bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 17987: Structural and Senescence Changes in the Atria of Lone Atrial Fibrillation Patients
Authors: Batlle Montserrat , Calvo Naiara , Castellà Manel , Sandoval Elena , Ramos Pablo , Pérez-Villa Félix , Ramírez José , Guasch Eduard , Brugada Josep , Mont Lluís
Published: July 2021

Introduction:
Hypertension and structural heart disease (SHD) are the most frequent causes of Atrial Fibrillation (AF). Hemodynamic overload and inflammation are key mediators of the arrhythmogenic substrate, at least partly by triggering accelerated senescence. Remarkably, up to one third of AF patients have no associated SHD (lone AF), and their arrhythmogenic substrate is largely unknown. We sought to compare structural and senescence changes in AF patients with or without SHD.

Methods:
Atrial appendage samples from four groups of patients were analyzed; patients with no SHD (AF_lone, n=10), AF patients with SHD (AF_Card, n=14), controls with no AF but with other cardiovascular diseases (CVD) (C_CVD, n=18) and controls with no CVD (C_Healthy, n=5). The percentage of intramyocardial collagen deposition was quantified by sirius red staining and morphometric analysis, and connexin-43 was analyzed by immunohistochemistry. Tissue senescence was evaluated with telomere length quantification and mRNA levels of a family of proteins involved in cellular senescence (Sirtuin-1, -2, -3 and -6).

Results:
There were no differences in age (overall mean 60 ± 2 years) and the percentage of male gender (overall 67%) between groups of patients. AF patients had a marked increase in atrial fibrosis, with no differences between AF_lone and AF_Card (Figure A). Connexin-43 quantification and distribution was similar in AF patients with or without SHD. Nevertheless, telomeres were longer in AF_lone than in AF_Card patients (Figure B). Also, AF_lone samples had higher mRNA levels of sirtuin-2 and -3 compared to AF_Card samples with no changes in sirtuin-1 and -6.

Conclusions:
Even though a similar degree of structural remodelling was found, AF_Card patients presented an accelerated atrial senescence when compared to AF_lone patients. These results could have important implications in the prognosis and therapeutic options of AF_lone patients.
Abstract 17996: Is There Gender Differences in Effect of CYP2C19 Polymorphisms or Low-grade Inflammation on Coronary Microvascular Disorder (CMVD)?
Authors: akasaka tomonori , Hokimoto Seiji , Ogawa Hisao
Published: July 2021

Background:
Specific CYPs localized in vascular smooth muscle and endothelium contribute to the regulation of vascular tone and homeostasis. CYP2C19 poor metabolizer(PM) is reported to be an independent risk factor for coronary artery disease. And, CYP2C19 PM is correlated with an increase in the circulating levels of hs-CRP in female. However, it is unknown whether CYP2C19 genotype is associated with the coronary microvascular disorder (CMVD).So, we examined gender differences in effect of CYP2C19 genotype and low grade inflammation on CMVD.

Methods:
We examined CYP2C19 genotypes in patients with CMVD (n=54) diagnosed by an intracoronary acetylcholine infusion test, with healthy subjects (n=76) serving as the control. CMVD was defined as the presentation of no coronary artery stenosis in angiography, no epicardial spasms, inversion of lactic acid levels between intracoronary and coronary sinuses in the intracoronary acetylcholine-provocation test, and an adenosine triphosphate-induced CFR<2.5. CYP2C19 genotypes were divided into 3 groups: (1) CYP2C19*1/*1 , extensive metabolizer (EM), (2) one loss-of-function allele (*1/*2, *1/*3; intermediate metabolizer [IM]), and (3) two loss-of-function alleles (*2/*2, *2/*3, *3/*3;[PM]).

Results:
The ratios of CYP2C19 genotype (EM,IM,and PM) were 31,39,and 30% in CMVD , and 32,49,and 19% in control. There is no significant difference in frequency of CYP2C19 genotype in overall (P=0.146). But, PM frequency was significantly higher in CMVD in only female (34% vs 16%, P=0.042). In level of hs-CRP, there is no significant difference between CMVD and control (0.111±0.080 vs 0.083±0.128,P=0.122), but significantly higher in CMVD in only female (0.112±0.106 vs 0.066±0.106,P=0.002). Moreover, in CMVD, mean of hs-CRP in CYP2C19 PM is significantly higher than that of EM in female (0.115±0.074 vs 0.046±0.039,P=0.034). Multivariate analysis for CMVD indicated that hypertension and chronic kidney disease are predictive factors among all subjects (OR 3.931,P=0.003, OR 3.146,P=0.026). High level of hs-CRP and CYP2C19 PM are predictive factors for CMVD in only female (OR3.864,P=0.047, OR6.079,P=0.042).

Conclusion:
CYP2C19 PM and low grade inflammation may be associated with CMVD, especially in female.
Abstract 18004: The Next Generation of Stretchable Sensors for Intravascular Electrochemical Impedance Spectroscopy of Varying Levels of Lipid Burden and Atherosclerosis
Authors: Packard Rene R , Zhang XiaoXiao , Luo Yuan , Ma Teng , Jen Nelson , Ma Jianguo , Demer Linda L , Zhou Qifa , Li Rongsong , Tai Yu-Chong , Hsiai Tzung K
Published: July 2021

Introduction:
Atherosclerosis, a chronic inflammatory arterial disease, persists as the leading cause of acute coronary events or stroke in developed countries. Developing a reliable, reproducible, safe and simple strategy to detect lipid-rich, metabolically active, and mechanically unstable plaques remains an unmet bioengineering challenge. It is recognized that oxidized low-density lipoprotein (oxLDL) and macrophages produce changes in the electrochemical properties of vessel walls that can be measured by electrochemical impedance spectroscopy (EIS).

Hypothesis:
We tested the hypothesis that a new, 2-point intravascular micro-electrode configuration enables flexible frequency-dependent EIS characterization of lipid-rich lesions.

Methods:
A simplified yet robust sensor design with higher differentiating capability, featuring individually addressable, flexible round electrodes (Æ = 240 μm), was developed and microfabricated for intravascular EIS investigation. We documented in vivo deployment of stretchable EIS sensors for endoluminal interrogation and impedimetric investigation at multiple levels of the aortic tree characterized by differing stages of atherosclerotic disease in a New Zealand White rabbit model, compared EIS values in vivo and ex vivo, confirmed endoluminal atherosclerotic lesions by intravascular ultrasound, histology and immunohistochemistry, and obtained EIS profiles in epicardial fat tissue.

Results:
The frequency sweep revealed overlapping tissue resistivity from 1-10 kHz, but distinct capacitive property from 10-300 kHz, thereby providing complementary differentiation in both impedance (Ω) and phase (f) between healthy arteries and varying levels of atherosclerotic lesions. The EIS measurements revealed a significant increase in impedance in the presence of oxLDL-rich lesions from 5219 Ω in control to 5949 Ω in mild, 6988 Ω in moderate and 8351 Ω in severe plaque at 300 kHz (P < 0.05, n = 5 controls, n = 3 atherosclerotic). The correlation between in vivo and ex vivo analyses using Spearman was r = 0.97 (P < 0.0001, n = 8 aortic segments).

Conclusion:
We demonstrate a new, paired-electrode based EIS sensor for intravascular interrogation of lipid-laden lesions to complement diagnostic angiography.
Abstract 18045: Mild Coarctation of the Aorta: To Touch or Not to Touch the Patient? Looking at Left Ventricular Function and Hemodynamics
Authors: Keshavarz Motamed Zahra , Randles Amanda , Rikhtegar Nezami Farhad , Partida Ramon , Nakamura Kenta , Staziaki Pedro V , Ghoshhajra Brian , Bhatt Ami , Edelman Elazer R
Published: July 2021

Introduction:
Coarctation of the aorta (COA) is an obstruction of the aorta distal to the left subclavian artery. A peak-to-peak trans-coarctation pressure gradient (P
K
dP) of greater than 20 mmHg warns of severe COA and the need for interventional/surgical repair. The optimal method and timing of the intervention remain uncertain especially when the severity of COA is mild (P
K
dP < 20 mmHg) and it is unclear if mild COA should be treated at all. Rosenthal (2001; J Am Coll Cardiol) suggested that treatment strategies for patients with mild COA may need to be redefined as transcatheter interventions emerge, and yet the risks and benefits of such interventions in patients with mild COA are unclear. The aim of this study is to investigate the effects of transcatheter intervention on hemodynamics of the aorta and left ventricle (LV) in eleven patients with mild COA.

Methods.
We used specially developed computational fluid dynamics and lumped parameter modeling framework along with highly-resolved particle image velocimetry data and clinical measurements (Doppler-echocardiography, cardiac catheterization, CT and MRI) in this study.

Results
. COA intervention can improve aortic hemodynamics to some extent (i.e., time-averaged wall shear stress, oscillating shear index, peak jet velocity and kinetic energy [all averaged in the descending aorta] were reduced by 20%, 13.3%, 26.7% and 25%, respectively). However there is no concomitant effect on the LV hemodynamics (i.e., stroke work, normalized stroke work and peak LV pressure were reduced by only 3.8%, 3.7% and 3.2%, respectively; arterial systemic compliance was also reduced by 17%; N=11; p < 0.05).

Conclusion
. Our computational approach can effectively model and predict clinical conditions. Herein one must question intervention for mild COA, as it has limited utility in reducing myocardial strain.

Figure 1.
Catheter data and results of lumped parameter modeling in patient No. 1.
Abstract 18055: Induced Growth of Hypoplastic Cardiac Structures to Facilitate Repair of Congenital Defects
Authors: Labuz Daniel F , Pyles Lee A , Berry James A , Foker John E
Published: July 2021

Introduction:
Congenital heart defects (CHD) may include hypoplastic valves, ventricles and vessels which complicate repairs. Our hypotheses were that hypoplastic structures are developmental rather than primarily genetic in origin and the correct biomechanical signal would induce catch up growth. Our corollary hypothesis was that the growth signal is provided by flow, not pressure. First stage operations, therefore, were designed to increase flow and induce growth. Once growth was sufficient, a second operation would often complete the repair. We report our results using flow induced growth of hypoplastic structures to facilitate repair in 3 types of CHD.

Methods:
Three groups of CHD patients with associated hypoplastic structures: unbalanced atrioventricular canal defects (UAVC); pulmonary atresia with intact ventricular septum (PAIVS); and coarctation of the aorta (CoA) were reviewed. Operations increased flow through the hypoplastic structures, such as creating restrictive septal defects to increase flow through the hypoplastic AV valves and ventricles (UAVC, PAIVS) or relieving obstruction (CoA) to enhance aortic valve and arch flow.

Results:
On follow up, virtually all (85/90) hypoplastic structures reached normal size and the rest had nearly comparable growth (Table).

Conclusions:
1) Operations designed to increase flow through hypoplastic structures reliably induced catch up growth of UAVC, PAIVS and CoA lesions.

2) The growth response supported underdevelopment as the cause of hypoplasia and flow as the growth signal to reverse it.

3) Growth induction allowed two ventricle repairs in UAVC and PAIVS patients and avoided extended arch repairs in CoA; all with decreased operative risk.

4) Following catch up growth of the hypoplastic lesions, the outlook improved to that of patients with balanced AVCs, normal sized RVs in pulmonary atresia and well repaired CoA.

5) Once normal size was reached growth continued, producing a durable result.
Abstract 18056: Modeling Duchenne Muscular Dystrophy (DMD) Cardiomyopathy Using Patient-specific Induced Pluripotent Stem Cell-derived Cardiomyocytes
Authors: Kamdar Forum , Klaassen Kamdar Andre , Chapman Christopher S , Kamp Timothy J , Wu Joseph C , Koyano-Nakagawa Naoko , Garry Daniel J
Published: July 2021

Introduction:
DMD is the most common muscular dystrophy and is characterized by the absence of dystrophin. Cardiomyopathy and associated arrhythmias have emerged as a leading cause of death in DMD.

Hypothesis:
We hypothesized that the pathophysiology of DMD cardiomyopathy can be modeled using DMD hiPSC-derived cardiomyocytes (CM), which can be interrogated at the cellular and molecular level.

Methods:
Dermal fibroblasts were obtained from patients with genetically confirmed DMD and healthy controls and reprogrammed to hiPSC using human reprogramming transcription factors. DMD and control hiPSC lines were differentiated to CMs using a directed differentiation protocol. Functional analysis including wheat-germ agglutinin co-immunoprecipitation and calcium handling was performed at d60.

Results:
DMD hiPSCs demonstrated
DYSTROPHIN
exon mutations consistent with patient mutations. DMD and control hiPSCs differentiated to beating, electrically coupled CM sheets. Quantitative western blot analysis for dystroglycan complex (DGC) components and novel cardiac DGC proteins Cryab and Cypher demonstrated expression of the majority of DGC and novel cardiac DGC proteins at d60 of differentiation in control hiPSC-derived CM. Dystrophin and DGC proteins including novel cardiac DGC proteins are associated with the DGC in all control hiPSC CM at d60. DMD hiPSC-derived CM have absence of dystrophin and a disrupted DGC. We identified that cypher is absent in DMD hiPSC CM and validated this in human DMD left ventricular tissue. Calcium imaging demonstrated significantly abnormal calcium transients in DMD hiPSC-derived CM correlating to arrhythmias.

Conclusion:
Our results suggest that the control hiPSC-derived CMs have a largely nucleated DGC at d60 including novel cardiac DGC associated proteins. DMD hiPSCs have the hallmark absence of dystrophin and a disrupted DGC. The phenotype of increased arrhythmias in DMD patients is also reflected in DMD hiPSC CM. DMD hiPSC-derived CMs can be used as a model for investigation of DMD cardiomyopathy and further evaluation of the molecular and physiologic phenotype of DMD hiPSC cardiomyocytes will serve as a platform for testing current therapies and developing novel therapies for patients with DMD cardiomyopathy.
Abstract 18085: Heparan Sulfate Proteoglycans Only Modestly Affect Postprandial Hepatic Remnant Clearance in Humans
Authors: Dallinga-Thie Geesje M , Levels Han , Schimmel Alinda M , Nieuwdorp Max
Published: July 2021

Introduction and Methods:
Elevated circulating levels of Triglyceride-rich Remnant Lipoproteins (TLR) are strongly associated with increased risk for CVD. The hepatic clearance of TRL involves lipoprotein receptors i.e. the low-density lipoprotein receptor (LDLr) and heparin sulfate proteoglycans (HSPG). The relevance of each pathway in humans remains to be established. To further dissect the relative contribution of each of these receptors, we studied postprandial TRL metabolism with an oral fat tolerance test using cream supplemented with retinyl palmitate (RP) in 1) patients with a heterozygous loss-of-function (LOF) variant in LDLR stratified for a low (n=10) or high (n=10) HSPG gene score; 2) patients with heterozygous LOF variants in EXT1 or EXT2 (n=13), characterised by decreased HSPG chains length but normal sulfation pattern, and compared to matched healthy controls (n=13) and 3) diabetic patients (n=29) stratified for a functional SNP in SULF2, that predisposes to lower SULF2 expression and increased 6-O-sulfation of HSPG chains.

Results:
Postprandial TRL clearance was significantly delayed in patients with FH compared to controls (AUC-RP FH: 1971±190 vs Con: 646±110 nmol/l/h;P<0.0001 and iAUC-TG FH 6.9±1.0 vs Con 3.8±10 mmol/l/h, P<0.05) supporting the important role of LDLr in TRL clearance. No additional effect was observed if the FH group was stratified for HSPG gene score. Also, in patients with LOF variants in EXT, resulting in shorter HSPG chains, no difference in TRL clearance versus controls could be observed. In contrast, improved 6-O-sulfation due to lower hepatic protein expression of SULF2 resulted in improved fasting and postprandial TG levels and significantly lower iAUC-RP (iAUC-TG AA 6.9±1.1 vs GG 4.1±1.2 mmol/l/h P<0.05; AUC-RP AA 97±15 vs GG 15±2 mg/l/h; P<0.001)

Conclusion:
Our findings clearly indicate an important role for the LDLr in postprandial TRL clearance in humans. In contrast to murine studies, HSPGs do only modestly contribute to hepatic TRL clearance in humans, and implicate that sulfation of HSPG’s is of more relevance for TRL clearance than HSPG chain length.
Abstract 18114: Differences Between Observed and Predicted Cardiovascular Event Rates Using the Framingham and REACH Equations: The Case of High-intensity Statin Users in the United Kingdom
Authors: Taylor Benjamin , Lothgren Mickael , Villa Guilllermo , Lindgren Peter , Van Hout Benjamin , Mark Danese
Published: July 2021

Background:
High-intensity statin users are a select group of patients, and their observed cardiovascular (CV) event risk may not align with the predicted risk from published risk equations.

Hypothesis:
Published risk equations accurately characterize the observed patient risk in high intensity statin users

Methods:
Five cohorts were studied in the Clinical Practice Research Datalink: high-risk primary prevention (HRPP - prevalent diabetes in the absence of any other CV event), evident CV disease (ECVD - prevalent stable angina, revascularization, transient ischemic attack, carotid stenosis, abdominal aortic aneurysm, or peripheral vascular disease), incident acute coronary syndrome (ACS), incident ischemic stroke (IS), and incident heart failure (HF). Patients were followed from 1/1/2005 (HRPP, ECVD) or first qualifying event (ACS/IS/HF) until the first CV hospitalization after cohort inclusion, death, or end of observation (December 31, 2011). Predicted 10-year overall risk was based on Framingham (D’Agostino 2008) for HRPP and on REACH (Wilson, 2012) for all other cohorts. Acute (<=12 mos) and long-term rates (12+ mos) were generated for recurrent events in the ACS, IS, and HF groups (Wilson, 2012). Predicted rates were compared to the observed event rates using rate ratios, (observed rate/predicted rate). Standard errors were estimated using Poisson regression.

Results:
Framingham was well calibrated to the observed event rate in the HRPP cohort (RR 0.92 (95% CI 0.87 to 0.97). For all secondary prevention cohorts, REACH consistently underestimated the observed event rate, though the magnitude of the difference varied (see Table 1).

Conclusions:
Traditional risk scores consistently underestimated event rates in all secondary prevention populations treated with a high intensity statin. Observed events are vital for anchoring predicted rates to accurately determine country level estimates in certain patient populations.
Abstract 18150: Ventricular Arrhythmia During Post Cardiac Arrest Care: Prognostic Importance and Influence of Pre-hospital Defibrillation - A TTM Substudy
Authors: Thomsen Jakob H , Kjærgaard Jesper , Nielsen Niklas , Erlinge David , Wanscher Michael , Gashe Yvan , Friberg Hans , Pehrson Steen , Køber Lars , Hassager Christian
Published: July 2021

Background:
Ventricular arrhythmias (VA) are life threatening, even in patients admitted to an intensive care unit following out-of-hospital cardiac arrest (OHCA). Post cardiac arrest care includes hemodynamic stabilization and targeted temperature management (TTM) and while most patients are stabilized, VA may occur. We assessed the prognosis of OHCA patients with in-hospital VA and whether the number of pre-hospital defibrillations was predictive of in-hospital arrhythmic events.

Method:
We studied 934 (99%) comatose OHCA survivors from the TTM-trial (year: 2010-13) with available data on VA during the first 2 days of post cardiac arrest care and the number of pre-hospital defibrillation used to achieve return of spontaneous circulation (ROSC). The TTM trial showed no benefit of TTM at 33°C over 36°C in terms of mortality and neurological outcome.

Results:
The prevalence of VA was 16% and did not differ between the TTM groups (33°C= 82 (17%) vs. 36°C= 67 (15%), p=0.23). Patients with VA had similar 180-day survival rates (VA= 52% vs. no-VA= 53%, plog-rank= 0.63, Figure) and odds of unfavorable neurological outcome (OR=1.04 (0.73-1.48, p=0.83), compared to patients without VA. The number of pre-hospital defibrillations ranged from 0 to >20 and a twofold increase was associated with significantly higher odds of in-hospital VA, both combined (OR= 1.39 (1.22-1.59, p<0.0001), and separately as risk of ventricular tachycardia (OR= 1.39 (1.20-1.60, p<0.0001) and fibrillation (OR= 1.54 (1.23-1.93 p<0.001). This remained significant when adjusting for STEMI, initial rhythm, age, sex, bystander CPR, time to ROSC and admission lactate.

Conclusion:
Risk of VA is directly related to the number of pre-hospital defibrillations, which may be of value in predicting patients at risk of arrhythmia. VA occurring during post cardiac arrest care has no significant impact on prognosis, which supports continued active treatment in patients with recurrent VA after OHCA.
Abstract 18183: Short-term Impact of Defibrillation Testing on Heart Failure Admission
Authors: Akdemir Baris , Krishnan Balaji , Tholakanahalli Venkatakrishna , Benditt David , Li Jian-Ming
Published: July 2021

Introduction:
SIMPLE trial showed that defibrillation testing (DT) is safe but does not improve shock efficacy or mortality. However, impact of DT on heart failure (HF) admission at 30 days is unclear.

Objectives:
The aim of this study was to compare mortality and HF admission of ICD recipients who underwent DT (DT+) compared with those who did not (DT-).

Methods:
In this retrospective study, we analyzed consecutive patients who received an ICD ( new implant or generator change ) with DT+ and DT- between January 2008 and May 2014 from our ICD registry. Primary endpoints were death ( 30 days and 1 year ) and HF admission ( 30 days) .

Results:
Of the 501 patients, 311 patients (62,1%) were in DT+ group vs 190 (37,9%) were in DT- group. The mean ages in DT+ and DT- were 66 ± 10 and 70 ± 10 respectively (p<0.0001). DT- group had more generator change than DT+ group ( 61,1% versus 30,9%, p < 0.0001). Other demographic features were not significantly different between two groups (Table 1). No significant difference in mortality was found between two groups at 30 days and 1 year. HF admission at 30 days was significantly higher in DT+ group than in DT- group ( 17,4 % versus 4,7%, p < 0.0001) (Table 2).

Conclusion:
No short-term and long-term mortality were associated with DT, but DT was associated with increased HF admission at 30 days. Future prospective studies are needed to prove this association.
Abstract 18189: Neointimal Response to Everolimus-eluting Bioresorbable Scaffolds Implanted at Bifurcating Coronary Segments: An Optical Coherence Tomography Study
Authors: Sato Takao , Abdel-Wahab Mohamed , El-Mawardy Mohamed , Tölg Ralph , Richardt Gert
Published: July 2021

Background:
Previous studies have described different patterns of neointimal coverage between the outer wall and inner wall at coronary bifurcations lesions (BL) treated with metallic drug-eluting stents (DES) due to endothelial shear stress. Everolimus-eluting bioresorbable scaffolds (BRS) have thicker struts and could therefore have a stronger influence on endothelial shear stress compared to DES. However, the neointimal coverage of BL treated with BRS has not been adequately studied. We sought to evaluate the vascular response to BRS struts deployed at BL using optical coherence tomography (OCT).

Methods:
50 patients (64 lesions) underwent follow-up OCT 11.0 ± 2.1 months after BRS implantation. Cross-sectional area of BL with a side branch more than 1mm using OCT was analyzed every 200μm. All images were divided into 3 regions according to shear stress: the 1/2 circumference of the vessel opposite to the ostium (OO), side branch ostium (SO), and the vessel wall adjacent to the ostium (AO). %uncovered strut of all struts and the averaged neointimal thickness (NIT) in 3 regions were evaluated. Additionally, to assess the impact of the side branch size on neointimal proliferation in BL, we calculated the ratio of the diameter of side branch ostium (Ds) to the diameter of main branch (Dm) (Ds/Dm) and divided patients into two groups based on median value of Ds/Dm of 0.318 as follow: large ratio side branch group (LRSB, n=32) and small ratio side branch group (SRSB, n=32).

Results:
Mean BRS diameter and length were 3.01±0.37 and 20.7±5.5mm. Mean diameter of all side branches was 1.69±0.51mm. In all patients, there was a significant difference in NIT among 3 regions (OO, 121±66 vs. AO, 96±32 vs. SO, 82±43μm, p=0.03). A significant difference was shown in %uncovered strut among 3 regions (OO, 0.45 vs. AO, 1.5 vs. SO, 4.7%, p=0.03). Further, in LRSB group, there was a significant difference in NIT among 3 regions (OO, 130±63 vs. AO, 92±38 vs. SO, 75±39 μm, p=0.01), and a significant difference was shown in %uncovered strut among 3 regions (OO, 0.37 vs. AO, 2.0 vs. SO, 8.8%, p=0.01).

Conclusion:
Different patterns of neointimal coverage are observed between the outer wall and inner wall of BL treated with BRS. Neointimal coverage is least at and adjacent to large side branches.
Abstract 18190: Associations Between Endothelial Injury, Severity of Post-cardiac Arrest Syndrome and Mortality After Out-of-hospital Cardiac Arrest
Authors: Bro-Jeppesen John , Kjaergaard Jesper , Wanscher Michael , Johansson Pär , Ostrowski Sisse , Hassager Christian
Published: July 2021

Background:
Post-cardiac arrest syndrome (PCAS) is characterized by systemic inflammation and endothelial dysfunction, which may exacerbate organ failure and may be related to adverse outcome.

We sought to investigate the associations between trombomodulin (TM), a marker of endothelial cell injury, and severity of PCAS and the possible prognostic importance in comatose survivors of out-of-hospital cardiac arrest treated with targeted temperature management (TTM).

Methods:
We included 163 patients, randomly assigned to TTM at 33°C or 36°C for 24 h in the TTM-trial at a single center. Serum TM was analyzed at 0, 24, 48 and 72 hours after cardiac arrest and stratified in median value of TM for outcome analysis at each time point to a high or low TM group. Severity of PCAS was assessed daily by the Sequential Organ Failure Assessment score. Survival status was recorded at 180 days.

Results:
Corresponding values of TM and severity of PCAS correlated at each time point, baseline (r=0.31, p=0.0001), 24 h (r=0.52, p<0.0001), 48 h (r=0.50, p<0.0001) and 72 h (r=0.36, p<0.0001). Levels of TM changed significantly within the first 3 days (p<0.0001) with no significant difference between temperature groups, p
interaction
=0.32. At 24 h, the 180-day mortality rate in patients with high TM levels (> 6.9 ng·ml
-1
= median) was 42% compared to 18% in patients with low TM levels, p=0.002 (Figure), corresponding to an unadjusted hazard ratio of 2.6 (95%CI: 1.4-4.9), p=0.003. When adjusting for pre-hospital prognostic factors the hazard ratio for high TM levels at 24 h was 1.5 (95%CI: 0.7-3.1), p=0.31, with no significant interaction between level of TM and TTM-group, p=0.74. Analysis of TM at 48 and 72 hours showed similar results.

Conclusions:
Levels of TM are significantly elevated and associated with severity of PCAS with no effect of target temperature at 33°C or 36°C. High TM levels were associated with increased mortality, but the association was explained by confounding factors.
Abstract 18195: 20 Year Experience of Aortic Arch Surgery in 1004 Case: Single Centre Study
Authors: Leontyev Sergey , Semenov Mikhail , Davierwala Piroze , Etz Christian , Holzhey David M , Seeburger Jörg , Funkat Anne K , Bakhtiary Farhad , Misfeld Martin , Mohr Friedrich W
Published: July 2021

Objective:
Treatment of patients with extensive thoracic aortic disease (TAD) is performed using the different surgical techniques and is associated with higher operative mortality and morbidity as compared to other heart operations. We retrospectively evaluated our 20-years experience in treatment of TAD by analysing the early and late outcomes and identifying the clinical and surgical factors influencing them.

Methods:
Between July 1995 and February 2015, 1004 patients (mean age 61±11 years) underwent elective and urgent aortic arch surgery. Chronic Type A and B aortic dissection were indications for surgery in 61 (6.1%) patients whereas degenerative or atherosclerotic aneurysms accounted for the remaining 943 (93.9%) patients. Circulatory arrest was used in all patients. Antegrade selective cerebral protection (ASCP) was used in 686 (68.3%) patients.

Results:
The overall in-hospital mortality was 5.5 % and was significantly lower in patients who received ASCP (4.4%) compared those who did not (7.9%). Stroke and paraplegia occurred in 8.3% and 1.4% of patients, respectively. Logistic regression analysis revealed age >70 years (OR2.5,p=0.004), coronary artery disease (CAD) (OR 2.4, p=0.002), left ventricle ejection fraction (LVEF) <30% (OR , p=0.05), prior cardiac surgery (OR 2.4, p=0.008), and total arch replacement (OR 3.2, p<0.001) as independent predictors of in-hospital mortality. Use of bilateral ASCP was protective for early survival (OR 0.4, p=0.01). One, five and ten-year survival was 88%, 80% and 61%, respectively. Cox regression analysis revealed that long-term survival was negatively influenced by age, NYHA III-IV, CAD, previously stroke, prior cardiac surgery and total arch replacement and positively influenced by good LVEF and bilateral ASCP. Five and ten-year freedom from aorta-related surgical and endovascular re-intervention was 91% and 86%, respectively.

Conclusions:
Elective aortic arch surgery was associated with low early and late mortality and aorta-related reoperation rate, but increased rate of neurological complications. Use of bilateral ASCP positively influenced survival after surgery. Total aortic arch replacement was associated with worse outcomes compared to partial arch replacement.
Abstract 18238: Cardiomyocyte-specific Bag3+ Mutation P209L Induces Mitochondrial Fragmentation, Increased Apoptosis, and Activates p38 Signaling in vivo
Authors: Quintana Megan T , Eaton Samuel C , Yates Cecelia C , Takayama Shinichi , Willis Monte S
Published: July 2021

Introduction:
There are 6 members of the Bcl2-related anthanogene (BAG) protein family, which act as co-chaperones expressed at high levels in skeletal and cardiac muscle. BAG3 is involved in chaperone-assisted selective autophagy (CASA). Mutations in the Z-disc protein BAG3 have recently been found to cause myofibrillar myopathy (MFM) with cardiac complications (dilated cardiomyopathy). The missense mutation Pro209Leu (P209L) is one of ten BAG3 mutations identified in human disease to date.

Hypothesis:
Cardiac BAG3 P209L expression inhibits CASA, evidenced by less autophagic flux of misfolded proteins.

Methods:
Cardiac specific transgenic mice with alphaMHC-driven human Bag3P209L were created and analyzed functionally over 12 months. Histological analysis of apoptosis (TUNEL), pre-amyloid oligomers (PAO), and fibroblasts were performed in parallel with transmission electron microscopy (TEM) and molecular analysis of autophagy and mitochondrial dynamics.

Results:
Starting at 8 months, Bag3 P209L Tg+ hearts had significantly depressed systolic function. By 12 months, significant deficits in both diastolic and systolic function were identified, along with increased number of fragmented mitochondria and significant alterations in genes regulating mitochondrial fusion (Opa1) and Fission (Drp1). Immunofluorescence analysis revealed no differences in apoptosis (TUNEL) or autophagic flux (LC3II). But increased levels of cardiomyocyte pre-amyloid oligomers (PAO) were identified by confocal immunofluorescence. As PAO proteotoxic intermediates found in neurodegenerative diseases reportedly activate p38 MAPK, we assayed BAG3 P209L Tg+ hearts and found a significant ~50% increase in phospho-p38/p38.

Conclusion:
As increased activated p38 activity has negative inotropic and restrictive diastolic effects in vivo, we conclude that inhibiting p38 activity in BAG3 P209L patients may attenuate and/or delay the onset of heart failure. Studies are underway testing this hypothesis using specific inhibitors of P38 and downstream signaling pathways in vivo.
Abstract 18262: Left Ventricle Strain Rate in Children Demonstrates Heart Rate Dependence and a Force-frequency Relationship
Authors: Alvarez Silvia , Alhabden Mohammed , Kantoch Michal , Atallah Joseph , Colen Timothy , Tham Edythe , Khoo Nee
Published: July 2021

Introduction:
In adult pigs and human studies, strain rate (SR) is a valid and reproducible marker of contractility. It is also heart rate (HR) independent, hence lacks force-frequency relationship (FFR). Isovolumic acceleration (IVA) is a proven non-invasive load-independent measure of LV contractility used in research settings. This study sought to assess SR behavior during tachycardia and inotropic stimulation in children, compared to IVA.

Methods:
Twenty-four patients (median age, 13.9; range 7.8 - 22.5 years) with no structural or functional heart abnormalities were evaluated after a radiofrequency ablation procedure. Echocardiogram was performed at baseline, during atrial pacing and isoprenaline infusion to achieve 130% of baseline HR. Speckle tracking global LV longitudinal SR and tissue Doppler septal IVA were measured. Relationships between HR, SR and IVA were assessed. Percent (%) change and absolute differences between SR and IVA at baseline, pacing and isoprenaline were evaluated. Data are reported as median and interquartile ranges.

Results:
SR and IVA showed a moderate correlation with HR at baseline (SR: r=-0.68, p=0.0002; IVA: r=0.46, p=0.01), and during pacing (SR: r=-0.56, p=0.003; IVA: r=0.58, p=0.002). Both SR and IVA increased with pacing and isoprenaline (table 1), however the greatest % change was seen during isoprenaline infusion for IVA (p < 0.006) and SR (p < 0.0001).

Conclusion:
SR enhances with increasing HR in children, demonstrating a relative HR dependence and a FFR. This is contrary to findings in adult studies, thus this study highlights that children show a different LV mechanical response to chronotropic effects and therefore caution should be use when extrapolating of adult findings to children.
Abstract 18284: Incidence of Epilepsy is Elevated in Children and Young Adults With Congenital Heart Defects Compared With the General Population: A Nationwide Cohort Study
Authors: Olsen Morten , Marino Bradley S , Leisner Michelle , Woo Jessica G , Madsen Nicolas L
Published: July 2021

Perioperative seizures related to surgery for congenital heart defects (CHD) are well described; however, few data exist on the long-term risk of epilepsy in patients with CHD. We aimed to estimate the incidence of epilepsy in children and young adults with CHD compared with the general population.

Methods:
Utilizing data from the Danish National Registry of Patients (DNRP) we identified all patients diagnosed with CHD before the age of 15 years between 1980 and 2010 who were born during the same period. The DNRP is a nationwide hospital discharge registry covering all Danish hospitals. Previously validated methodology using the DNRP was applied to measure the outcome, epilepsy, as well as presence of extra cardiac defects (ECD) and/or syndromes. We used the Danish Medical Birth Registry to identify preterm birth (gestational age<37 weeks). For each CHD subject, we identified 10 controls from the general population using the Danish Civil Registration System, matched by sex and birth year. A unique personal identifier assigned at birth and used in all Danish public registries enabled virtually complete follow up for migration, death, or epilepsy until January 1, 2013. We computed cumulative incidences and hazard ratios (HR) (split at 5 years of age to obtain proportional hazards) of time from CHD diagnosis (index date for controls) to epilepsy.

Results:
We identified 14,665 CHD subjects with a median age at diagnosis of 2 (IQR 19) months. By 15 years of age, the cumulative incidence of epilepsy was 4% among CHD subjects. The HR of epilepsy among CHD subjects compared with the control cohort was 3.7 (95% CI: 3.2-4.3) below 5 years of age, and 2.4 (95% CI: 2.1-2.7) from 5 to 33 years of age. In the older age group, HR for patients with severe CHD was 2.8 (95% CI: 2.3-3.5), and for mild and moderate CHD was 2.2 (95% CI: 1.8-2.6). After exclusion of all subjects with ECDs and/or syndromes and preterm birth, corresponding HRs were 2.2 (95% CI: 1.6-3.0) and 1.7 (95% CI: 1.3-2.2), respectively.

Conclusion:
The epilepsy risk was markedly increased in CHD subjects compared with the age and gender matched controls. These findings add evidence to support the importance of developing neuro-protective measures and potentially long-term epilepsy surveillance strategies in the CHD population.
Abstract 18363: Type 1 and Type 2 Cardiac Autonomic Neuropathy in Type 1 and Type 2 Diabetes Mellitus
Authors: Pelchovitz Daniel J , Ng Jason , Subacius Haris , Chicos Alexandru B , Bergner Daniel W , Banthia Smriti , Molitch Mark , Goldberger Jeffrey J
Published: July 2021

Introduction:
Cardiac autonomic neuropathy (CAN) is a complication of diabetes mellitus (DM) that is associated with increased mortality. The severity of CAN may be related to type and duration of DM.

Methods:
16 subjects with type 1 DM (age 32.9±10.1 years), 18 subjects with type 2 DM (55.4±8.0 years) and 30 controls (44.0±11.6 years) underwent exercise-based assessment of CAN. Two 16-minute submaximal bicycle tests were performed followed by 45 minutes of recovery. Continuous 12-lead electrocardiography was performed. On the 2nd test, atropine (0.04 mg/kg) was administered at peak exercise so that all of recovery occurred under parasympathetic blockade. Plasma epinephrine and norepinephrine levels were measured at rest, during exercise, and during recovery. For each subject and at each time point in recovery, parasympathetic effect on the RR interval was defined as the difference of the RR interval at baseline without atropine and the RR interval after parasympathetic blockade with atropine.

Results:
There were no differences in resting or peak exercise heart rates in the 3 groups. Parasympathetic effect on RR intervals during recovery (p<0.03) and heart rate recovery (p=0.02) were blunted in type 2 DM. Type 1 DM had higher baseline epinephrine and norepinephrine levels (p<0.03), and exhibited persistent sympathoexcitation during recovery.

Conclusions:
Both type 1 and type 2 DM exhibit subtle abnormalities in autonomic function, but differentially affect the parasympathetic and sympathetic limbs of the autonomic nervous system. This is the first report of variable pathophysiology for CAN in type 1 versus type 2 DM.
Abstract 18396: Low Rate of LDL-Goal-Attainment in 57,855 High-Risk-Patients in Europe, Canada, South-Africa, Middle East and China - Results of DYSIS
Authors: Gitt Anselm K , Lautsch Dominik , Horack Martin , Ambegaonkar Baishali , Ferrieres Jean ,   DYSIS Study Group
Published: July 2021

Background:
Statin treatment is routinely used for secondary prevention world-wide. Little is known about the prevalence of persistent lipid abnormalities under chronic statin treatment for secondary prevention and possible differences in LDL-Cholesterol (LDL-C) goal attainment in clinical practice between countries in different parts of the world.

Methods:
Between 2008 and 2012, consecutive statin-treated outpatients were enrolled in 26 countries worldwide, (DYSIS = Dyslipidemia International Study; list of countries in table) to assess LDL-C goal attainment for secondary prevention. European Society of Cardiology recommendations were used to classify patient risk, and to define LDL-cholesterol treatment goals. Data were collected under real life conditions in physicians’ offices and hospital outpatient wards.

Results:
Serum lipid values of 57,885 consecutive statin-treated outpatients were studied in the context of their cardiovascular risk factors, and the potency and composition of their lipid-lowering treatment. In the very-high risk patients only 21.7% did reach the currently recommended LDL-Chol target <70mg/dl with large differences between the countries varying from 9.2% to 44.3%. In the high-risk population the LDL-Chol target <100mg/dl was achieved in 38.0% oft he patients, varying between 16.6% and 66.7% between countries

Conclusion:
Despite chronic statin treatment, only 21.7% of the very-high-risk patients reached the current recommended LDL-Chol target <70mg/dl in this large multinational cross-sectional trial, highlighting the persistent large gap between guideline recommendations and clinical practice. Further treatment escalations are necessary to reduce the risk of subsequent cardiovascular events.
Abstract 18402: Human Atrial Fibrillation Drivers Seen Simultaneously by Focal Impulse and Rotor Mapping and High-resolution Optical Mapping
Authors: Hansen Brian J , Briggs Carey , Moore Brandon T , Csepe Thomas A , Li Ning , Zhao Jichao , Garikipati Naga V , Janssen Paul M , Mohler Peter J , Hummel John D , Fedorov Vadim V
Published: July 2021

Background:
A mechanism of AF maintenance has been suggested to be a limited number of patient-specific AF drivers seen by optical mapping in animals and now Focal Impulse and Rotor Mapping (FIRM) in patients. The higher resolution optical mapping can only be performed ex vivo and, thus, these two different mapping approaches have never been evaluated simultaneously in human hearts.

Methods:
Coronary-perfused explanted human atria (n=5, 19-57 y.o.) were optically mapped using voltage sensitive near-infrared di-4-ANBDQBS with 2-4 high resolution CMOS cameras (100x100 pixels with 330-1000μM resolution) simultaneously with a 64-electrode basket catheter or a 64-electrode custom flat catheter from either the endocardium or epicardium. AF (>10 min, 6.8±2.1Hz) was induced by perfusion of adenosine (10-100μM) and/or isoproterenol (10-100nM). AF drivers were defined as localized stable reentrant activity in areas of highest dominant frequency for optical mapping, while unipolar signals from the catheters were analyzed using experienced FIRM user interpretation and RAP, a signal analysis tool that highlights driver regions on commercially available systems.

Results:
Optical mapping identified reentrant AF drivers in 7/8 episodes of AF in both the left and right atria. Interestingly, one episode of AF was driven by two competing reentrant drivers. Six AF drivers seen by optical mapping were also seen with the same location and rotation by FIRM, while FIRM identified an AF driver in an 8th episode from an endocardial basket that was unseen by optical mapping from the epicardium. In one episode, the intramural AF driver was only defined by dual sided optical mapping and unseen by endocardial FIRM.

Conclusions:
Our study demonstrates that most localized reentrant AF drivers in ex vivo human hearts have similar spatiotemporal characteristics whether identified by high resolution optical mapping or FIRM and may represent the clinical phenomena seen in AF patients.
Abstract 18409: Longer Ambulatory Monitoring Increases Identification of Clinically Significant Ectopy
Authors: Loring Zak , Hanna Peter , Pellegrini Cara
Published: July 2021

Introduction:
Frequent premature ventricular contractions (PVCs) can cause a reversible reduction in left ventricular systolic function. Prior studies have found that this cardiomyopathy is associated with PVC counts exceeding 13-37% of total heart beats. Most of these studies used 24-hour ambulatory electrocardiograms (AECG) to assess PVC burden; however, PVC counts may vary across 24-hour periods.

Hypothesis:
Extended monitoring with AECG will improve detection of clinically significant ectopy.

Methods:
Records from all patients receiving 14-day AECGs at the San Francisco Veterans Affairs Medical Center between March 2012 and March 2015 (N=694) were reviewed and those with total PVC counts ≥ 1.0% of total heart beats were included (N= 105). Each patient’s daily PVC count was abstracted, and the range of these values across 24-hour periods was assessed. The median time for these ranges to cross clinically significant thresholds (PVCs ≥ 10, 15 or 20% of total heart beats) was determined.

Results:
Median PVC burden was 2.8% of total heart beats (interquartile range, IQR 1.8-6.8%) and the median range across 24-hour periods was 4.7% (IQR 2.9-10.4%). Individual ranges of daily PVC burden crossed thresholds of 10, 15 and 20% of total heart beats in 23.8%, 17.1% and 12.4% of patients, respectively. Median time to detecting an individual’s maximum PVC burden was 6 days (IQR 2-11 days). While 88% of those who reached the 20% threshold did so on the first day of monitoring, only 53% of those reaching the 10% threshold did similarly, with a continually increasing yield throughout the 14 day monitoring period (Figure).

Conclusions:
Individual PVC burden varies widely from day-to-day. While the majority of patients who ultimately crossed clinically significant thresholds did so on the first day of monitoring, extended monitoring nearly doubled those reaching the 10% threshold.
Abstract 18417: Clinical Presentation, Cardiac Phenotype and Long Term Prognosis of Patients With Late Onset Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy
Authors: Bhonsale Aditya , te Riele Anneline S , Sawant Abhishek , Groeneweg Judith , James Cynthia A , Murray Brittney , Tichnel Crystal , Dooijes Dennis , Heijden Jeroen v , Tandri Harikrishna , Tintelen Peter v , Judge Daniel P , Hauer Richard , Calkins Hugh
Published: July 2021

Introduction:
The phenotypic features and clinical course of elderly Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C) patients (age> 50 years at diagnosis) is unknown.

Methods:
Demographic, phenotypic and genotypic data of 502 patients with ARVC diagnosis (2010 Task Force Criteria) from Johns Hopkins and Utrecht (NL) ARVD/C registries was obtained and long term clinical outcomes ascertained.

Results:
Late presentation was seen in 104 (21%) patients (38% with PKP2 mutation; no DSP or DSG2 mutation carrier) with 3% being ≥ 65 years at diagnosis. Sustained ventricular tachycardia (VT) is the major (43%) mode of presentation in the elderly while cardiac syncope is infrequent (p<0.001). The elderly are significantly less likely to harbor a pathogenic mutation (53%; p=0.005), have precordial T wave repolarization changes (p<0.001) and have lower ventricular ectopy burden (median count 1503 vs 2497; p=0.026) compared to younger patients. In the elderly, over 7±5 years of follow up, 68(65%) patients experienced sustained ventricular arrhythmias with similar (p=0.08) arrhythmia free survival at 5 years of follow up (73% vs.60% in younger). LV dysfunction and heart failure was seen in 24(32%) and 15(14%) patients respectively without need for cardiac transplantation. Male gender (OR 2.12, 95%CI (1.3-3.45); p=0.002), absence of a pathogenic mutation (OR 1.94, 95%CI (1.20, 3.12); p=0.006) and family member status (OR 2.09, 95%CI (1.24, 3.51); P=0.006) were independently associated with late presentation. In the elderly, EP study inducibility (<0.001), major RV structural disease (p=0.022), absent family history (p<0.001), male gender (p=0.002) and pathogenic mutation (p=0.001) were associated with increased risk of ventricular arrhythmias while ECG abnormalities and ventricular ectopy (p=0.489) were not.

Conclusion:
One fifth of all ARVD/C patients present after 50 years of age, often with sustained VT and are less likely to have prior syncope or identifiable pathogenic mutation. In ARVD/C, late presentation does not confer a benign prognosis and is associated with high arrhythmic risk. Electrocardiographic changes and ventricular ectopy are significantly less common in the elderly and are not associated with arrhythmic events.