bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 15923: Dose-dependent Effect of Sevoflurane Postconditioning on Coronary Perfusion Pressure During Early Cardiopulmonary Resuscitation in a Pig Model of Prolonged Cardiac Arrest
Authors: Riess Matthias L , Matsuura Timothy R , Bartos Jason A , Olson Matthew D , Tsangaris Adamantios , Rees Jennifer N , Aufderheide Tom P , Bienengraeber Martin , Neumar Robert W , Yannopoulos Demetris
Published: March 2022

Introduction:
Pharmacologic postconditioning with the inhaled anesthetic sevoflurane (SEVO) during cardiopulmonary resuscitation (CPR) has been shown to improve outcomes in a porcine model of prolonged cardiac arrest.

Hypothesis:
We hypothesized that SEVO works in part by improving coronary perfusion pressure (CPP) during CPR.

Methods:
Following 15 min of untreated ventricular fibrillation (VF), 16 pigs received mechanical CPR for 4 min without (CON) or with low- (2 Vol%) or high-dose (4 Vol%) inhaled SEVO for 3 min. CPP was measured as the difference between mean aortic pressure and right atrial pressure during chest decompression.

Results:
CPP (mean±SEM in mmHg) at min 3 and 4 of CPR was higher in high-dose SEVO (46±4) than in low-dose SEVO (23±3) or CON (34±4); there was no significant difference between the latter two.

Conclusions:
Our data show that pharmacologic postconditioning with SEVO resulted in improved CPP during mechanical CPR if a sufficiently high dose is given. Combined with negligible metabolism and fast uptake and washout by ventilation due to its low solubility coefficient, SEVO may be a suitable drug to improve outcomes after cardiac arrest when given short-term during early CPR. If SEVO is associated with enhanced blood flow generation due to its known vasodilatory effect needs to be determined in future studies.
Abstract 15924: Early Non-contrast Head Computed Tomography for Prognostication of Neurologic Outcomes Following Cardiac Arrest
Authors: Chakravartti Jaidip , Klein Joshua P , O'Brien Molly , Henderson Galen V , Massaro Anthony , Pierce Carol , Seethala Raghu R , Strojwas Stefan , Kyller Michael G , Chase AnnMarie , Silverman Michael G , Scirica Benjamin M
Published: March 2022

Introduction:
Prognostication of neurologic outcomes in patients achieving return of spontaneous circulation (ROSC) following cardiac arrest poses a difficult challenge. A low ratio of gray matter to white matter (GWR) attenuation on early non-contrast head computed tomography (NCHCT) may be a specific predictor of poor neurologic outcome following arrest. We sought to validate this finding and to determine if there is a GWR cutoff that is completely specific for predicting poor neurologic outcomes.

Methods:
We identified 145 patients from our institution with a cardiac arrest between February 2007 and March 2015 who underwent NCHCT within 24 hours following ROSC. GWRs were calculated by measuring the attenuation of 10-15 mm
2
regions of interest in Hounsfield units, identifying the head of the caudate nucleus for gray matter and the posterior limb of the internal capsule for white matter. Neurologic outcomes were recorded by cerebral performance category (CPC) upon hospital discharge. A CPC score of 1 or 2 defined a favorable neurologic outcome, whereas a score of 3, 4, or 5 marked a poor neurologic outcome.

Results:
Fifty patients had favorable neurologic outcomes, with a median GWR of 1.29 and an interquartile range (IQR) of 1.24-1.34. Ninety-five patients had poor neurologic outcomes, with a median GWR of 1.25 and an IQR of 1.18-1.30. Performance of the GWR as a predictor of neurologic outcome was examined by plotting a receiver operating characteristic curve; the area under the curve was 0.658. However, a GWR below 1.16 was found to have 100% specificity for predicting a poor neurologic outcome following arrest (20 cases, 21.1% sensitivity).

Conclusion:
In our study, a GWR below 1.16 was shown to be a completely specific predictor of poor neurologic outcome following cardiac arrest. In combination with other modalities, GWR on NCHCT could help guide management by lending prognostic information early in the post arrest course.
Abstract 15926: Impact of Small Body Surface Area on Para-valvular Leak After Balloon-expandable Transcatheter Aortic Valve Replacement
Authors: Maeno Yoshio , Takahashi Nobuyuki , Abramowitz Yigal , Kazuno Yoshio , Kawamori Hiroyuki , Kashif Mohammad , Chakravarty Tarun , Nakamura Mamoo , Cheng Wen , Jilaihawi Hasanian , Makkar Rajendra
Published: March 2022

Aims:
The efficacy and safety of balloon-expandable transcatheter aortic valve replacement (TAVR) in patients of small body surface is not well understood. The aim of this study was to evaluate that the efficacy and safety and association between small BSA (S-BSA) and para-valvular leak (PVL) after balloon-expandable TAVR.

Methods:
Between January 2013 and April 2015, a total of consecutive 379 patients with severe aortic stenosis underwent balloon-expandable TAVR (SAPIEN =82 or XT =297) and had suitable contrast cardiac CT. Patients with S-BSA were defined as <1.75cm2. The S-BSA group included 149 patients and the remaining 230 patients were included in the large BSA (L-BSA) group. Major adverse cerebro-cardiac vascular events (MACCE) at 30-days were recorded. Post procedural PVL and mean pressure gradient were also evaluated by transthoracic echocardiography at 30-days.

Results:
Mean aortic annulus area in the S-BSA group was significantly smaller than in the L-BSA group (412.7 ± 70.8 cm2 vs. 498.5 ± 88.8 cm2; p< 0.001) but degree of device oversizing was similar between groups (16.6% vs 17.0%, p=0.74). MACCE were similar between both groups (6.7% vs. 6.1%; p =0.483), however major vascular events were significant higher in S-BSA (15.4% vs. 7.0%; p=0.007). There was one patient with aortic annulus injury in the S-BSA group. Similar post-procedural mean pressure gradient was achieved in both groups (10.2 ± 4.1 mmHg vs. 9.6 ± 3.9 mmHg; p=0.17). S-BSA was significantly associated with the incidence of PVL (PVL ≤mild: 41.6% vs. 23.5%; p<0.001; moderate PVL ≤; 12.1% vs. 5.0%; p=0.009). Post-dilatation was higher in S-BSA (14.8% vs. 7.4%; p=0.017). Multivariate analysis demonstrated that aortic valve calcium was an independent strong predictor of PVL (Odds ratio (OR): 1.002; 95% confidence interval (CI) 1.001-1.003; p=0.001). S-BSA was found to be independently protective for PVL (OR: 0.38; 95% CI 0.24-0.61; p<0.001).

Conclusions:
TAVR in patients with S-BSA was associated with similar MACCE overall but with higher incidence of major vascular events compared to L-BSA. S-BSA was found to be independently protective for post procedural PVL at 30-days in patients that underwent balloon-expandable TAVR. This appeared independent to the degree of oversizing.
Abstract 15963: Understanding Hospital Readmissions in Female Patients Admitted With Heart Failure Complicated by Atrial Fibrillation: A Get With the Guidelines - Heart Failure (GWTG-HF) Study
Authors: Daneshvar Mitra , Desai Nayan , Ortman Matthew , Andriulli John , Hunter Krystal , Eno Eben , Russo Andrea
Published: March 2022

Background:
Over 2.5 million women in the US have heart failure (HF) accounting for the leading cause of hospitalization in women over 65. Despite the high prevalence, women with HF are understudied and little remains known about how concurrent atrial fibrillation (AF) complicates the condition. Understanding key risk factors for readmission in female HF patients with AF may help to reduce the morbidity and mortality associated with this condition and help reduce the significant financial and resource burden these events have on the US healthcare system.

Methods:
The GWTG-HF study enrolled 615 female HF patients with AF between 2005 – 2012 at our center. Pearson χ
2
tests and the Student t-tests were used to compare patient characteristics and index hospital admission by future all-cause readmission status.

Results:
92% of female patients with HF complicated by AF had a history of HF prior to index admission. 35% of these patients had a hospital readmission during the study period. Those who were readmitted were more likely to be black (p<0.001). There was no difference in past medical history between groups. Isosorbide was slightly more likely to be prescribed in patients who had a subsequent readmission (p=0.043), without differences in other medications.

Conclusion:
Over one-third of female patients with HF complicated by AF had an all-cause readmission. Readmitted patients were more likely to be black with similar past medical history and mediations prescribed on discharge. Further study is needed to identify why black women are more likely to be readmitted, with investigation into the possible role of high medication costs, complex medical regimens, and other barriers to accessing the healthcare system. By understanding possible barriers that increase the risk of hospital readmission, efforts can be made to reduce these obstacles and improve the overall health of this group.
Abstract 15968: Rescue of Bupivacaine-induced Cardiac Arrest by Lipid Emulsion is Prevented by Inhibition of Free Fatty Acid Receptor GPR40
Authors: Umar Soban , Centala Alex , Barseghyan Mariam , Rahavard Behnoosh B , Sharma Salil , Partownavid Parisa , Eghbali Mansoureh
Published: March 2022

Introduction:
Bupivacaine overdose leads to lethal arrhythmias and cardiac arrest. Lipid emulsion (LE) is cardioprotective and rescues Bupivacaine toxicity. Although both lipid sink and metabolic theories have been proposed, yet the exact molecular mechanism is not known. G protein-coupled receptor 40 (GPR40), also known as free fatty acid receptor-1 is activated by medium and long chain fatty acids. Among free fatty acid receptors, GPR40 expression is one of the highest in heart.

Hypothesis:
As GPR40 is activated by medium and long chain fatty acids, we hypothesized that GPR40 may mediate LE’s rescue of Bupivacaine cardiotoxicity.

Methods:
Male Sprague-Dawley rats were used. Continuous Echocardiography and ECG were done. In protocol-1 (n=6), rats received Bupivacaine bolus (10mg/kg, IV) to induce asystole. Resuscitation with LE 20% (5ml/kg bolus, and 0.5ml/kg/min maintenance) and chest compressions were initiated. In Protocol-2 (n=6) rats were pre-treated with GPR40-antagonist GW1100 (200uM, IV) 30-min before inducing asystole. Heart rate (HR) and ejection-fraction (EF) were measured before and 30-min after GW1100. In both protocols, HR, EF and fractional shortening (FS) were measured before asystole (baseline) and at 1, 5 and 10-min after LE. Means±SEM are reported.

Results:
In protocol-1, baseline HR and EF were 321±21 beats/min and 72.3±4.6%. Bupivacaine resulted in asystole. LE improved HR gradually within 10min; HR was 86±13 at 1min (27% recovery), 216±10 at 5min (67% recovery), and 228±14 at 10min (71% recovery). LV function fully recovered within 5 min of LE treatment as EF and FS were similar to baseline (EF=72±5%, FS=42±4%). To test our hypothesis, rats were pretreated with GW1100, 30-min before inducing asystole. There were no significant differences between HR and EF before (HR=316.6±3.3, EF=68.0±2.3%) and 30-min after GW1100 (HR=330±5.7, EF=71.6±1.5%) excluding GW1100 effects on hemodynamics. GW1100 pre-treatment however prevented LE rescue, with no recovery of cardiac function even after 10min of LE.

Conclusions:
This is the first report of involvement of GPR40 in rescue of Bupivacaine-induced cardiac arrest by LE. Discovery of GPR40 as a potential receptor for effects of LE may help us understand LE-induced cardioprotection.
Abstract 15992: Ventricular Tachyarrhythmia Sensing Following Magnetic Resonance Imaging in Patients With an ICD System Designed for the MRI Environment
Authors: Gold Michael R , Sommer Torsten , Schwitter Juerg , Kanal Emanuel , Bernabei Matthew , Love Charles , Surber Ralf , Ramza Brian , Cerkvenik Jeffrey , Merkely Béla
Published: March 2022

Objective:
To evaluate the impact of MRI on ICD sensing of ventricular tachyarrhythmias.

Methods:
The Evera MRI study is the first randomized trial of an ICD designed specifically to be MRI safe. This was a world-wide trial of 263 pts implanted with an Evera MRI single or dual chamber ICD in 42 centers. Patients were randomized to either undergo an MRI scan (MRI group) or to not receive a study MRI scan. Per protocol, 156 MRI group pts underwent an MRI procedure at 9-12 weeks post-implant. Device detected spontaneous and induced VT/VF episodes in the MRI group occurring prior to and following MRI were evaluated by an independent Episode Review Committee blinded to the timing of events. Detection delay was computed as the sum of RR intervals of under sensed beats. A ≥5 second delay in detection due to under sensing was prospectively defined as clinically significant. P-values are adjusted for multiple episodes within a patient.

Results:
There were a total of 34 post-MRI VT/VF episodes in 24 pts, with 16 of those pts having 27 VT/VF episodes prior to MRI. The mean detection delay due to under sensing in the 23 pre-MRI treated episodes was 0.37 ± 0.57 seconds, compared to 0.25 ± 0.57 in 27 treated post-MRI episodes (p=0.29). The maximum detection delay was 2.19 seconds pre-MRI and 2.87 seconds post-MRI. Monomorphic VT and non-sustained VT/VF rarely had any under sensing with 1/11 (9%) pre-MRI episodes and 1/14 (7%) post-MRI episodes (p=0.81) having 2 and 1 under sensed beats, respectively. For polymorphic VT/VF episodes, 13/16 (81%) pre-MRI episodes had some detection delay vs. 10/20 (50%) in post-MRI episodes (p=0.052), but no detection delay was clinically significant. The duration of delay was 0.54 ± 0.61 vs 0.32 ± 0.64, respectively, p=0.28).

Conclusion:
Detection of VT/VF was excellent with no significant impact of MRI with this system.
Abstract 16035: Cryoablation Achieves More Consistent Deeper Lesions With Improved Safety Compared to Radiofrequency Energy: An Experimental Model
Authors: Kaszala Karoly , Huizar Jose , Tan Alex , Ellenbogen Kenneth
Published: March 2022

Introduction:
Ablation strategies that require linear lesions often fail due to non-transmural tissue injury. In the current study we compared the efficacy and safety of cryoablation to radiofrequency ablation in an in-vivo canine model.

Hypothesis:
Cryoablation and radiofrequency ablation are equivalent in creating conduction block in ventricular tissue

Methods:
Anesthetized, ventilated canines (n=13) underwent thoracotomy. In in-situ RV outflow tract, blind alley (BA) that conducted to and from the RV only via an isthmus (IS) was created by cut and sew method by making a surgical incision. Cryoablation (7Fr, 8 mm tip FreezorMax3, Medtronic) or radiofrequency ablation (8Fr, 3.5 mm tip, saline irrigation 15-30cc/min Thermocool, Biosense Webster) was performed (4 -6 min and 2 min duration, respectively) from the endocardium at the IS. Epicardial temperature was monitored by a thermal camera (FLIR, Danderyd, Sweden). Entry and exit block was assessed by pacing and recording from inside the BA and from the LV. Acute and chronic block was defined as bidirectional block through the IS at 15 min and 90 min, respectively. Ablation was continued until acute block was achieved and observation continued for 90 min.

Results:
Data is summarized in the Table below. It was difficult to achieve transmural block using radiofrequency ablation unless high power settings (40-50W) and prolonged duration was used. These settings were associated with high incidence of steam pop and ventricular arrhythmias, yet chronic block was infrequently achieved. No complications were seen during cryoablation and conduction block was achieved at a higher rate. Development of chronic conduction block correlated with presence of transmural tissue injury.

Conclusions:
Cryoablation is safer and achieves deeper lesions and more persistent conduction block than RFA in this right ventricular experimental model.
Abstract 16113: Upregulation of Cardiac β3-Adrenergic Signaling Promotes Heart Failure Progression
Authors: Zhang Xiaowei , Li Tiankai , Cheng Heng-Jie , Zhou Peng , Callahan Michael , Cheng Che Ping
Published: March 2022

Background.
The negative inotrope and upregulation of β
3
-adrenergic receptors (AR) in failing human and animal hearts suggest a direct and contributing role of cardiac β
3
-AR activation on heart failure (HF) progression. However, its precise role is still being debated. We hypothesize that up-regulation of β
3
-AR is detrimental and chronic β
3
-AR blockade may limit or prevent the progression of HF.

Methods.
We determined Left ventricular (LV) and myocyte functional response and β
1
- and β
3
-AR expressions in 3 groups of rats (6/group) for a period of 4 months: 1) Isoproterenol (ISO)-treated, 4 months after receiving ISO (170 mg/kg, sq, for 2 days); 2) ISO/β
3
-ANT, two months after receiving ISO, L-748,337, a selective β
3
-AR antagonist (β
3
-ANT) (10
-7
M/kg/day by implanted osmotic mini pump) was initiated after established HF and was given for 2 months; and 3) sham controls.

Results.
Compared with controls, ISO-treated rats had HF onset at one month after ISO and progressed to severe HF at 4 months. Plasma norepinephrine (NE, 1482 vs 247 pg/ml) increased 6 fold. Both stroke volume (SV) and ejection fraction (EF, 32% vs 61%) decreased more than 48%, and LV end-diastolic pressure (P
ED
, 15.4 vs 6.0 mmHg) doubled, parallel with 48% reductions in cell contraction (dL/dt
max,
78 vs 149 μm/s) and relaxation (dR/dt
max
, 66 vs 128 μm/s) and a much less increase in dL/dt
max
(30% vs 74%) in response to superfusion of ISO (10
-8
M). These changes were associated with significantly decreased β
1
-AR mRNA (0.30 vs 0.64) and protein levels (0.36 vs 0.62), but increased β
3
-AR mRNA (1.29 vs 0.52) and protein levels (0.35 vs 0.18). Treatment with β
3
-ANT significantly decreased P
ED
and plasma NE (191 pg/ml). Both SV and EF (59%) increased to more than 76% from ISO-treated values. The signal ratios of β
1
-AR mRNA (0.61) and β
3
-AR mRNA (0.59) remained close to control levels. ISO-induced increase in dL/dt
max
(75%) was also significantly augmented.

Conclusion.
Chronic β
3
-ANT prevented plasma norepinephrine elevations and causes normalization of β
1
- and β
3
-AR gene expression, restores normal responsiveness of myocyte to β-AR stimulation, and leads to regression of LV and myocyte dysfunction in a rat model of progressive HF. Thus, β
3
-AR blocker may provide a new therapeutic strategy for the treatment of HF.
Abstract 16115: Rapamycin Protects Diabetic Heart Against Ischemia-reperfusion Injury by Inhibiting JNK and STAT4
Authors: Salloum Fadi N , Kukreja Rakesh C , Das Anindita
Published: March 2022

Background:
Persistent activation of the mammalian target of rapamycin (mTOR) is implicated in diabetic complications and plays a critical role in myocardial injury following ischemia/reperfusion. Recently we reported that mTOR inhibition with rapamycin improves cardiac function in type 2 diabetic (T2D) mice through attenuation of oxidative stress and alteration of antioxidants and contractile protein expression. Since increased JNK and STAT4 activities have been strongly associated with T2D-induced cardiovascular complications, we hypothesized that rapamycin would reduce myocardial infarction (MI) in T2D mice through inhibition of JNK and STAT4.

Methods and Results:
Adult male wild type (C57) or db/db T2D mice were treated daily for 28 days with rapamycin (0.25 mg/kg, i.p.). Following treatment, the hearts were subjected to global I (30 min) and R (60 min) in Langendorff mode. In addition, cardiomyocytes were isolated from treated mice and subjected to 40 min simulated ischemia (SI) and 1 hr or 18 hr reoxygenation (RO) to assess necrosis (by trypan blue staining) or apoptosis (by TUNEL assay), respectively. Diabetes exacerbated ischemic infarct size (measured by tetrazolium chloride staining) in db/db mice as compared to C57 mice (Fig. A), and also enhanced cardiomyocyte necrosis (Fig. B) and apoptosis (Fig. C). Rapamycin treatment reduced infarct size following I/R and protected adult cardiomyocytes against necrosis and apoptosis following SI/RO. Rapamycin also improved post-ischemic contractile function in db/db mice (Fig. D). Western blot analysis revealed a marked increase in phosphorylation of JNK and STAT4 in diabetic hearts, which were reduced in rapamycin-treated diabetic hearts (Fig. E).

Conclusion:
Rapamycin treatment reduces MI possibly by inhibiting JNK and STAT4 in T2D heart. We propose that inhibition of JNK and STAT4 with rapamycin therapy may be an attractive strategy to improve prognosis in diabetics following MI.
Abstract 16124: Aurora - A Noninvasive, Wrist-worn Device for Ambulatory Hemodynamic Monitoring
Authors: Wander Jeremiah D , Morris Dan , Tan Desney
Published: March 2022

Introduction:
Continuous, minimally invasive monitoring of arterial health has significant potential for both improving our understanding of early progression of arteriosclerosis/atherosclerosis and enabling early treatment. Though devices exist that can report heart rate and heart rate variability in fully ambulatory settings, monitoring of pulse pressure wave morphology, including pulse wave velocity (PWV) and augmentation index (AIx) - two emerging indicators of arterial stiffness - is still currently limited to benchtop systems requiring an expert operator or cuff-based systems that are not well tolerated.

Objective:
To develop and validate a device capable of continuous monitoring of hemodynamic and electrophysiological signals, including computation of derived vascular stiffness indicators (peripheral PWV and AIx) comparable to current standards.

Methods:
We developed a wrist-worn device for continuous radial pulse wave capture and analysis (e.g., peripheral AIx computation) and pulse wave velocity measurement (measured from EKG landmarks to the radial pulse arrival time). The core sensors on the device are (1) a pressure sensor that rests over the radial artery, (2) a pair of dry EKG electrodes in lead-I configuration, and (3) a six-axis motion sensor. It includes a Bluetooth radio for data streaming, and sufficient on-board storage for 2 weeks of ambulatory studies. To validate the device against the current gold standard for radial tonometry, we recorded multiple 60-second sessions of tonometric data using both our device (2 sessions) and the standard Millar SPT-301 tonometer (3 sessions) in 28 subjects. We then compared AIx computed from these two devices.

Results:
Using our wrist-worn device we calculated AIx values that were highly consistent with those of the Millar tonometer (r = 0.927, mean difference ± SD of 0.026 ± 0.049).

Conclusions:
This platform enables continuous non-invasive hemodynamic monitoring. We intend to utilize it in future studies about how peripheral AIx and PWV behave over longer time periods, how they correlate to daily activities, including sleep, exercise, and food/medication intake, and - most importantly - whether they can serve as new, ambulatory indicators of cardiovascular risk.
Abstract 16137: Essential Role of Cdc42 in Cardiomyocyte Proliferation and Cell-cell Adhesion During Heart Development
Authors: Li Jieli , Liu Yang , Jin Yixin , Wang Rui , VanBuren Vincent , Dostal David E , Zhang Shenyuan L , Peng Xu
Published: March 2022

Cdc42 is a member of the Rho GTPase family and functions as a molecular switch in regulating cell migration, proliferation, differentiation and survival. However, the role of Cdc42 in heart development remains largely unknown. To determine the function of Cdc42 in heart formation, we have generated a Cdc42 cardiomyocyte knockout (CCKO) mouse line by crossing Cdc42 flox mice with myosin light chain (MLC) 2a-Cre mice. The inactivation of Cdc42 in embryonic cardiomyocytes induced lethality after embryonic day 12.5. Histological analysis of CCKO embryos showed cardiac developmental defects that included thin ventricular walls and ventricular septum defects. Microarray and real-time PCR data also revealed that the expression level of p21 was significantly increased and cyclin B1 was dramatically decreased, suggesting that Cdc42 is required for cardiomyocyte proliferation. Phosphorylated Histone H3 staining confirmed that the inactivation of Cdc42 inhibited cardiomyocytes proliferation. In addition, transmission electron microscope studies showed disorganized sarcomere structure and disruption of cell-cell contact among cardiomyocytes in CCKO hearts. Accordingly, we found that the distribution of N-cadherin/β-Catenin in CCKO cardiomyocytes was impaired. Taken together, our data indicate that Cdc42 is essential for cardiomyocyte proliferation, sarcomere organization and cell-cell adhesion during heart development.
Abstract 16139: Mast Cells Promote Proliferation and Suppress Myogenic Differentiation of Mesenchymal Stem Cells
Authors: Nazari Mansoreh , Ni Nathan C , Ludke Ana L , Li Shu-Hong , Guo Jian , Yau Terrence M , Weisel Richard D , Li Ren-Ke
Published: March 2022

Introduction:
Efficient scar formation post-myocardial infarction (MI) depends on fibroblast/mesenchymal stem cell (MSC) accumulation and myofibroblast transdifferentiation. Mast cell (MC)-deficient mice exhibit reduced cardiac myofibroblast accumulation and undergo rapid left ventricular dilation post-MI. Thus, we sought to investigate how MCs modulate MSC proliferation and their myogenic differentiation into myofibroblasts.

Methods:
MC/MSC co-culture was used to examine MC effects on MSC proliferation and differentiation. MC granulate (MCG) was then used to further examine the mechanisms by which MCs exerted their effects on MSC proliferation, migration, and myogenic differentiation. The effects of MCs on MSC activity in vivo was evaluated by immunohistological analysis on MC- and saline-treated infarcted mouse hearts at 3 and 7 days post-MI

Results:
MC co-culture suppressed expression of the myogenic differentiation marker α-smooth muscle actin in MSCs. Similarly, MCG dose-dependently decreased myogenic differentiation by up to ~90% (P<0.01, n=4) and increased MSC proliferation ~two-fold (P<0.01, n=5) and migration by ~75% (P<0.01, n=4). Pharmacological antagonism of platelet-derived growth factor receptor (PDGFR) rescued MSC differentiation despite MCG treatment, suggesting MC suppression of MSC differentiation occurs through PDGFR. MCG treatment resulted in up to ~70% decreased miR-145 and -143 expression (P<0.05, n=4), as well as increased Klf4 (~25%) and decreased myocardin (~50%) protein expression in MSCs, indicating that the myocardin-Klf4 axis mediates MSC proliferation/differentiation. Finally, infarcted hearts from mice treated with MCs showed ~five-fold increased CD29+ MSC proliferation at day 3 vs saline-treated animals (P<0.05, n=3). This effect was absent by day 7 post-MI.

Conclusions:
MSCs can oscillate between proliferative and differentiated states. MCs promote proliferation at the expense of differentiation early after MI through PDGFR, downregulation of miR-145 and -143, and the Klf4-myocardin signalling axis to promote MSC accumulation. This in turn results in a larger cardiac MSC pool for later myofibroblast differentiation, facilitating improved wound healing.
Abstract 16179: A Novel Protocol for Dispatcher Assisted Cardiopulmonary Resuscitation Improves Quality of Cardiopulmonary Resuscitation: A Randomized Controlled Simulation Study
Authors: Rasmussen Stinne E , Nebsbjerg Mette A , Bjørnshave Katrine , Krogh Lise Q , Krogh Kristian , Povlsen Jonas A , Riddervold Ingunn S , Grøfte Thorbjørn , Kirkegaard Hans , Løfgren Bo
Published: March 2022

Introduction:
Dispatcher assisted CPR (DA-CPR) increases rate and quality of CPR and improves survival. Several studies have shown that changing one element in a dispatcher’s protocol improve CPR performance. Whether one improvement counter the effect of another improvement is unknown and the effect of combining several beneficial elements in a dispatcher protocol remains to be clarified.

Hypothesis:
A novel DA-CPR protocol, combining several single elements improving CPR performance, is superior to a standard DA-CPR protocol.

Methods:
Based on previous research and pilot studies a novel DA-CPR protocol including new wording on chest compression depth and hand position, the use of a metronome, provision of encouragements and introducing a 10-sec rest per minute was developed. Subsequently, laypersons were randomized to perform chest compression-only DA-CPR on a manikin with either the novel DA-CPR protocol or a standard DA-CPR protocol. Data on CPR quality was collected on video recordings and from the manikin and evaluated by two assessors blinded to the experimental groups. The primary outcome was a composite endpoint of time to first compression, hand position, compression depth and -rate and hands-off time, which were rated separately each minute and merged into an overall score (max 22 points).

Results:
128 laypersons were included in the study. The novel protocol (n=61, three were excluded) significantly improved the CPR quality compared to the standard protocol (n=64) (mean (SD)): 18.6 (1.4) points vs. 17.5 (1.7) points, p<0.001. The novel protocol resulted in significantly deeper (mean (SD): 58 (12) mm vs. 52 (13) mm, p=0.02) and faster (mean (SD): 114 (11) min-1 vs. 110 (13) min-1, p=0.04) compressions when compared to the standard protocol. The novel protocol resulted in shorter time to first compression (median (IQR): 65 (59, 70) sec vs. 72 (66, 81) sec, p<0.001) and better hand position for compressions (61% vs. 36%, p=0.01) compared to the standard protocol. As intended, hands-off time per minute was prolonged with the novel protocol (median (IQR): 6 (5, 7) sec vs. 0 (0, 1) sec).

Conclusions:
In a simulated cardiac arrest scenario, a novel protocol for DA-CPR was superior to a standard DA-CPR protocol. Both protocols resulted in high quality CPR.
Abstract 16204: Knock-down of 24-dehydrocholesterol Reductase Suppresses SREBP2: A Novel Approach to Reduce PCSK9 in vivo
Authors: Parathath Saj , Rosa Ray , Zhou Heather , Wang Sheng-ping , Bojic Lazar A , Previs Stephen , Vogt Thomas F , Johns Douglas G
Published: March 2022

Introduction:
Current therapeutic approaches to suppress the actions of proprotein convertase subtilisin/kexin type 9 (PCSK9) primarily involve monoclonal antibody. An alternative approach could be to suppress the SREBP2 pathway. Inhibition of sterol regulatory element-binding protein cleacage-activating protein (SCAP) will prevent SREBP mediated transcription of sterol biogenesis genes and PCSK9.24-dehydrocholesterol reductase (DHCR24) catalyzes the last step of cholesterol synthesis, converting desmosterol to cholesterol. Desmosterol is a strong LXR agonist and an inhibitor of SCAP.

Hypothesis:
We tested our hypothesis that reduction of DHCR24 expression would result in an increase in desmosterol, resulting in the suppression of SCAP and reduction of PCSK9 in vivo.

Methods:
In these studies, we used AAVshRNA to knock-down DHCR24 in the livers of CETP transgenic mice and WT mice.

Results:
Animals injected with AAVshRNA-DHCR24 resulted in 85% knockdown of DHCR24, with a concomitant 75% suppression of cholesterol synthesis, as measured by deuterium incorporation into newly made cholesterol. Knock-down of DHCR24 was also associated with up-regulation of fatty acid oxidation genes and suppression of fatty acid biosynthetic and SREBP-2 cholesterol biosynthetic pathways. Interestingly, DHCR24 knockdown was associated with a 60% decrease in plasma PCSK9 levels in CETP Tg mice (n=10, P<0.001) and similar results were observed in WT mice.

Conclusions:
To our knowledge, this is the first
in vivo
study to demonstrate that PCSK9 levels can be decreased via suppression of DHCR24
in vivo
. These results suggest that DHCR24 might represent a novel therapeutic target for reducing LDL-cholesterol.
Abstract 16207: RNA Polymerase II-associated Factor 1 Complex Drives Cardiac Progenitor Formation and Differentiation
Authors: Lu Fei , Langenbacher Adam , Huang Jie , Chen Jaunian
Published: March 2022

Cardiac differentiation from pluripotent progenitor cells requires well-orchestrated transcriptional and epigenetic regulations. The evolutionarily conserved RNA polymerase II-associated factor 1 complex (PAF1C) functions as a transcription platform required for a wide range of cell signaling processes. From zebrafish genetic screens, we identify critical roles for PAF1C in the formation and differentiation of cardiac progenitor cells. Overexpression of Rtf1, a PAF1C component, activates cardiac transcription program and promotes the formation of cardiac progenitor cells in zebrafish. Conversely, knockdown of Rtf1 prevents cardiac differentiation in mouse embryonic stem cells and Rtf1 ablation in zebrafish and mice eliminates the entire cardiac progenitor population resulting in a heartless embryo. Molecular dissection identifies the histone modification and DNA binding domains of Rtf1. Structure-function analysis in zebrafish reveals distinct requirements for these domains in heart development; the DNA binding domain of Rtf1 is essential for the specification of the cardiac fate whereas the histone modification domain is dispensable for the formation of cardiac progenitor cells, but is required for the maturation of cardiomyocytes. Chromatin immunoprecipitation and luciferase reporter assays show that Rtf1 regulates the expression of cardiac transcription factors such as Nkx2.5 and Tbx20 by direct interaction with these promoters via the DNA binding domain. In addition, mutations in the histone modification domain reduce the abundance of epigenetic marks associated with actively transcribed genes and compromise the maturation of cardiomyocytes. Together these findings demonstrate that Rtf1 regulates cardiac differentiation by controlling transcription and epigenetic modification.
Abstract 16238: Intracellular Targeting of Hsp70 for Myocardial Cytoprotection After an Infarction
Authors: Tanimoto Takashi , Petrov Artiom D , Nakahara Takehiro , Kawai Hideki , Nishimura Robert , Weisbart Richard H , Chan Grace , Richieri Richard A , Reynolds Glenn T , Newcomb Robert , Sengupta Partho P , Strauss H. W , Narula Jagat , Parseghian Missag H
Published: March 2022

Background:
Myocardial cells affected by an infarction endure oxidative stress during reperfusion. It has been suggested that the induction of a heat-shock protein 70 (Hsp72) in myocardial cells counteracts oxidative stress and improves post-ischemic contractile recovery, but clinically relevant methods of inducing Hsp70 in myocardium have yet to be successfully employed.

Methods:
Mab 3E10 binds extracellular nucleosides, a target that is quite accessible in damaged tissues, allowing 3E10 to penetrate still viable cells through an equilibrative nucleoside salvage pathway. We have developed the scFv fragment of the cell-penetrating 3E10 as an intracellular transporter to deliver exogenous Hsp70. Primary cardiomyocytes exposed to H
2
O
2
were incubated
in vitro
with a 3E10 scFv-Hsp70 fusion (Fv-Hsp) to demonstrate cytoprotection against oxidative damage. In addition, rabbits were subjected to occlusion of the left coronary artery followed by reperfusion of the heart and intravenous injection of Fv-Hsp (20 mg) or a molar equivalent of a sham control. SPECT imaging and tissue gamma counting of
99m
Tc-labeled annexin V was used to visualize the infarct volume and quantify cell death, respectively.

Results:
In vitro
, 30-40% fewer dead cells were observed with Fv-Hsp treatment 30 minutes after exposure, even when 3E10 scFv was added as a competitor (p<0.0003). Reduced to oxidized glutathione ratios were greater in treated cells suggesting less oxidative stress. Measurement of annexin uptake (% injected dose of
99m
Tc /gram tissue) revealed Fv-Hsp-treated rabbits had less uptake compared to controls (ANOVA); 49% less in the entire area of risk (p<0.0001) and 43% less at the heart apex (p=0.01) where the maximum damage was expected/occurred. The annexin-verified damage was substantially higher in the control rabbits injected either with PBS or with a molar equivalent of 3E10 scFv. Echocardiographic left ventricular ejection fraction demonstrated recovery of significantly superior contractility in Fv-Hsp-treated rabbits 3 hours after reperfusion compared with no recovery in control rabbits.

Conclusion:
Targeted accumulation of Hsp70 at infarcted tissue is achievable and worth investigating further for clinical cytoprotection post-infarction.
Abstract 16240: Tristetraprolin (TTP) is a Novel Regulator of Branched-chain Amino Acid (BCAA) Catabolism in the Heart
Authors: Yar Sumeyye , Chang Hsiang-Chun , Shang Meng , Ardehali Hossein
Published: March 2022

Introduction:
Heart failure (HF) is associated with the accumulation of branched-chain amino acids (BCAAs) in heart and plasma. Besides, BCAAs are essential for normal cell growth and function. Therefore, tight regulation of BCAA metabolism is crucial to maintain normal cellular homeostasis. Tristetraprolin (TTP), an mRNA binding protein that promotes the degradation of its targets and regulates a number of biological processes including cellular metabolism. In
in silico
analyses, we identified the E2 subunit of branched-chain α-ketoacid dehydrogenase complex (BCKDC), the rate-limiting enzyme complex in BCAA catabolism, as a potential target of TTP. Here we assess the hypothesis that TTP plays a regulatory role in BCAA catabolism through regulating BCKDC-E2 in the heart. We also investigate TTP’s contribution in the pathogenesis of HF by modulating BCAA catabolism.

Results:
We observed a significant increase in TTP levels in cardiac tissue of human HF and mouse myocardial infarct induced HF samples. We also showed that deletion of TTP significantly decreases BCAA levels
in vitro.
As BCAA accumulation in the heart is associated with the pathogenesis of HF, we investigated whether TTP can regulate cardiac BCAA catabolism. Computational analysis of mRNAs of enzymes, which are involved in BCAA catabolism, revealed highly conserved TTP binding sites in BCKDC-E2 mRNA, suggesting that it is a potential target of TTP. BCKDC-E2 mRNA levels were significantly higher in the heart of TTP knock-out mice and TTP siRNA treated cardiomyocytes. Additionally, the mRNA stability of BCKDC-E2 was higher in cardiomyocytes with TTP downregulation, further confirming that TTP regulates the stability of this mRNA. Moreover, RNA co-immunoprecipitation studies demonstrated that TTP physically interacts with the BCKDC-E2 mRNA. Finally, we showed that BCKDC-E2 mRNA levels were significantly decreased in human HF samples.

Conclusion:
Our data indicate that TTP levels are increased in HF samples and TTP regulates BCAA catabolism in the heart by binding to and degrading BCKDC-E2 mRNA. These findings suggest that alterations in TTP expression may play a role in the development of HF based on its effect upon BCKDC-E2 and BCAA catabolism.
Abstract 16254: Heart Rate as a Prognostic Marker in Patients With Heart Failure With Preserved Ejection Fraction
Authors: Bilen Ozlem , Marks Sarah , Wruck Lisa M , Khalid Umair , Virani Salim S , Nambi Vijay , Jneid Hani , Cunningham Luke , Chang Patciria , Bozkurt Biykem , Deswal Anita
Published: March 2022

Introduction:
Higher heart rate is associated with worse outcomes in patients with heart failure (HF) and reduced left ventricular ejection fraction (EF). This association is less certain in patients with HF and preserved EF (HFpEF).

Methods:
The Atherosclerosis Risk in Communities (ARIC) HF community surveillance study sampled HF hospitalizations from 2005-2010 identified by ICD discharge codes (for patients aged ≥ 55 years from 4 US communities). Patients with validated acute decompensated HF (ADHF) and EF ≥50% were categorized as HFpEF. We examined the association between quartiles of heart rate (HRt) at admission and 1-year mortality in HFpEF patients using multivariable Cox-proportional hazard models. Patients with atrial fibrillation, pacemakers and ICDs, and patients with missing covariates were excluded. Analyses were weighted to account for the stratified sampling design.

Results:
The final study sample included 874 HFpEF hospitalizations (weighted n=3934). Patients with lower HRt were more often male; more often had hypertension, less lung disease, had lower eGFR values and were more often on beta-blockers and diuretics. Unadjusted Kaplan Meier curves showed significant survival differences between the HRt quartiles (Fig). After adjusting for demographics, comorbidities, labs and medications (including beta blockers), compared to patients in the lowest HRt quartile, patients with HRt in the highest quartile had the highest risk of mortality (hazard ratio [95% CI] 2.07 [1.22-3.52]); patients in the 3rd and 2nd quartiles also had elevated risks (1.92 [1.22-3.04] and 1.44 [0.90-2.23]).

Conclusions:
There is a strong association between increasing HRt at admission and 1-year mortality in acute decompensated HFpEF.
Abstract 16281: Comparison of Guideline Recommendations and Trial Evidence for Statins in Primary Prevention of Cardiovascular Disease in a Population-based Cohort: The Rotterdam Study
Authors: Pavlovic Jelena , Brugts Jasper J , Deckers Jaap W , Kavousi Maryam , Hofman Albert , Stricker Bruno H , Franco Oscar H , Leening Maarten J
Published: March 2022

Introduction:
The 2013 ACC/AHA and the 2012 European Society of Cardiology (ESC) guidelines recommend lipid-lowering treatment for primary prevention based on cardiovascular disease (CVD) risk. Randomized clinical trials for statin use in primary prevention, however, included participants with specific risk factor profiles.

Hypothesis:
For most individuals in the general population recommended for primary prevention of CVD with statins direct trial evidence is available. Evidence of benefit may be available for persons currently not recommended treatment.

Methods:
We used data from 8925 participants (57% women), aged 45-79, free of CVD from the population-based Rotterdam Study to compare treatment recommendations by the ACC/AHA and ESC guidelines, with eligibility for any of 10 major statin trials.

Results:
The ACC/AHA guidelines recommend statin use in 3196 (83.2%) men and 2611 (51.4%) women; the ESC guidelines in 1992 (51.8%) men and 1702 (33.4%) women (95.3% overlap with ACC/AHA). A total of 2243 (58.4%) men and 2438 (48.0%) women met the eligibility criteria for at the least one trial. Guideline recommendations and trial eligibility overlapped for 2245 (25.2%) participants (Figure). A total of 2480 (27.8%) participants would be considered for statin initiation solely by the ACC/AHA and/or ESC guidelines, while 1180 (13.2%) would have been eligible for at the least one trial and would not be recommended for statin therapy based on the guidelines (Figure). Correspondence of guideline recommendations with trial eligibility varied greatly by trial, with virtual complete alignment for trials done in individuals with diabetes, while for trials done in individuals with hypercholesterolemia alignment was poor.

Conclusions:
For the majority of persons recommended for lipid-lowering therapy in primary prevention, efficacy of statins has been established. Statins have been proven efficacious in many persons currently not recommended for treatment.
Abstract 16293: Predictors of Late Presentation After an ST Elevation Myocardial Infarction
Authors: Bolorunduro Oluwaseyi , Smith Blake , Chumpia Mason , Valasareddy Poojitha , Heckle Mark , Crouse Mary , Zambetti Benjamin , Ellis Robert , Hwang Inyong , Efeovbokhan Neffertiti , Khouzam Rami , Reed Guy , Ibebuogu Uzoma
Published: March 2022

Introduction:
Time to reperfusion has been shown to be a major predictor of mortality after an ST elevation myocardial infarction (STEMI). Reducing delays to ER presentation should significantly improve time to reperfusion. This study sought to explore the factors that predict late presentation to ER after STEMI.

Methods:
A retrospective analysis was conducted using data from our tertiary institution 2008-2013. All patients admitted for STEMI during this period were identified. The “Symptom onset to door time (SODT)” was computed and a binary outcome variable (late presentation) was defined as a SODT >180 minutes. The role of patient demographics, insurance status, socioeconomic factors, mode of transportation, and comorbidities were controlled for in the multivariable regression analysis to identify the predictors of late presentation. A subset analysis was conducted excluding patients transferred from outlying facilities.

Results:
During this period, 1144 patients were admitted for acute STEMI, with 348 of these patients having been transferred from outlying facilities. Mean age was 59 (+12.8) years, males accounted for 67% of this population, 28% had private insurance, 50% had public insurance and 22% were uninsured; 56% of this population was Black. 47.5% of patients presented after 180 minutes. On bivariate analysis, blacks, older age, insurance status, female gender and a family history of coronary artery disease were predictors of late presentation after STEMI. On controlling for confounders in our model, the only significant predictors for late presentation were race and insurance status. A subset analysis excluding transferred patients showed qualitatively similar results.

Conclusion:
Minority patients, publically insured and uninsured patients are more likely to present late after a STEMI, this difference in time to presentation may be a surrogate for health literacy in these populations and may be ameliorated by better health education.
Abstract 16305: Cardiac and Circulatory Adaptation to Volume Overload: The Impact of Reduction of High-flow Arterio-venous Fistula
Authors: Wohlfahrt Peter , Rokosny Slavomir , Balaz Peter , Palous Daniel , Melenovsky Vojtech
Published: March 2022

Introduction:
Heart failure is present in one out of three patients on hemodialysis and is the leading cause of death. Because increased blood flow through the arteriovenous fistula (AVF) leads to volume overload potentially causing high-output heart failure, reduction (e.g. aneurysmorrhaphy) or occlusion of a hyperfunctional AVF (hAVF) is commonly performed. However, there are no clear indications for these procedures. The aim of this study was to evaluate the impact of aneurysmorrhaphy on hemodynamics and cardiac structure in patients with hAVF.

Methods:
Thirty patients (age 52 ± 12 years, 73% male) with hAVF (flow ≥ 1.5 L/min) were examined before, at 6 and 12 months after aneurysmorrhaphy.

Results:
Relationship between AVF flow and cardiac index (CI) was weak and nonlinear. In total, 16 patients had normal CI (2.5 - 3.8 L/min/m2) and 14 high CI (4.0 - 6.0 L/min/m2). While the AVF flow did not differ between groups (3.1±1.4 vs. 3.5±0.8 L/min, p=0.34), there was a difference in CI (3.3±0.7 vs. 4.7±0.5, p<0.001). After operation AVF flow significantly and similarly decreased in both groups, while CI decreased only in the high CI group (Table 1). Similarly, there was a significant decrease in left ventricular end-diastolic diameter and mass, left atrial and right ventricular diameter and pulmonary systolic pressure in the high CI, but not in the normal CI group (Table 1).

Conclusions:
Aneurysmorrhaphy of a hAVF leads to positive heart remodeling only in patients with elevated CI. Increased CI, but not increased AVF flow, should be used as an indication for aneurysmorrhaphy.