bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 19131: The Advanced Life Support Termination of Resuscitation Rule: A Local Evaluation of the Impact on Termination Rates
Authors: Nas Joris , Bonnes Judith L , Verhaert Dominique V , Keuper Wessel , van Grunsven Pierre , de Boer Menko-Jan , Smeets Joep L , Brouwer Marc A
Published: July 2021

Introduction:
Termination of Resuscitation (TOR) rules have been designed to guide in-field termination decisions and reduce futile hospital transportations. The impact of such a rule may depend on regional infrastructure, arrest characteristics and pre-existent termination rates. Our region is characterized by high rates of bystander cardiopulmonary resuscitation (CPR), and Advanced Life Support (ALS) trained rescuers authorized to make termination decisions. We aim to investigate the actual in-field termination rates and the termination rates as recommended by the ALS-TOR rule. Furthermore, we studied factors associated with the actual termination decisions.

Methods:
Cohort of out-of-hospital cardiac arrest patients who were resuscitated in the Nijmegen area, the Netherlands (2008-2011). The ALS-TOR rule recommends termination in case all following criteria are met: unwitnessed arrest, no bystander CPR, no shock delivery, no return of spontaneous circulation (ROSC).

Results:
The observed percentage of in-field termination was 46% (275/598), while the ALS-TOR rule recommended termination in only 6% (35/588), owing to high percentages of witnessed arrests (73%) and bystander CPR (54%) in our region. Factors independently associated with the actual decisions to terminate resuscitation were absence of ROSC [aOR 35.6 (95% CI 18.3-69.3)], non-shockable initial rhythm [aOR 6.0 (95% CI 3.2-11.0)], unwitnessed arrest [aOR 2.7 (95% CI 1.4-5.2)], non-public arrest [aOR 2.5 (95% CI 1.2-5.0)] and longer EMS-response times [aOR 1.1 per minute increase (95% CI 1.0-1.2)].

Conclusions:
Contrary to previous studies, implementation of the ALS-TOR rule in our region would have decreased termination rates from almost half to less than 10% due to the favourable arrest characteristics. In light of the prognosis after OHCA, this finding suggests that adherence to this set of criteria does not contribute to efficient triage in our population. Therefore it seems prudent to locally evaluate the utility of the ALS-TOR rule prior to implementation.
Abstract 19135: Impact of New Cardiac Conduction Disturbances After TAVI on Myocardial Contractility and Mortality
Authors: Dimitriadis Zisis , Scholtz Smita , Scholtz Werner , Wiemer Marcus , Piper Cornelia , Ensminger Stephan , Fox Henrik , Horstkotte Dieter , Faber Lothar
Published: July 2021

Introduction:
Our study aimed to evaluate the impact of procedure-related cardiac conduction disturbances (CCD) on myocardial performance (standard and speckle-tracking-based LV function parameters) after transfemoral aortic valve implantation (TAVI TF).

Hypothesis:
New cardiac conduction disturbances after TAVI impair LV function and morphology as well as survival.

Methods:
Between 2010 and 2013, 168 patients (pts.) underwent TAVI TF using the Core Valve at our institution. 95 of them with complete follow-up (mean follow up 264± 241 days) were evaluated with respect to the presence of new CCD and their effect on myocardial performance.

Results:
Aortic valve orifice and mean gradient significantly improved (from 0.7 ± 0.2 to 1.8 ± 0.4 cm
2
, p<0.001 and from 42.4 ± 17.7 to 8.3 ± 4.0 mmHg, p<0.001, respectively). After TAVI, 37.9% of pts. presented with new CCDs. Pts. without additional CCDs showed an improvement of left ventricular systolic and diastolic function (LVEF from 43.7 ± 16.5% to 48 ± 16.2%, p= 0.004; E/A-ratio from 1.4 ± 1.0 to 1.0 ± 0.9, p= 0.006), whereas pts. with procedure-related CCDs had a mild LVEF deterioration (from 51.8 ± 13.9% to 47.3 ± 8.5%, p=0.16). Comparison of the changes between groups without and with CCDs revealed significant differences (Table 1). However, on Kaplan Meier analysis survival was not significantly different between both groups (p=0.73).

Conclusions:
Procedure-related conductions abnormalities after TAVI impair LV function, however in our pt. cohort with no impact on overall survival.
Abstract 19177: Loss of Coronary Perfusion Efficiency in Microvascular Disease
Authors: Lumley Matthew , Ryan Matthew , Asrress Kaleab , Williams Rupert , Ari Satpal , Ellis Howard , Briceno Natalia , Redwood Simon , Clapp Brian , Marber Michael , Perera Divaka
Published: July 2021

Introduction:
Coronary Microvascular Disease (MVD) is associated with an unfavorable prognosis, even in the absence of significant epicardial disease. The pathophysiological basis of increased cardiac events is unclear. The aim of this study was to characterize the forces that govern myocardial perfusion at rest and during stress.

Methods:
Patients with chest pain syndromes requiring Fractional Flow Reserve (FFR) assessment were screened and those with a FFR>0.80 were included. MVD was defined by coronary flow reserve (CFR) < 2.0. Controls were those with CFR>2.0. Simultaneous intracoronary pressure (P
d
) and flow velocity (U) recordings were made at rest and hyperemia. Microvascular Resistance (MR)= P
d
/U. Wave intensity = dP
d
/dt x dU/dt and wave separation analysis was used to identify the waves that accelerate and decelerate flow. The proportional contribution of accelerating waves was assessed as an index of coronary perfusion efficiency.

Results:
39 consecutive patients were enrolled, 21 had MVD and 18 comprised controls. The groups were matched for atherosclerotic risk factors, rate-pressure-product and P
d
. Coronary flow velocity in MVD patients was higher at rest (21.5±6.4 vs. 14.1±4.5cms
-1
, p < 0.001) but lower during hyperemia (28.3±13.0 vs. 45.1±13.1cms
-1
, p < 0.001) compared to controls. While resting MR was lower in MVD (501±162 vs. 755±262 mmHg.cm
-1
.s, p = 0.001), hyperemic MR was significantly lower in controls. At rest the magnitude of the accelerating waves was higher in the MVD group than controls. The percentage contribution of accelerating waves increased with hyperemia in controls but decreased in MVD patients (figure).

Conclusion:
MVD manifests as resting microvascular dilation as well as diminished response to stress. While the normal heart has improved efficiency during hyperemia, in MVD efficiency decreases and as a result, flow augmentation is attenuated. These processes render the myocardium more susceptible to ischemia.
Abstract 19197: No Difference in Retention of BLS/AED Skills When Teaching Laypersons Using Four-stage and Two-stage Teaching Technique: A Randomized Comparison
Authors: Bjørnshave Katrine , Krogh Lise Q , Hansen Svend B , Nebsbjerg Mette A , Thim Troels , Løfgren Bo
Published: July 2021

Introduction:
The ability of laypersons to perform BLS/AED increases immediately after resuscitation training. Studies indicate that resuscitation skills rapidly decay after initial training, however it is unknown whether teaching technique influence retention of skill.

Aim:
To study the retention of BLS/AED skills three months after training when teaching laypersons using a four-stage and two-stage teaching technique.

Methods:
Laypersons (exclusion: health care professionals/students) were randomized to a standardized ERC BLS/AED courses using the four-stage teaching technique or to courses with the same content but modified to a two-stage teaching technique. Participants were tested in a simulated cardiac arrest scenario three months (±five days) after their course to assess retention of BLS/AED. Tests were video recorded and reviewed by two independent assessors blinded to training technique. Skills were assessed using the ERC BLS/AED assessment form. The primary endpoint was passing the test (17 out of 17 skills adequately performed).

Results:
A total of 160 participants were included in the study. No difference was found in pass rate immediately after training (diff. -1.6%; 95%CI -17.9%; 14.6%). There was no statistical difference in retention of BLS/AED skills (pass rate: both 11%, diff. -0.4%; 95%CI -28%-27%) three months after training . Total average skills adequately performed (of 17) were 13.7 versus 13.3 among laypersons trained with the four-stage (n=64) and the two-stage technique (n=64). No difference was found in number of chest compressions delivered per compression cycle (29±2.8 vs 30±3.1), chest compression rate (107±17 vs 108±19 minute-1), chest compression depth (46±11 vs 43±12 mm), number of effective rescue breaths between compression cycles (1.6±0.7 vs 1.6±0.5) and tidal volume (0.6±0.4 0.7±0.4 L).

Conclusion:
We found no difference in retention of BLS/AED skills among laypersons taught using a four-stage teaching technique compared to a two-stage teaching technique.
Abstract 19201: Clinical Impact of Cardiac Regenerative Therapy With Autologous Skeletal Stem Cell Sheet Implantation on Treating Severe Heart Failure
Authors: Domae Keitaro , Miyagawa Shigeru , Toda Koichi , Nakamura Teruya , Yoshikawa Yasushi , Fukushima Satsuki , Saito Shunsuke , Yoshioka Daisuke , Saito Atsuhiro , Shimamoto Tomomi , Kuratani Toru , Ueno Takayoshi , Sawa Yoshiki
Published: July 2021

Background:
Transplantation of autologous somatic tissue-derived cells into the heart has been shown to yield functional recovery of the failing heart via “paracrine effects” that enhance the native regenerative process. We have introduced skeletal stem cell (SSC) sheet methods for treating severe heart failure (HF), in which scaffold-free cell-sheets are attached on the epicardial surface to maximize the paracrine effects. We herein report feasibility, safety and efficacy of SSC sheet transplantation for treating advanced HF.

Methods:
This study enrolled 27 patients (mean age, 51±15 years, DCM in 15 patients and ICM in 12 patients) with chronic advanced HF despite optimum treatments. Scaffold-free cell-sheets containing SSC (average: 3.5±1.9х108 cells) was transplanted over the left ventricular (LV) free wall via the left thoracotomy. Average follow-up was 2.5 (0.6-5.1) years.

Results:
All patients discharged from the hospital without procedure-related complications. Re-In-hospital treatment for congestive HF was required in 8 patients, who we defined as non-responder (Group N: n=8), while the other patients who were free from in-hospital cardiac treatments were defined as responder (Group R: n=19). The Group R exhibited decreased NYHA functional class (2.8±0.6 to 1.6±1.1 p<0.05) and increased 6-minute walk test (444±110 to 499±114m p<0.05) at 6 months, while these values maintained until the latest follow-up. Echocardiographically, LV systolic and diastolic diameters significantly decreased and ejection fraction significantly increased. In addition, both LV end-systolic and diastolic wall stress, assessed by cardiac CT scanning, significantly decreased (systolic: 377±76 to 317±88, diastolic: 116±98 to 51±32 kdynes/cm2, p<0.05 respectively) in the Group R. Multivariate analysis showed that preoperative duration of HF was a single independent risk factor for Group N with its hazard ratio 1.8 (p<0.05). Three-year freedom from cardiac death was 92%, while that from recurrence of HF was 70%.

Conclusions:
SSC sheet transplantation was feasible and safe in advanced HF patients. Functional recovery, including reduced LV wall stress, was gained in the selected patients, who received this treatment in early stage of advanced HF.
Abstract 19204: Higher Physical Activity and Lower Sedentary Time are Associated With Less Insulin Resistance and Favorable Adipokine Profile: The Framingham Study
Authors: Spartano Nicole L , Stevenson Meredith D , Xanthakis Vanessa , Larson Martin G , Andersson Charlotte , Murabito Joanne M , Vasan Ramachandran S
Published: July 2021

Background:
Physical activity (PA) and sedentary time (ST) are associated with metabolic diseases. More PA and less ST may also be associated with a more favorable adipokine profile and greater insulin sensitivity, even in the absence of weight loss. We tested this hypothesis by relating a comprehensive panel of adipokines in relation to accelerometry-determined PA measures in a community-based cohort.

Methods:
We assessed PA and ST using Actical accelerometers in 2109 participants from Framingham Heart Study Generation 3 and Omni 2 cohorts (mean age 40 y, 54% F) free of diabetes. Circulating adipokines, C-reactive protein (CRP), insulin-like growth factor (IGF)-1 and insulin resistance (HOMA-IR) were dependent variables, and steps/day, moderate to vigorous PA (MVPA), and ST/weartime were independent variables in multivariable regression analyses. We adjusted for cohort, age, sex, season of exam, overnight wear, residence (New England or other), body mass index (BMI), cardiovascular disease, hypertension, and smoking. Models for PA were also adjusted for ST, and models for ST also adjusted for MVPA.

Results:
Overall, 49% of participants met the PA Guidelines (>150 min/wk MVPA). Higher MVPA and more steps per day were associated with lower insulin resistance and CRP levels. More steps were also associated with lower leptin and higher IGF-1 levels. ST was positively associated with insulin resistance (p<0.001), but this relation was not significant after adjusting for MVPA. ST was associated with higher leptin, adipocyte fatty acid-binding protein (FABP)4 and retinol binding protein (RBP)4 levels.

Conclusions:
Our cross-sectional study of a community-based sample demonstrated associations of PA and ST with metabolic factors and several adipokines, after adjusting for BMI. These findings may provide clues linking PA to cardiometabolic risk by influencing insulin resistance and inflammation, compared to ST potentially modulating fatty acid binding proteins.
Abstract 19222: Hypoxia Regulated Circular RNAs Control Endothelial Cell Functions
(Best of Basic Science Abstract)
Authors: Heumüller Andreas W , Boeckel Jes-Niels , Jaé Nicolas , Ponomareva Yuliya , Chen Wei , Boon Reinier A , John David , Zeiher Andreas M , Uchida Shizuka , Dimmeler Stefanie
Published: July 2021

Circular RNAs (circRNAs) are non-coding RNAs generated by back-splicing. Back-splicing has been considered as a rare event, but circRNAs were recently found to be abundantly expressed among a variety of human cells and tissues. Nevertheless, the expressional regulation, processing and biological functions of circRNAs are largely unknown. Cytoplasmic circRNAs can bind and trap microRNAs, whereas nuclear circRNAs may affect host gene expression. However, the expression, regulation and functions of circRNAs in endothelial cells have not been determined so far.

In this study, basal expression and regulation of circRNAs by hypoxia in human umbilical endothelial cells (HUVEC) were analyzed using deep sequencing. Among the identified 7,388 circRNAs, 2,875 had not been annotated before. We further validated the expression of 40 selected circRNAs by RT-PCR and found that the majority is resistant to RNase R digestion, lacks polyadenylation and is localized to the cytoplasm. Cloning and subsequent sequencing validated the newly generated back splice sites for selected circRNAs. Furthermore, analysis of RNA-seq data revealed that circRNAs, particularly the cytoplasmatic circular RNA cZNF292, are significantly regulated by hypoxia in HUVECs. The siRNA-mediated knockdown of HIF-1α had no effect on cZNF292 induction under hypoxia, suggesting a HIF-1α independent regulation. Most importantly, siRNA-mediated knockdown of cZNF292 significantly reduced spheroid sprouting and network formation of endothelial cells. Furthermore, knockdown of cZNF292 had no effect on its host gene expression. Exon array analysis after cZNF292 knockdown revealed a significant expressional upregulation of 167 as well as a significant expressional downregulation of 123 genes of which most were associated with metabolic processes according to GO annotation. Analysis of Ago-HITS-CLIP data revealed no putative miR-binding sites, suggesting that cZNF292 does not act as a miR-sponge.

Taken together, we show for the first time the expression, regulation and function of circRNAs in endothelial cells. The circRNA cZNF292 is regulated by hypoxia and has an important angiogenic function in endothelial cells.
Abstract 19234: Exercise Echocardiography is Efficacious With Superior Cost Profile Compared to Exercise ECG as First Line Test in Patients With no History of Coronary Artery Disease and New Suspected Stable Angina; A Randomized Prospective Study
Authors: Zacharias Konstantinos , Ahmed Asrar , Gurunathan Sothinathan , Shah Benoy N , Senior Roxy
Published: July 2021

Introduction:
Exercise ECG (ExECG) is the initial investigation of choice according to AHA/ACC guidelines in patients with suspected stable angina, normal ECG and able to exercise.We hypothesized that Exercise Stress Echo (ESE), given its high feasibility (with contrast use) and superior diagnostic accuracy would confer a cost advantage over ExECG.

Methods:
Consecutive consenting patients with no previous history of coronary artery disease (CAD) and a calculated pre-test CAD risk of >10%, seen in our Rapid Access Clinic and able to exercise on the treadmill, were randomized into same day ExECG or ESE.Tests were classified as positive, negative or inconclusive for ischemia. Patients with negative tests were discharged from the clinic, with inconclusive tests were offered additional tests and with positive tests were offered Coronary Angiography (CA). Cost to diagnosis was calculated using the NHS tariff by adding the cost of all requested investigations up to an including CA on an intention to treat basis. Follow-up data on Death, Myocardial Infarction and Unplanned Revascularization were collected for a period of at least 1 year after the enrollment of the last study patient.

Results:
A total of 194 patients underwent ExECG (mean age 53, 66% male) and 191 patients ESE(mean age 55, 70% male).There were no significant differences in age, gender and in prevalence of diabetes mellitus, smoking and hyperlipidemia. Pre-test probability of CAD was also similar(39% vs. 40% p=0.6). Results of ExECG were:108(55.7% Negative), 14 (7.2%) Positive, 72(37.1%) Inconclusive and of ESE:191(94.8%) Negative, 9 (4.7%) Positive, 1(0.5%) Inconclusive. The positive predictive value for patients undergoing CA after a positive ESE was higher than that for positive ExECG (9/9 vs 9/14 p=0.04). Average cost to diagnosis was significantly lower for ESE vs Ex ECG (
£
265 vs
£
331p=0.02). Over a mean follow-up period of 21±5 months there was no significant difference in cardiac event rates (1% vs. 0% p=0.1) in the ESE vs. ExECG groups.

Conclusion:
In this first randomized study, same day ESE was shown to be feasible, efficacious conferring superior cost advantage when compared to ExECG. This study suggests that ESE could be used as first line investigation in patients with suspected stable angina.
Abstract 19284: Myocardial Perfusion Imaging Has a Higher Rate of False Positivity Compared to CT Angiography in Intermediate Risk Chest Pain Patients Undergoing Catheterization
Authors: Mukundan Shey , Levsky Jeffrey , Spevack Daniel , Travin Mark
Published: July 2021

Introduction:
Although noninvasive testing continues to hold an important role in the assessment of chest pain, imprecise categorization of coronary artery disease (CAD) severity may lead to unnecessary invasive procedures. We compared the frequency with which noninvasive tests were falsely positive for severe coronary stenosis in patients hospitalized for intermediate risk chest pain who underwent cardiac catheterization.

Methods:
We identified 400 subjects hospitalized with chest pain, who had been randomized to either myocardial perfusion imaging (MPI) [n=200] or coronary CT angiography (CTA) [n=200] as part of a clinical trial. Invasive angiography, performed at the discretion of the treating physicians within one year following noninvasive testing, occurred in 30 subjects assigned to CTA and in 32 assigned to MPI. MPI, CTA and invasive angiogram exams were each interpreted for the presence or absence of severe coronary stenosis (>70% diameter) by the study investigators.

Results:
Subjects catheterized were 60 ± 10 years, 52% female, 55% obese, 42% diabetic, 76% hypertensive and 48% smokers. On presentation, chest pain occurred for greater than 15 minutes in 66%, while 78% had an abnormal ECG. Amongst those catheterized, false positivity was common in the MPI group (n=11, 34%) and was rare in the CTA group (n=2, 7%), p< 0.01. The odds for false positivity were increased in those undergoing MPI, odds ratio 6.9 [95% confidence interval: 1.1, 72.1, p = 0.02]. On multivariate analysis, after considering multiple clinical and electrocardiographic potential contributors to false positivity, the presence of slight ST segment depression (< 1mm) on presenting ECG was the only independent predictor of having a false positive MPI exam.

Conclusion:
In patients having catheterization for intermediate risk chest pain, the rate of falsely positive noninvasive test was substantially higher in those having MPI compared to those undergoing CTA.
Abstract 19308: Metoprolol Protects Against AMI Through the Inhibition of Psgl1-Dependent Neutrophil-platelet Interactions
Authors: Garcia-Prieto Jaime , Garcia-Lunar Ines , Gomez-Parrizas Monica , Fernandez-Jimenez Rodrigo , Pizarro Gonzalo , Sreeramkumar Vinatha , Villena-Gutierrez Rocio , Martinez-Bourio Rafael , Hidalgo Andres , Fuster Valentin , Ibanez Borja
Published: July 2021

Introduction:
Early intravenous administration of metoprolol has been shown to reduce infarct size and improve long-term cardiac function in the randomized clinical trial METOCARD-CNIC led by our group. However, the mechanisms underlying its favorable benefits remain unclear. PSGL1-dependent neutrophil-platelet interactions have critical implications on microvascular obstruction and neutrophil infiltration both of which determine the extent of infarct size. We hypothesized that intravenous administration of metoprolol before reperfusion blocks neutrophil-platelet interactions formation limiting the extent of infarct size.

Methods & Results:
Using a mouse model of myocardial ischemia/reperfusion injury we confirmed that intravenous metoprolol administration prior to reperfusion significantly reduces infarct size. Neutrophil migration and infiltration evaluated in the injured myocardium after 6h of reperfusion was reduced in metoprolol’s treated mice. Neutrophil depletion, lack of beta-1-adrenergic receptor and PSGL1 blockade abrogated metoprolol’s cardioprotective effect. Interestingly, restitution of β1AR expression in circulating cells rescues the metoprolol′s cardioprotection. With a model of intravital microscopy we showed metoprolol systemic administration reduces neutrophil-platelet interactions after TNFα local inflammation. Additionally, metoprolol was capable to reduce epinephrine-induced neutrophil-platelet coaggregates formation in human blood. Finally, the extent of microvascular obstruction evaluated by cMRI in METOCARD-CNIC patients was significantly reduced by the pre-reperfusion administration of metoprolol.

Conclusion:
Intravenous administration of metoprolol exerts cardioprotection against AMI by inhibiting acute deleterious neutrophil-platelet interactions at reperfusion.
Abstract 19325: Hemodynamic Effects of Guideline-compliant Asynchronous vs. Synchronous Ventilations During Cardiopulmonary Resuscitation in a Porcine Model
Authors: Skåre Christiane , Olasveengen Theresa , Kramer-Johansen Jo , Nordum Fredrik , Morten Eriksen , Norseng Per Andreas , Skjerven-Martinsen Marianne , Wik Lars
Published: July 2021

Background:
Current guidelines for cardiopulmonary resuscitation (CPR) emphasize reducing pauses in chest compressions, and suggest ventilating with 1 second inspiration time and with enough volume to produce normal chest rise 10 times per minute. No specific advice is provided on how ventilations should be timed with ongoing chest compressions. We have compared hemodynamic effects of ventilating synchronously vs. asynchronously during chest compressions in a porcine model.

Methods:
Twenty anaesthetized domestic pigs (approx. 30 kg) were randomized into two groups; synchronous vs. asynchronous ventilation. Ventricular fibrillation is induced electrically and left for 2 minutes before initiation of basic 30:2 CPR for 4 minutes. CPR with continuous mechanical chest compressions was continued for another 8 minutes with either synchronous or asynchronous ventilation before defibrillation was attempted. Aortic, right atrial and intracerebral pressures, carotid and cerebral blood flow and cardiac output (thermodilution) were measured. Airway monitoring included capnography and spirometry.

Results:
Hemodynamics, blood gas analysis and airway pressures were similar for both groups during baseline and 30:2 CPR periods. The asynchronous group had higher median peak inspiratory airway pressure (94 vs. 57 cm H
2
O, p<0.001) and lower EtCO
2
(1.8 vs. 3.5 kPa, p=0.023) compared to synchronous group during the last 30 seconds of CPR (after 12 minutes). Asynchronous group also had higher pH (7.55 vs. 7.35, p<0.001), lower pCO
2
(2.4 vs. 4.7, p<0.001) and higher pO
2
(62.1 vs. 29.4, p<0.001) compared to synchronous group. There were no significant differences in any of the measured hemodynamic variables between the two groups with similar coronary and cerebral perfusion pressures. ROSC was achieved in 5/10 vs. 3/10 animals in the synchronous and asynchronous groups, respectively.

Conclusion:
Synchronous and asynchronous ventilation during mechanical chest compressions provide similar hemodynamics, but guideline-compliant asynchronous ventilation yields significantly higher airway pressures and hyperventilation. Implications for lung injury need to be assessed.
Abstract 19334: Management and Outcomes of Acute Retrograde Type A Aortic Dissection: Insights From the International Registry of Acute Aortic Dissection
Authors: Nauta Foeke J , Kim Joon Bum , Patel Himanshu J , Peterson Mark D , Eckstein Hans-Henning , Conklin Lori D , Khoynezhad Ali , Ehrlich Marek P , Di Eusanio Marco , Della Corte Alessandro , Montgomery Daniel G , Isselbacher Eric M , Eagle Kim A , Nienaber Christoph A , Sundt Thoralf M , Trimarchi Santi
Published: July 2021

Background:
Presentations and outcomes of acute aortic dissection (AD) with an entry tear in the ascending aorta may differ from retrograde dissection with an entry tear in the descending aorta. However, guidelines recommend urgent surgical repair for both entities.

Methods and Results:
All patients with AD enrolled in the International Registry of Acute Aortic Dissection (IRAD) between 1996 and 2014 were analyzed. We identified 99 patients (67 men; 63.2±14.0 years) with an entry tear in the descending aorta and retrograde extension into the arch or ascending aorta. Overall, independent predictors of retrograde type A AD were increasing age(OR 1.0; 95% CI, 1.0 to 1.0; P=0.004), history of cocaine abuse (OR 4.9; 95% CI, 1.7 to 13.6; P=0.003), back pain at presentation (OR 2.1; 95% CI, 1.3 to 3.3; P=0.002), and non-white race (OR 0.4; 95% CI, 0.2 to 0.6; P<0.001). During initial hospitalization, 44 of these patients were managed medically (MED), 33 with open surgery(SURG) and 22with endovascular therapy (ENDO). Patients in the SURG group presented with larger ascending aortic diameters than MED and ENDO patients (P=0.04). The majority of the MED (72.7%) and ENDO (86.4%) patients had AD extension confined to zone 1 (proximal arch, P<0.001), whereas most of the SURG patients (71.8%) presented with AD extension into zone 0 (proximal to the innominate artery, P<0.001). Early (30-day or in-hospital) mortality rates of the MED, SURG and ENDO groups were 9.1%, 18.2%, and 13.6%, respectively (P=0.51), with 5-year survival of 86.7%, 80.0%, and 90.9%, respectively (mean follow-up, 3.3 years, log rank P=0.67). A trend of favorable early mortality was observed in patients with retrograde extension till zone 1 (8.6%) versus into zone 0 (18.6%, P=0.14).Early mortality of patients with retrograde type A AD (12.9%) was lower than those with type A AD (20.0%, P=0.001), while 5-year survival was similar (86.8% and 89.5%, respectively, mean follow-up, 3.0 years, log rank P=0.96).

Conclusion:
There is a subset of patients with acute retrograde type A AD who can be managed non-operatively with acceptable short and long-term results. This implies that a selective approach may be reasonable, particularly among those with proximal extension limited to the arch distal to the innominate artery.
Abstract 19337: Transcoronary Delivery of Allogeneic Cardiac Stem Cells Reduces Ventricular Arrhythmia Inducibility in a Post Myocardial Infarction Swine Model
Authors: Loughlin Gerard , Ruiz Hernandez Pablo M , Avila Pablo , Crisostomo Veronica , Sanz Ricardo , Fernandez-Portales Javier , Baez-Diaz Claudia , Baez-Diaz Claudia , Blazquez Rebeca , Datino Tomas , Torrecilla Esteban G , Atienza Felipe , Perez-David Ester , Sanchez-Margallo Francisco M , Bermejo Javier , Fernandez-Aviles Francisco , Arenal Angel
Published: July 2021

Introduction:
Post myocardial infarction (MI) patients are at risk of scar related ventricular tachycardia (VT).

Hypothesis:
Stem cell therapy reduces post-MI scar size, potentially leading to a reduction in the risk of ventricular arrhythmias (VA).

Methods:
A post-MI scar model of VT was created by transient occlusion of the mid left anterior descending artery in 56 swine. Five weeks after infarct creation 29 subjects were treated with allogeneic cardiac stem cells (CSC): 10 underwent transcoronary delivery of CSC, 9 direct transepicardial delivery (via a minithoracotomy) and 10 underwent a combined transcoronary and VT substrate guided (late potentials) direct transendocardial CSC delivery procedure using an electroanatomic mapping system. Of the remainder, 8 subjects underwent a “sham” transepicardial procedure and 19 served as controls. Seventeen weeks after infarct creation an electrophysiological study was performed in each subject to assess for ventricular arrhythmia inducibility. VA inducibility was compared in each group vs. the control group.

Results:
Of the 19 control subjects, 17 were inducible (89,5 %). As presented in the figure, CSC delivery with a combined transcoronary/transendocardial approach was associated with a significant reduction in VT inducibility rates compared to controls (20 % vs. 89,5 %; p value 0,001). Subjects treated with transcoronary CSC also experienced significantly lower VA inducibility rates (40 % vs. 89,5 %; p value 0,009). There were no differences in VA inducibility compared with controls in patients in the “sham” (62,5 % vs 89,5 %; p value 0,136) or the transepicardial group (66,7 % vs 89,5 %; p value 0,290).

Conclusions:
Combined transcoronary and VT substrate-guided transendocardial CSC delivery is associated with a significant reduction in VA inducibility in a post-MI swine model. Future human studies should evaluate the effects of allogeneic CSC therapy on ventricular arrhythmia burden in post-MI patients.
Abstract 19359: Local Injection of First Trimester Human Umbilical Cord Perivascular Cells (FTM-HUCPVCs) After Myocardial Infarction Increases Extracellular Matrix Processing Activity, Vascular Density and Blood Vessel Size Within the Infarct Scar
Authors: Szaraz Peter , Lucato Alexandra , Li Shu Hong , Wu Jun , Gauthier-Fisher Andree , Li Ren-Ke , Librach Clifford L
Published: July 2021

Introduction:
During myocardial infarction (MI) the ischemic heart muscle loses a substantial number of cells, and a poorly vascularised fibrotic scar forms. We previously showed that local injections of first trimester human umbilical cord perivascular cells (FTM-HUCPVCs) diminish scar tissue and significantly improve cardiac output after MI in rats.

Hypothesis:
We hypothesised that FTM-HUCPVCs induce superior tissue remodeling and revitalization post-MI by 1: elevating ECM processing gelatinase/collagenase activity, 2: increasing blood vessel penetration and revascularisation of the infarct scar.

Methods:
MI was induced by left ventricular coronary artery ligation on 8 week old Foxrnu rats. 1 week post-MI, FTM-HUCPVC, term HUCPVC or human BMSC (n=6 per group) were injected into the injured myocardium (3X106 cells each). Histology was performed 2 weeks after cell implantation. In situ gelatinase activity was assessed by fluorescent gelatinase substrate (DQ gelatin). Vascular density was assessed by endothelium-specific fluorescent isolectin (IB4). Fluorescent microscopy images were quantified for vascular density and blood vessel size by ImageJ (6 sections per heart, 9 random fields per section). Statistical analysis: ANOVA.

Results:
FTM-HUCPVC treatments resulted in increased fluorescent gelatine signal in the scar tissue of post-MI rat hearts (A) and displayed gelatinase activity in a structured pattern. Vascular density of the ischemic myocardium (B) was significantly higher (p<0.01) in FTM- and term HUCPVC treated hearts compared to untreated (C). BMSC treatment did not result in significant improvement. Median area of blood vessel cross-sections was the highest after FTM-HUCPVC treatment and significantly higher (p<0.01) than of BMSC treated hearts.

Conclusion:
FTM-HUCPVCs induce superior ECM processing and revascularisation in scar tissue after myocardial infarction compared with later gestation HUCPVCs and BMSCs.
Abstract 19363: Prevention of Progressive Worsening of Heart Failure Over Time With The Angiotensin-receptor Neprilysin Inhibitor Sacubitril/valsartan (lcz696)
Authors: McMurray John , Jhund Pardeep , Gong Jianjian , Rouleau Jean , Lefkowitz Martin , Desai Akshay , Rizkala Adel , Shi Victor , Swedberg Karl , Zile Michael , Solomon Scott , Packer Milton
Published: July 2021

Background:
The aim of this analysis was to examine the effect of the angiotensin receptor neprilysin inhibitor (ARNI) sacubitril/valsartan (LCZ696), compared with enalapril, on progressive worsening over time in patients with heart failure and reduced ejection fraction (HF-REF) enrolled in the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidly in Heart Failure trial (PARADIGM-HF).

Methods:
In PARADIGM-HF, 4212 patients were randomized to enalapril and 4187 to sacubitril/valsartan. The primary outcome was the composite of cardiovascular (CV) death or hospitalization for heart failure (HF). To make a more comprehensive evaluation of HF worsening over time, we analysed the broader composite of CV death, HF hospitalization, emergency department visit for HF or intensification of therapy for HF (as time-to-first event) using the Kaplan-Meier (KM) method.

Results:
At baseline, 71% of patients were in NYHA functional class II and 24% in class III. Their mean LVEF was 27% and 93% were treated with a beta-blocker and 56% with a mineralocorticoid receptor antagonist. The median duration of follow-up was 27 months. The 1, 2 and 3 year KM rates for the composite outcome in the enalapril group were 16.5 (95% CI 15.5, 17.7)%, 27.6 (26.2, 29.1) and 34.8 (33.1-36.6)%, respectively. The corresponding rates in the sacubitril/valsartan group were 13.4 (12.4, 14.5), 22.1 (20.8, 23.4) and 29.5 (27.9, 31.2)%, respectively. Overall 1275 enalapril treated and 1038 sacubitril/valsartan treated patients had an event, giving a hazard ratio 0.79 (95% CI 0.73, 0.86), p<0.0001. Over the course of the trial, 55 fewer patients per 1000 treated with sacubitril/valsartan, compared with enalapril, experienced worsening (number needed to treat = 18).

Conclusions:
Even in patients with predominantly mild symptoms, well treated with evidence-based pharmacological therapy, worsening of HF over time was common, with more than a third of patients exhibiting progression within 3 years. The ARNI sacubitril/valsartan led to clinically important relative and absolute reductions in progressive worsening, compared with enalapril.
Abstract 19380: Synchronized Pulsatile Extracorporeal Life Support Preserves Left Ventricular Functions in Comparison With Continuous Extracorporeal Flow in Porcine Model of Cardiogenic Shock
Authors: Ostadal Petr , Mlcek Mikulas , Strunina Svitlana , Hrachovina Matej , Kruger Andreas , Vondrakova Dagmar , Janotka Marek , Kittnar Otomar , Neuzil Petr
Published: July 2021

Introduction:
Veno-arterial extracorporeal life support (ECLS) is increasingly used for the therapy of rapidly progressing or severe cardiogenic shock. However, it has been repeatedly shown that increased afterload associated with ECLS significantly deteriorates left ventricular (LV) performance. Recently, new ECG-synchronized pulsatile cardiac assist system was introduced that offers full circulatory support with increased diastolic and decreased systolic extracorporeal flow. The aim of the present study was to compare the parameters of LV function during standard continuous flow ECLS support and ECG-synchronized pulsatile flow ECLS in cardiogenic shock.

Methods:
Ten female swine (body weight 45 kg) underwent ECLS implantation under general anesthesia and artificial ventilation. Subsequently, acute cardiogenic shock with signs of tissue hypoperfusion was induced by global myocardial hypoxia. Hemodynamic and cardiac performance parameters were then measured at different levels of continuous or pulsatile ECLS flow (ranging from 1 L/min to 4 L/min) using arterial and venous catheters, a pulmonary artery catheter and a LV pressure-volume loop catheter.

Results:
Myocardial hypoxia resulted in a decline in mean (±SD) cardiac output to 2.3±1.2 L/min, systolic blood pressure to 61±7 mmHg and LV ejection fraction (EF) to 21±7%. Synchronized pulsatile flow was associated with significant reduction of LV end-systolic volume (ESV), increase in LV stroke volume (SV), and higher EF at all ECLS flow levels in comparison with continuous ECLS flow (Figure 1). At selected ECLS flow levels, pulsatile flow reduced also LV end-diastolic pressure (EDP), end-diastolic volume (EDV), and systolic pressure (SP) (Figure 1).

Conclusion:
Our results indicate that ECG-synchronized pulsatile ECLS flow preserves LV function in comparison with standard continuous-flow ECLS in cardiogenic shock.
Abstract 19387: Extracellular Matrix Remodelling in Porcine Coronary Arteries Upon Stent Implantation
Authors: Suna Gonca , Wojakowski Wojtek , Barallobre-Barreiro Javier , Yin Xiaoke , White Steve J , Milewski Krzysztof P , Gasior P , Buszman Piotr P , Buszman Pawel E , Hill Jonathan M , Mayr Manuel
Published: July 2021

Introduction:
Extracellular matrix (ECM) remodeling upon vascular stent injury contributes to both neointimal hyperplasia (restenosis) as well as endothelialization (propensity for thrombosis). Despite its important clinical implications little is known about ECM changes post stent implantation.

Hypothesis:
ECM remodelling, a determinant of stent healing, differs between drug-eluting (DES) and bare-metal stents (BMS).

Methods:
Using proteomics, we profile changes of vascular ECM proteins over time following implantation of DES and BMS in porcine coronary arteries in an overstretch model.

Results:
DES (n=14) or BMS (n=14) were implanted in coronary arteries of pigs. Quantitative coronary angiography and optical coherence tomography were performed at 1, 3, 7, 14 and 28 days after stent deployment. Animals were sacrificed at each of these time-points and their coronary arteries were retrieved for subsequent analysis by proteomics. A total of 126 ECM and ECM-associated proteins were identified by mass spectrometry. Within the first week after stent injury, proteins involved in inflammation and thrombosis were elevated in DES and BMS stented arteries. After one week, significant changes in regulatory ECM proteins such as small leucine rich proteins or matricellular proteins were observed. By day 28, differences between BMS and DES became apparent: basement membrane proteins as markers of cellularity were reduced in DES compared with BMS. In contrast, large aggregating proteoglycans such as aggrecan and versican were increased. Both belong to the lectican protein family that act as linkers of ECM molecules with their highly charged glycan side chains. The proteomics findings were validated by immunoblot analysis and real-time polymerase chain reaction. We were also able to detect aggrecan by immunohistochemistry in clinical specimen confirming differential expression patterns of aggrecan and versican in stented human coronary arteries.

Conclusions:
In the early course after BMS and DES implantation the ECM changes were similar. Significant differences were identified in the regulation of ECM proteins in long-term follow-up consisting of suppression of basement membrane proteins and up-regulation of large aggregating proteoglycans in DES.
Abstract 19408: Impact of Perioperative Liver Dysfunction on In-hospital Mortality and Long-term Survival in Infective Endocarditis Patients
Authors: Diab Mahmoud , Sponholz Christoph , Bauer Michael , Kortgen Andreas , Scheffel Philipp , Lehmann Thomas , Faerber Gloria , Pletz Matthias W , Doenst Torsten
Published: July 2021

Background:
Infective endocarditis (IE) is a dangerous disease with high mortality (20-40%). A leading cause of death is multi-organ failure (MODS) with liver dysfunction (LD) as major contributor. Data on LD in IE patients are scarce. We assessed the impact of preoperative - and newly occurring LD on in-hospital mortality and long-term survival in IE patients.

Methods:
We retrospectively reviewed our database for surgery of left-sided endocarditis between 1/07 and 4/13. We used the hepatic Sepsis-related Organ Failure Assessment (hSOFA) score to assess the degree of LD. We performed Chi-Square, Cox regression and multivariate analyses.

Results:
The 308 patients had a mean age of 62 ±13.9. Preoperative LD (hSOFA > 0, Bilirubin > 32 μmol/L) was present in 1/4 (n=81) of patients and was associated with severely elevated in-hospital mortality (51.9% vs.14.6% without preoperative LD, p<0.001). Newly-occurring postoperative LD developed in another quarter (n=57 of 227 patients without LD) of patients and was associated with elevated in-hospital mortality (24.6% vs. 11.2%, p<0.001). Kaplan-Meyer 5-year survival was significantly better in patients without LD (51% vs. 19.9%, p<0.01). Survival curves were practically identical after the perioperative phase was over (Fig.). Quality of life in survivors was also the same. Cox regression analysis revealed preoperative LD as independent predictor of long-term survival (adjusted hazard ratio 1.695, 95% confidence interval 1.160-2.477, p=0.009) and duration of cardiopulmonary bypass (CPB) and S. aureus infection as independent predictors of newly-occurring postoperative LD. Conclusions: LD in patients with endocarditis is a significant independent risk factor for in-hospital mortality. A considerable fraction of patients develop LD perioperatively, which is associated with cardiopulmonary bypass-duration and S. aureus infection. However, after surviving surgery, prognosis no longer seems to be predicted by LD.
Abstract 19409: β2-Adrenergic Receptor Regulation of Innate Immune Responses Following Acute Myocardial Injury
Authors: Grisanti Laurel A , Gumpert Anna , Gorsky Joshua , Repas Ashley A , Gao Erhe , Carter Rhonda L , Rabinowitz Joseph E , Koch Walter J , Tilley Douglas G
Published: July 2021

Inflammatory responses are important for cardiac remodeling and tissue repair after myocardial infarction (MI). The sympathetic nervous system is known to regulate immune responses, in large part through the β2-adrenergic receptor (β2AR), however the influence of β2AR in regulating the inflammatory response following MI is unknown. Thus, to examine the contribution of β2AR on immune cells following MI, wild-type (WT) mice were irradiated and then received β2ARKO or WT control bone marrow (BM) transplants to create immune cell-specific knockout (KO) animals. Lack of β2AR expression in BM resulted in 100% mortality from cardiac rupture within two weeks of receiving MI, in contrast to their WT counterparts that had ∼20% death. Granulocyte populations were sequestered in the spleen of β2ARKO chimeric mice resulting in reductions in post-MI infiltration of monocyte/macrophage, neutrophil and mast cell populations into the heart. Additionally, alterations in chemokine receptor levels, particularly CCR2, on BM resulted in decreased cellular migration, and use of a CCR2 antagonist in vivo recapitulated the β2ARKO chimeric mouse phenotype following MI. Administration of β2AR agonists
in vitro
and
in vivo
increased CCR2 expression and BM migration while β2AR antagonists decreased CCR2 expression and increased splenic leukocyte retention
in vivo
. Use of pepducins as allosteric modulators of β2AR signaling demonstrated the importance of β-arrestin-mediated signaling in increasing CCR2 expression and responses. The impact of β2AR deletion on BM cell CCR2 expression and migration, splenic retention of leukocytes and reciprocal cardiac leukocyte infiltration following MI could be reversed via lentivirus-mediated β2AR rescue in the β2ARKO BM prior to transplantation. These results demonstrate the critical role of β2AR in the regulation of CCR2 expression on hematopoietic cells and its importance in mounting an immune response to promote healing following acute cardiac injury.
Abstract 19419: Anti Atherogenic Effects of Micro RNA - 21
Authors: Hamed-Berair Rihab E , Agarwal Abhinav , Wysoczynski Marcin , Sithu Srinivas D , Wickramasinghe Nalinie S , Winner Millicent G , Bhatnagar Aruni , Li Yong , Srivastava Sanjay
Published: July 2021

Micro RNA-21 (miR-21), an evolutionary conserved micro RNA has been implicated in the pathogenesis of restenosis, myocardial infarction and heart failure. However, little is known about the role of miR-21 in atherosclerosis. Our data show that in vitro, LDL, oxidized LDL, acetylated LDL and LPS induced miR-21 by 2-3-fold (P<0.05) and down regulated its target protein PDCD4 in bone marrow derived macrophages (BMDM). Feeding the LDL receptor-knockout (LDLR-KO) mice with western diet (WD, 8-20 weeks) increased the abundance of miR-21 in BMDM by 1.5-fold (P<0.05). Basally, BMDM isolated from miR-21-KO mice showed induction of TNF alpha, interferon gamma, M-CSF, RANTES, IP10 and LIF by (1.5-3.0-fold); increased early and late apoptosis (2-3-fold, P<0.05); and induced PDCD4 and PTEN. We also observed 40% decrease in the survival of F4/80+ cells during differentiation of bone marrow derived cells isolated from miR-21-KO mice. Stimulation of miR-21-KO BMDM with interferon gamma+LPS polarized the macrophages to pro-inflammatory M1 phenotype (increased expression of CD11c and CD86) and decreased IL-10 formation as compared with WT BMDM. Staurosporin and oxidized lipids derived aldehyde 4-hydroxynonenal significantly increased both early and late apoptosis of miR-21-KO BMDM (2-4-fold, P<0.05). This was accompanied by increased cleavage of caspase 3. Characterization of miR-21-KO mice showed 30% decrease in white blood cells and neutrophils in KO mice. However, levels of circulating immune cells and common progenitor cells in bone marrow of miR-21-KO mice were comparable with wild type mice. Transplantation of bone marrow cells from miR-21-KO into LDLR-KO mice, followed by 12 weeks of WD increased the lesion formation (1.7-fold, P<0.05), apoptosis (3-fold, P<0.05) and necrosis (1.6-fold, P<0.05) in the aortic valve of the chimeric mice. This was accompanied by increased accumulation of macrophages in the non-necrotic areas of the lesion and decrease in lesional smooth muscle cells. Plasma cholesterol levels, and lesional collagen and T-cell levels in the miR-21 chimeric mice were comparable with wild type chimeric mice. Collectively, these data suggest that miR-21 prevents atherosclerosis by inhibiting macrophage apoptosis, necrosis and inflammation.