bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 17907: Challenges of Anticoagulation during Cardiopulmonary Bypass in Children: Impact of Low Antithrombin Levels
Authors: Manlhiot Cedric , Gruenwald Colleen E , Holtby Helen M , Brandao Leonardo R , Van Arsdell Glen S , McCrindle Brian W
Published: July 2021

Introduction:
Heparin-based anticoagulation in children is challenging as they have a high prevalence of heparin resistance. Antithrombin, one of the main natural anticoagulant inhibitors that potentiate heparin anticoagulation activity, might be a critical component of heparin response and anticoagulation effectiveness.

Objectives:
Determine the impact of antithrombin levels on anticoagulation (heparin sensitivity and effectiveness) during cardiopulmonary bypass (CPB) in children <1 year old.

Methods:
Secondary analysis of a randomized controlled trial of individualized vs weight based heparin management in 90 infants <1-year-old undergoing cardiac surgery. All analyses combined both patient groups and were used linear regression models.

Results:
As expected, older patients had higher blood antithrombin levels (relative increase of 16±6% for patients >6 months old vs. those <6 month old, p=0.009). Response to heparin, reflected by change in anti-Xa levels from baseline after the initial heparin bolus (a laboratory measure of heparin sensitivity), was highest in patients with higher baseline antithrombin circulating levels (top tier: +0.94(0.16) U/ml per 100U/kg heparin vs. middle tier: +0.89(0.19) U/ml vs. lowest tier: +0.77(0.20) U/ml, p<0.001). Those patients with very low antithrombin levels during CPB (<0.35U/ml) had much greater heparin requirements (+165(30) U/kg/hr representing an increase of 243%, p<0.001) indicating greater heparin resistance. Insufficient anticoagulation on bypass (as measured by end of bypass anti-Xa level) was associated with higher clotting potential, reflected by higher plasma levels of thrombin-antithrombin complexes (+4.8(2.4) ng/ml per anti-Xa U/ml, p=0.05), and prothrombin activation fragment 1.2 (+85(32) pg/ml per anti-Xa U/ml, p=0.008). Moreover, lower circulating antithrombin level was associated with increased D-dimer levels after CPB (+53(25) ng/ml per 0.1 U/ml antithrombin, p=0.03).

Conclusions:
Low antithrombin level is associated with resistance to heparin and decreased anticoagulation activity, ultimately leading to lower ability to suppress thrombin generation during CPB. Antithrombin supplementation may potentially individualize and improve anticoagulation.
Abstract 17910: Patients with Newly Diagnosed Diabetes Have Comparable Long Term Mortality with Known Diabetics After ST Segment Elevation Myocardial Infarction
Authors: Aggarwal Bhuvnesh , Shah Gautam , Randhawa Mandeep S , Lincoff A M , Ellis Stephen G , Menon Venu
Published: July 2021

Background:
A significant proportion of patients presenting with ST segment elevation myocardial infarction (STEMI) have newly diagnosed diabetes mellitus (DM).

Hypothesis:
Our aim was to identify patients with previously undiagnosed DM and compare their outcomes to those with known DM and without DM after STEMI.

Methods:
Consecutive patients undergoing primary PCI for STEMI at our center between Jan 2005 - Dec 2012 were included. Routinely performed admission Glycated hemoglobin (HbA1c) was utilized to identify patients with previously undiagnosed DM (HbA1c ≥ 6.5 and no history of DM or diabetes therapy). Patients were compared for in-hospital and long-term mortality based on follow up data from our institutional PCI registry.

Results:
1,734 consecutive patients underwent primary PCI for STEMI and follow up data was available for 1,566 (90%) patients. Mean age was 60 years and 67.3% were males. A quarter of the patients (24.3%, n = 382) had prior history of DM and 8% (n=95) of the remainder had undiagnosed DM. Median follow up was 35 months. Mortality was comparable in patients with known DM and newly diagnosed DM both in hospital (11.2% vs. 12.5%, p=0.87) and at long term follow up (Figure 1, 2). Mortality was significantly worse with both groups when compared with patients with no DM (In-hospital mortality 5.6%; p<0.001 for both groups).

Conclusions:
One in twelve patients presenting with STEMI have previously undiagnosed DM. Cardiologists have a unique opportunity for identification and initiation of diabetic therapy in this vulnerable population. Patients with newly diagnosed DM have similar short and long-term outcomes when compared with patients with a prior history of DM.
Abstract 17944: Effects of School-Based Interventions on Body Mass Index in Children and Adolescents: a Systematic Overview and Meta-analysis
Authors: Park Jiyoon J , Bakhet Randa , Karl Danica , Yuan Fei , Lonn Eva
Published: July 2021

Background:
Childhood obesity is a major public health threat. Various school-based interventions (SBIs) to prevent obesity through physical activity and/or dietary modifications were implemented. However, the effectiveness of such SBIs remains unproven. Therefore, we conducted a meta-analysis of randomized controlled trials (RCTs) of SBIs.

Methods:
We searched for RCTs of SBIs published since 1990. To be eligible studies had to have an RCT design, to include children aged 6-18 years and SBIs were defined as non-pharmacological and non-surgical interventions carried out in a school setting with a minimum duration of 12 weeks. The primary outcome was change in body mass index (BMI. For each study the difference in the mean change in BMI between the intervention and the control groups was computed. The summary estimate for the difference in mean change in BMI and the 95% confidence interval (CI) was computed using a weighted inverse variance approach and a random- effects model. The

I
2

statistic was used to test for heterogeneity.

Results:
Of 504 studies identified, 41 involving 42 430 participants met the inclusion criteria. SBIs varied greatly between studies by type, duration and delivery. In 10 RCTs the SBI focused on physical activity, in 6 on dietary modifications and in 25 on both physical activity and dietary modifications. SBIs duration ranged from 12 weeks to 4 years. There was no significant difference in mean BMI change between the intervention and the control groups (mean difference = -0.281kg/m
2
; 95% CI -0.584 to 0.022), although there was significant heterogeneity between the RCTs’ findings (Figure). We found also no consistent impact on other measures of adiposity, physical activity patterns, dietary intakes and psychosocial health and wellbeing.

Conclusions:
SBIs had no substantial impact on BMI in children aged 6-18 years. Further research is needed to identify effective interventions to prevent childhood obesity.
Abstract 17986: Molecular Beacon-based Purification of Ventricular Cardiomyocytes From Differentiating Embryonic Stem Cells by Targeting Intracellular Mrna
Authors: Ban Kiwon , Wile Brian , Cho Kyu-Won , Kim Sangsung , Singerd Jason , Syed Anum , Wagner Mary , Bao Gang , Yoon Young-sup
Published: July 2021

Background:
Ventricular cardiomyocytes (CMs) are an ideal cell type for cardiac cell therapy since they are the main cells generating cardiac forces. However, isolating them from differentiating pluripotent stem cells (PSCs) has been challenging due to the lack of specific surface markers. Here we show that ventricular CMs can be purified from differentiating mouse embryonic stem cells (mESCs) using molecular beacons (MBs) targeting specific intracellular mRNAs. MBs are dual-labeled oligonucleotide hairpin probes that emit a fluorescence signal when hybridized to target mRNAs, allowing isolation of specific target cells by fluorescence activated cell sorting (FACS) with high specificity and sensitivity.

Methods and Results:
We generated three different MBs (IRX4-1, -2, -3) designed to target specific regions of mRNAs of iroquois homeobox protein 4 (Irx4), a specific transcription factor for ventricular CMs. Among three IRX4 MBs, IRX4-2 MB demonstrated the highest sensitivity and specificity, thus IRX4-2 MB was selected to purify mESC-derived ventricular CMs. Subsequently, IRX4-2 MBs were delivered into cardiomyogenically differentiating mESC cultures and cells showing strong signals from IRX4-2 MBs were FACS-sorted. Flow cytometry demonstrated that 92~97% of IRX4-2 MB-positive cells expressed a marker for ventricular CMs myosin light chain 2 ventricular isoform (Myl2) as well as cardiac troponin 2 (Tnnt2). Importantly, higher than 98% of IRX4-2 MB-positive cells displayed ventricular CM-like action potentials during electrophysiological analyses. These IRX4-2 MB-based purified ventricular CMs continuously maintained their CM characteristics verified by synchronous beating, Ca2+ transient, and expression of ventricular CM-specific proteins.

Conclusions:
We established a novel MB-based cell sorting system targeting a transcription factor that is specific for ventricular CM to generate homogeneous and functional ventricular CMs. This is the first report to show the feasibility of isolating pure ventricular CMs without modifying host genes, and this platform will be useful for therapeutic applications, disease modeling, and drug discovery.
Abstract 18040: Effect on Survival of an Early versus Late Coronary Angiography Approach in Patients With Out-of-hospital Cardiac Arrest Without ST-Segment Elevation Myocardial Infarction
Authors: Miranda David F , Sandoval Yader , Goldsmith Steven R , Bart Bradley A , Bachour Fouad A
Published: July 2021

Background:
The optimal timing of coronary angiography (CA) if performed in the management of patients presenting with out-of-hospital cardiac arrest (OHCA) in the absence of ST-Segment elevation myocardial infarction (STEMI) has not been examined by any randomized controlled trial (RCT), though some retrospective studies have suggested benefit of an early approach.

Methods:
We performed a retrospective analysis of 93 consecutive patients with OHCA and shockable rhythm, without STEMI between July 2007 and April 2014. Patients were categorized by those receiving early (24 hrs.) CA, and the relationship between timing of CA and mortality was assessed, along with key relevant clinical and angiographic variables in each group (Table).

Results:
Among 93 patients, 45 (48%) received early CA and 48 (52%) late CA. Door-to-angiography median time was 69 (50, 89) minutes in patients undergoing early CA. Patients undergoing early CA were more likely to have a culprit lesion on CA (31% vs. 10%, p=0.01), and a trend toward more frequent PCI (31% vs. 15%, p =0.06) in comparison to late CA. However, they also had a higher baseline lactate level. Inpatient mortality was significantly higher in patients undergoing early CA (27%) compared to those undergoing late CA (4%) (p=0.002).

Conclusions:
In a series of 93 consecutive patients presenting with OHCA without STEMI, early CA was associated with higher mortality despite a higher frequency of culprit lesions and successful PCI. These results contrast with those from other post-hoc analyses and clearly demonstrate the need for a RCT comparing early vs. late CA in this patient population.
Abstract 18092: Nitroxyl (HNO) Improves Ventricular Relaxation and Ca2+-Handling in Rats with Induced Chronic Diastolic Dysfunction
Authors: Roof Steve R , Hartman Craig , Reardon John , del Rio Carlos , Ziolo Mark , Hamlin Robert
Published: July 2021

Despite the morbidity and clinical burden of primary diastolic cardiac dysfunction, effective therapies for patients presenting with heart failure with preserved ejection fraction (HFpEF) are limited. Nitroxyl (HNO) produces cAMP-independent functional support, in part by improving myocardial calcium-handling. We hypothesize that HNO can rescue lusitropic function when acutely administered to rats with chronic diastolic dysfunction, mimicking HFpEF.

Diastolic dysfunction, as demonstrated by decreased E/A ratios via echocardiography, was induced by either 4 weeks of chronic isoproterenol administration (via a mini-osmotic pump; ISO) or by renoprival hypertension (secondary to renal wrapping; RW) for 5 weeks. In vivo left-ventricular hemodynamics/pressure-volume relationships were assessed before/during a 30 minute IV administration of a HNO pro-drug (CXL-1020, 100 μg/kg/min). Ca2+ handling in isolated cardiomyocytes was also studied (CXL-1020, at 50 μM). In both cases, milrinone (mil) was used as a cAMP-dependent positive control (at a matched-efficacy in healthy rats, i.e., 10 μg/kg/min and 0.5 μM)

In the setting of chronic diastolic dysfunction, HNO lowered the LV filling pressures in both models by a combined average of 46 ± 8% versus baseline, accelerated the time-constant (tau) of relaxation (-26 ± 3%) and improved compliance (flattened the end-diastolic PV relationship) (-61 ±3%). In myocytes isolated from dysfunctional hearts, HNO accelerated the time for Ca2+ to decline to 50% of its max amplitude (RT50) by -10 ± 2% and myocyte relengthening by -12 ± 3% in ISO rats. Despite eliciting comparable responses in healthy animals/myocytes, the HNO-mediated effects on both tau (in vivo) (-33 ± 3% vs mil -25 ± 2%) and Ca2+ decline (myocyte) (-10 ± 2% vs mil -6 ± 1%) were greater than those of milrinone in the ISO rats, which had greater impairment at baseline compared to RW rats.

In conclusion, acute-therapy with HNO improved ventricular relaxation, compliance and Ca2+ handling, in the setting of chronic diastolic dysfunction. Moreover, these effects were greater than observed with the cAMP-dependent agent milrinone.
Abstract 18165: Fluoroscopic-Free Ablation with 3D Imaging: Immediate Procedural Success and Complications
Authors: Kipp Ryan T , Oujiri James A , Boynton Jason , Von Bergen Nicholas , Eckhardt Lee
Published: July 2021

Introduction:
Ablation is a curative procedure for many supra-ventricular tachycardia’s. Classically, fluoroscopic imaging has been used to guide catheter placement and ablation. Prolonged radiation exposure from complicated or repeat ablation may increase the lifetime risk of cancer through stochastic effects, particularly in young patients and healthcare providers. In addition, protective lead aprons and vests required for healthcare providers and can result in physical injury from extended, repeated use. Use of 3D electro-anatomical navigation systems has significantly reduced the amount of fluoroscopy used for ablation. We extended this further by using of 3D navigation systems in a complete fluoro-free (FF) ablation. Here, we report safety and efficacy of this technique in a large patient cohort.

Methods:
From February, 2010 - March, 2013 all ablations performed FF at a single academic medical center were enrolled in an ablation registry. Patient and procedural characteristics for each ablation were collected. We report the ablation characteristics, acute procedural success, and complication rate associated with FF ablation.

Results:
During the study period, 102 consecutive ablations by two operators were performed with the intention of FF. 14 of 102 cases required fluoro guidance at the discretion of the operator (13.7% cross-over). The average patient age was 22.1 years, 49% were male. The 2 most common diagnoses for FF ablation were AVNRT (58.4%) and AVRT (24.8%). Of the 88 FF cases, the acute procedural success rate was 97%. 77.9% were performed with cryoablation. 4.6% of FF cases suffered minor complications including: 2 with transient heart block, 1 groin hematoma managed conservatively, and 1 transient prolongation of the AH interval. There were no cases of permanent heart block. There were no significant complications in the FF group.

Conclusions:
Ablation of supra-ventricular tacharrhythmias without use of fluoroscopy has a high acute procedural success rate with low incidence of procedural complication. Use of this technique completely relieves the patient and healthcare of radiation exposure, eliminating radiation stochastic effects and obviating the need for protective shielding.
Abstract 18172: Rhythm Control with Catheter Ablation Improves Ejection Fraction Compared to Rate Control: A Meta-Analysis of Randomized Controlled Studies
Authors: Vallakati Ajay , Kanmantha Reddy Arun , Dunlap Mark , Lewis William
Published: July 2021

Background:
Atrial fibrillation (AF) can exacerbate/worsen heart failure. A randomized study showed that rhythm control with anti-arrhythmic drugs (AADs) is not superior to rate control for heart failure patients who develop AF. However, a recent study revealed catheter ablation can improve the ejection fraction (EF) compared to medical rate control.

Hypothesis:
We performed a meta-analysis to compare the effect of rhythm control and medical rate control on EF in heart failure patients with AF.

Methods:
We searched PubMed, Embase, Google Scholar and Cochrane databases for all randomized controlled trials (RCTs) comparing rhythm control versus rate control for AF in heart failure. Primary outcome was change in EF. Random effects model was used to pool and analyze data across the studies.

Results:
Of a total of 7 RCTs (4 - AADs, 3 - catheter ablation) which compared rhythm control and medical rate control, 4 studies (n=202) reported quantitative data on EF. There was significant heterogeneity between the studies (I2=82%, p <0.001). Compared to rate control, the mean improvement in EF with rhythm control was 5.94% (95% CI 0.63- 11.26, p=0.03). Sub-group analysis revealed catheter ablation improved the EF by 6.67% (95% CI 0.23 -13.11, p=0.04) whereas rhythm control with AADs did not significantly change EF (3.50, -1.76 -8.76).

Conclusion:
Rhythm control is associated with greater improvement in EF compared to rate control therapy in heart failure patients with AF. Catheter ablation of AF significantly improves the EF in these patients. Further studies are needed to determine if this improvement in EF is associated with decreased morbidity and mortality.
Abstract 18264: Abnormalities in the Electrocardiogram: a Meta-Analysis Comparing Chagas Disease to Other Cardiomyopathies
Authors: Cardoso Rhanderson N , Fernandes Gilson , Garcia Daniel , Ansari Mohammad , Mitrani Raul D
Published: July 2021

Introduction:
Chagas Disease (CD) has been associated with a variety of abnormalities in the electrocardiogram (ECG). For epidemiologic purposes and differential diagnosis, we sought to perform a systematic review and meta-analysis of the relative frequencies of various ECG findings in patients with CD compared to a non-CD group.

Hypothesis:
ECG abnormalities differ significantly based on etiology of cardiomyopathy.

Methods:
PubMed, EMBASE, Cochrane Central and Latin American databases were searched for studies that directly compared the prevalence of ECG abnormalities in CD patients to a non-CD group. Odds-ratios were computed using a random-effects model due to anticipated heterogeneity. We further performed a subanalysis on studies that included only patients with known cardiomyopathy.

Results:
A total of 17 studies and 10,550 patients were included, of whom 4,192 (39.7%) had a positive serology for CD. Ten studies included only patients with known cardiomyopathy in both the control and CD groups. Table 1 reports the odds-ratios for the relative frequencies of various ECG abnormalities between groups.

Conclusions:
Our analysis suggests that amongst patients with cardiomyopathies, Chagas Disease etiology is significantly associated with an increased prevalence of right bundle branch block, premature ventricular complexes and permanent pacemaker implantation, whereas left bundle branch block is more prevalent among other cardiomyopathies. The combination of right bundle branch block with left anterior fascicular block had the highest odds ratio for prevalence among Chagas Disease patients.
Abstract 18304: Clinical Impact of Initial Reduction of Low-density Lipoprotein Cholesterol Level on Long-term Outcome of Acute Myocardial Infarction in the Statin Era
Authors: Miura Takashi , Izawa Atsushi , Motoki Hirohiko , Miyashita Yusuke , Kashima Yuichiro , Tomita Takeshi , Tomita Takeshi , Koyama Jun , Ikeda Uichi
Published: July 2021

Background:
In terms of secondary prevention of acute myocardial infarction (AMI), optimal period for achievement of target percent reduction of LDL-C level has not yet been well established.

Methods:
The Assessment of Lipophilic vs. Hydrophilic Statin Therapy in AMI (ALPS-AMI) study enrolled a total of 508 patients (mean age, 66.0±11.6 years, 80.6% male) hospitalized for AMI. Of these patients, 248 patients achieved percent reduction of LDL-C ≧ 30% until 8 week after randomization, 204 patients achieved at 4 week (early reduction group), 44 patients achieved at 8week (late reduction group). The two groups were identified prospectively and analyzed with regard to the composite end point (MACE: all-cause death, myocardial infarction, stroke). We evaluated long term clinical outcomes of AMI patients after PCI in terms of the period for achievement of target percent reductions in LDL-C.

Results:
MACE were significantly higher in the late reduction group compared to early reduction group (20.5% vs. 3.9 %, P<0.0001). The incidence of cardiac death were[[Unable to Display Character:  ]]significantly higher in the late reduction group than early reduction group (6.8% vs. 0.5%, P=0.003). In multivariate Cox proportional hazards analysis, percent reduction level of LDL-C during initial 4 week (HR, 0.93; 95% CI: 0.89-0.96, P<0.0001) and baseline LDL-C level (HR, 0.98; 95% CI: 0.96-0.99, P=0.038) predicted adverse events after adjustment for age.

Conclusions:
The earlier reduction of LDL-C level is important for the patients with AMI in terms of reduction of ischemic events. We should reduce LDL-C level to target percent reductions for at least moderate-intensity statin therapy as early as 4 weeks after primary PCI in patients with AMI.
Abstract 18318: Percutaneous Epicardial Access for Mapping and Ablation is Feasible in Patients With Prior Cardiac Surgery, Including Coronary Bypass Surgery
Authors: Killu Ammar M , Ebrille Elisa , Asirvatham Samuel J , Munger Thomas M , McLeod Christopher J , Packer Douglas L , Friedman Paul A , Mulpuru Siva K
Published: July 2021

Introduction:
Prior cardiac surgery, especially the presence of coronary bypass grafts, is thought to preclude percutaneous epicardial access (EpiAcc) and, due to limited catheter maneuverability, mapping and ablation. The objective of our study was to evaluate the feasibility and safety of EpiAcc in patients with prior cardiac surgery.

Methods:
We retrospectively analyzed all patients who underwent EpiAcc as part of an ablation procedure between 01/01/2004-06/30/2013 at Mayo Clinic, Rochester, MN. All had documented VT or recurring, symptomatic PVCs. Baseline clinical characteristics and procedural characteristics were collected.

Results:
Of 162 patients that underwent EpiAcc, 18 had prior cardiac surgery (mean age 61 years, all male). This included 10 CABG, 2 epicardial ICD placement, 5 valve surgery (3 aortic valve, 2 mitral valve), 2 septal myectomy, 1 aortic arch replacement, 1 myocardial bridge unroofing and 1 myocardial perforation repair (3 patients had multiple procedures). Access was successful in 12 patients (66.7%); the inferior approach was utilized in 78%. Of patients with prior CABG, successful access was attained in 6 (60%). The average procedural time was 441.6 ± 141.3 minutes. Adhesiolysis was required in 10 patients with the sheath, access wire, pigtail catheter or ablation catheter. Intra-procedural coronary angiography was performed in 8 patients. There were a total of 45 VTs/PVCs ablated in 18 patients (average 2.5 ± 1.7), mean cycle length 463.6 ± 95.9ms. Ultimately, 12 patients (66.7%) underwent endocardial only ablation, 1 (5.5%) had epicardial only ablation while 5 (27.8%) had endocardial/epicardial ablation. The procedure was deemed successful in 13 patients (72.2%). Four patients had bleeding complications (pericardial effusion, pericardial hematoma, hemoperitoneum and pericardial tamponade [the latter required repair of the RV wall]). In patients with coronary grafts, there was no evidence of acute graft disruption.

Conclusions:
Percutaneous epicardial access is feasible in patients with previous cardiac surgery, including CABG. However, adhesiolysis is frequently required. Although the risk of coronary graft injury is low, life-threatening complications may occur.
Abstract 18353: The Comparative Safety and Effectiveness of the Oral Anticoagulant (OAC) Dabigatran versus Warfarin Utilized in a Large Healthcare System in Non-valvular Atrial Fibrillation (NVAF) Patients
Authors: Villines Todd C , Schnee Janet , Fraeman Kathy , Siu Kimberly , Reynolds Matthew W , Collins Jenna , Schwartzman Eric
Published: July 2021

Objectives:
This study evaluated the safety and effectiveness of dabigatran versus warfarin for stroke risk reduction in NVAF patients in routine clinical care using the Department of Defense Military Health System database.

Methods:
In this retrospective cohort study, patients were included if they had an AF diagnosis within 12 months prior to first OAC treatment, were 18-89 years, and had a first prescription claim for either dabigatran or warfarin between 01-Oct-2010 and 31-Jul-2012 (index date). Patients were excluded if they had heart valve disorders or prosthetic heart valves, transient causes of AF, or any OAC use during the baseline period. Patients were censored when their prescriptions exceeded a 30 day allowable gap, at OAC switch, at disenrollment, at death, or at study end. A total of 14,813 dabigatran and 24,500 warfarin patients were available for propensity score matching (PSM). PSM based on baseline demographics and clinical characteristics was achieved 1:1 with 12,793 matched subjects per group (within a 0.20 caliper of standard deviation). Comparisons of safety and effectiveness outcomes were made based on Cox-proportional hazards models of PSM groups. All FDA-approved dosages were included in this analysis.

Results:
Results are summarized in Table 1.

Conclusions:
Hazard ratios in the post-PSM dabigatran cohort suggest that there is a lower likelihood for stroke, hemorrhagic stroke, major intracranial bleeding, major urogenital and other bleeding, MI, and death than in the warfarin cohort. The hazard ratio in the post-PSM dabigatran cohort suggests a higher likelihood for major lower GI bleeding, but a lower likelihood for intracranial, urogenital, and other bleeding than seen with warfarin. These results are generally consistent with findings of the randomized controlled clinical trial, RE-LY, and support that the benefits of dabigatran demonstrated in clinical trials also may be achieved in a broad population receiving routine clinical care.
Abstract 18391: Accumulation of Adiponectin in Association With Up-regulated T-cadherin in the Aortic Wall of Acute and Chronic Aortic Dissection
Authors: Watanabe Yoshiki , Miyagawa Shigeru , Fukushima Satsuki , Maeda Norikazu , Saito Atsuhiro , Torikai Kei , Toda Koichi , Kuratani Toru , Shimomura Iichiro , Sawa Yoshiki
Published: July 2021

Introduction:
Adiponectin (APN) is a major adipokine, which has been reported to accumulate into the damaged tissues in multiple organs. However, the role of APN and its receptor, T-cadherin (T-cad), in the pathology of the human aortic wall (AW) is poorly understood. In this study, we examined the distributions of APN and T-cad in the dissected AW and measured the serum APN concentration in patients with aortic dissection (AD).

Methods:
Diseased AW tissues were collected from patients with acute or chronic AD at the time of surgery, and a healthy aorta was used as a control (n = 6 per group). Blood was serially sampled to measure the APN concentrations in non-surgically-treated patients with acute type B AD (n = 10).

Results:
Immunohistochemically, normal aortic walls weakly expressed APN or T-cad on the intimal surface, whereas the AWs of acute AD patients showed marked expression of both APN and T-cad on the surface of the dissected aortic media. In chronic AD, APN and T-cad were diffusely expressed on the medial layers of the thickened AW (Fig. A-C). Western blot analysis showed that APN expression in the AW was significantly greater in acute and chronic AD than in the normal aorta (151 ± 2% and 220 ± 27% vs. normal, respectively) (Fig. D). RT-PCR revealed no expression of APN mRNA in any AW, and stronger expression of T-cad mRNA in acute and chronic AD than in the normal aorta (108 ± 9% and 194 ± 101% vs. normal, respectively). The blood concentration of APN in type B AD patients decreased by 13.3 ± 3.8% in 24-78 hours, and by 22.7 ± 7.2% in over 78 hours, as compared to those monitored within 24 hours after the onset, indicating that APN was supplied to the affected aortic wall from the blood.

Conclusions:
APN markedly accumulated into the dissected aortic media in acute and chronic AD, and T-cad was upregulated in the corresponding area. In contrast, the blood concentration of APN reciprocally decreased after AD onset, indicating a possibility of APN contribution to protect a diseased aortic wall of AD.
Abstract 18405: Epidrug Treatment Rescues Proliferation and Differentiation in Human Cardiac Mesenchymal Cells of Type 2 Diabetic Patients: A Case of Epimetabolic Memory
Authors: Spallotta Francesco , Cencioni Chiara , Farsetti Antonella , Zeiher Andreas M , Gaetano Carlo
Published: July 2021

Introduction:
The origin of metabolic/epigenetic memory remains elusive. It, however, may be at the basis of chronic diseases and functional alteration associated to ageing and cardiovascular disease.

HYPOTHESIS:
Diabetes is known to alter cellular metabolism causing defects in tissue/organ regeneration. In this study we asked whether human cardiac stromal cells from diabetic and normoglycaemic voluntary donors revealed differences associated to their original metabolism and whether the alterations could be rescued by epigenetically active drugs.

METHODS and RESULTS:
D-CMSC were characterized by a reduced proliferation rate, diminished phosphorylation at histone H3 serine 10 (H3S10P), decreased differentiation potential, and premature cellular senescence. A global histone code profiling of D-CMSC revealed that acetylation on histone H3 lysine 9 (H3K9Ac) and lysine 14 (H3K14Ac) was decreased, whereas the trimethylation of histone H3 lysine 9 and lysine 27 significantly increased. These observations were paralleled by a downregulation of the GCN5- related N-acetyltransferases (GNAT) p300/CBP-associated factor and its isoform 5-a general control of amino acid synthesis (GCN5a), determining a relative decreasein total HAT activity. DNA CpG island hypermethylation was detected at promoters of genes involved in cell growth control and genomic stability. Remarkably, treatment with the GNAT proactivator SPV106 restored normal levels of H3K9Ac and H3K14Ac, reduced DNA CpG hypermethylation, and recovered D-CMSC proliferation and differentiation.

CONCLUSIONS:
This study investigated the diabetes-associated alterations present in cardiac mesenchymal cells (CMSC) obtained from normoglycemic (ND-CMSC) and type 2 diabetic patients (D-CMSC), identifying the histone acetylase (HAT) activator pentadecylidenemalonate 1b (SPV106) as a potential pharmacological intervention to restore cellular function. These results suggest that epigenetic interventions may reverse alterations in human CMSC obtained from diabetic patients.
Abstract 18414: Malat1 Regulates the Inflammatory Response of Endothelial Cells
Authors: Michalik Katharina , John David , Chen Wei , Uchida Shizuka , Schober Andreas , Weber Christian , Boon Reinier A , Dimmeler Stefanie
Published: July 2021

Laminar blood flow has an anti-inflammatory effect on endothelial cells (ECs) and prevents local atherosclerotic lesion formation. Long non-coding RNAs (lncRNAs) have been described to play a role in many biological processes, including epigenetic regulation of gene expression. We previously showed that the lncRNA MALAT1 is highly expressed in ECs and plays a role in angiogenesis. Since we showed that MALAT1 is induced by anti-inflammatory laminar shear stress (3.4+0.6 fold), we assessed whether MALAT1 regulates the inflammatory response of ECs. Therefore, we used several siRNAs and LNA GapmeRs to specifically silence MALAT1. We noticed that targeting different regions of MALAT1 showed opposite effects on TNFα-induced inflammatory response. Whereas 3 different siRNAs and GapmeRs directed against the 5’end enhanced the TNFα-induced expression of E-selectin, VCAM1 and ICAM1, a GapmeR directed against the 3’end reduced the inflammatory response of ECs (Fig.1).

To determine whether these effects are due to targeting of different transcript variants, we designed different PCR primers and identified a novel 1.3 kb 5’ variant of MALAT1, which was confirmed by deep sequencing. Interestingly, the two transcript variants are inversely regulated in human atherosclerotic plaques. Whereas the anti-inflammatory 1.3 kb 5’ variant was down-regulated in advanced plaques in AHA classification type 3 vs. 4 (42%+9%), the long pro-inflammatory variant was increased (158+28%).

We further characterized MALAT1 variants and showed that both are transcribed by RNA Polymerase II and are nuclear localized. RNA-IP experiments showed that the short MALAT1 variant binds to Histone H3 whereas the long MALAT1 predominantly binds to H3K27me3 suggesting that the variants exhibit different epigenetic effects.

In summary, our data identify for the first time a new 5′ variant of MALAT1, which reduced EC activation by TNFα, whereas the long MALAT1 augments the inflammatory activation of ECs.
Abstract 18420: Myozap-deficiency Inhibits SRF Signaling and Causes Severe Cardiomyopathy in Response to Pathological Biomechanical Stress in vivo
Authors: Rangrez Ashraf Y , Frank Derk , Poyanmehr Reza , Bernt Alexander , Eden Matthias , Kuhn Christian , Frey Norbert
Published: July 2021

Background:
We recently showed that the intercalated disc (ID) protein Myozap activates Rho-dependent SRF signaling both in vitro, and in vivo. Conversely, knockdown of its ortholog in Zebrafish led to severe contractile dysfunction and cardiomyopathy.

Methods and Results:
We generated a Myozap null mutant (MZP-ko) by global deletion of Myozap in mice. The absence of Myozap caused neither structural defects nor a baseline cardiac phenotype and led only to mild cardiac hypertrophy upon aging. Of note, induction of SRF target genes and the activation of SRF per se were markedly inhibited in MZP-ko mice. Nevertheless, biomechanical stress induced by transverse aortic constriction (TAC) triggered an excessive increase in cardiac hypertrophy (43% or 36% increased heart wt:body wt or LV wt:body wt ratios, p<0.001), an increased cell surface area, as well as accelerated fibrosis, followed by “super”- induction of the hypertrophic gene program (ANF/BNP). Moreover, MZP-ko mice revealed a severe reduction of fractional shortening (average %FS for MZP-ko 14.5% compared to 33.5% for wild-type littermates, p<0.001) and clinical signs of heart failure (54% increase in lung/body weights, p<0.001) which also caused a profound increase in mortality in response to TAC. Furthermore, expression of other ID proteins like N-Cadherin, Desmoplakin and Connexin 43 was found significantly altered upon pressure overload in MZP-ko mice. Finally, we observed a downregulation of Dysbindin, a novel interaction partner of Myozap and known inducer of ERK1/2 signaling in TAC operated MZP-ko mice. Consistently, activation of ERK1/2 was blunted in MZP-ko mice after TAC.

Conclusions:
We here show that myozap deficiency in vivo inhibits SRF- and ERK1/2-signaling leading to a maladaptative response to increased biomechanical stress, followed by cardiomyopathy, heart failure and cardiac death. Moreover, myozap deficiency severely altered the expression of its direct ID interaction partners such as Dysbindin and Desmoplakin. In a broader perspective, our data identify signaling at the level of the intercalated disc as a critical component of cardiac remodeling.
Abstract 18427: Rotors and Focal Sources for Human Atrial Fibrillation Are Spatially and Temporally Stable
Authors: Swarup Vijay , Baykaner Tina , Zaman Junaid , Daubert James , Hummel John , Krummen David E , Miller John , Tomassoni Geri , Narayan Sanjiv
Published: July 2021

Introduction:
Several groups now report electrical rotors or focal sources sustaining human atrial fibrillation (AF) after it has been triggered. However, some groups report stable sources while others report transient rotational activity.

Hypothesis:
We hypothesized that AF rotors would be spatially stable in a large multi center experience, using phase mapping.

Methods:
We prospectively mapped AF in 277 patients (181 persistent, 61±12 years) at 6 centers in the FIRM-registry, using basket catheters with 64 contact electrodes per atrium. AF was mapped by RhythmView (Topera Inc) before ablation. FIRM uses phase analysis and dynamic physiological analysis of repolarization and conduction. AF propagation movies were interpreted by each operator to assess the stability and dynamics of AF sources in multiple maps over tens of minutes prior to ablation.

Results:
Sources were identified in 258 of 260 of patients in whom AF was mapped (99%), for 2.8±1.4 sources/patient. Patients showed 1.8±1.1 left atrial and 1.1±0.8 right atrial sources. On FIRM mapping, each source was stable for 4196±6360 cycles, with no difference between patients with paroxysmal vs persistent AF (4290±5847 vs 4150±6604, p=0.78), or right vs left atrial sources (p=0.26) (Figure). Rotors showed precession ('wobble') in ~2 cm2 areas, and spiral arms disorganized (‘fibrillatory conduction)’ beyond a spatial domain that varied around each rotor core for each patient, and between patients.

Conclusions:
Rotors and focal sources for human AF are stable for thousands of cycles during mapping using FIRM. These data show that AF rotors are distinct from macro-reentry. Notably, rotors precess within small atrial regions, and emanating spiral arms disorganize variably into the fibrillatory milieu in agreement with basic science studies. These results provide a rationale for FIRM-guided ablation at AF sources, and explain why rotors have been difficult to detect using traditional mapping approaches.
Abstract 18448: Laminar Flow and Klf2 Regulate the Paracrine Activity of Endothelial Cells by Modulating the Balance of Cxcr4 versus Cxcr7 Expression
Authors: Manavski Yosif , Doddaballapur Anuradha , Hu Junhao , Augustin Hellmut , Boon Reinier , Dimmeler Stefanie
Published: July 2021

Recent studies suggest that endothelial cells are not only important for oxygen delivery but act as paracrine source for signals that determine tissue regeneration versus fibrosis. The paracrine regulation of liver regeneration by endothelial cells was shown to be critically controlled by the SDF-1 receptors CXCR4, which was shown to control the release of pro-fibrotic cytokines, whereas signaling via the CXCR7 receptor was shown to provide a pro-regenerative niche. The regulation of the endothelial CXCR4 versus CXCR7 expression and their role in heart regeneration is unclear. Here we show that laminar flow as well as the expression of the flow-induced transcription factor Krüppel-like factor 2 (KLF2) reduced mRNA expression of CXCR4 by (0.34±0.01 fold; p<0.005) and (0.22±0.05 fold; p<0.0005), respectively, whereas CXCR7 expression was significantly increased (flow: 6.59±0.52 fold; p<0.005, KLF2: 36±12.3 fold; p<0.05). Western blots confirmed that flow and KLF2 critically modulate the CXCR4 / CXCR7 protein expression. Interestingly, shear stress and KLF2 induce the expression of the CXCR7-downstream inhibitor of DNA binding 1 (Id1), a transcription factor known to induce pro-regenerative angiocrine factors. Cytokine arrays further demonstrate that flow and KLF2 overexpression change the paracrine release of important growth factors. For example, Activin A (1.7±0.69 fold) and IGF-binding proteins were increased (1.7±0.87 fold), whereas the release of pro-inflammatory cytokines IL-8 (0.16±0.02 fold) and MCP1 (0.43±0.01 fold) and growth factors VEGF-C (0.16±0.01 fold), PlGF (0.09±0.01 fold) and Endoglin (0.27±0.09 fold) were reduced. The changes in the release of these paracrine growth factors were partially reduced by siRNA-mediated silencing of CXCR7. In summary these data suggest that flow and KLF2 critically regulate the paracrine secretion of endothelial growth factors by modulating the balance of CXCR4 versus CXCR7 expression. Ongoing studies address the contribution of endothelial KLF2 in liver and heart regeneration in vivo.
Abstract 18459: CT-guided Planar Imaging for the Assessment of Right Ventricular Myocardial Perfusion: a Novel, Noninvasive Monitoring Tool for Patients With Pulmonary Hypertension
Authors: Kato Ken , Miyauchi Hideyuki , Iimori Takashi , Sawada Koichi , Kuwabara Yoichi , Sakao Seichiro , Tatsumi Koichiro , Kobayashi Yoshio
Published: July 2021

Introduction:
In patients with pulmonary hypertension (PH), right ventricular (RV) dysfunction as a consequence of increased RV pressure may result in RV enlargement and hypertrophy, which also increases the RV myocardial perfusion.

Hypothesis:
We assessed the hypothesis that RV myocardial perfusion detected by planar thallium-201 (201Tl) imaging is useful for quantitative evaluation for RV dysfunction in PH patients.

Method:
The study groups included 16 PH patients with chronic thromboembolic pulmonary hypertension (CTEPH) and 24 healthy controls. All subjects underwent myocardial perfusion SPECT/CT. Cardiac CT was used to obtain the optimal angle to differentiate the RV from the left ventricle (LV). Forty minutes after intravenously administration of 111 MBq of 201Tl, planar acquisition from the optimal angle was performed. In the planar image, we measured the total counts of 201Tl in the RV and LV. The relative count of the RV to LV (HR/HL) was calculated as RV myocardial perfusion indicator for this study. Mean pulmonary artery pressure (mPAP) by cardiac catheterization was obtained in all PH patients to estimate the severity.

Results:
HR/HL was significantly elevated in the PH group compared with control (0.57 ± 0.13 vs. 0.36 ± 0.07, p <0.01). In the PH group, average mPAP was 42.2 ± 8.84mmHg, which was significantly correlated with HR/HL (r=0.70, p<0.01). In 7 patients with CTEPH who underwent pulmonary endarterectomy (PEA), HR/HL significantly decreased after PEA (from 0.57±0.16 to 0.42±0.07, p<0.05). The decrease of HR/HL was significantly associated with the decrease of mPAP after PEA (r=0.78, p<0.05).

Conclusion:
Relative RV accumulation in CT-guided 201Tl planar imaging by SPECT/CT was associated with the severity of PH in CTEPH patients and decreased after surgical treatment of CTEPH in parallel with the reduction of mPAP. This method may represent a novel, noninvasive monitoring tool for PH patients.
Abstract 18544: Bloods Loss in Dabigatran Anticoagulated Pigs With Polytrauma is Significantly Reduced by Early Therapy With Activated and Non-activated Prothrombin Complex Concentrates
Authors: Grottke Oliver , Honickel Markus , van Ryn Joanne , ten Cate Hugo , Spronk Henri , Rossaint Rolf
Published: July 2021

Introduction:
The reversal of the new oral anticoagulants in severely bleeding patients with prothrombin complex concentrates remains uncertain with conflicting evidence. This study assessed the ability of a four-factor PCC and activated PCC (aPCC) to reverse dabigatran anticoagulation in a porcine polytrauma model.

Methods:
After ethical approval, male pigs (n=30) were given dabigatran etexilate for 3 days (30 mg/kg bid PO), the sham group (n=6) received placebo. To accomplish supratherapeutic anticoagulation, dabigatran was infused for 90 min (30 min: 0.77 mg/kg/h; 60 min 0.52 mg/kg/min) prior to injury on day 4 in anaesthetized pigs. A standardized blunt liver injury and bilateral femur fractures were induced. Following hemorrhagic shock, resuscitation was started 5 min after trauma and blood loss (BL) was recorded 12 min post trauma. Randomized animals (n=6/group) received a single injection of PCC or aPCC (25 and 50 IU/kg), or vehicle (control). BL and hemodynamic variables were monitored over 5 h or until time of death. Data were analyzed by ANOVA (± SD).

Results:
After infusion and prior to injury dabigatran levels were 559 ± 36 ng/mL and remained elevated throughout. In contrast to sham animals (BL: 601 ± 137 mL), BL in in all anticoagulated animals was significantly elevated 12 min post injury (BL : 791 ± 54 mL). Anticoagulation with dabigatran without PCC therapy resulted in a total BL of 3774 ± 628 mL) with 100% mortality (survival time: 65-146 min; p<0.05 vs PCC/aPCC 50 IU/kg treated animals). Although the onset of bleeding was reduced in animals receiving 25 IU/kg PCC or aPCC, total BL (PCC: 3679 ± 782 mL; aPCC: 3638 ± 474 mL) was similar to control animals. In contrast, application of 50 IU/kg PCC (1767 ± 135 mL) or aPCC (1647 ± 302 mL) showed a significant reduction in total BL with 100% survival.

Conclusions:
This porcine model demonstrates that high doses of PCC and aPCC application of PCC may be a reasonable intervention for dabigatran-treated patients with life-threatening haemorrhage, though these data need clinical confirmation.
Abstract 18567: Impact of Participation in Cardiac Rehabilitation on Long-term Survival after Coronary Artery Bypass Graft Surgery
Authors: Lee Jong-Young , Park Eun-Kyung , Ahn Jung-Min , Park Heesoon , Cheon Sang Soo , Kim Min Su , Park Duk-Woo , Kim Young-Hak , Lee Seung-Whan , Kang Soo-Jin , Choi Hyo In , Lee Cheol Whan , Park Seong-Wook , Park Seung-Jung
Published: July 2021

Background:
Although cardiac rehabilitation (CR) is recommended after coronary artery bypass grafting (CABG) surgery, there are still deficient data about the long-term benefit of CR after CABG.

Methods:
We analyzed a single-center prospective registry, which included patients who had undergone CABG between 2000 and 2011. We evaluated the relationship between participation in CR and long-term survival. We identified 3975 patients (62.4±9.1 years old, 74.3% male) who survived for at least 3 months after surgery.

Results:
Of these, 2419 (60.9%) participated in phase I of CR while hospitalized, and 383 (9.6%) participated in phase II of CR at an outpatient clinic. During a median follow-up of 6.0 years (IQR, 4.3 to 9.5), the all-cause Kaplan-Meier mortality rate was 28.8% (616 deaths). Based on the propensity score matching method, participation in phase I CR was associated with a 20% relative risk reduction in all-cause mortality (hazard ratio [HR], 0.80; 95% confidence interval [CI], 0.64 to 0.98; p=0.043) and a 40% reduction in all-cause mortality after participation in phase II CR (HR, 0.60; 95% CI, 0.40 to 0.90; p=0.012). After multivariate Cox-proportional analysis, participation in any CR phase was associated with a significant reduction in mortality (HR, 0.77; 95% CI, 0.64 to 0.93; p=0.006 in phase I CR and HR, 0.57; 95% CI, 0.39 to 0.84, p=0.004 in phase II CR).

Conclusions:
CR participation is associated with a significant reduction in all-cause mortality after CABG. As well as outpatient CR participation, early CR during hospitalization has a beneficial impact in reducing mortality.