bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 14881: Shortened Telomere Length is Associated with Paroxysmal but Not Persistent/Permanent Atrial Fibrillation in Cardiovascular Patients Referred for Angiography
Authors: Carlquist John F , Knight Stacey , Cawthon Richard M , Horne Benjamin D , Rollo Jeffrey S , Huntinghouse John A , Bunch T J , Muhlestein Joseph B , Anderson Jeffrey L
Published: July 2021

BACKGROUND:
Telomeres are hexanucleotide repeats at chromosome ends that prevent chromosome degradation. Short telomere length (TL) correlates with biological ageing and is associated with risk for age-associated diseases. Atrial fibrillation (AF) can occur as paroxysmal (Px), persistent (Ps) or permanent (Pm). Progression from Px to Ps/Pm AF is accompanied by increased risk for AF-associated adverse events. We t found that short TL is associated with a history of AF; for the present study we examined TL in relationship to the types of AF.

METHODS:
Peripheral blood DNA was obtained from sequential consenting patients (pts) (n=3576) at angiography. TL was measured in triplicate by monochrome (SYBR Green I) multiplex quantitative PCR (Bio-Rad CFX384 Detection System) and normalized to a quantitatively-measured, single-copy gene (albumin). AF history was extracted from Intermountain Healthcare’s electronic records and AF type determined by chart review for 246 of 325 (75.7%) AF patients. Non-parametric tests were used.

RESULTS:
For the 246 subtyped AF pts, 66.3% were male, 94.3% Caucasian, mean age was 70 yrs. The leading AF type was Px (43.5%), followed by Pm (32.9%), and Ps (23.6%). Mean TL for non-AF pts was 0.954 ±0.325 and the mean TL for AF pts was 0.912±0.30. The mean Px TL (Table) was significantly shorter than for Ps or Pm AF. Ps and Pm TL did not differ. Adjusting for age, gender, prior CVA, PCI, statin use, disease severity; TL (per unit of decrease) was associated with Px AF compared to Ps/Pm AF (OR=6.64; CI 2.17, 20.32; p=0.0009).

CONCLUSIONS:
The association of shorter TL with Px AF but not Ps/Pm AF suggests that decreased TLs is associated with an etiologic AF subtype. No association between shortened TL and Ps/Pm AF may further suggest that TL measurement for pts with Px AF may have prognostic utility with respect to AF progression. Further study into the physiological basis of these observations is warranted.
Abstract 14919: Short Adult Stature is an Independent Predictor of Cardiovascular Disease Risk Factors and Subclinical Vascular Changes in a Larger Population Based Sample
Authors: Thanikachalam Mohan , Harivanzan Vijaykumar , Sunderarajan Jahnavi , Griffiths Jeffrey , Thanikachalam Sadagopan
Published: July 2021

Background:
Studies have demonstrated strong association between short adult stature (a marker of adverse nutritional and sanitary environment in early years) and cardiovascular disease (CVD) mortality. The reasons for this association are not understood although early childhood epigenetic programming has been invoked. Here we analyze the association between adult height and CVD risk factors and subclinical vascular changes in a Southeast Asian population that has experienced rapid income growth with increasing prevalence of CVD over the last decade.

Methods:
In a population-based study of 8,080 South Indians (mean age 42 years; 58% women), assessments included blood pressure, socioeconomic (SE) and physical activity (PA) status, triglycerides (TG), total cholesterol (TC), glucose tolerance test, carotid intimal medial thickness (IMT), arterial stiffness by carotid-femoral pulse wave velocity (PWV) and endothelial function by brachial artery flow mediated dilatation (FMD).

Results:
The prevalence of CVD risk factors and values of subclinical vascular parameters by height quartile is shown in the Table. After adjustments for age, weight, SE and PA status and smoking, in comparison to highest height quartile the odds ratio (95% CI) for diabetes, hypertension and elevated levels of TG (≥ 150 mg/dl) and TC (≥ 200 mg/dl) in the lowest height quartile was 1.3 (0.97, 1.6), 1.7 (1.4 - 2.2), 1.4 (1.1, 1.8), 1.5 (1.2, 1.9) in women and 2.01 (1.5, 2.7), 1.9 (1.5, 2.5), 1.5 (1.2, 1.9), 1.9 (1.5, 2.5) in men, respectively. In multi-linear regression models that included both genders, height was independently correlated with FMD (β= 0.31, p <0.01), IMT (β= 0.06, p <0.01) and PWV (β= -0.06, p <0.01).

Conclusion:
Adult Stature is an independent predictor of CVD risk factors and subclinical vascular changes. Adverse environment in early years may be one of the contributing factors to the increasing prevalence of CVD in the Southeast Asian adult population.
Abstract 14997: Zn2+ and mPTP Mediate ERS Inhibition-induced Cardioprotection Against Ischemia/Reperfusion Injury
Authors: Xi Jinkun , He Yonggui , Fei Shuo , Zheng Huan , Xu Zhelong
Published: July 2021

While the role of endoplasmic reticulum stress (ERS) in myocardial ischemia/reperfusion (I/R) injury has been extensively investigated, the precise mechanism by which inhibition of ERS induces cardioprotection remains unclear. We aimed to explore the mechanism of ERS inhibition-induced cardioprotection against I/R injury, focusing on the role of Zn
2+
and the mitochondrial permeability transition pore (mPTP). Exposure of H9c2 cells to 800 μM H
2
O
2
for 20 min increased GRP78 and GRP94 expressions (296.2 ± 41.0 and 150.6 ± 13.5 %, respectively), suggesting that H
2
O
2
can induce ERS. Cells treated with H
2
O
2
showed a significant decrease (40.6 ± 7.4 %) in TMRE fluorescence compared to the normal group (92.6 ± 0.1 %), indicating that H
2
O
2
can induce the mPTP opening. In contrast, ERS inhibitor TUDCA (30 μM) prevented the loss of TMRE fluorescence (77.8 ± 6.8 %), implying that inhibition of ERS can prevent the mPTP opening. This effect of TUDCA was blocked by zinc chelator TPEN (37.7 ± 13.0 %), indicating a role of Zn
2+
in the action of TUDCA on the mPTP opening. In support, TUDCA increased intracellular free zinc, as indicated by a marked increase in Newport Green DCF fluorescence intensity. In isolated rat hearts, GRP78 expression was not increased during ischemia but was increased upon reperfusion (1.3, 1.5, 1.9, and 1.6-fold increases at 10, 30, 60, and 120 min of reperfusion). Hearts treated with TUDCA showed a significant reduction of GRP78 expression 30 and 60 min after the onset of reperfusion, an effect that was reversed by TPEN. The immunofluorescence study also showed that the effect of TUDCA on GRP78 expression was reversed by TPEN. TUDCA reduced infarct size, and this was reversed by the mPTP opener atractyloside, indicating that ERS inhibition may protect the heart by modulating the mPTP opening. Experiments with transmission electron microscopy and hematoxylin-eosin staining revealed that TUDCA prevented endoplasmic reticulum and mitochondrial damages at reperfusion, which was blocked by TPEN. In conclusion, reperfusion but not ischemia initiates ERS and inhibition of ERS protects the heart from reperfusion injury through prevention of the mPTP opening. Increased intracellular free Zn
2+
accounts for the cardioprotective effect of ERS inhibition.
Abstract 15020: Ablation of Paroxysmal Atrial Fibrillation Applying an Improved Cryoballoon: is Reduction of Freezing Time Possible?
Authors: Nölker Georg , Molatta Stephan , Koch Frauke , Hossain M. Sajid , Bullert Kevin , Horstkotte Dieter , Gutleben Klaus-Jürgen
Published: July 2021

Introduction:
Cryoballoon (CB) ablation has been adopted by many centers worldwide for treatment of atrial fibrillation (AF). An improved version of the CB providing homogeneous cooling at its total frontal side has been introduced (Arctic Front Advance™, Medtronic).

Hypothesis:
We aimed to evaluate whether reduction of cooling times in application of this advanced CB is possible without affecting the outcome.

Methods:
A total of 94 patients (pts) (44 male, 58 ± 13 years) suffering from paroxysmal AF were prospectively assigned to CB pulmonary vein isolation choosing either 2 x 4 minutes (group 1) or 2 x 3 minutes (group 2) of freezing per vein. In case of pull-down maneuvers 120 s application time at the superior edge was followed by additional freezing of 3 or 4 minutes respectively after pull-down. Follow-up at 3, 6 months completed in all pts. included a clinical visit and a 7-day Holter or a readout of an implanted device for evaluation of AF burden.

Results:
Groups were well balanced in terms of left atrial size, left ventricular function, concomitant diseases and duration of AF. Total procedure time was reduced from 116±28 to 109±23 minutes (p=n.s.). Freezing time per pt decreased from 38.7±8.2 to 31.2±6.9 minutes (p<0.00001). Fluoroscopy time was similar between the groups (10.3±5.8; 12.1±5.5 min.; p=n.s.). During a follow-up of 6.4±1.8 months recurrence of AF was observed in 11 % of pts in group 1 versus 29 % of pts in group 2 (p=0.04). No major complications occurred in either group.

Conclusions:
Based on our preliminary findings, reduction of freezing time in CB ablation applying the improved version of the CB catheter seems to increase recurrence of AF. Therefore, it might be advisable to maintain longer freezing times. A prolonged follow-up will be available and presented at the meeting.
Abstract 15086: Transendocardial CD34+ Cell Transplantation Improves Left Ventricular Segmental Wall Motion in Patients With Ischemic Cardiomyopathy
Authors: Poglajen Gregor , Zemljic Gregor , Sever Matjaz , Bervar Mojca , Cukjati Marko , Haddad Francois , Wu Joseph C , Vrtovec Bojan
Published: July 2021

Introduction:
We investigated the effects of transendocardial transplantation of CD34+ stem cells on left ventricular segmental wall motion in patients with ischemic cardiomyopathy (ICM).

Methods:
We performed transendocardial CD34+ cell transplantation in 31 ICM patients with NYHA class III heart failure and LVEF <40%. Peripheral blood CD34+ cells were mobilized by G-CSF, collected via apheresis, and injected transendocardially in the areas of hibernating myocardium as defined by electromechanical mapping (unipolar voltage ≥9 mV and linear shortening <6%). Left ventricular segmental wall motion analysis was evaluated with TomTec software using a 17-segment model of the left ventricle. Of 31 patients enrolled, 85% were male, their age was 57±6 years; their creatinine, bilirubin and NT-proBNP levels were 89±22 μmol/L, 17±9 μmol/L, and 3,322±3,411 pg/mL respectively. The average Syntax score was 27.9±10.5 and the average number of injected CD34+ cells was 90.6±7.5 million. Patients were followed for 6 months and good clinical response was defined as an increase of left ventricular ejection fraction (LVEF) ≥5%.

Results:
During follow-up, we found a significant improvement in LVEF (from 27.1±6,6% to 34.7±10.9%; P=0.001), left ventricular end-systolic diameter (from 5.3±0.7 cm to 4.9±0.9 cm; P=0.04), and left ventricular end-systolic volume (from 152±45 mL to 135±44 mL; P=0.03). Left ventricular segmental wall motion analysis showed significantly improved myocardial longitudinal strain in injected segmentes as opposed to noninjected segments (2.4±8.3 vs. -0.9±6.1; P=0.05). We also established a correlation between improvement in myocardial strain and clinical response to cell therapy: responders demonstrated a significant improvement in longitudinal strain in injected segments, but non-responders did not (6.29±8.1 vs. -3.4±5.1; P=0.007). No difference was seen between responders and nonresponders with regards to myocardial strain of noninjected segments (2.4±8.4 vs. -0.97±6.1; P=0.59).

Conclusions:
Intramyocardial CD 34+ cell transplantation appears to improve left ventricular segmental wall motion in patients with ischemic cardiomyopathy.
Abstract 151: AMSA-Dependent Association Between Shock Energy and Shock Success
Authors: Li Yongqin , Chen Bihua , He Mi , Ristagno Giuseppe , Quan Weilun , Herken Ulrich
Published: July 2021

Purpose:
Previous studies have demonstrated that quantitative analysis of ventricular fibrillation (VF) waveform has the potential to optimize the timing of defibrillation. However, the interaction between energy and the predictability of quantitative VF analysis is unknown. In the present study, we investigated the relationship between shock success and shock energy in the different amplitude spectrum area (AMSA) ranges and the possibility of using AMSA to guide the shock energy selection.

Materials and Methods:
Digitized ECG recordings were analyzed from a registry data of out-of-hospital cardiac arrests. Current-based impedance compensation automated external defibrillators with an escalating defibrillation energy protocol from 120J to 150 and 200 J were used in this study. A waveform episode of 2.05 seconds (512 data points) ending at 0.5 second before each shock attempt was selected for analysis. Shock success was defined as an organized rhythm that was present for a minimum of 30 seconds, started within 60 seconds after the shock, and had a rate of 40 beats per minute or greater.

Results:
A total of 1219 shocks from 536 patients with VF were analyzed. The shock success rate was increased with escalated energies when AMSA was greater than 12 mvHz (50.0% for 120J, 64.6% for 150J and 82.5% for 200J, p<0.05). When AMSA was low (<12 mvHz), escalated energies did not increase the shock success rate (9.3% for 120J, 12.4% for 150J and 10.4% for 200J, p:NS). Multivariable logistic regression demonstrated that the only independent predictor of shock success for low AMSA values was the AMSA (OR=1.494, 95% CI:1.362-1.638, p<0.001), while for high AMSA values, it was the shock energy (OR=1.011, 95% CI=1.004-1.018, p=0.003)

Conclusions:
In this patient population, escalating energy protocol improved defibrillation success when AMSA was high. When AMSA was low the escalating energy protocol did not improve defibrillation success and a fixed low energy protocol may perform equally well as the escalating energy protocol. This may help to reduce myocardial damage associated with higher cumulative energy delivery. Real-time AMSA analysis during CPR could optimize not only the timing of defibrillation, but also provide robust energy selection for defibrillation.
Abstract 15113: A Novel Purification Method for Cardiomyocytes and Endothelial Cells Derived From Human Pluripotent Stem Cells Using Microrna-responsive Messenger Rna
Authors: Miki Kenji , Takahashi Seiya , Funakoshi Shunsuke , Yamanaka Shinya , Saito Hirohide , Yoshida Yoshinori
Published: July 2021

MicroRNAs (miRNAs) are small non-coding RNA that controls gene expression through translational regulation or mRNA cleavage. Recent progress in synthetic biology demonstrated that synthetic “RNA switches” enable to regulate gene expression depending on the intracellular environment. Here we show that synthetic mRNA technologies that modulate reporter protein expression by sensing miRNA activities enable purification of target cells in a safe and effective manner.

To select cardiac-specific miRNA candidates, we performed miRNA microarray analyses using human induced pluripotent stem cell (hiPSC) line integrated MYH6 promoter driven EGFP cassette. We found 14 candidates, and synthesized individually these 14 miRNA-responsive OFF switch mRNAs (miR-switches) containing the sequence of blue fluorescent protein (TagBFP). We individually transfected them with EGFP mRNA into differentiated cells including cardiomyocytes derived from human pluripotent stem cell (hPSCs). We found that several cells transfected with miR-1- or miR-208-switches diminished TagBFP intensity, and sorting of these cells yielded high populations of troponin T-positive cardiomyocytes reproducibly and significantly (e.g., up to >98% in five hPSC lines). In addition, we developed a non-sorting system for purification of cardiomyocytes using miR-switch that code apoptosis-inducible protein (up to >97%). These cardiomyocytes purified by miR-switches were successfully engrafted in mouse heart and did not form tumor even when injected into testes of SCID mice. We next examined whether the system can be applied to purify endothelial cells, and confirmed that several miR-switches enabled high purification of CD31+ cells from differentiated derivatives of hPSCs (up to >98%), which have the function of tube formation like HUVEC. Moreover, the use of multiple miRNA-responsive mRNAs enabled simultaneous and high purification of cardiomyocytes and endothelial cells from heterogeneous population derived from hPSCs induced by single differentiation method (up to >98%).

Our results suggest that miR-switch technology can be used for a variety of purposes including purification in any type of cells.
Abstract 15225: Post-ischemic Myocardial Insulin Resistance Induced by Tnf-α Overproduction Precipitates the Development of Heart Failure After Myocardial Infarction
Authors: Fu Feng , Li Jia , Xu Jie , Zhang Yuan , Gao Chao , Li Jun , Zhang Haifeng , Gao Feng
Published: July 2021

Objectives:
Clinical evidence has demonstrated a decreased myocardial insulin response in HF patients. However, the role of myocardial insulin resistance and the underlying mechanisms in HF are largely unclear.

Methods and Results:
Sprague Dawley rats subjected to myocardial infarction (MI) resulted in a progressive left ventricular (LV) remodeling and dysfunction. Echocardiographic assessment showed preserved LV end-systolic dimension (LVESD 0.453 ± 0.027 cm) and ejection fraction (EF 57.03 ± 2.35%) at 1 wk after MI, and evident LV dilation (LVESD 0.612 ± 0.026 cm) and dysfunction (EF 40.21 ± 3.09%) at 4 wk after MI. Myocardial insulin sensitivity decreased significantly at 1 wk after MI as evidenced by reduced insulin-stimulated myocardial fluorodeoxyglucose uptake (Standardized Uptake Value: 2.71 ± 0.42 vs. 5.13 ± 0.51 of sham+insulin, n=6,
P
<0.01) and GLUT-4 translocation and altered insulin signaling, whereas systemic insulin sensitivity remained unchanged. Mechanistically, myocardial TNF-α production was increased following MI. Treatment with etanercept (a TNF-α inhibitor) post-MI improved myocardial insulin sensitivity, while adenovirus-mediated overexpression of TNF-α resulted in myocardial insulin resistance in non-MI hearts. In addition, TNF-α overexpressed rat hearts exhibited LV dysfunction (EF 41.32 ± 4.21%) and LV dilation as early as 1 wk after MI. Moreover, insulin treatment during the first week following MI suppressed myocardial TNF-α production and increased myocardial insulin sensitivity, resulting in alleviated cardiac dysfunction and remodeling at 4 wk after MI. Importantly, in a separate experiment, cardiomyocyte-specific insulin receptor knockout mice exhibited aggravated post-ischemic LV remodeling and dysfunction compared with littermate controls.

Conclusions:
Our data provide novel insights that myocardial insulin resistance, independently of systemic insulin resistance, precipitates the development of post-ischemic HF. Myocardial insulin resistance is an early event partly attributed to myocardial TNF-α overproduction following MI. This finding indicates the essential role of myocardial insulin signaling in protection against ischemic HF.
Abstract 15301: Skilled Nursing Facilities and 30-day Hospital Readmissions in Heart Failure
Authors: Manemann Sheila M , Chamberlain Alanna M , St. Sauver Jennifer , Weston Susan A , Jiang Ruoxiang , Roger Veronique L
Published: July 2021

Background:
Referral to a skilled nursing facility (SNF) should contribute to reducing hospital readmissions; however, a “revolving door” phenomenon after admission to SNF has been hypothesized to drive readmissions. The urgent need to study the impact of SNF on readmissions in heart failure (HF) was recently emphasized, yet this has never been studied in the community.

Objectives:
To evaluate the association between discharge to SNF and 30-day readmissions in a community cohort of hospitalized incident HF patients.

Methods:
Olmsted County, MN residents hospitalized with first ever (incident) HF (International Classification of Diseases-9
th
Revision code 428) from 1995 through 2010 were identified. HF was validated by Framingham criteria. Patients residing in a SNF prior to hospitalization were excluded from the analysis. Logistic regression was used to examine the association between discharge to SNF and 30-day readmissions.

Results:
Among 1360 HF patients (mean age 74±14, 47% male), 241(18%) were referred to a SNF. Overall, 296 (22%) patients were readmitted within 30-days after index hospitalization. The proportion of 30-day readmissions was greater among patients discharged to a SNF compared to patients discharged home (27% vs 21%, p=0.031). After adjustment for age and sex, patients discharged to a SNF had a 40% increase in the odds of having a hospital readmission within 30 days post HF compared to those discharged home (OR: 1.42, 95% CI 1.01-1.99). Further adjustment for year of HF diagnosis, ejection fraction, anemia, renal function, dementia and cancer did not alter the strength of the association (OR: 1.43, 95% CI: 0.99-2.09).

Conclusion:
Among community patients with HF, 30-day readmissions remain frequent and are more likely to occur among patients discharged to a SNF compared to those discharged home. These data provide new insight into the drivers of HF readmissions and suggest that interventions targeted to HF patients in SNFs may be warranted.
Abstract 15397: Enhanced AKAP12/GRAVIN Expression Leads to Myocardial Injury by Disrupting Angiogenic Signals Related to HSP/Thioredoxin-1/VEGF Cascade in Type I Diabetic Rats
Authors: Selvaraju Vaithinathan , Suresh Sumanth C , Thirunavukkarasu Mahesh , Palesty J.Alexander , Sanchez Juan A , Maulik Nilanjana
Published: July 2021

Background:
Our earlier studies showed that AKAP12 and Thioredoxin-Interacting Protein (TXNIP) interfere with HSPA12B-induced angiogenic signaling in rat myocardium. HSPA12B appears to play an essential role in myocardial angiogenesis, which is impaired during diabetes. This study explores the impact of HSPA12B overexpression on heart function, neovascularization, and downstream target proteins, AKAP12, Thioredoxin-1 (Trx-1) and VEGF, in non-diabetic and diabetic animals following myocardial infarction (MI).

Methods:
Rats were divided into 6 groups: 1) Non-Diabetic Sham (NDS), 2) Non-Diabetic LacZ MI (NDLZMI), 3) Non-Diabetic HSPA12B MI (NDHSPMI), 4) Diabetic Sham (DS), 5) Diabetic LacZ MI (DLZMI), 6) Diabetic HSPA12B MI (DHSPMI). Ad.LacZ/Ad.HSPA12B was administered intramyocardially at 4 sites around the infarct border zone in NDLZMI/DiaLZMI or NDHSPMI/DiaHSPMI animals immediately after permanent LAD ligation.

Results:
Co-immunoprecipitation followed by immunoblot analysis showed significant increase in HSPA12B/AKAP12 association in diabetic group suggesting that diabetes impairs HSPA12B availability triggering impairment of angiogenesis. This result was also confirmed by docking analysis (insilico models). Trx-1 activity (1.73 fold) along with HSPA12B and VEGF expression was increased in DHSPMI and NDHSPMI compared to respective controls. Both AKAP12 (1.31 fold) and TXNIP (2.22 fold) appeared to be down-regulated in HSPA12B-treated groups compared to controls. Echocardiography demonstrated increased fractional shortening and ejection fraction 4 weeks post-MI in DHSPMI-treated rats compared to DLZMI. Increased capillary and arteriolar density in DHSPMI compared to DLZMI was obesrved by morphometric analysis. In addition Picrosirius red staining documented decreased fibrosis in DHSPMI vs. DLZMI myocardium.

Conclusion:
Therefore overexpression of HSPA12B enhances neovascularization and cardiac function following MI in diabetic animals by down-regulating Trx-1/TXNIP and HSPA12B/AKAP12 association, resulting in increased HSPA12B, Trx-1 and VEGF. These findings support a role for HSPA12B gene therapy in mitigating the morbid expression of ischemic heart disease in the setting of diabetes.
Abstract 154: Continuous Intravenous Administration of Adrenaline May Prevent the Biphasic Reaction of Anaphylaxis
Authors: Fujizuka Kenji , Nakano Minoru , Nakamura Mitsunobu , Ogura Takayuki
Published: July 2021

Objective:
Anaphylaxis is a multi-system syndrome resulting from the release of chemical mediators upon exposure to an allergen. Biphasic anaphylactic reactions may occur due to secondary elevation of the chemical mediators following the initial reaction. The initial treatment of anaphylaxis generally includes adrenaline injection, which results in decreased chemical mediator release. We hypothesize that continuous intravenous administration, rather than intramuscular injection of adrenaline, may inhibit the release of chemical mediators following the initial reaction, and thereby prevent biphasic reactions. Accordingly, in this study, we aimed to investigate the occurrence of biphasic reactions according to the type of administration of adrenaline.

Methods:
We included patients with anaphylaxis admitted to our hospital, who were treated with adrenaline between April 2005 and March 2014. We retrospectively investigated the occurrences of biphasic reactions after admission in patients treated with continuous intravenous adrenaline or intramuscular adrenaline injections. Patients were excluded if they had received intravenous bolus or complex methods of administration. The risk of biphasic reactions according to the method of administration was analyzed by logistic regression.

Results:
A total of 104 patients were included in the study (continuous intravenous administration: 56, intramuscular injection: 48). Eight patients (7.69%) experienced biphasic reactions, out of which one had received continuous intravenous administration, and seven had received intramuscular injection (p = 0.02). No patient had received adrenaline during the biphasic reaction in the continuous intravenous administration group compared to the three patients in the intramuscular injection group (p = 0.10). Logistic regression analysis revealed that the odds ratio of biphasic reactions for continuous intravenous administration vs. intramuscular injection of adrenaline was 0.11 (p = 0.04, 95% confidence interval: 0.01-0.90).

Conclusions:
Continuous intravenous administration of adrenaline may prevent the biphasic reaction of anaphylaxis.
Abstract 15414: Ablation of Aryl Hydrocarbon Nuclear Translocator (ARNT) in the Heart Leads to Diabetic Cardiomyopathy Phenotype Through PPARα Activity
Authors: Wu Rongxue , Chang Hsiang Chun , Tran Minh , Chawla Kusum , Khechaduri Arineh , Chai Xiaomeng , Ghanefar Mohsen , Bayeva Marina , Wagg Cory , Gonzalez Frank , Lopaschuk Gary , Ardehali Hossein
Published: July 2021

Background:
Metabolic changes decrease cardiac efficiency and energetics in diabetes. Impaired hypoxia inducible factor (HIF) signaling may contribute to cardiac metabolic abnormalities. ARNT, also known as HIF1β, is a transcription factor that regulates several cellular processes by dimerizing with certain proteins, including HIF-1α or -2α, and its function in the heart is unknown. We hypothesized that cardiac deletion of ARNT leads to metabolic derangement and cardiac dysfunction.

Methods and Results:
Cardiac-specific ARNT knockout (csARNT-KO) mice were generated by our lab as previously described. ARNT deletion in the heart resulted in dilated cardiomyopathy and significant lipid accumulation, which was determined by electron microscopy, oil-red staining and triglyceride level quantification. We found that loss of ARNT in the heart increased PPARα activity, as confirmed by 2-fold increase in fatty acid oxidation (FAO) in ex-vivo csARNT+/- working hearts, increased PPARα protein content and increased PPARα target gene expression.To study the mechanism by which ARNT regulates PPARα, luciferase reporter assays revealed that ARNT knockdown resulted in increased PPARα promoter activity and deletion of the second hypoxia response element (HRE) upstream of the initiation site removed the inhibitory effect of ARNT on the PPARα promoter, suggesting that this site is likely involved in the regulation of the gene. ARNT binding to this sequence was confirmed by chromatin immunoprecipitation analysis. Moreover, a reduction in HIF-2α, but not HIF-1α or AHR, also significantly increased the levels of PPARα. These results suggest that the effects of ARNT deletion on PPARα are, at least partially, through its association with HIF-2α and through the binding of this complex to the second HRE upstream of the PPARα initiation site. Finally, mice with double deletion of ARNT and PPARα demonstrated rescue of the cardiac dysfunction phenotype, improved survival, and complete reversal of FA accumulation.

Conclusion:
Reduction in ARNT levels leads to cardiomyopathy by increasing lipid accumulation through a PPARα pathway. Thus, ARNT is a critical regulator of fatty acid metabolism in the heart, and a potential target for the treatment of diabetic cardiomyopathy.
Abstract 15421: Central Hemodynamic Response to Oral Glucose Loading Are Blunted in Patients with Impaired Glucose Tolerance or Diabetes
Authors: Higaki Tadanao , Kurisu Satoshi , Watanabe Noriaki , Ikenaga Hiroki , Shimonaga Takashi , Iwasaki Takatoshi , Ishibashi Ken , Fukuda Yukihiro , Kihara Yasuki
Published: July 2021

Introduction:
Impaired glucose tolerance (IGT) as well as diabetes is associated with the development of cardiovascular disease. We tested the hypothesis that central hemodynamic responses to oral glucose loading were different according to the status of glucose tolerance.

Methods:
This study enrolled 89 patients with known or suspected coronary artery disease who underwent 75g oral glucose tolerance test (OGTT). Augmentation index (AIx) and central systolic blood pressure (cSBP) were measured using radial applanation tonometry (Omron, HEM 9000-AI) at fasting, and 1, 2 hours after oral glucose loading.

Results:
In overall patients, oral glucose loading increased pulse rate (60.0 ± 10.4 to 64.7 ± 11.9 bpm, p<0.001), and decreased AIx normalized to a heart rate of 75 bpm (AIx@75) (81.6 ± 13.9 to 74.5 ± 14.1 %, p<0.001) and cSBP (114.7 ± 22.2 to 108.6 ± 21.3 mmHg, p<0.001) at 2h. OGTT identified normal glucose tolerance (NGT) in 40 patients, IGT in 36 patients and diabetes in 13 patients. Decrease in AIx@75 during OGTT was blunted in IGT as well as diabetes patients compared to NGT patients. Decrease in cSBP during OGTT was blunted in IGT patients than NGT patients, and no significant decrease was found in diabetes patients.

Conclusions:
Our data suggested that central hemodynamic responses to oral glucose loading were blunted in patients with impaired glucose tolerance or diabetes. This blunted fluctuation might be associated with adverse outcome in patients with IGT or diabetes through persistently high levels of AIx and cSBP.
Abstract 15425: Is Accurate Stroke Risk ssessment with CHADS
2
Necessary in Managing Patients with Atrial Fibrillation? Insights from the Stroke Prevention and Rhythm Interventions in Atrial Fibrillation (SPRINT-AF) Registry
Authors: Ha Andrew C , Singh Narendra , Cox Jafna L , Dorian Paul , Fournier Carl , Mancini G.B. J , Shuaib Ashfaq , Kajil Mahesh , Tsigoulis Michelle , Gupta Milan K
Published: July 2021

Introduction:
Guidelines have advocated use of scoring schemes such as CHADS
2
to assess stroke risk for patients with atrial fibrillation (AF). However, recent studies had demonstrated poor agreement between physician-reported and scoring-derived stroke risk. From a national registry, we assessed if rates of oral anticoagulant (OAC) use differ between patients whose stroke risks are concordantly or discordantly categorized.

Methods:
From December 2012 to July 2013, a cross-sectional analysis of 936 consecutive AF patients was performed, enrolled from 109 primary care and specialty practices in 10 Canadian provinces. Based on clinical judgment, physicians categorized each patient as low, moderate, or high risk for stroke. We categorized patients’ stroke risk based on their CHADS
2
score (low: 0; moderate: 1, high: ≥2). Agreement between physician-reported and CHADS
2
risk was reported by the weighted kappa. We compared rates of OAC use between patients whose stroke risk was concordantly or discordantly categorized by clinicians, relative to those derived from CHADS
2
.

Results:
Complete data were available in 929 (98.8%) patients for analysis. The weighted kappa between physician-reported and CHADS
2
-derived stroke risk was 0.41 (95% CI: 0.34 to 0.48). Physician-determined stroke risk was concordantly categorized to CHADS
2
scores in 544 (58.6%) patients. Among patients with CHADS
2
≥2, rates of OAC use were similar between the concordant and discordant groups (91.7% vs. 90.4%, p=0.66). For patients with CHADS
2
=1, rates of OAC use were higher in the concordant group (84.2% vs. 66.4%, p<0.01). For patients with CHADS
2
=0, rates of OAC use were lower in the concordant group (43.5% vs. 80.0%, p<0.01).

Conclusions:
In this contemporary AF registry, the agreement between physician-reported and CHADS
2
-derived stroke risk was only modest. Despite this, the rate of OAC use in patients at high risk (CHADS
2
≥2) was similarly high between the concordant and discordant groups. However, rates of OAC use between the 2 groups differed among patients at lower stroke risk. Our results suggest that discrepancy in stroke risk categorization is associated with guideline-discordant OAC use, particularly for patients with lower CHADS
2
scores.
Abstract 15517: Receipt of Special Education Services Among Children with Congenital Heart Defects in Atlanta, Georgia
Authors: Colarusso Tiffany , Andrew Autry , Razzaghi Hilda , Boyle Coleen , Mahle William , Van Naarden Braun Kim , Correa Adolfo
Published: July 2021

BACKGROUND:
Population-based information on special education service needs among children with congenital heart defects (CHDs) is limited. We investigated the prevalence of receipt of special education services among children with CHDs.

METHODS:
Children born from 1982-2004 in metropolitan Atlanta with CHDs (n=3,744) were identified from a population-based birth defect surveillance program, and contemporaneous children born without major birth defects (n=860,715) were identified from birth certificates. Cohorts were linked to special education files for 1992-2012 school years to identify receipt of special education services. Children with CHDs and non-cardiac defects or genetic syndromes were excluded; children with isolated CHDs were classified by presence or absence of critical CHDs (i.e., defects needing intervention in the first year of life). We evaluated prevalence of special education services and calculated prevalence ratios (PRs) using children without birth defects as reference.

RESULTS:
Children with CHDs were 50% more likely than those without birth defects to use special education services (PR 1.5; 95% Confidence interval 1.4-1.7). Similar to children without birth defects, the most common eligibility among children with CHDs was speech/language impairment. Compared to children without birth defects, the prevalence of several special education eligibilities were significantly higher among children with all CHDs: any intellectual disability (PR 3.8), sensory impairment (PR 3.0), other health impairment (PR 2.8), significant developmental delay (PR 1.9), orthopedic impairment (PR 1.9), and specific learning disability (PR 1.4). For most special education eligibilities, there was no significant variation in the elevated prevalence ratios by presence or absence of critical CHDs.

CONCLUSIONS:
Children with many types of CHDs received special education services more often than children without birth defects. These findings highlight important resource needs for children with CHDs. Furthermore, they suggest that recommendations to perform developmental screening only on children with select CHDs may miss or delay identification of children with other CHDs, who may also need special education services.
Abstract 15528: Myocardial Deformation Imaging and Obstruction in Hypertrophic Cardiomyopathy, Insights from Cross-sectional and Post-myectomy Analysis
Authors: Kobayashi Yukari , Finocchiaro Gherardo , Giraldeau Genevieve , Boulate David , Kobayashi Yuhei , Ha Richard , Lee David , Liang David , Schittger Ingela , Haddad Francois , Ashley Euan
Published: July 2021

Background:
Hypertrophic cardiomyopathy (HCM) has been reported to alter left ventricular deformation. However, little is known about the differences of left ventricular (LV) strain values among healthy and varying levels of HCM patients including non-obstructive and obstructive, nor about the impact of septal reduction therapy on strain values.

Methods:
Age- and sex matched patients with HCM and varying degree of obstruction as well as 48 healthy controls were studied. Among HCM patients, 28 subjects had non-obstructive HCM, 27 had mildly symptomatic obstructive HCM, and 34 had HCM requiring septal reduction therapy (either myectomy or alcohol ablation). LV global longitudinal strain (LV-GLS) and circumferential strain as well as routine echocardiography were evaluated. Detailed LV longitudinal strain was assessed with septal and lateral longitudinal strain (Sept.-LS and Lat.-LS). In HCM patients treated with septal reduction, echocardiography was performed before, 3-months, and 1-year after the procedure.

Results:
LV-GLS, Sept.-LS, and Lat.-LS of all HCM patients were significantly lower than controls (p<0.001, p<0.001, p<0.05, respectively), and circumferential endocardial and mid strain were higher (p<0.05). Significant differences among controls and varying levels of HCM subgroups were detected only in Sept.-LS, which enabled to stratify the HCM severity (left panel in Figure). In addition, Sept.-LS has the strongest correlation with the average LV wall thickness (right panel in Figure). Furthermore, Sept.-LS was significantly improved after septal reduction, whereas Lat.-LS and circumferential strain did not change.

Conclusions:
The strongest relationship between myocardial deformation and obstruction in HCM was found for Sept.-LS. Also, septal reduction procedure preferentially improves Sept.-LS.
Abstract 15552: Acute Estrogen-GPER1 Stimulation Preserves Mitochondrial Inner Membrane Protein (Mitofilin) From Degradation caused by Ischemia/Reperfusion Stress
Authors: Harris Tanoya L. C , Olde Bjorn , Leeb-Lundberg Fredrik , Bopassa Jean C.
Published: July 2021

Introduction:
We recently found that acute estrogen treatment delays the mitochondrial permeability transition pore opening and reduces ROS production after ischemia/reperfusion, suggesting that estrogen promotes mitochondrial integrity. As mitochondrial inner membrane protein (mitofilin) has been found to control mitochondrial cristae morphology and function, we investigated whether estrogen effect on mitochondrial integrity after ischemia/reperfusion involved regulation of mitofilin via G-Protein Coupled Estrogen Receptor1 (GPER1) activation.

Methods:
Isolated hearts from male WT (C57BL/6NCrL), and GPER1-/- mice were perfused using Langendorff technique, with and without estrogen (40 nM). Hearts were subjected to 20 min global ischemia followed by 10 min reperfusion. Mitochondria were isolated, and 2D-DIGE followed by mass spectrometry was performed. Mitofilin expression was confirmed by Western blot analysis in mitochondrial fractions. Mitofilin distribution in cardiomyocytes, and its spatial organization in single mitochondria were visualized using high resolution microscopy. Electron microscopy was used to observe the state of mitochondrial cristae morphology.

Results:
Analysis revealded 52 unique proteins of interest, in which mitofilin was identified. Immunoblot analysis confirmed an increased in mitofilin level with estrogen treatment as compared to control in WT but not in GPER1-/-. We found, as observed in non-ischemic myocytes, that mitofilin in estrogen-treated cardiomyocytes was distributed in the peri-membrane and T-tubules, while only peri-membrane mitofilin was more visible in control group. High resolution microscopy showed a better spatial organization of mitofilin in single mitochondria with estrogen treatment compared to control, in which mitofilin was almost absent. Electron microscopy revealded that mitochondrial morphology was preserved with estrogen treatment, as cristae were well organized compared to control, in which cristae were disrupted.

Conclusion:
These data indicate that estrogen up-regulates mitofilin expression during ischemia/reperfusion. Estrogen effect on mitofilin may contribute to improved mitochondrial integrity and function.
Abstract 15583: Toll-Like Receptor 4 Knockout Preserves Cardiac Function in High Fat Diet-Induced Obesity
Authors: Hu Nan , Zhang Yingmei , Ren Jun
Published: July 2021

Background:
Toll-like receptor 4 (TLR4) is an innate proinflammatory mediator found in a wide variety of cell types including cardiomyocytes. The autophagy-lysosome pathway, a major pathway governing protein and organelle degradation and recycling, plays a pivotal role in maintaining cardiac homeostasis under physiological and pathological conditions. The aim of this study was to evaluate the impact of TLR4 knockout (TLR4
-/-
) on high fat diet (HFD)-induced cardiomyopathy and the underlying mechanisms involved, with a focus on inflammation and autophagy pathways.

Methods:
Wild type (WT) and TLR4
-/-
mice were fed on low fat diet (LFD) or HFD for 12 weeks. Metabolic rate and glucose tolerance were measured in WT and TLR4
-/-
mice at the end of fat diet intake. Echocardiographic, cardiomyocyte mechanical function, morphological feature, aconitase activity, ROS generation and immunoblotting were assessed.

Results:
TLR4
-/-
did not prevent HFD-induced obesity and insulin resistance, as evidenced by body weight gain and glucose intolerance. In addition, there was little difference in metabolic parameters (V
O2
, V
CO2
, RER, energy expenditure and physical activity) between WT and TLR4
-/-
mice fed with HFD. However, TLR4
-/-
alleviated HFD-elicited cardiac hypertrophy and contractile dysfunction. HFD-feeding caused extensive mitochondrial injury and ROS generation, which were alleviated by TLR4
-/-
. TLR4
-/-
dramatically attenuated inflammation signaling (up-regulated p-IKβ, NF-κB and p-JNK) in the face of HFD intake. Cardiac autophagy was significantly suppressed by HFD, as evidenced by up-regulated p-mTOR, down-regulated p-AMPK, Atg5, Atg12, LC3BII, and up-regulated P62 in HFD-induced cardiomyopathy. Furthermore, in vitro study revealed that the TLR4 inhibitor-TAK-242 reconciled palmitic acid-induced cardiomyocyte autophagy and contractile anomalies.

Conclusions:
Our results suggested that TLR4
-/-
does not prevent HFD-induced obesity and insulin resistance. However, TLR4 is a culprit factor for cardiac dysfunction following HFD intake. The cardioprotective effect of TLR4
-/-
against HFD-induced cardiomyopathy is associated with attenuation of myocardial inflammation and recovery of cardiac autophagy activity.
Abstract 15597: Acute Venous Congestion Causes Angiotensin II formation via Angiotensin-Converting Enzyme Activation in Compensated Ambulatory Patients with Systolic Heart Failure
Authors: Wong Ka Yuk , Hayashi Yacki , Onat Duygu , Harxhi Ante , Wakabayashi Michiyori , Ahmad Myra M , Uriel Nir , Jorde Ulrich P , Demmer Ryan T , Colombo Paolo C
Published: July 2021

Background:
Plasma levels of angiotensin II (AII) are increased in congestive states such as heart failure (HF). The current study examined i) whether venous congestion (VC) itself promotes AII formation, and ii) the contributions of angiotensin-converting enzyme (ACE) vs. other enzymes such as chymases to AII generation in patients with systolic HF.

Methods:
42 ambulatory patients with NYHA functional class II or III, an LVEF <40%, no evidence of VC on physical exam and on stable medical therapy were studied. To experimentally model VC, venous arm pressure was increased to 30 mmHg above baseline by inflating a pressure cuff around the dominant arm. Blood was sampled from test and control arm (lacking an inflated cuff) before and after 90 minutes of VC. Radioimmunoassay was used for plasma AII measurements.The effect of ACE inhibitor (ACEI) based therapy (N=29) vs. non-ACEI (N=13) was compared.

Results:
The age of the study cohort was 53±12 years, 29% were female, 31% had an ischemic etiology and the LVEF was 22±8%. Baseline AII levels were 3-times lower in the ACEI vs. non-ACEI group (24±10 vs. 76±40 pg/mL, P<0.001). Plasma AII was significantly higher in the congested over control arm only in non-ACEI group after 90 minutes of VC (figure). No adverse event was observed during the test.

Conclusions:
Our study provides the first direct evidence that VC is sufficient to cause AII formation in compensated ambulatory HF patients on non-ACEI based therapy. ACEI treatment completely abolished this increase suggesting activation of ACE, rather than other enzymes such as chymases, to be the cause of volume-dependent AII formation in response to peripheral VC.
Abstract 15610: The Infusion of Mesenchymal Stromal Cells Post Myocardial Infarction Increases Myocardial S100A6, Attenuates Myocyte Hypertrophy, Reduces Myocyte Apoptosis and Improves Cardiac Function
Authors: Tsoporis James , Izhar Shehla , Desjardins Jean-Francois , Proteau Gerald , Yannarelli Gustavo , Keating Armand , Parker Thomas G
Published: July 2021

The beneficial effects originally attributed to the ability of bone-marrow derived mesenchymal stromal cells (BM-MSCs) to differentiate into cardiomyocytes have been questioned due to the transient presence of donor cells at injury site following myocardial infarction (MI) suggesting that the MSC-induced improvement in hemodynamic function may be attributable to paracrine effects. We showed that S100A6, a 20 kDa EF-hand calcium-binding dimer, is upregulated and secreted following MI and forced expression post-MI was beneficial to the preservation of cardiac function. The aim of this study was to determine whether the beneficial effects of infused BM-MSCs may be related to the autocrine secretion of S100A6. Balb/c murine cultured green fluorescence protein (GFP)-marked BM-MSCs express S100A6 at baseline and in response to hypoxia (5%C02/95% N2) for 1 hr increase S100A6 mRNA and protein (2-3 fold, and release S100A6 (1 nM) in the culture media, responses inhibited in BM-MSCs transfected with S100A6 siRNA. Treatment of neonatal Balb/c cardiac myocytes with human recombinant S100A6 (1nM) for 1-24 hrs attenuated baseline apoptosis (30 per cent decrease in BAX/BCL2 ratio), induced cyclin-dependent kinase 1(CDK1) mRNA 1.5 fold, miR199a 2 fold and myocyte proliferation 2.5 fold, the latter inhibited by anti-miR 199a. In 12 week old Balb/c mice, saline or GFP-marked BM-MSCs transfected with either a scrambled or S100A6 siRNA were infused intravenously 3-4 hrs post coronary artery ligation. After 3-4 days the GFP-marked cells were confined to ischemic areas and represented approximately 10% of total cellularity and co-expressed collagen type IV and myosin heavy chain, characteristic of MSCs and cardiomyocytes, respectively, and were CD45(-). Despite the absence of donor cells in the infarcted myocardium 21 days after infusion, mice that have received MSCs alone compared to MSCs transfected with an S100A6 siRNA or saline alone showed a 6-fold increase in S100A6 mRNA and protein, 3-fold increase in miR199a in peri-infarcted myocardium, attenuated myocyte hypertrophy, decreased fibrosis and apoptosis, and preservation of cardiac function. In conclusion, the secretion of S100A6 by infused BM-MSCs may contribute in limiting adverse LV remodeling post-MI.