bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 17340: High Fat Diet Exacerbates Uridine Adenosine Tetraphosphate (Up4A)-Mediated Decrease in Coronary Flow in Atherosclerotic ApoE Knockout Mice: Role of Purinergic P2X1 Receptors
Authors: ZHOU ZHICHAO , Teng Bunyen , Labazi Hicham , Sun Changyan , Yang Yan , Zeng Xiaorong , Mustafa S. Jamal
Published: July 2021

Introduction:
Up4A, a novel endothelium-derived vasoactive agent, is proposed to play a role in cardiovascular disorder via activation of P2 receptors (P2R). Here, we evaluated the vasoactive effect of Up4A on coronary flow (CF) in ApoE knockout mice (KO) with and without high fat diet (HFD).

Methods:
Functional studies were conducted in isolated mouse hearts using Langendorff and isolated coronary arteries (diameter≈100 μm) using wire Myograph. Immunofluorescence was performed for P2X1R expression in isolated coronary arteries.

Results:
There was no significant difference in baseline CF (ml/min/g) among wild type (WT, 18.4±0.5), ApoE KO (17.6±1.1) and ApoE KO+HFD (15.9±1.0). Infusion of Up4A (10-9-10-5 M) resulted in a dose-dependent reduction in CF in WT (by ~38%), which was similar to ApoE KO (by ~40%). In isolated coronary arteries of WT, Up4A produced a mild contraction up to ~20%, indicating a vasoconstrictor effect of Up4A. Notably, Up4A further decreased CF in ApoE+HFD as compared to ApoE. Moreover, selective P2X1R antagonist MRS2159 (10 μM) restored Up4A-mediated decrease in CF more in ApoE+HFD than ApoE (Figure). Finally, the percentage expression of vasoconstrictor P2X1R on smooth muscle cells (SMC) of coronary arteries was higher in ApoE+HFD than ApoE, which was due to a markedly reduced vasodilator P2X1R expression on EC in ApoE+HFD (8.7±0.6 fluorescence intensity in A.U.) than ApoE (22.1±0.5), while P2X1R expression on SMC was similar between ApoE+HFD (6.3±0.4) and ApoE (8.4±0.3).

Conclusion:
Up4A exerts a vasoconstrictor influence in mouse coronary microcirculation. Up4A decreases CF in WT to a similar extent in ApoE, whereas HFD exacerbates Up4A-decreased CF in ApoE possibly through downregulation of vasodilator P2X1R on EC. These findings indicate that Up4A alters CF in atherosclerosis and P2X1R may represent a potential therapeutic target.
Abstract 17347: De novo Ceramide Synthesis is Upregulated by Cardiac Ischemia and is Associated With Cardiomyocyte Apoptosis and Mitochondrial Dysfunction
Authors: Ji Ruiping , Liao Xianghai , Zhang Xiaokan , Jiang Hongfeng , Drosatos Konstantinos , Kennel Peter J , Castillero Estibaliz , Chang Jennifer Y , Homma Shunichi , Goldberg Ira , Schulze Paul Christian
Published: July 2021

Background:
Serine palmitoyltransferase (SPT) is the rate-limiting enzyme of de novo ceramide formation.However, ceramides can be produced through various pathways. The role of de novo ceramide synthesis via SPT in cardiac ceramide synthesis in ischemic cardiomyopathy has not been conclusively studied.

Hypothesis:
Ceramide synthesis via SPT may be linked to myocardial infarction-induced mitochondrial dysfunction and cardiac remodeling.

Methods:
Left coronary artery ligation and sham surgery was performed in C57BL/6J (8 wks, n=69) and Sptlc2 gene deletion mice (8 wks, n=9). Echocardiography confirmed MI-related cardiomyopathy at 2 and 8 wks. Groups of mice were treated either with SPT inhibitor, myriocin (300 ug/kg/d) or placebo for 8 wks. Ceramides were analyzed by LC/MS lipidomics. Sptlc2 (p3xFLAG-CMv7) overexpression in AC16 human cardiomyocyte-like cells was assessed.

Results:
Post-MI, total cardiac ceramides and certain species increased (total: +19%; C16: +19%; C24: +39%; C24:1: +44%; all p<0.05 vs sham), consistent with cardiac Sptlc2 protein levels (+68% vs sham; p<0.05). Sptlc2 overexpression, in cells, also resulted in increased ceramides (total: +33%; p<0.05), C14 (+66%; p<0.001), C16 (+39%; p<0.01), C16:1(+47%; p<0.001) and C24:1 (+37%; p<0.01), increased apoptosis (+64%; p<0.01), decreased cellular respiration (-69%; p<0.001) and lowered respiratory capacity (-36%; p<0.001). Myriocin treatment resulted in reduced LV dilation (4.8±0.3 vs 5.9±0.3 mm in placebo; p<0.05), improved fractional shortening (19.8±2.4% vs 13.4±2.2 in placebo; p<0.05), decreased myocardial collagen (0.08% vs 0.7%, p<0.05) and prevented the increase of ceramides, post-MI (+4% vs. +17% in placebo; p<0.05). C16, C24:1, and C24 ceramides decreased by 19, 20, and 32%, respectively (all p<0.05 vs placebo). Sptlc2 KO mice trended towards less progressive remodeling with reduced fractional shortening compared to WT post-MI (-7% vs -14%; p=0.06).

Conclusion:
Pharmacologic and genetic inhibition of de novo ceramide synthesis decreases cardiac ceramides and prevents cardiac remodeling post-MI. Increased ceramides induce apoptosis and mitochondrial dysfunction. Inhibition of ceramide synthesis can be a supplemental therapy for heart failure treatment.
Abstract 17433: Improved Outcomes in Septic Shock With Pre-hospitalization Use of Angiotensin-converting Enzyme Inhibitors (ACEI) and Angiotensin Receptor Blockers (ARB)
Authors: Mawri Sagger , Shah Jainil , Tarun Jain , Dirani Rami , Michaels Alexander , Gibbs Joseph , Sudasena Daryl , Alsafadi Yasser , Sengupta Ruchira , Albashaireh Derar , Ananthasubramaniam Karthik
Published: July 2021

Background:
The neurohormonal effects of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) are well recognized. Recent molecular studies have also demonstrated novel immune-modulating properties of ACEI/ARB through reduction of pro-inflammatory cytokines. In a recent study, obese trauma patients on pre-injury ACEI/ARB had reduced multi-organ failure scores and improved T cell function and monocyte maturation as compared to those not on ACEI/ARB. We sought to determine whether pre-hospital use of ACEI/ARB conferred improvements in outcomes in patients with septic shock (SS).

Methods:
We evaluated 248 patients admitted to the ICU with SS from January 2011 to April 2013. Comprehensive baseline demographic, clinical and echocardiographic data was obtained at time of ICU admission. We identified 90 patients on ACEI/ARB prior to ICU admission. Chi-square and t-tests were used to assess for differences in clinical parameters and outcomes in patients who were on ACE/ARB prior to ICU admission (ACE/ARB group) versus those not on ACEI/ARB prior to ICU admission (non-ACEI/ARB group).

Results:
Patients in the ACE/ARB group (36%) had significantly lower heart rate (95.8 bpm vs 102.3 bpm, p<0.05), higher MAP (80 mmHg vs 74 mmHg, p<0.05), higher serum potassium level (4.3 mEq/L vs 4.0 mEq/L, p<0.05), and less urine output (522cc vs 708cc per initial 24 hours, p<0.05) with a non-significant trend towards lower respiratory rate, WBC count, lactate level and APACHE 2 score. The ACEI/ARB group had higher left ventricular systolic diameter (1.26 cm vs 1.17 cm, p<0.05) and left ventricular posterior wall diameter (1.18 cm vs 1.07 cm, p<0.05); however, there were no other statistically significant echocardiographic differences between both groups. In-hospital and 90-day mortality was significantly less in the ACE/ARB group compared to the non-ACE/ARB group (20% vs 31.7%, p <0.05) and (25.6% vs 38%, p <0.05), respectively.

Conclusion:
ACEI/ARB use prior to ICU admission is associated with improved outcomes in SS patients, not explained by laboratory or echocardiographic differences. This provides further support for the possible immunomodulating benefits of ACEI/ARBs; however, more studies are needed to confirm these findings.
Abstract 17492: Extent and Pattern of Late Gadolinium Enhancement Predict Arrhythmic Events in Patients With Nonischemic Dilated Cardiomyopathy
Authors: Shin Dong Geum , Lee Hye-Jeong , Park Junbeom , Kim Young Jin , Uhm Jae-Sun , Park Hui-Nam , Leee Moon-Hyoung , Joung Boyoung
Published: July 2021

Background:
Late gadolinium enhancement (LGE) by cardiac MR (CMR) has been related to adverse clinical outcomes in patients with nonischemic dilated cardiomyopathy (NIDC). But, a statistically significant association between LGE and arrhythmic risk in NIDC has not been demonstrated consistently. This study evaluated the impact of the presence, location and pattern of LGE on arrhythmic risk prediction in NICM.

Methods:
This study included 365 patients (54±15years) with NICM who underwent CMR. The extent, location and pattern of LGE were categorized. We analyzed for the primary outcome of ventricular arrhythmia (VA) including sustained or nonsustained ventricular tachycardia (VT), appropriate implantable cardioverter-defibrillator (ICD) intervention and ventricular fibrillation (VF). Cardiac death and hospitalization for heart failure (HF) were evaluated as secondary outcomes.

Results:
LGE was seen in 267 (73 %) patients. During median follow-up of 44±36 months, patients with LGE had higher incidence of cardiac death (15 % vs. 2 %, p<0.001), hospitalization for HF (40 % vs. 15 %, p<0.001) and VA (14% vs. 6%, p=0.03). In multivariable analysis, the presence of LGE (HR 2.78; 95% CI 1.10-7.02; p=0.03) was the independent predictor of arrhythmias. Patients with extensive LGE had higher VA (32% vs. 10%, p<0.001) with lower cumulative survival free of VA than those without extensive LGE (p=0.001). The frequent LGE location was as follows: LV septum 64%, LV-RV junction 42% and inferior 10%. VA was lower in patients with than without localized LGE limited to LV-RV junction (21% vs. 46%, p=0.005). Interestingly, while the incidence of ventricular arrhythmia was higher in patients with transmural LGE (29% vs. 10%, p=0.003), it was lower in those with patch LGE (2% vs. 16%, p=0.02) than the other patients.

Conclusions:
In patients with NICM, the LGE was an independent prognostic predictor of VA. Extensive LGE and specific location of LGE was related with the arrhythmic events.
Abstract 17534: The Most Appropriate Number of Personnel Needed for Chest Compressions for In-hospital Cardiac Arrest: A Randomized, Crossover Manikin Study
Authors: Yamanaka Shunsuke , Nishiyama Kei , Hayashi Hiroyuki , Huh Ji Young
Published: July 2021

Background:
Effective chest compression (CC) is vital in cardiopulmonary resuscitation (CPR), and rescuer’s fatigue negatively affects quality of CPR. However, there is no consensus on the appropriate number of personnel needed for CC to avoid rescuer’s fatigue.

Objective:
We determined the appropriate number of personnel needed for 30-min CPR in a rescue-team in a hospital.

Methods:
We conducted a preliminary randomized, crossover, manikin trial on healthcare providers. We divided them into Groups A to D according to the intervals between the 2-min CC and assigned a different interval to each group. Groups A, B, C, and D performed CCs at 2-, 4-, 6-, and 8-min intervals as in 2, 3, 4, and 5 personnel, respectively. All participants performed CCs for 30 min with different intervals depending on the assigned group; participants allocated to Groups A, B, C, and D performed 8, 5, 4, and 3 cycles, respectively. We compared the differences between first cycle and the second to the last cycle

Results:
We enrolled 42 participants (age: 25.2±4.2, men 47.6%) for the preliminary evaluation. We used Kruskal-Wallis for the analysis. Participants in the less interval Groups A and B performed faster (A: -24.28±15.18, B: -7.90±13.49, C: -11.27±17.01, D: -2.38±3.31, P=0.03) and shallower CCs (A: -4.42±6.92, B: -3.18±5.43, C: -0.18±5.74, D: -1.23±4.10, P=0.62). Women-rescuers performed faster (A: -27.25±12.23, B: -7.00±13.97, C: -8.16±19.26, D: 3.16±4.66, P= 0.05) and shallower CCs (A: -6.25±7.54, B: -3.00±6.89, C: -3.66±3.32, D: -0.16±4.35, P=0.58). However, CCs of men-rescuers were not faster (A: -20.33±20.65, B: -9.00±14.44, C: -15.00±15.11, D: -7.14±16.70, P= 0.60) or shallower (A: -2.00±6.55 B: -3.40±3.78, C: 4.00±5.33, D: -2.14±3.98, P=0.06).

Conclusion:
At least four rescuers (Group C) may be needed to reduce rescuer’s fatigue for 30-min CPR. If the team only includes women, more personnel would be needed as women experience fatigue faster.
Abstract 17608: Identification of a Tissue-specific Very Long-chain Acyl-CoA Synthetase Involved in the Inhibition of ATP-Citrate Lyase (ACL) by ETC-1002: A Novel Mechanism for Cholesterol Biosynthesis Inhibition in the Liver
Authors: Pinkosky Stephen L , Newton Roger S , Birch Carolyn M , Filippov Sergey , Groot Pieter H , Lalwani Narendra D
Published: July 2021

ETC-1002 is a first-in-class oral small molecule that significantly lowers levels of low- density lipoprotein-cholesterol (LDL-C) by 30-40% in hypercholesterolemic patients with reduced potential for muscle-related adverse events. Our previous investigations into the mechanism of action demonstrated a requirement for acyl-CoA synthetase- (ACS) dependent coenzyme A (CoA) activation of ETC-1002 (ETC-1002-CoA) to inhibit its molecular target, ATP-citrate lyase (ACL), an enzyme upstream of HMG-CoA reductase in the cholesterol biosynthesis pathway. In the present study, we have elucidated a mechanistic basis for tissue-specific inhibition of ACL by providing evidence that ACSVL1 is the ACS isoform that catalyzes the CoA activation of ETC-1002. Genetic silencing of ACSVL1 in McArdle cells prevented the CoA activation of ETC-1002 and consequently its inhibition of de novo cholesterol synthesis. We demonstrate that ACSVL1 is highly expressed in primary human hepatocytes and human liver microsomes. Furthermore, we establish a statin-like regulatory link between ACL activity and cholesterol metabolism by showing that ACL siRNA silencing or pharmacological inhibition by ETC-1002-CoA, leads to increased LDLR expression and activity. Using primary human hepatocytes, we demonstrate the concentration-dependent inhibition of cholesterol synthesis by ETC-1002, an associated increase in mRNA expression of the sterol responsive genes srebp2, hmgr, pcsk9, and ldlr mRNA, and increased LDLR activity. In addition, we demonstrate that ACSVL1 is not expressed in L6 myotubes, primary human skeletal muscle cells, or human skeletal muscle microsomes. Unlike statins, ETC-1002 did not inhibit the de novo synthesis of sterols in skeletal muscle cell cultures, nor promote caspase 3/7 activation. Therefore, by establishing a regulatory link between ACL inhibition and LDLR up-regulation, and by identifying ACSVL1 as the ACS isoform that catalyzes the CoA activation of ETC-1002, we provide evidence for the tissue-specific inhibition of ACL by ETC-1002-CoA that results in LDL-C-lowering without activity in skeletal muscle or associated side effects.
Abstract 17612: Hypertension Severity is Associated With Impaired Cognitive Performance
Authors: Muela Henrique C , Costa-Hong Valeria A , Machado Michel F , Moraes Natália C , Memória Claudia M , Yassuda Mônica S , Shu Edson B , Nogueira Ricardo C , Massaro Ayrton R , Feitosa Raul R , Merlin Silvia , Trés Eduardo S , Nitrini Ricardo , Mansur Alfredo J , Bortolotto Luiz A
Published: July 2021

B: Hypertension affects the target-organs diversely. Most evidence on target-organ damage in hypertension is related to kidney and heart. The cerebrovascular and cognitive impairment are less studied.

O: To study the cognitive function changes in patients with hypertension on different stages compared to the control pairs and their correlation with the arterial stiffness properties assessed by non-invasive methods and cerebral circulation assessed by transcranial Doppler.

M: In a cross sectional study 162 patients (42 controls and 120 hypertensive) were comparatively evaluated. Hypertensive patients were divided in three stages according to the blood pressure levels or medication use (HTN-1: BP 140-159/90-99 or use of one antihypertensive drug; HTN-2: BP 160-179/100-109 or use of two drugs and HTN-3: BP ≥180/110 or use of three or more drugs). The following variables were evaluated: pulse wave velocity, intima medial thickness, cerebral blood flow velocities by transcranial Doppler (TD) and cognitive function. Mean velocity of middle cerebral artery was continuously monitored at resting and during the breath holding test (30 seconds) and 3 minutes handgrip maneuver. Cognitive function was assessed by mini mental state examination and Montreal Cognitive Assessment.

R: Compared to control group, HTN-3 group was older, had higher BMI, IMT and PWV and lower educational level and family income (Table 1). Interestingly, the higher the hypertension stage the poorer was the performance in cognitive tests even after age correction. There was no difference among the groups related to TD velocities at rest and the hand-grip maneuver. However, it was noted a lower breath holding index in the hypertensive group (HTN-1=0.94±0.56; HTN-3=0.97±0.59 vs Control=1.5±0.68; p=0.002) which could infer less vasomotor reactivity in these patients.

C: Cognitive impairment was more frequent in patients with hypertension and this frequency was related to hypertension severity.
Abstract 17639: Predictors of Poor Neurocognitive Performance and Neuropsychological Phenotypes in Adolescents and Young Adults With Congenital Heart Disease
Authors: Areias Maria Emilia G , Peixoto Bruno , Pinheiro Ana Carolina , Monteiro Helena , Araújo Sara Filipa , Carvalho Tânia , Melo Stefanie , Lopes João Pedro , Rodrigues Filipa , Nascimento Ana Catarina , Miranda Joana , Vilacova Filipa , Moura Cláudia , Soares Joana Luz , Viana Victor , Quintas Jorge , Areias José Carlos
Published: July 2021

Objectives:
to determine the predictors of neurocognitive performance (NP) of patients with Congenital Heart Disease (CHD), analysing its relation to parameters of fetal development, as head circumference (HC), weight (W) and length (L) at birth, neonatal parameters (APGAR 1, 5), quality of life (QOL), psychiatric morbidity (PM), psychosocial adjustment (PSA) and traits of personality (TP); to identify different phenotypes of NP in CHD patients.

Methods:
337 CHD patients, 189 male, ages 12 to 30 years (mean= 16.34 ± 3.12), 117 cyanotic, and 119 healthy controls (56 males, mean=18.41±3.20) participated. Clinical data were collected. Neuropsychological assessment included Wechsler’s Digit Test (direct and reverse) and Symbol Search, Rey’s Complex Figure, BADS’s Key Searching Test, Color-Word Stroop Test, Trail Making Test (A, B) and Logical Memory Task. Participants were interviewed on social support, family educational style, self-image, physical limitations, completed a psychiatric interview (SADS-L) and self-report questionnaires on QOL (WHOQOL-BREF), PSA (YSR and ASR) and TP (NEOPI-R). HC, W and L and APGAR were collected.

Results:
CHD patients had a significantly worse NP than healthy controls in all tests, and the cyanotic worse than the acyanotic patients. Several correlations were apparent between fetal parameters (HC, W and L) and neuropsychological abilities in CHD. However, the HC was the main predictor of bad NP later on in CHD patients (R=0.435; R2=0.189; F=14.692; p=0.000; β=0.201; t=2.487; p=0.016). We identified 3 neurocognitive phenotypes in CHD patients, minimally, moderately and globally impaired. The last showed lower HC (p=0.003), W (p=0.022) and L, and a bigger number of retentions in school (p=0.017) than the first. The last reported more aggressive behaviors.than the other 2 (p=0.007; p=0.006) and their caregivers reported more social (p=0.025), thought (p=0.041) and attention problems (p=0.001) in their children than the parents of the other 2.

Conclusion:
CHD patients have worse NP than controls; small HC at birth was the main predictor of poor NP; We identified 3 patterns of neurocognitive disability among CHD patients: mild, moderate and severely impaired, all showing significant differences compared to controls.
Abstract 17739: Modelling Long-QT Syndrome Associated With a Calmodulin Mutation Using Human Induced Pluripotent Stem Cells
Authors: Yamamoto Yuta , Makiyama Takeru , Harita Takeshi , Sasaki Kenichi , Hayano Mamoru , Nishiuchi Suguru , Wuriyanghai Yimin , Kohjitani Hirohiko , Hirose Sayako , Chen Jiarong , Ishikawa Taisuke , Ohno Seiko , Yoshida Yoshinori , Horie Minoru , Makita Naomasa , Kimura Takeshi
Published: July 2021

Background:
Calmodulin (
CALM
) is a ubiquitous Ca2+-sensor molecule, and it modulates various proteins including several ion channels, ryanodine receptor 2, and Ca
2+
/calmodulin-dependent protein kinase. Recently, several studies reported that
CALM
mutations are associated with severe early-onset long-QT syndrome (LQTS). However, the underlying mechanism remains unknown.

Purpose:
The present study aims to establish the in-vitro disease model of
CALM
-related LQTS and elucidate the pathophysiological mechanism using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs).

Methods:
The hiPSC clones were generated from a 12-year-old boy with LQTS carrying a missense
CALM2
mutation (c.293A>G, p.N98S), and differentiated into cardiomyocytes via embryoid body (EB) formation. The electrophysiological characteristics of
CALM2
-N98S hiPSC-CMs, including action potential (AP) and L-type Ca
2+
channel (LTCC) currents, were analyzed by patch-clamp technique, and compared with those of hiPSC-CMs derived from healthy control.

Results:
The beating rate of
CALM2
-N98S EBs was significantly lower than that of control (23.8 ± 1.6 bpm vs 47.3 ± 1.7 bpm, p < 0.01). The corrected AP duration at 90% repolarization (cAPD90) of
CALM2
-N98S hiPSC-CMs was significantly prolonged compared to that of control (480.9 ± 59.4 ms vs 201.5 ± 19.5 ms, p < 0.01, Figure). At 1 Hz pacing,
CALM2
-N98S hiPSC-CMs exhibited significantly longer APD90 than control (495.5 ± 47.7 ms vs 227.8 ± 21.6 ms, p < 0.01). The time constants of LTCC inactivation tau fast of
CALM2
-N98S hiPSC-CMs were significantly larger than those of control at 0, +10, and +20 mV test potentials (Figure).

Conclusion:
The hiPSC-CMs model of
CALM2
-related LQTS successfully recapitulated the disease phenotypes, and elucidated the pathophysiological mechanism: impaired inactivation of LTCC currents. This model might be useful for drug discovery in
CALM2
-related LQTS.
Abstract 17750: Prolyl Hydroxylase Inhibition Induces Sdf-1 and Cxcr4 Expression to Increase Cxcr4+ Cell Homing and Myocardial Repair
Authors: Ghadge Santhosh Kumar , Pham Thi Van , Messner Moritz , Doppelhammer Maximilian , Husse Britta , Franz Wolfgang-Michael , Zaruba Marc-Michael
Published: July 2021

Objective:
Stabilization of the cardiac SDF-1/CXCR4 axis attenuates ischemic cardiomyopathy. However, HIF-1α dependent SDF-1 upregulation lasts only for 48-72 hours after myocardial infarction (MI) limiting the targeting of regenerative cells. Therefore, we hypothesized that activation of the HIF-1α target genes SDF-1 and CXCR4 by stabilization of HIF-1α through inhibition of prolyl hydroxylase stimulates myocardial repair.

Methods:
Genetically tagged SDF1-EGFP and CXCR4-EGFP mice were subjected to optimal doses (80mg/kg i.p.) of the prolyl hydroxylase Inhibitor dimethyloxalylglycine (DMOG). To examine the time frame of SDF-1 and CXCR4 expression
in vitro
(HEK cells) and
in vivo
(BM & heart), DMOG was treated at different dosing regimens (50μM to 1000μM & 80mg/kg i.p.) and time intervals (1 to 6 hrs). FACS and immunhistochemical analyses of CXCR4+ BM, peripheral blood, and heart cells as well as infarct size measurements and hemodynamic analyses were performed with and without DMOG treatment after MI.

Results:
SDF1-EGFP mice treated with DMOG showed robust induction of SDF-1 in heart vessels.
In vitro
, SDF-1 was transiently upregulated within 60 mins to 2 hrs after DMOG treatment, followed by significant decrease after 6hrs. CXCR4 was elevated at later time points (6h).
In vivo
, CXCR4 expression was significantly upregualted in BM (6h). FACS analyses of transgenic CXCR4-EGFP BM and hearts revealed that CXCR4+ was frequently expressed on CD11b+ monocytes, and at lower Levels on angiogenic CD31+ , CD34+, c-kit+, and Flk1+ cells, and stem cell populations like CD133+ and Lin-/c-kit+/Sca-1+. DMOG treatment after MI revealed a robust upregulation of CXCR4+ cell populations, predominantly of angiogenic CXCR4+/CD11b+ monocytes. Subanalysis of the latter showed that DMOG treatment leads to a shift of the CD206+/CD86 ratio in favor of M2 macrophages associated CD206+ subpopulation after MI associated by attenuated infarct remodeling. Myocardial function was significantly improved after DMOG treatment (EF: 33,5 vs. 16%).

Conclusion:
Our data suggest that inhibition of prolyl hydroxylase may be a promising target for HIF-1a mediated SDF-1 activation to increase CXCR4+ stem cell homing and myocardial repair.
Abstract 17757: Plasma Concentrations of Molecular Lipids are Associated With Coronary Plaque Characteristics and 1-Year Cardiovascular Outcome in Patients With Coronary Artery Disease
Authors: Cheng Jin M , Suoniemi Matti , Kardys Isabella , Vihervaara Terhi , De Boer Sanneke , Akkerhuis Martijn , Sysi-Aho Marko , Ekroos Kim , Garcia-Garcia Hector , Oemrawsingh Rohit , Regar Evelyn , Koenig Wolfgang , Serruys Patrick , Van Geuns Robert-Jan , Boersma Eric , Laaksonen Reijo
Published: July 2021

Introduction:
Previous lipidomics analyses have demonstrated that several lipid molecules in plasma are associated with fatal outcome in patients with coronary artery disease (CAD). This study aims to investigate the associations of previously identified high risk lipid molecules in plasma with coronary plaque characteristics derived from intravascular ultrasound virtual histology (IVUS-VH) imaging, with coronary lipid core burden index (LCBI) on near-infrared spectroscopy (NIRS), and with one year cardiovascular outcome in patients with CAD.

Methods:
Between 2008 and 2011, IVUS-VH imaging of a non-culprit coronary artery was performed in 581 patients who underwent coronary angiography for acute coronary syndrome (ACS) or stable CAD. NIRS imaging was additionally performed in 191 patients. Plasma concentrations of molecular lipids were measured with mass spectrometry.

Results:
Several cholesteryl ester, ceramide and lactosylceramide species and ceramide ratios were associated with vulnerable plaque characteristics on IVUS-VH and NIRS imaging and with 1-year major adverse cardiac events (MACE, defined as all-cause mortality, ACS and unplanned coronary revascularization). In particular, ceramide d18:1/16:0 was consistently associated with higher necrotic core fraction on IVUS-VH (p=0.001), higher LCBI (p=0.024) on NIRS and higher MACE rate (adjusted HR 1.79 per standard deviation increase in log-transformed lipid concentration, 95%CI 1.24-2.59, p=0.002)(Figure).

Conclusions:
Several molecular lipid species, and particularly ceramide(d18:1/16:0), are associated with the fraction of necrotic core tissue and lipid core burden in coronary atherosclerosis, and are predictive for 1-year clinical outcome after coronary angiography. These molecular lipids may improve risk stratification in CAD and may also be interesting therapeutic targets for the treatment of atherosclerotic disease.
Abstract 17808: Fasting Levels of High-sensitive Growth Hormone in Males are Associated to Carotid Intima Media Thickness and are Reduced by Treatment With Fluvastatin
Authors: Hallengren Erik , Almgren Peter , Rosvall Maria , Östling Gerd , Persson Margaretha , Bergmann Andreas , Struck Joachim , Engström Gunnar , Hedblad Bo , Melander Olle
Published: July 2021

Introduction:
Growth hormone (GH) has been linked to cardiovascular disease and lipid metabolism but the exact mechanisms of this association are still unclear.

Objectives:
We here test if GH is cross-sectionally associated to carotid intima media thickness (IMT) and whether treatment with fluvastatin have any effects on the fasting level of GH in a randomized controlled trial of carotid IMT progression.

Methods:
We examined the association between GH and IMT in 4425 individuals (aged 46-68 years) included in the baseline examination (1991-1994) of the Malmö Diet and Cancer cardiovascular cohort (MDC-CC). From that cohort we then studied 472 individuals (aged 50-70 years) who also participated (1994-1999) in the β-Blocker Cholesterol-Lowering Asymptomatic Plaque Study (BCAPS), a randomized, double blind, placebo-controlled, single-center clinical trial. Using multivariate linear regression models we related the change in GH-levels at 12 months compared to baseline to treatment with fluvastatin.

Results:
In MDC-CC fasting values of GH exhibited a positive cross-sectional relation to the IMT at the carotid bifurcation after adjustment for traditional cardiovascular risk factors (p=0.002). In a gender-stratified analysis the association were positive and significant for males (p=0.005), but not for females (p=0.09). In males in BCAPS treated with fluvastatin there tended to be a greater reduction of GH after 12 months when compared to subjects not receiving fluvastatin (p=0.05) (Table). Fasting levels of GH did not interact with the different treatment regimes’ effect on the IMT.

Conclusions:
We here demonstrate that higher fasting levels of GH are associated to thicker IMT in the carotid bulb and that statin treatment may reduce fasting levels of GH in males. Our results are in line with previous results with GH being associated to cardiovascular disease. The effects of statin treatment on GH are small and need to be confirmed in a larger trial.
Abstract 17874: Aerobic Exercise Training Improves Exercise Capacity, Reduces Arrhythmia Susceptibility but Does Not Normalize Ryanodine Receptor Mediated Aberrant Calcium Release in Catecholaminergic Polymorphic Ventricular Tachycardia
Authors: Swain Zoe , Ho Hsiang-Ting , Minagawa Minori , Knollmann Bjorn C , Gyorke Sandor , Periasamy Muthu , Kalyanasundaram Anuradha
Published: July 2021

Introduction:
Loss of Calsequestrin (CASQ2) promotes abnormal calcium (Ca2+) release events via the cardiac Ryanodine receptor (RyR2) during adrenergic stimulation, which trigger Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT).

Rationale:
Since aerobic exercise training (AET) has been shown to normalize Sarcoplasmic reticulum (SR) Ca2+ cycling parameters in diseased hearts, we explored if AET impacts RyR2 dysfunction and CPVT susceptibility in CASQ2-/- mice.

Methods and Results:
Age matched wildtype (WT) and CASQ2-/- male mice (n=8) were subjected to treadmill running for 6 weeks (16mts/min for 1hr, 5 days/week at 10% incline). Subsequently, a graded exercise test showed that sedentary (Sed) CASQ2-/- mice have a significantly lower exercise capacity relative to SedWT. Compared to trained (Ex) WT mice, AET moderately increased maximal running speed, time, and RER values in ExCASQ2-/- mice, indicating improved aerobic capacity. Electrocardiographic analyses showed that ExCASQ2-/- mice were resistant to triggered arrhythmias compared to their Sed controls. Spectral analyses of heart rate variability indicated that the high frequency band power increased significantly in ExCASQ2-/- mice, especially during Isoproterenol (Iso) challenge compared to ExWT. Despite fewer arrhythmias, confocal Ca2+ imaging revealed that ExCASQ2-/- ventricular cardiomyocytes are prone to spontaneous Ca2+ sparks and waves even at baseline (compared to ExWT) along with a concomitant decrease in Ca2+ transient amplitude and SR Ca2+ load, both at baseline and during Iso challenge.

Conclusions:
Our results thus far indicate that AET partially improves exercise capacity and aerobic fitness in the CASQ2-/- mouse model of CPVT. Paradoxically, although arrhythmia incidence is reduced, RyR2 mediated dysfunctions in SR Ca2+ cycling are not normalized after 6 weeks of AET. Importantly, the parasympathetic tone is significantly enhanced in the ExCASQ2-/- mice particularly during Iso challenge. Ongoing studies will address mechanisms (SR protein expression, post translational modifications and pharmacological interventions to investigate the observed autonomic imbalance) that could underlie the intriguing effects of exercise in this model of CPVT.
Abstract 18009: Clinical-officer Led Echocardiographic Screening is Sensitive for Diagnosing Rheumatic Heart Disease in Malawi, Africa
Authors: Sims Amy E , Sable Craig A , Hosseinipour Mina , Karlsten Melissa , Kazembe Peter N , Minard Charles G , Penny Daniel J
Published: July 2021

Malawi, Africa has a high prevalence of rheumatic heart disease (RHD). Echocardiographic (echo) screening for RHD in asymptomatic children may enable early diagnosis and treatment in order to prevent progression of RHD. Malawi has few physicians, and no pediatric cardiologists in the country. Therefore, physician-led RHD screening is not feasible. Clinical officers (CO’s) are mid-level providers who may be able to perform RHD echo screening.

Hypothesis:
After training, CO’s will have similar results in identifying RHD by echocardiography as a pediatric cardiologist.

Methods:
8 CO’s with no previous echo experience completed 3 half-days of didactic and computer-module based training as well as 2 days of clinical attachments at a local school. On the attachments, CO’s completed an average of 60 mentored RHD screening echos with a Philips portable CX50 echo machine. CO’s were evaluated by performing screening echos on 20 children with and without RHD who were screened in the previous year. They indicated whether the children should be referred for follow-up. Screening protocol called for referral if a mitral regurgitation jet measured more than 1.5 cm or an aortic regurgitation jet measured more than 1 cm. Kappa statistic was calculated based on agreement with a pediatric cardiologist’s screening result (referral vs. no referral). Sensitivity and specificity were estimated using a generalized linear mixed model.

Results:
The mean kappa statistic comparing CO reads to the pediatric cardiologist was 0.72 (95% CI: 0.62, 0.82). Kappa ranged from a minimum of 0.57 to a maximum of 0.90. Overall, sensitivity was 0.92 (95% CI: 0.86, 0.95), and specificity was 0.80 (95% CI: 0.68, 0.88).

Conclusion:
There is substantial agreement between the CO and pediatric cardiologist diagnoses. In addition, CO’s had a high sensitivity in detecting RHD. With short-course training, CO-led echo screening for RHD is a viable alternative to physician-led screening in resource-limited settings.
Abstract 18017: The Modified History in Young Patients With Repaired Tetralogy of Fallot: A Longitudinal Magnetic Resonance Study
Authors: Gazzaz Tamadhir , Elders Bernadette , Manlhiot Cedric , Yoo Shi-Joon , Seed Mike , Mccrindle Brian , Grosse-Wortmann Lars
Published: July 2021

Introduction:
No large scale longitudinal information is available on the change of ventricular size and function as well as of exercise tolerance in survivors after Tetralogy of Fallot (TOF) repair during childhood and adolescence.

Objective:
The objective of this study was to assess the rate of progression of right ventricular (RV) size and pulmonary regurgitation (PR) in relationship to clinical status and outcomes in pediatric TOF patients from a contemporary surgical era.

Methods:
We analyzed 429 cardiac magnetic resonance (CMR) studies (from 2001-2014) of 267 patients (age at CMR 13.5 +/-2.8 years) after TOF repair prior to any pulmonary valve replacement (PVR), including 96 patients with serial CMRs. Measurements of biventricular volumes, mass, function, and PR were performed by a single observer. Serial ECGs, Holters, echocardiograms, and exercise tests were reviewed.

Results:
No deaths occurred in our cohort. Three patients (1.1%) had non-sustained ventricular tachycardia and 4 (1.5%) had supraventricular tachycardia. Sixty seven (25%) patients underwent PVR at a mean age15.5 +/- 2.3 years.There was a linear progression of BSA-indexed RV end-diastolic volume (EDVi) at 3 ml/m2 per year (p.a., p<0.001). PR volume changed only minimally over time while PR fraction progressed at a rate of 0.7% p.a. (p<0.001). RV and LV ejection fractions (EFs) deteriorated over time (0.5% p.a., p<0.001 and 0.4% p.a., p=0.001, respectively). RV and LV EDVi increased (p=0.02 and p=0.001, respectively) and RV EF (p<0.001) decreased more rapidly in boys than in girls. Right atrial (RA) length correlated inversely with VO2max (% predicted, p=0.02). In a multivariable analysis, worsening PR fraction, RV EF, RA length, and LV EDVi were all predictors of PVR in the future.

Conclusions:
This study describes the rate and dynamic of progression of biventricular size and function in children after TOF repair in the hitherto largest cohort, with apparent differences between boys and girls. RA length was inversely correlated with exercise intolerance.The need for PVR is predicted by the degree of RV dysfunction as well as LV and RA enlargement. The latter may deserve routine assessment in patients after TOF repair.
Abstract 18070: Therapies Optimizing Organ Perfusion and Protection After Out-of-hospital Cardiac Arrest Improves Survival With Favorable Neurologic Outcome
Authors: Jacobs Michael J , Derevin Leo S , Duval Sue , Pointer James E , Sporer Karl A
Published: July 2021

Introduction:
Survival rates with favorable neurologic function after out-of-hospital cardiac arrest (OHCA) have remained low for decades.

Hypothesis:
Use of therapies focused on better perfusion during CPR using mechanical adjuncts and protective post-resuscitation care would improve survival and neurologic outcomes after OHCA compared to conventional CPR and care.

Methods:
OHCA outcomes in Alameda County, CA, USA, population 1.5 million, from December 2009-2011 when there was incomplete availability and use of impedance threshold device [ITD], mechanical CPR [MCPR], and hospital therapeutic hypothermia [HTH], were compared to 2012 when all were available and more widely used. Return of Spontaneous Circulation (ROSC), survival and Cerebral Performance Category (CPC) scores were compared using univariate and multivariable analyses.

Results:
Of the 3008 non-traumatic OHCAs who received CPR during the study period, >95% of survival outcome data were available. From 2009-11 to 2012, there was an increase in ROSC from 28.6% to 34.1% (p=0.002; OR=1.28; CI=1.09, 1.51) and a non-significant increase in hospital discharge from 10.5% to 12.3% (p=0.14; OR=1.17; CI=0.92, 1.49). There was, however, an 80% increase in survival with favorable neurological function between the two periods, as determined by CPC≤2, from 4.4% to 7.9% (p<0.001; unadjusted OR=1.85; CI=1.35, 2.54). After adjusting for witnessed arrest, bystander CPR, initial rhythm (VT/VF vs. others), placement of an advanced airway, EMS response time, and age, the adjusted OR was 1.60 (1.11, 2.31; p=0.012). Using a stepwise regression model, the most important independent positive predictors of CPC≤2 were 2012 (p=0.019), witnessed (p<0.001), initial rhythm VT/VF (p<0.001), and advanced airway (inverse association p<0.001). Additional analyses of the three therapies, separately and in combination, demonstrated that for all patients admitted to the hospital, ITD use with HTH had the most impact on survival to discharge with CPC≤2 of 24%.

Conclusions:
Therapies (ITD, MCPR, HTH) developed to enhance circulation during CPR and cerebral recovery after ROSC, significantly improved survival with favorable neurological function by 80% following OHCA.
Abstract 18106: 2d Strain is a More Accurate Measure of Systolic Function Than Shortening Fraction and Ejection Fraction in Pediatric Patients Following Orthotopic Heart Transplant
Authors: Patel Meghna D , Groh Georgeann K , Varughese Justin , Myers Craig , Sekarski Tim , Hartman Diana , Murphy Joshua J , Singh Gautam K , Anwar Shafkat
Published: July 2021

Introduction:
2D strain by echocardiography is a sensitive technique for assessing LV systolic function in pediatric heart transplant patients, although it is under-utilized clinically.

Methods:
We prospectively compared 2D LV 4-chamber Lagrangian longitudinal strain (LS) in 34 echo studies against cardiac output indexed to body surface area (cardiac index, Ci) via cardiac catheterization to assess accuracy of LS. Of those echos, 31/34 were simultaneous with cath, and 3/34 were within 10 days of catheterization. Ci was also compared to LV shortening fraction (SF) and single plane ejection fraction (EF). FS via M-mode in parasternal short-axis and EF via 4 chamber were measured. Strain was obtained in the 4 chamber apical view as an average of 6 segments. Right heart catheterization was performed and evaluated by a cardiac interventionalist blinded to echo data. Pearson’s correlation coefficient was used to assess relationships.

Results:
Mean age was 10.2 years (0.3 - 19 years), 11 males. Mean HR was 99 bpm (64-155) for catheterization, and 97 bpm (66-148) for echocardiography, mean frame rate 72 f/sec (47-109). Mean Ci was 3.8 L/min/m2 (95% CI 1.9 to 5.73). LS was diminished for this cohort, mean -13.7 (95% CI - 4 to -23.3), however, EF and SF were normal (mean EF 59.1% (95% CI 32.58%- 85.6%), mean FS 35.6% (95% CI 24%- 47%)).

There was moderate positive correlation between LS and Ci, (r = 0.48, p = 0.002). FS and EF did not correlate with Ci (r = 0.34, p = 0.03, and r = 0.15, p = 0.39 respectively). There was fair positive correlation between LS and EF and LS and SF (r = 0.36, p = 0.03 and r = 0.38, p = 0.02 respectively).

Conclusion:
4 chamber LV LS may be a more sensitive and reliable non-invasive method to assess systolic function in pediatric heart transplant patients. Further investigation in a larger sample using global (18 segment) strain is warranted.
Abstract 18181: Left Ventricular Myocardial Mechanics at Rest and During Exercise in Children After Arterial Switch Operation
Authors: Cifra Barbara , Dragulescu Andreea , Grotenhuis Heynric , Manlhiot Cedric , Friedberg Mark K , Mertens Luc
Published: July 2021

Introduction:
Arterial switch operation (ASO) is the standard surgical procedure for transposition of the great arteries allowing a complete anatomical and physiological repair. In these patients the functional impact of myocardial perfusion on global and regional myocardial function has not been investigated. Stress echocardiography with visual myocardial assessment has been used to detect regional myocardial dysfunction. Studying LV mechanics using speckle-tracking echocardiography during exercise could provide more quantitative information. The aim of the study was to study the myocardial response to exercise in children after ASO using semi-supine cycle ergometry stress echocardiography (SSCE).

Materials and Methods:
Forty children after ASO and 29 age and gender matched controls were included. Median age was 14 years. A stepwise SSCE protocol was used. LV global longitudinal strain and circumferential strain was measured in all subjects at rest and at incremental heart rate.

Results:
Resting HR was similar between groups, peak HR was lower in the ASO group compared with controls (142 ±11 vs 157±14 bpm, p=0.0007). LV global longitudinal strain was lower at rest (19±2.3% vs. 21±2.5%, p=0.004) but not at peak exercise (22.7±5.6 % vs. 24±4.5 % p=0.2) in the ASO group compared to controls. No significant difference was found in LV global circumferential strain at rest (23.7±2.3% vs. 24±3.2 %, p=0.6) and peak exercise (28±2.6% vs. 27.9±4.1 %, p=0.9). Also when plotted versus heart rates the increase in longitudinal and circumferential strain values were not significantly different.

Conclusions:
These data show that circumferential and longitudinal myocardial deformation during exercise is preserved in children after ASO compared to controls. Earlier data obtained using Tissue Doppler in the same study cohort, showed a normal increase in systolic tissue Doppler velocities. These data suggest a preserved LV reserve during exercise in this patient cohort.
Abstract 18288: The Total-to-high Density Lipoprotein-cholesterol Ratio Associates With Coronary Atheroma Progression Rates and Reclassifies Disease Progression Across Populations With Varying Metabolic Risk
Authors: Elshazly Mohamed B , Nicholls Stephen J , Nissen Steven E , St. John Julie , Martin Seth S , Jones Steven R , Stegman Brian , Kapadia Samir R , Tuzcu E. Murat , Puri Rishi
Published: July 2021

Introduction:
Total to high-density lipoprotein cholesterol (TC/HDL-C), routinely available from the standard lipid profile, is postulated to characterize atherogenic lipids beyond low density lipoprotein cholesterol (LDL-C) and non-HDL-C

Hypothesis:
On-treatment TC/HDL-C significantly associates with coronary atheroma progression rates at variable levels of LDL-C, non-HDL-C, apolipoprotein B (apoB), triglycerides (TG), C-reactive protein (CRP), and irrespective of diabetes status, obesity or intensity of statin therapy

Methods:
We analyzed data from 9 trials involving 4957 patients with coronary disease undergoing serial intravascular ultrasonography and assessed the effect of on-treatment levels of TC/HDL-C [</≥ median: 3.3] on changes in percent atheroma volume (ΔPAV, annualized and controlled for baseline PAV and clinical trial) at variable levels of LDL-C, non-HDL-C, apoB [</≥ median: 80, 107, and 76 mg/dL, respectively], CRP [</≥ 2mg/L] and TG [</≥150 mg/dL], and in patients with/without diabetes or obesity, and in those receiving high-intensity statin therapy (HIST) or not

Results:
Discordance, defined by median cut points, between TC/HDL-C vs. LDL-C, non-HDL-C and apoB was sizeable at 26, 20 and 27%, respectively. Lower (< median) on-treatment TC/HDL-C associated with PAV regression (ΔPAV <0) while higher (≥median) TC/HDL-C associated with PAV progression across all levels of LDL-C, non-HDL-C, apoB, TG as well as the presence/absence of obesity or HIST. Lower (<median) TC/HDL-C associated with lower PAV progression irrespective of CRP levels or the presence/absence of diabetes

Conclusion:
TC/HDL-C, available at no extra cost, correlates significantly with coronary atheroma progression rates when discordant with other lipid-metabolic parameters and in clinical scenarios such as diabetes, obesity and in patients receiving HIST. Future studies are needed to determine the implications of applying TC/HDL-C for reducing residual risk
Abstract 18289: New Roles of the Interplay Between Endothelin and Insulin-like Growth Factor 1 in the Regulation of Vascular Redox State in Patients With Type 2 Diabetes and Coronary Atherosclerosis
Authors: Akoumianakis Ioannis , Margaritis Marios , Sanna Fabio , Herdman Laura , Psarros Constantinos , Sayeed Rana , Krasopoulos George , Wohlfart Paulus , Channon Keith , Antoniades Charalambos
Published: July 2021

Background:
Insulin resistance (IR) is associated with increased cardiovascular risk. Given that plasma endothelin (ET) is elevated in IR, we explored whether the variations in ET levels mediate the vascular complications of type 2 diabetes (T2DM), by exploring its links with vascular redox state in human vessels.

Methods:
The study population consisted of 383 patients undergoing coronary bypass surgery (CABG), 30% with T2DM. Levels of ET, insulin growth factor 1 (IGF1), insulin and glucose (to calculate HOMA-IR as an index of insulin resistance) were measured in plasma, while vascular superoxide (O2) was measured in saphenous vein segments obtained during surgery.

Results:
Patients with untreated T2DM had elevated plasma ET, contrary to treated patients with T2DM (A). A positive association was observed between plasma endothelin and IGF1 levels in non-T2DM, which was reversed in T2DM (B). Elevated plasma ET was associated with increased NADPH-stimulated O2- (indicative of higher NADPH oxidase activity) and more LNAME inhibitable O2- (suggestive of more eNOS uncoupling) in human vessels (C, D).

Conclusions:
We demonstrate that circulating ET is elevated in untreated T2DM but its levels are normalised after intensive glycaemic control. We also document a striking effect of DM on the balance between ET and IGF1, and we demonstrate for the first time in humans, that elevated plasma ET is associated with increased O2- generation in the vascular wall through activation of NADPH-oxidase and uncoupling of eNOS. This study shows that ET and its interplay with IGF1 is possibly a key mechanism linking T2DM with its vascular complications in humans