. All known TLR-3 signaling pathways were involved as shown by significant increase of key proteins Trif, TRAF6 and IRF3.

Conclusion:
Low energy shock waves induce angiogenesis in ischemic muscle by stimulation of Toll-like receptor 3 signaling in endothelial cells. Effects are suppressed in TLR-3 silenced cells and in TLR-3 knock-out mice.
Abstract 18259: A Novel Approach to Address Door-to-ECG Time for Walk-In Patients by Training Non-Medical Staff to Recognize Symptoms of Possible Acute Coronary Syndrome
Authors: Stanton Joshua A , Spitzer John A , Becker Lea A , Craighead Barbara , Burt David , Johnson Tyler
Published: April 2024

Problem:
The ACTION Registry®--GWTG™ Dashboard revealed in previous studies that triage personnel are having difficulty identifying when to perform an appropriate ECG in the recommended 10 minute time frame. Those studies showed that 80% of the missed ECG’s were walk-in patients whose first point-of-contact was registration or security. We have since used this information to implement a novel approach to decrease the time between presentation and 1
st
ECG completion for patients with ACS symptoms.

Methods:
A pilot training program was developed and aimed at registration and security staff. Six, 1 hour classes trained all 84 Emergency Department (ED) auxiliary staff to focus on risk factors and clinical symptoms of ACS using specific case studies. A five question post-test was given to gauge understanding and retention. Class participants also completed a survey highlighting what they learned, enjoyed, and how to improve the course.

Results:
All of the participants passed the 5 question post-test focusing on ACS recognition and appropriate action. Eighty-five percent reported that they now feel comfortable in identifying MI symptoms. Fifteen percent of the course participants reported feeling gratification at being a member of the healthcare team with an increased sense of empowerment. All participants were offered an additional web-based training regarding STEMI’s and 10% have volunteered to observe a cardiac catheterization in their free time. The triage personnel course participants have overwhelmingly requested more sessions or yearly classes as the course’s only improvement.

Conclusions:
This program demonstrates that non-medical staff can be trained to quickly recognize symptoms concerning for ACS which can expedite evaluation and treatment. This program has the potential to improve door-to-ECG times and in addition increases morale. Anecdotally, a registration staff member has already identified a patient and facilitated an ECG within 7 minutes who was quickly identified to be having a STEMI. This program could be a model for other departments across the country to successfully improve patient care with the additional benefit of increasing departmental morale.
Abstract 18293: Predicting In-Hospital Mortality in Acute Type B Aortic Dissection: Evidences From IRAD
Authors: Tolenaar Jip L , Froehlich William , Jonker Frederik H , Upchurch Gilbert R , Rampoldi Vincenzo , Tsai Thomas T , Bossone Eduaro , Evangelista Arturo , O’Gara Patrick , Pape Linda , Montgomery Daniel G , Isselbacher Eric M , Nienaber Christoph A , Eagle Kim A , Trimarchi Santi
Published: April 2024

Introduction:
The outcome of acute type B aortic dissection (ABAD) patients is strongly related to the clinical presentation. The purpose of this study was to investigate predictors for mortality among patients presenting ABAD and to create a predictive model to estimate individual risk of in-hospital mortality using the International Registry of Acute Aortic dissection (IRAD).

Methods:
All ABAD patients enrolled in IRAD between 1996 and 2013 were included for analysis. Multivariate logistic regression analysis was used to investigate predictors of in-hospital mortality. Significant risk factors for in-hospital death were used to develop a prediction model.

Results:
A total of 1034 ABAD patients were included for analysis (673 male; mean age 63.5 ± 14.0), with an overall in-hospital mortality of 10.4%. In multivariate analysis, the following variables at admission were independently associated with increased in-hospital mortality: increasing age (OR 1.03, 95%CI 1.00-1.06, p=.044), hypotension/shock (OR 6.43, 95%CI 2.88-18.98), periaortic hematoma (OR 3.06, 95%CI 1.38-6.78, p=.006), descending diameter >5.5cm, (OR 6.04, 95%CI 2.87-12.73, p<.001), mesenteric ischemia (OR 9.03, 95%CI 3.49-23.38, p<.001), acute renal failure (OR 3.61, 95%CI 1.68-7.75) and limb ischemia (OR 3.02, 95%CI 1.05-8.68, p=.040). Based on these multivariate results, a reliable and simple bedside risk prediction tool was developed.

Conclusion:
The clinical presentation of ABAD is heterogeneous and strongly predicts in-hospital outcome. We present a simple prediction model using variables that are independently associated with in-hospital mortality in ABAD patients. This model could be used to assist physicians in their choice of management and for informing patients and their families.
Abstract 18342: Post Discharge and Early Clinical Benefits of Eplerenone in Patients With Systolic Nyha Ii Heart Failure: Insight From Emphasis-hf
Authors: Zannad Faiez , Collier Timothy J , Girerd Nicolas , McMurray John J , Swedberg Karl , van Veldhuisen Dirk J , Krum Henry , Pocock Stuart J , Shi Harry , Vincent John , Pitt Bertram
Published: April 2024

Purpose:
Patients with heart failure (HF) have a high adverse event rate in the early post-discharge period after hospitalization for HF. No treatment initiated during this period is proven to improve outcome. In EMPHASIS-HF, which evaluated the impact of eplerenone (epl) in patients with HF with reduced ejection fraction (HFrEF) and mild symptoms, most participants were included within 180 days following a cardiovascular hospitalization (CVH). We examined the effect of eple on outcomes early after hospital discharge.

Methods:
In EMPHASIS-HF, eple was compared to placebo (pbo) in 2737 patients with NYHA class II HF and LVEF ≤35%. In a first
post-hoc
analysis in 2338 patients randomized within 180 days of a CVH, we assessed the interaction between the time from index CVH to randomization and the primary outcome of CV death or HF hospitalization (HHF) using multivariable Cox survival models. In a second analysis, the effect of epl on 30-day outcome was assessed in the complete cohort.

Results:
The most common reason for CVH within 180 days was HHF (N=1496, 64.0%). The median time from index CVH to randomization was 42 days. In the <42 days group, median time from the index CVH was 12 days (IQR 5-26 days). The relative risk reductions in CV death/HHF and HHF were similar (p for interaction=0.65 and 0.44) whether treatment was initiated <42 days or ≥42 days after the index CVH. Because event rates were higher in the <42 days group, this subgroup had higher absolute risk reductions (rate of CV death/HHF 11.4% in epl versus 17.0% in the pbo arm in the <42 days group, 10.0% versus 13.6% in the ≥42 days group). In the second analysis, patients randomized to epl had a lower risk for CV death/HHF at 30 days compared to patients receiving pbo (HR=0.51, CI=0.31-0.85, p<0.01). Similarly effects were observed for 30 day HHF (HR=0.44, CI=0.25-0.78, p<0.01).

Conclusion:
These analyses show that in patients with HFrEF and mild symptoms, epl 1) improves outcome when initiated shortly after a CVH, 2) leads to a significant decrease in CV death/HFH as early as 30 days. These data suggest that initiating eple in patients with HF and mild symptoms soon after hospitalization might reduce the high event rate observed.
Abstract 18346: Common Genetic Variants and Subclinical Atherosclerosis in the Multi-Ethnic Study of Atherosclerosis
Authors: Vargas Jose D , Manichaikul Ani , Rich Stephen S , Rotter Jerome I , Post Wendy S , Pollack Joseph F , Bluemke David A
Published: April 2024

Introduction:
Subclinical atherosclerosis (sCVD), measured by coronary artery calcium (CAC), carotid intima media thickness (CIMT) and carotid plaque (CP), has been associated with cardiovascular disease (CVD). Genome Wide Association Studies (GWAS) of CVD have focused on Caucasian populations.

Hypothesis:
This study tested the hypothesis that these associations would differ in populations from distinct genetic backgrounds.

Methods:
The associations between sCVD and 42 single nucleotide polymorphisms (SNPs) from published GWAS of sCVD and CVD were tested in 8224 Multi-Ethnic Study of Atherosclerosis (MESA) participants and MESA Family participants (2685 Caucasians (EUA), 777 Chinese (CHN), 2588 African Americans (AFA), and 2174 Hispanic (HIS)). An additive model was adjusted for SNPs, age, gender, site of ascertainment, principal components, and CVD risk factors, with SNP significance defined by a Bonferroni-corrected p<0.001. Relatedness was accounted for by a linear mixed-effects model for quantitative traits or generalized estimating equations for binary traits.

Results:
The 9p21 region (rs1333049 and rs4977574) was associated with CAC in EUA (p=5E-6 and 1E-5), and in HIS (p=2E-4 and 1E-4), same direction of association to EUA) but not in AFA or CHN. In CHN, rs1878406 (EDNRA) associated with CIMT (p=6E-4). In HIS,
rs964184
(APOA5) associated with CAC (p=2E-5). Meta-analysis across the four ethnic/racial groups confirmed the association between the 9p21 SNPs and CAC (p=2E-9 and 3E-11) (heterogeneity p-values of 0.09 and 0.4) and showed associations between
rs216172
(SMG6) and CIMT and rs1994016 (ADAMTS7) and CAC (p=1E-4 for both). Of the 42 SNPs tested, only rs1333049 and rs4977574 replicated in EUA. There were no significant associations in AFA. A smaller sample size limited power in CHN.

Conclusion:
In non-Caucasians in MESA, associations were found with SNPs previously identified in EUA GWAS for CVD and sCVD, but not in all loci, suggesting novel variants and/or pathways in risk of CVD in minority populations.
Abstract 18363: Activation of the Hippo Pathway, Associated With Suppression the Canonical Wnt Signaling, Contributes to the Pathogenesis of Arrhythmogenic Right Ventricular Cardiomyopathy
Authors: Chen Suet Nee , Gurha Priyatansh , Lombardi Raffaella , Ruggiero Alessandra , Willerson James , Marian Ali J
Published: April 2024

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an enigmatic disease characterized by excess fibro-adipocytes in the heart, cardiac arrhythmias and heart failure. Molecular genetic studies have identified mutations in several desmosome proteins as causes of ARVC. Our objective is to delineate the molecular links between the desmosomes and fibro-adiposis in ARVC.

Expression levels and localization of plakophilin 2 (PKP2), plakoglobin (JUP), desmocollin 2 (DSC2), desmosome proteins and connexin 43 (GJA1), a member of Gap junction, in the human hearts with ARVC, were reduced. To test whether molecular remodeling of the junctions affected signaling pathways, we analyzed the Hippo kinase pathway, which is regulated by cell-cell contact and known to suppress the canonical Wnt signaling, the latter implicated in the pathogenesis of ARVC. Accordingly, Merlin, an upstream regulator of the Hippo kinase cascade, was activated and YAP, the downstream effector was inactivated by phosphorylation. To gain mechanistic insights, expression of Pkp2, the most common causal gene for ARVC, was stably knocked down using shRNA in the HL-1 cells. Transcriptome analysis showed reduced mRNA levels of the canonical Wnt and Hippo targets including Ctgf, an inhibitor of adipogenesis. KD of PKP2 was associated with a dramatic reduction in pPKC-α level, in accord with the known function of PKP2 as a platform for phosphorylation of PKC-α. Reduced pPKCα, an inhibitor of Merlin through phosphorylation, was associated with activation of Merlin and cascade phosphorylation of MST1, LATS1/2 and YAP, constituents of the Hippo pathway. Consequently, signaling through TEAD, the transcription factor of the Hippo pathway, was reduced and sequestration of pβ-catenin in the cytoplasm was increased, leading to suppression of the canonical Wnt signaling and enhanced adipogenesis. KD of pLAT1/2 using shRNAs partially rescued the molecular phenotype.

Thus, human ARVC is characterized by molecular remodeling of the intercalated discs, which results in inactivation of PKCα, phosphorylation of the Hippo kinases, suppression of the canonical Wnt signaling and enhanced adipogenesis. The findings implicate the Hippo pathway in the pathogenesis of ARVC.
Abstract 18379: Echocardiography for Right Ventricular Failure Prediction After Implantation of Left Ventricular Assist Devices: Preliminary Results From a Prospective Cohort Study
Authors: Kalogeropoulos Andreas P , Georgiopoulou Vasiliki V , Siwamogsatham Sarawut , Sims Daniel , Kelkar Anita , Wittersheim Kris , Pekarek Ann , Pernetz Maria A , Nguyen Duc Q , Smith Andrew L , Vega J David , Butler Javed
Published: April 2024

Background:
Right ventricular failure (RVF) occurs in 20%-40% of left ventricular assist device (LVAD) recipients. Preoperative clinical scores inadequately predict RVF risk in these patients.

Methods:
Beginning 6/2012, all adults with INTERMACS ≥2 profile scheduled for LVAD implantation, without planned right ventricular (RV) support, were prospectively enrolled in an ongoing study evaluating standard and speckle-tracking echocardiographic parameters of RV function for RVF prediction. Preoperative echocardiograms were performed 5±5 days prior to LVAD implantation by study protocol. The primary endpoint was RVF, defined (by INTERMACS) as need for (1) inotropes or pulmonary vasodilators any time past 7 days post-LVAD implant with concomitant high central venous pressure and low cardiac index or (2) mechanical RV support. The secondary endpoint was RVF or death from any cause.

Results:
As of 5/2013, 26 patients have been enrolled. Table 1 summarizes the preoperative clinical and hemodynamic characteristics. At 30 days, 7 patients (26.9%) developed RVF and 3 (11.5%) died. Intensive care length of stay (LoS) was 8.0±3.6 days and total LoS was 16.3±9.5 days. Among echocardiographic parameters (Table 2), RV global longitudinal strain (GLS) was the strongest predictor of RVF with a C statistic of 0.86 (95% CI, 0.60-0.99). At a cut-off -6.0%, sensitivity and specificity were 86% and 79%, respectively. Similarly, RV GLS was the strongest predictor of death or RVF combined. Standard RV function parameters were weak outcome predictors.

Conclusion:
Among preoperative echocardiographic parameters, RV GLS by speckle tracking appears to be the strongest predictor of post-LVAD RVF.
Abstract 18397: Left Ventricular End Diastolic Pressure as a Tool to Detect Intracoronary Ergonovine-Induced Myocardial Ischemia During Provocation Test
Authors: Jang Ho-Jun , Shim Won-Heum
Published: April 2024

A drug-induced coronary spasm provocation test is regarded as the gold standard for detection of variant angina. However, a suitable method to detect myocardial ischemia during provocation test is still lacking. We evaluated the feasibility of left ventricular end diastolic pressure (LVEDP) as a tool to detect myocardial ischemia caused by intracoronary (IC) bolus injection of ergonovine. Twenty-nine patients having chest pain without any significant (> 80%) coronary stenosis underwent IC ergonovine provocation test. Epicardial artery spasm of more than 90% was considered as positive. LVEDP was monitored during the entire procedure using a pig-tail catheter. Of the overall 29 patients, ischemic symptom occurred in 16 (55%) and provocation positive was confirmed in 6 (21%). The amount of LVEDP change (ΔLVEDP) was significantly larger in symptomatic group (5.6±4.2 vs. 1.2±2.0 mmHg, p=0.002). The optimal cut-off value of ΔLVEDP for symptom was 4.4 (area under the curve 0.803, sensitivity 69%, specificity 92%) (Figure 1). Of the 6 patients of positive test, five occurred in RCA, one in LAD. Two patients with big patent LCX were not associated with LVEDP elevation more than 4.4 despite significant RCA spasm (Figure 2). Except for the 2, LVEDP elevated significantly in positive test group (7.9±2.9 mmHg, p <0.001, n=4). Elevation of blood pressure and heart rate by IC ergonovine did not correlate with ΔLVEDP (p=0.142 and 0.154, respectively). In conclusion, ΔLVEDP is a specific marker for myocardial ischemia independent of hemodynamic parameters. LVEDP may aid detection of myocardial ischemia which is not associated with significant epicardial spasm during provocation test.
Abstract 18565: Trends and Outcomes in the Use of Extracorporeal Membrane Oxygenation for Adults in the United States: A 10 year survey
Authors: Yarmohammadi Hirad , Duval Sue , Jain Renuka
Published: April 2024

Introduction:
Extracorporeal membrane oxygenation (ECMO) has been used in hospitalized patients with severe cardiac and respiratory failure. However, little is known about trends in ECMO utilization and survival, particularly in adults.

Methods:
We evaluated the use of ECMO in the United States between 2001 to 2009 using the Nationwide Inpatient Sample (NIS) database. National estimates were measured using sampling weights of NIS. We excluded children and those patients who underwent ECMO during open-heart surgery.

Results:
National estimates of ECMO use in the United States increased from 165 patients in 2000 to 1450 patients in 2009. The incidence rate was significantly increased from 5.4 patients per million to 44.3 per million (p <0.0001). Despite 9-fold increase in use of ECMO in ten years, the mortality rate remained high and did not significantly change (p=0.5) (Figure). ECMO use in the elderly (>65) accounted for one quarter of hospitalizations, and did not change in frequency over last 10 years (p<0.15).

Conclusions:
This is the largest study of ECMO utilization in adults. Over ten years, despite widespread increase in use of this technology, there was no significant change in mortality rate and mortality remains high. Further studies will need to identify those patients most likely to benefit from ECMO
Abstract 18566: V1A Receptor Overexpression in the Murine Heart Depresses the Inotropic Response to Catecholamines
Authors: Barr Larry A , Zhu Weizhong , Myers Valerie D , Tilley Douglas G , Feldman Arthur M , Houser Steven R
Published: April 2024

Background:
—
Circulating levels of arginine vasopressin (AVP), a vasoconstrictor, are elevated in patients with heart failure. In the heart, AVP induces effects through the V1A receptor. The goal of this study was to better define the role of AVP in cardiac contractile dysfunction in the diseased heart. We utilized an inducible, cardiac-specific V1A receptor overexpression (V1A-OE) mouse model to explore the effects of AVP signaling in cardiac myocytes.

Methods and Results:
—
Isolated WT and V1A-OE hearts were studied using a Langendorff apparatus. A fluid-filled balloon was inserted into the LV to record isovolumic ventricular pressure. Each heart underwent a 20min equilibration period, followed by administration of ISO or IBMX for 3min each. ISO [10
-5
] had significantly smaller inotropic effects in V1A-OE (n=8) compared to WT hearts (n=5) (LVDP% V1A-TG: 129±14.04% increase vs. WT: 191.5±20.80%). WT hearts (n=4) pretreated with exogenous AVP [10
-9
] also had significantly smaller inotropic responses to ISO [10
-5
] (LVDP% WT+AVP: 118.8±12.30). The phosphodiesterase inhibitor IBMX [10
-5
] had enhanced contractility in WT (n=5) significantly more than in V1A-OE (n=5) (LVDP% V1A-OE: 99.40±6.61 vs. WT 149.4±8.135). Western blot analysis showed reduced levels of phospholamban (PLB) phosphorylation at Serine-16, a PKA phosphorylation site, in the V1A-OE+IBMX compared to WT+IBMX.

Conclusions:
—
These results suggest that V1A overexpression reduces myocardial inotropic regulation by inhibiting PKA-induced phosphorylation of Ca
2+
regulatory proteins that are involved in β-adrenergic regulation of cardiac contractility. Increased AVP signaling plays a role in the depression of cardiac contractility in heart failure and AVP antagonists may improve heart function by enhancing cardiac contractility reserve.
Abstract 18577: Survival Benefits of Transcatheter Mitral Valve Repair is Comparable to Surgery, but Superior to Conservative Treatment in High Risk Patients
Authors: Swaans Martin J , Bakker Annelies L , Alipour Arash , Eefting Frank D , Rensing Benno W , van der Heyden Jan A , Post Martijn C
Published: April 2024

Objective:
Up to 50% of patients with symptomatic severe mitral valve regurgitation (MR) are denied for surgery due to high perioperative risk. Transcatheter repair using MitraClip might be a good alternative. We compared mortality outcome between MitraClip, surgery and conservative treatment in high risk patients.

Methods:
Consecutive patients treated with the MitraClip system were included. Comparator surgical and conservative treated patients were identified retrospectively and consented to compare survival. Surgical risk was based on logistic EuroSCORE or the presence of relevant risk factors, judged by the heart team.

Results:
Mean follow-up time was 3.8±0.2 years. 251 patients were included of whom 59 were treated conservatively, 139 treated with MitraClip and 53 underwent surgery. Logistic EuroSCORE was higher in MitraClip (23.9±16.1) than in surgical (14.2±8.9) and conservative (18.7±13.2, P<0.0001) treated patients. MitraClip patients (74.6±9.4) were older than those in the surgical (70.2±9.5) and conservative (71.7±9.6, P=0.009) groups. Majority of patients had functional MR. LVEF was better in surgery group (43.9±14.4%), with similar values for MitraClip (36.8±15.3%) and conservative treated subjects (34.5±16.5%, P=0.003). PHT (sPAP >31mmHg) was more prevalent in MitraClip than in conservative and surgery patients. Incidence of other risk factors did not differ. The mortality rates were 23,0%, 45,3%, and 67,8% for Mitraclip, high risk surgery and conservative treatment, respectively. However due to the retrospective character of the comparator groups, the Mitraclip group had a shorter follow-up time. After weighting for propensity score and controlling for age, COPD and PHT both MitraClip (HR=0.50 95%CI [0.28 - 0.88], p=0.02) and surgical group (HR=0.53 95%CI [0.32 - 0.89], p=0.02) showed better survival than the conservative group. MitraClip and surgical groups did not differ (HR=1.06 95%CI [0.60 - 1.88], p=0.84).

Conclusion:
Despite higher logistic EuroSCORE, high risk patients with severe symptomatic MR treated with the MitraClip have similar mortality outcomes compared to those treated surgically, both showing survival benefit compared to conservative treatment.
Abstract 18584: Alpha-2 Agonist Attenuates Ischemic Injury in Isolated Spinal Cord Neurons
Authors: Freeman Kirsten A , Puskas Ferenc , Bell Marshall T , Mares Joshua M , Weyant Michael J , Cleveland Joseph C , Fullerton David A , Meng Xianzhong , Herson Paco , Reece Thomas B
Published: April 2024

Background:
Paraplegia secondary to spinal cord ischemia-reperfusion injury remains a devastating complication of thoracoabdominal aortic surgery. The complex interactions between the injured neurons and activated leukocytes have made investigation of neuron specific injury elusive. We hypothesize that isolated spinal motor neuron cell cultures subjected to oxygen-glucose deprivation (OGD) would simulate ischemia-reperfusion (IR) injury seen in aortic surgery, which could be attenuated by specific alpha-2a agonism, using dexmedetomidine, in an Akt dependent fashion.

Methods and Results:
Spinal cords from perinatal mice were harvested and neurons cultured
in vitro
for 7-10 days. Cells were pretreated with 1μM dexmedetomidine (Dex) and subjected to OGD in a humidified hypoxic chamber. Indexed to non-ischemic controls, pretreatment with Dex significantly preserves neuronal viability after one hour of OGD with 88% viability compared to untreated OGD with 59% viability (p<0.05) . TUNEL staining demonstrated pretreatment with Dex significantly decreased the apoptotic cells compared to untreated OGD cells by over 50% (p<0.05). OGD increased IL-6 production nearly three-fold compared to non-ischemic control (p<0.05) with Dex reducing this production by half (p<0.05). Mechanistically, Dex treatment significantly increased phosphorylated Akt (p<0.05), but the protective effects of Dex seen by MTT assay were eliminated using an alpha-2a antagonist or an Akt inhibitor (p<0.05), with viability nearly half of non-ischemic control.

Conclusion:
Using a novel spinal cord neuron cell culture, oxygen-glucose deprivation mimics neuronal metabolic derangement responsible for paraplegia following aortic surgery. Dexmedetomidine preserves neuronal viability and decreases apoptosis in an Akt dependent fashion. Dexmedetomidine demonstrates clinical promise for reducing the risk of paraplegia following high risk aortic surgery.
Abstract 18596: Regional Assessment of Lower Extremity Tissue Oxygenation in Athletes Using Blood Oxygen Level-Dependent Magnetic Resonance Imaging
Authors: Stacy Mitchel R , Caracciolo Christopher M , Pal Prasanta , Qiu Maolin , Sampath Smita , Sinusas Albert J
Published: April 2024

Background:
Blood oxygen level-dependent (BOLD) MRI allows for evaluation of hemoglobin oxygenation within skeletal muscle, providing a non-invasive index of microvascular function. This study evaluated differences in relative signal intensity of BOLD MRI among lower extremity muscle groups during transient ischemia and reactive hyperemia in college football athletes, while also comparing strength and functional exercise results.

Methods:
BOLD MRI was performed on the lower leg of 19 males (19.8 ± 1.0 yrs) with a 3T magnet to evaluate regional changes in signal intensity among individual muscle groups during ischemia and reactive hyperemia induced by proximal cuff occlusion. Athletes were separated by position (larger linemen vs. smaller position players) for comparison purposes. The peak hyperemic value (PHV), or the maximum percent change in BOLD signal intensity from baseline, was assessed for each muscle group. Athletes’ lower body strength and jumping ability were evaluated and compared to BOLD responses.

Results:
Linemen presented with higher body fat and systolic blood pressure (p<0.05). Athletes did not differ in maximal lower body strength; however, position players had greater vertical and broad jump performance (p<0.0001). In analysis of all athletes, the soleus muscle, a slow twitch muscle generally with high capillary density, exhibited the largest PHV. The PHVs of gastrocnemius muscles for position players were significantly higher than linemen (p=0.03) and were associated with greater jumping performance. No differences were observed in other muscle groups when comparing position players and linemen.

Conclusions:
BOLD MRI offers a non-invasive technique for quantifying regional differences in lower extremity tissue oxygenation in the evaluation of microvascular function in relation to functional performance. Evaluation of changes in BOLD responses may help to evaluate and optimize exercise training for improved function.
Abstract 18599: Comparison of Outcomes for Eldelry Patients Treated With Pre-Hospital Reduced Dose Fibrinolytic Followed by Urgent Percutaneous Coronary Intervention versus Percutaneous Coronary Intervention Alone for Treatment of ST-Elevation Myocardial Infarction
Authors: Solhpour Amirreza , Chang Kay-Won , Denktas Ali E , Balan Prakash , Sdringola Stefano M , Cai Chunyan , Anderson H Vernon , Smalling Richard W
Published: April 2024

Background:
The ultimate treatment goal in ST-elevation myocardial infarction (STEMI) is rapid restoration of coronary blood flow. In general, fibrinolysis can be initiated earlier than primary percutaneous coronary intervention (PPCI) but it could be associated with bleeding risk, especially in elderly patients. For over 7 years we have used a strategy of field evaluation for STEMI using 12 lead EKGs obtained and transmitted by emergency services (EMS) personnel with over-read by emergency center physicians. Appropriate STEMI patients receive pre-hospital reduced dose fibrinolytic (10 units reteplase) along with aspirin, clopidogrel, and heparin, and are transported to our STEMI center for urgent PCI (termed FAST-PCI strategy).

Methods:
We examined the data for elderly patients (≥ 75 years) treated by either a FAST-PCI strategy or conventional PPCI. We compared demographic, clinical, angiographic data and outcomes. Ischemic time was defined as time from onset of pain to device activation. Bleeding was assessed using GUSTO criteria.

Results:
Between February 2006 and April 2013, we treated 1323 STEMI patients of which 214 (16.2%) were ≥75 years. FAST-PCI was employed in 120 (56%) and PPCI in 94 (44%) patients. The groups were well matched for age, cardiac risk factors and ischemic time. Data are shown in the table.

Conclusions:
In the elderly patients, compared with a PPCI strategy, the FAST-PCI strategy was associated with earlier infarct artery patency (Less TIMI 0 flow) and reduced 30 day mortality, as well as with lower incidence of cardiogenic shock at presentation without a bleeding penalty.
Abstract 18600: Hemodynamic Predictors of Renal Dysfunction in Left Ventricular Systolic Dysfunction and Pulmonary Hypertension
Authors: Purushottam Bhaskar , Gajanana Deepakraj , Janzer Sean , Morris Dennis L , Figueredo Vincent M
Published: April 2024

Background:
There is limited data on hemodynamic predictors of renal function in patients with left ventricular systolic dysfunction and pulmonary hypertension. Our objective was to analyze the strength of correlation between standard and novel hemodynamic indices, including right atrial to pulmonary capillary wedge ratio (RA:PCWP) and pulmonary artery pulsatility index (PAPi), with renal function in patients with systolic dysfunction {left ventricular ejection fraction (LVEF) ≤35%} who had pulmonary hypertension (mean pulmonary artery pressure ≥ 25 mm Hg).

Methods:
We retrospectively screened 250 patients with systolic dysfunction and pulmonary hypertension, who underwent a right heart catheterization (RHC) between 2007 and 2012 at Einstein Medical Center, Philadelphia. Patients with underlying chronic kidney disease (GFR <60 mL/min/1.73m
2
) were excluded. Correlation between standard RHC variables, pulmonary artery pulse pressure (PAPP), PAPi (PAPP/RA) and RA:PCWP ratio with renal function were studied.

Results:
The final cohort consisted of 108 patients, with mean age 59±12 years and 66% male. Forty-six patients had worsening creatinine from the time of admission to RHC. The group with worsening creatinine (n=46) had a higher RA:PCWP ratio (0.64±0.25 vs. 0.52±18; p<0.01) than the group with no change or an improvement in the creatinine (n=59). When comparing these two groups, RA:PCWP ratio was the only hemodynamic variable which was significantly different. Patients with a RA:PCWP ratio of ≥0.86 (n=11) had a higher creatinine at the time of RHC (2.13±0.84 vs. 1.64±0.75 mg/dL; p=0.04) and an increase in creatinine from the time of admission to the RHC (increased by 0.38±0.62 vs. decreased by 0.04±59 mg/dL; p=0.02) when compared to the group with a RA:PCWP ratio <0.86 (n=94).

Conclusion:
RA:PCWP ratio is a better predictor of renal dysfunction than the standard RHC variables in patients with systolic dysfunction and pulmonary hypertension.
Abstract 18632: The Potent, Selective Cardiac Acetylcholine-Activated Potassium Current Inhibitor XEN-R0706 Prolongs Human Atrial Action Potential Duration
Authors: Milnes James , Loose Simone , Poulet Claire , Kuenzel Stephan , El-Haou Said , Jackson Claire , Tang Raymond , Madge David , Ford John , Ravens Ursula
Published: April 2024

Aim:
In the heart Kir3.1/3.4 conducts the acetylcholine-activated potassium current IKACh. Increased vagal-tone and constitutive-activation of IKACh are believed to be contributing factors to the substrate of atrial fibrillation (AF) in man. This study set out to characterise the novel drug XEN-R0706 and investigate its effect on human atrial IKACh and action potential duration (APD).

Method:
Ion channel pharmacology was investigated in whole-cell patch-clamp studies using either HEK293 or CHO cells expressing the ion channel gene of interest (~20°C) or isolated human atrial myocytes (37 °C). Action potentials were recorded (1Hz, 37 °C) from human atrial myocytes isolated from right atrial appendage obtained from consenting patients in sinus rhythm. The study was approved by the university ethics committee and complied with the declaration of Helsinki.

Results:
XEN-R0706 potently inhibited recombinant Kir3.1/3.4 (IC50 =30 nM, nH =0.7 ± 0.1) and had nominal effect on other cardiac channels displaying over 100-fold selectivity over hERG (IC50 3.3 μM, nH = 0.98 ± 0.1) and >300-fold selectivity over Nav1.5, Cav1.2, Kir2.1, Kir6.2/SUR2A (IC50 >> 10 μM for each). In human right atrial cardiomyocytes, carbachol (CCh, 10 μM) activated IKACh from 6.8 ± 0.76 pA/pF to a maximum of 9.7 ± 0.9 pA/pF which quickly desensitized to 8.8 ± 0.8 pA/pF within 20 s (n=24). This current was completely inhibited by XEN-R0706 (0.3 - 3 μM) whereas basal IK1 was not affected. XEN-R0706 completely reversed the CCh-shortened APD in isolated atrial cardiomyocytes, i.e. mean APD90 values were: control 186.3 ± 20.3 ms, CCh (2 μM) 111.7 ± 11.1 ms (P<0.05 vs control), CCh plus XEN-R0706 (1 μM) 168.2 ± 19.4 ms (P<0.05 vs CCh, n=5).

Conclusion:
This is the first report of the effect of a potent, small-molecule inhibitor of IKACh on the human atrial APD. The selective IKACh inhibitor XEN-R0706 prolonged the CCh-shortened atrial APD90. Selective IKACh inhibitors have the potential to be new, safe and effective anti-arrhythmic therapies for the treatment of AF.
Abstract 18668: Is Functional Capacity a Reliable Predictor in Pre-Operative Cardiac Risk Stratification?
Authors: Nagarajan Vijaiganesh , Jaikumar Likhitesh , Halkar Meghana , Sharma Prashant , Prabhakaran Anbazhagan , Kaw Roop
Published: April 2024

Introduction:
Functional capacity has been used both in guidelines and clinical practice as an important predictor of adverse events in pre-operative cardiac risk stratification. It is measured in metabolic equivalents (METs). Current guidelines advise that patients can proceed with surgery if the functional capacity is more than 4 METs with no further investigations. But it is unclear whether a history of good functional capacity is reliable predictor.

Methods:
In this retrospective study, we reviewed 614 patients who were evaluated in our pre-operative clinic (IMPACT clinic) and had stress test within 90 days of evaluation. Functional capacity in METs and stress test results were obtained from electronic records. Patients have been divided into ‘good’ and ‘poor’ functional capacity (FC) groups based on patients’ capacity to do more than 4 METs. Revised cardiac risk index (RCRI) was calculated using clinical risk factors. Patients were divided into risk groups based on RCRI. We used chi-square test to compare functional capacity and stress test results.

Results:
84% of patients underwent intermediate risk surgery. 82% of patients had functional capacity of more than 4 METS. 24.8% of patients with ‘poor FC’ had reversible ischemia in stress test, but 14.3% with ‘good FC’ had reversible ischemia as well (p=0.023). When patients with intermediate (1-2 risk factors) and high risk groups (≥ 3 risk factors) are considered, reversible ischemia was present in 12.9% and 22.5% of patients respectively even if they had good functional capacity (> 4 METs). This shows very high number of patients with good functional capacity may have reversible ischemia.

Conclusion:
Functional capacity by history may not be a reliable predictor in pre-operative cardiac risk assessment as lot of patients may have undiagnosed cardiac ischemia. This may be more relevant in patients with multiple clinical risk factors. Further studies are warranted before final conclusions can be made.
Abstract 18721: Diacylglycerol Kinase ? (DGKB) Genotype Predicts Response to Niacin Induced Flushing and Changes in Insulin in the Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides and Impact on Global Health Outcomes (AIM-HIGH) Trial
Authors: Tuteja Sony , Qu Liming , Dunbar Richard L , Li Mingyao , Mucksavage Megan , DerOhannessian Stephanie , Reilly Muredach P , Rader Daniel J
Published: April 2024

Niacin has been used for decades as a lipid lowering agent but its use is limited by flushing. Stimulation of a G-protein coupled receptor (GPR109A) on immune cells of the skin by niacin results in generation of prostaglandinD
2
/E
2
and flushing. An evoked phenotype genetic study (termed the GENE study) was undertaken to determine genes associated with flushing and the findings were validated in the AIM-HIGH cohort receiving niacin.

The GENE study recruited n=294 healthy volunteers (51% Female, 65% Caucasian (Cau)) to an IR 1 gm niacin challenge. Flushing was assessed by laser Doppler and quantified as the flux index (peak blood flow divided by baseline). In the AIM-HIGH cohort, 2100 Cau and 75 African-Americans (AA) subjects for whom DNA was available were classified as cases and controls based on flushing severity and frequency during the run-in period of the trial. Genotyping was performed on Human Cardio-Metabo BeadChip (Illumina). Insulin was assayed before and after niacin treatment was begun.

In the GENE study, two independent loci in
DGKB
, a downstream mediator of GPCR signaling (lead SNPs Chr7:14349921, p=1 x 10
-6
and chr7:14281125, p=1.8 x10
-5
) were associated with the flux index. Fasting insulin levels increased after niacin 94 ± 106% (p<0.0001) at 5 hr compared to baseline. The same SNPs were also associated with the change in insulin. Subjects with the minor alleles had the greatest severity of flushing but the smallest change in insulin.
DGKB
SNPs were associated with flushing in the AIM-HIGH trial (lead SNP Chr7:14594540p=4 x 10
-4
). Subjects in the genotype group most associated with flushing had the smallest change in insulin, similar to the GENE study. SNPs in
DGKB
were associated with flushing in AA in both cohorts, but underpowered for significance.

Summary:
SNPs in
DGKB
were associated with flushing and change in insulin levels following niacin and may mediate several pharmacological effects of niacin. Variation in
DGKB
may alter the GPR109A receptor desensitzation and response to flushing. Since GPR109A has also been found to be expressed on murine islet beta cells, variation in
DGKB
in this tissue type may modulate insulin production. The role of
DGKB
in additional pharmacological responses to niacin is currently under study.
Abstract 18763: Characteristics and Anti-Atherosclerotic Properties of (-)-Epigallocatechin Gallate Loaded Lipid Nanoparticles in vitro
Authors: Zhang Jia , Nie Shufang , Wang Shu
Published: April 2024

BACKGROUND:
Atherosclerotic cardiovascular disease is the leading cause of death and disability in the United States and other developed countries. Macrophages are major cells responsible for atherosclerotic lesion development. (-)-Epigallocatechin gallate (EGCG), a natural compound found in green tea, is valuable to prevent atherosclerosis. But EGCG’s low level of stability, bioavailability and targeting specificity in the body makes administering it in therapeutic doses unrealistic.

METHODS AND RESULTS:
We have successfully synthesized EGCG loaded lipid nanoparticles (ENP), which are composed of biocompatible and biodegradable lipids, surfactants and EGCG. The size of nanoparticles was less than 100 nm in diameter measured using a dynamic light scattering method and a transmission electron microscope. The encapsulation efficiency was around 90%. As compared to native EGCG, ENP significantly increased EGCG stability and macrophage EGCG content at 37°C. Remarkably, ENP significantly decreased human macrophage cholesteryl ester content measured using a high performance liquid chromatography (HPLC) system. ENP also significantly lowered both gene expression and protein secretion of monocyte chemoattractant protein 1 (MCP-1) in/from human macrophages measured using real-time PCR and ELISA assays, respectively. We also incorporated target ligands on the surface of ENP. The target ligands further increased the binding and uptake of those nanoparticles in human macrophages.

CONCLUSIONS:
ENP significantly enhanced EGCG stability, increased its cellular bioavailability, decreased cholesteryl ester content and MCP-1 expression in macrophages. Target ligands increased the target specificity of those nanoparticles to human macrophages. ENP with target ligands have a potential for preventing atherosclerotic lesion development through enhancing EGCG uptake by macrophages and decreasing macrophage cholesterol accumulation and inflammatory responses.

Funding support:
The project described was supported by Grant Number R15AT007013 from NIH NCCAM.
Abstract 18857: Outcomes of Surgical Aortic Valve Replacement in Intermediate Risk Octogenarians: Insight From a Prospective Clinical Study
Authors: Desai Nimesh D , Cheung Anson , Patracek Michael R , Groh Mark , Borger Michael A , Schaff Hartzell V , Bavaria Joseph E
Published: April 2024

Introduction:
Aortic valve replacement approaches have shifted towards catheter-based therapies in older patients. While this strategy is appropriate in extreme risk cases, concerns regarding aortic insufficiency(AI)/paravalvular leak and stroke with catheter valves may favor use of surgical aortic valve replacement in intermediate and low risk patients. We present outcomes of intermediate risk octogenarian patients undergoing surgical aortic valve replacement enrolled in a prospective trial with robust endpoint assessment and follow-up.

Methods:
The St. Jude Trifecta IDE trial was a prospective approval study for a new aortic valve prosthesis. The Trifecta bioprosthesis was implanted in 210 pts over 80 years of age between 2007 and 2009 at 28 centers in the US, Canada, and Europe. Mean age was 83.5 ± 2.7 years(range 80-95) of which 103[49.0%] were female. 62[29.5%] subjects had undergone previous cardiac surgery. Concomitant CABG was performed in 103 [49.0%] patients.

Results:
The mean STS predicted mortality score was 4.02 +/- 2.16. Follow-up was 399.4 late patient-years. Early (≤ 30 day) mortality occurred in 3 [1.4%] patients and there were 17 late (≥ 31 days) deaths yielding a survival of 91.7% at 2 years and 87.1% at 3 years. There was no paravalvular leak, valve thrombosis, early endocarditis or hemolysis. There were 7 early neurologic events including 2 [1.0%] strokes, and 5 [2.4%] reversible neurologic events. There were 9 late thromboembolic events, including 3 strokes and 6 reversible neurologic events or transient ischemic attacks (linearized rate 2.25%/year of follow-up). Freedom from valve explant was 99.4% at 3 years. Mean gradient and effective orifice area at 3 year follow-up was 10.2 mmHg +/- 5.0 and 1.43 cm2 +/- 0.26, respectively. 88.9% of patients demonstrated none or trivial AI, 2.2% and 0% demonstrated moderate and severe AI, respectively.

Conclusions:
In conclusion, surgical valve replacement in elderly intermediate risk patients demonstrates superb clinical outcomes and results. Extremely low rates of stroke and aortic insufficiency in combination with excellent 3-4 year survival show a favorable profile for intermediate risk patients to undergo surgical aortic valve replacement.
Abstract 18887: Ruboxistaurin Improves Cardiac Function in the Swine Heart After Myocardial Infarction
Authors: Sharp Thomas E , Scimia Maria C , Berretta Remus M , Starosta Timothy , Molkentin Jeffery D , Houser Steven R
Published: April 2024

Introduction:
Myocardial Infarction (MI) is a major health problem that causes cardiac dysfunction and often leads to heart failure. Previously, we and others have demonstrated that protein kinase C alpha (PKCα) activity is up-regulated in cardiac disease. This enhanced PKCα activity has been linked to depressed cardiac contractility in the diseased heart. In the present study we tested the effects of Ruboxistaurin, a PKCα inhibitor, on cardiac contractile function in a swine MI model.

Hypothesis:
Increased PKCα activity is involved in the progression of myocardial contractility defects in the post MI heart.

Methods and Results:
MI was induced in female Göttingen mini- pigs (6-7 months of age) by occlusion of the left anterior descending coronary artery (LAD) using an inflated percutaneous transluminal coronary angioplasty (PTCA) balloon for 90 minutes, followed by reperfusion. Cardiac structure and function was evaluated using echocardiography before and 4, 8, and 12 weeks post MI. During the 12 weeks after MI there was a progressive depression of pump function (Ejection Fraction [EF] 66.52% ± 1.16 [baseline] to 32.66 % ± 1.02 [12 weeks after MI] p <0.0001) and dilation of the LV volumes (End-diastolic volume [EDV] was 40.38 ml ± 3.01[baseline] to 75.73 ml ± 3.18 [12 weeks post MI] p = 0.0123 and End-systolic volume [ESV] was 15.14 ml ± 2.32 to 50.75 ml ± 1.86 p= 0.0004). The acute inotropic effects of an oral dose of ruboxistaurin (20mg/kg) were tested in animals 12 weeks post MI. Ruboxistaurin treatment significantly increased EF (from 32.66% ± 1.02 to 41.43% ± 2.87 p =0.0282). Ruboxistaurin treatment also significantly reduced EDV and ESV (from 75.73 ml ± 3.18 to 63.58 ml ± 4.06 p =0.0494, and from 50.75 ml ± 1.86 to 37.45 ml ± 3.52 p =0.0156 respectively).

Conclusion:
These data show that acute administration of the PKCα inhibitor ruboxistaurin can increase cardiac contractility and reduce heart size in swine with post MI cardiac dysfunction. These results suggest that PKCα activity suppresses cardiac contractile function and that removal of this inhibitory activity enhances cardiac pump function.