bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 14911: Dipeptidyl Peptidase-4 Deteriorates Cardiac Function During Autoimmune Myocarditis by Facilitating Cathepsin-G Activity
Authors: Maejima Yasuhiro , Ito Yusuke , Tamura Natsuko , Watanabe Ryo , Isobe Mitsuaki
Published: July 2021

Post-myocarditis dilated cardiomyopathy is the most common cause of non-hereditary heart failure developing at a young age. Our colleagues have shown previously that dipeptidyl peptidase-4 (DPP-4) worsens the development of experimental autoimmune myocarditis (EAM) by promoting expression of inflammatory cytokines and cardiac fibrosis in mice. In order to clarify how DPP-4 mediates this detrimental effect in the EAM heart, mouse EAM model generated by immunizing with α-MHC peptide in BALB/c mice were given a diet mixed with linagliptin, a selective DPP-4 inhibitor (83 mg/kg chow corresponding to around 3 mg/kg oral dosing) (LINA group, N = 6), or normal diet (CONT group, N = 6). After 21 days of EAM induction, lung weight / body weight were significantly smaller in LINA group than in CONT group (7.7 ± 0.1 mg/g* vs. 8.3 ± 0.1 mg/g, *P < 0.05). Left ventricular ejection fraction after induction of EAM was significantly higher in LINA group than in CONT group (72.6 ± 6.6%* vs. 60.1 ± 9.2%, *P < 0.05). Immunostaining demonstrated that the number of RORγt-positive Th17 cells infiltrated to inflamed myocardium was significantly smaller in LINA group than in CONT group. Consistent with this result and the previous finding that Th17 cells express high level of enzymatically active DPP-4, the DPP-4 activity in inflamed myocardium was significantly lower in LINA group than in CONT group (46.9 ± 2.4 RFU* vs. 116.8 ± 8.6 RFU, *P < 0.05). Mass spectrometry analysis using lysates from inflamed myocardium co-immunoprecipitated with Flag-DPP-4 recombinant protein revealed that DPP-4 bound to cathepsin-G (CTSG), a plasma membrane-bound serine protease, in the EAM heart. Co-immunoprecipitation - western blot analysis verified the physical interaction between DPP-4 and CTSG. The activity of CTSG in inflamed myocardium was significantly higher in EAM mice compared to those in untreated mice, and CTSG activity in the EAM heart was significantly lower in LINA group than in CONT group. The amount of angiotensin II, a major product catalyzed by CTSG, in the EAM heart was also significantly lower in LINA group than in CONT group. Collectively, these results suggest that DPP-4 derived from Th17 cells aggravates cardiac dysfunction during EAM, possibly through enhancing CTSG activity in the heart.
Abstract 14920: Uric Acid is Neither the Risk Factor nor Prognostic Factor for 3-year Clinical Events in Vasospastic Angina Patients Regardless of Gender
Authors: Park Sang-Ho , Rha Seung Woon , Jun Ung , Choi Byoung Geol , Choi Se Yeon , Byun Jae Kyeong , Na Jin Oh , Choi Cheol Ung , Lim Hong Euy , Kim Jin Won , Kim Eung Ju , Park Chang Gyu , Seo Hong Seog , Oh Dong Joo
Published: July 2021

Background:
It has been reported that a major cause of vasospastic angina is endothelial dysfunction of the coronary artery. However, it is controversial whether the uric acid level is associated with vasospastic angina, and can be a prognostic factor for vasospastic angina.

Methods:
A total 3828 patients (pts) underwent coronary angiography with acetylcholine (Ach) provocation test from Mar 2004 to Sep 2012 were enrolled. The definition of positive coronary artery spasm (CAS) was defined as transient luminal narrowing more than 70%. The uric acid level was categorized into 4 quartile groups; less than 3.8, 3.9~4.7, 4.8~5.7, and more than 5.8 mg/dL. Major adverse cardiovascular events (MACEs) defined as the composite of recurrent chest pain, cardiac death, myocardial infarction, and cerebrovascular accident were valuated up to 3 years.

Results:
The follow-up rate was the 61.1% (2340/3828). There was no difference in uric acid level between negative and positive CAS groups in female gender but in male gender, uric acid level was higher in negative CAS group (Table 1). However, when adjusted by age, the difference was disappeared (OR, 0.965; 95% CI, 0.898-1.037; P-value, 0.335). The incidence of MACE was 11.1% in male gender and 8.6% in female gender. In male gender, the serum uric acid level between the groups with and without MACE was similar but in female gender, the uric acid level was higher in the group with MACE. However, when adjusted by age, uric acid was not associated with MACE (Table 2).

Conclusions:
In our study, uric acid was neither the risk factor nor prognostic factor for 3-year clinical events in CAS patients regardless of gender.
Abstract 14972: Sub-clinical Atrial Fibrillation in Elderly Primary Care Patients Without Clinical Atrial Fibrillation
Authors: Healey Jeff S , Connolly Stuart J , Manja Veena , Liu Yan , Simek Kim D , Quinn Russell , Sandhu Roopinder K , Ivers Noah , Gladstone David J
Published: July 2021

Introduction:
Sub-clinical AF has been reported in 10% of pacemaker patients (≥ 6 minutes, with 3 months of monitoring) and 16% of patients following cryptogenic stroke (≥ 30 seconds, with 1 month of monitoring). It is unknown how common sub-clinical AF is among other patient groups, including the elderly. These data are needed to give context to the detection of sub-clinical AF in clinical practice.

Methods:
We prospectively investigated the prevalence of sub-clinical AF among individuals ≥ 80 years, without known AF or symptoms of arrhythmia, attending primary care clinics. Subjects had a history of hypertension and at least one of the following: diabetes, BMI ≥ 30, sleep apnea, smoking, coronary disease, heart failure or left ventricular hypertrophy. Patients were recruited from 7 Ontario family practice clinics (n=119) and one general medicine clinic (n=10). Patients underwent 30 days of continuous, non-invasive ambulatory ECG monitoring using a device with automatic AF detection (Vitaphone 3100). The primary outcome was a composite of atrial flutter (AFL) or AF ≥ 6 minutes in duration. Those without AF were invited to complete an additional 30 days of monitoring.

Results:
Of 129 patients screened and consented, 100 patients initiated monitoring for an average monitoring duration of 36± 21 days. The mean (SD) age was 84 ± 3 years and systolic blood pressure was 138 ± 17 mmHg; 50% had coronary disease, 28% had diabetes and 6% had heart failure. Only 4% had a history of prior stroke. Thirty days of monitoring was completed by 57% of patients and 31% completed an additional 30 days. AFL or AF ≥ 30 seconds duration was documented in 19/100 patients; ≥ 6 minutes in 15; ≥ 30 minutes in 12; ≥ 6 hours in 8 and ≥ 24 hours in 2. Shorter episodes of atrial tachycardia lasting less than 30 seconds were observed in 47 patients.

Conclusions:
In this prospective, outpatient study, using non-invasive ECG monitoring, we found AFL or AF ≥ 6 minutes in 15% of elderly individuals with stroke risk factors. This high background prevalence of AFL/AF among elderly patients suggests a possible role for AF screening in this population; but also should be taken into consideration when interpreting the prevalence of AFL/AF in other populations.
Abstract 15090: Circulating miR-503 and miR-374b-5p are associated With Heart Failure
Authors: Wong Lee Lee , Saw Eng Leng , Lilyanna Shera , Martinez Eliana C , Lam Carolyn S.P. , Richards Arthur M
Published: July 2021

Introduction:
Circulating microRNA (miRNAs) profiles are dysregulated in heart failure (HF) suggesting possible diagnostic and prognostic applications. In addition, miRNAs may yield insights into the pathophysiology of HF and provide targets for therapeutic intervention. We sought to identify miRNAs diagnostic utility in HF and to further investigate selected miRNAs as potential targets for therapeutic intervention.

Hypothesis:
We hypothesized that distinct circulating miRNAs are dysregulated in HF and may be potentially important targets of therapy to improve outcomes for HF.

Methods:
Plasma miRNAs levels were profiled from 338 well-characterized HF patients and 208 age-matched controls without HF. We also examined selected miRNAs expression in a rat post-myocardial infarction (MI) model. Target predictive databases were used to identify potential miRNA targets.

Results:
Comparison between HF and non-HF controls was carried out by multivariate analysis. Seventy five miRNAs differed significantly between HF and non-HF controls after adjustment for age, hypertension, diabetes and atrial fibrillation (p-value after FDR<0.01). Twenty four miRNAs with AUC>0.65 , p<0.001 (for discrimination of HF from non-HF controls on receiver-operator analysis) were highly up- or down-regulated significantly in clinical data comparing HF vs non-HF controls and were further examined in plasma samples from a rat post-MI model. Results showed that levels of miR-503 (AUC=0.73, FC (Fold Change) =1.69, p<0.001) was higher and of miR-374b-5p (AUC=0.71, FC=-1.45, p<0.001) lower when comparing HF patients with non-HF controls. In rat experimental model, levels of miR-503 (FC=2.21, p=0.017) increased and of miR-374b-5p (FC=-1.35, p=0.02) decreased after post-MI at Day 2 and Day 7, but not significant in Day 14 comparing with sham. MiR-503 has been reported to target CCNE1 and cdc25A. The predicted target for miR-374b is
NPPB
. The roles of miR-503 and miR-374b-5p in HF warrant further investigation using both in-vitro and in-vivo preclinical HF models.

Conclusion:
We provide a detailed study of circulating miRNA profiling in both clinical HF and experimental model. We demonstrated that circulating miR-503 and miR-374b-5p are associated with HF.
Abstract 15112: NADPH Oxidase 4 Protects Against Development of Endothelial Dysfunction and Atherosclerosis in LDL Receptor Deficient Mice
Authors: Langbein Heike , Brunssen Coy , Hofmann Anja , Cimalla Peter , Bornstein Stefan R , Koch Edmund , Morawietz Henning
Published: July 2021

Introduction:
Endothelial dysfunction is an early step in the development of atherosclerosis. Increased formation of superoxide anions by NADPH oxidase Nox1, 2 and 5 reduce NO availability and can promote endothelial dysfunction. In contrast, recent evidence supports a vasoprotective role of H2O2 produced by main endothelial isoform Nox4. Therefore, we assessed the hypothesis genetic deletion of Nox4 influences endothelial dysfunction and atherosclerosis in the low-density lipoprotein receptor (Ldlr) knockout model.

Methods and Results:
Ex vivo analysis of endothelial function by Mulvany myograph showed impaired endothelial function in thoracic aorta of Nox4-/-/Ldlr-/- mice. Further progression of endothelial dysfunction by high-fat diet increased atherosclerotic plaque burden and galectin-3 staining in Nox4-/-/Ldlr-/- mice compared to Ldlr-/- mice. In addition, we obtained evidence that under physiological conditions the loss of Nox4-derived H2O2 production could partially be compensated by nNOS upregulation. Using a self-developed optical coherence tomography device we were able to analyse endothelial function by flow-mediated vasodilation in the murine saphenous artery in vivo. This new approach observed an altered flow-mediated dilation in Nox4-/- mice, indicating a role for Nox4 under physiological conditions in vivo likewise.

Conclusion:
Nox4 plays an important role under physiological and pathological conditions to maintain endothelial function. Loss of Nox4-derived H2O2 could partially be compensated by nNOS upregulation, but severe endothelial dysfunction is not reversible. This leads to increased atherosclerosis under atherosclerotic prone conditions.
Abstract 15117: Undiagnosed Diabetes at the Time of Acute Myocardial Infarction is Frequent and Associated With Poor Cardiovascular Outcomes
Authors: Le Viet T , Knight Stacey , Anderson Jeffrey L , Lappé Donald L , May Heidi T , Horne Benjamin D , Muhlestein Joseph B
Published: July 2021

Introduction:
Diabetes mellitus (DM) is associated with poor cardiovascular disease (CVD) outcomes, especially in the setting of acute myocardial infarction (AMI). As both a first diagnosis (dx) of DM and missed dx of incident DM also may be associated with poor outcomes; we sought to determine their frequency and related CVD impact in patients presenting with AMI.

Hypothesis:
Many individuals with AMI have undiagnosed DM based on standard criteria, which leads to poor MACE outcomes.

Methods:
Patients (pts) presenting with AMI between 2002 and 2013 were studied (n=5719). Criteria-defined (CD)-DM was a fasting glucose (FG) ≥126 mg/dL, a random glucose (RG) ≥200, or a hemoglobin A1c ≥6.5%. DM groups were: 1) history (hx) of DM (n=1941, 34%), 2) no hx of DM, with CD-DM undiagnosed at AMI (n=500, 9%), 3) no hx of DM, with CD-DM diagnosed (dx) at hospitalization (n=207, 4%), and 4) no hx of DM and no CD-DM (n=3071, 53%). MACE (all-cause death, MI, stroke, heart failure hospitalization) was determined at 1 year post discharge.

Results:
Univariate comparisons are shown in the Table. After adjusting for covariables in a multivariate logistic regression using subjects with no hx of DM as the referent, hx of DM (OR=1.6; 95% CI: 1.3, 2.0; p<0.0001) and CD-DM without dx at AMI (OR=1.5; 95% CI: 1.3, 1.7; p<0.0001) were associated with greater risk of MACE. The difference between those with CD-DM with dx at AMI and those with no DM was not significant (OR=1.3; 95% CI: 0.9, 1.7; p=.15).

Conclusions:
The prevalence of DM is high in those presenting with AMI. Recognition of undiagnosed DM in the setting of CD-DM remains poor. Furthermore, MACE outcomes are 1.5 times higher with CD-DM undiagnosed than without DM, whereas outcomes are moderated if CD-DM is recognized at the time of AMI. Protocols for more aggressive identification of incident DM should be instituted and may importantly impact clinical outcomes for pts with previously undiagnosed DM.
Abstract 15154: T1-mapping and Outcomes in Non-ischemic Cardiomyopathies- An Investigator-led Multicenter Observational Longitudinal Study
Authors: Puntmann Valentina O , Carr-White Gerry , Jabbour Andrew , Yu Chung-Yao , Gebker Rolf , Kelle Sebastian , Hinojar Rocio , Doltra Ada , Varma Niharika , Child Nick , Rogers Toby , Arroyo Ucar Eduardo , Goodman Ben , Suna Gonca , Khan Sitara , Dabir Darius , Herrmann Eva , Zeiher Andreas M , Nagel Eike
Published: July 2021

Introduction:
Nonischemic cardiomyopathy (NICM) is a recognised cause of poor clinical outcome. NICM is characterised by intrinsic myocardial impairment, which is driven by interstitial myocardial fibrosis in a considerable majority of NICM. The lack of accurate and noninvasive characterisation of interstitial myocardial fibrosis limits recognition of disease and effective clinical management in NICM. Hypothesis: T1 mapping by CMR is a novel non-invasive imaging application with a recognized potential to significantly improve the management of patients with NICM, supporting characterization of interstitial myocardial disease, assessment of severity of disease, risk stratification as well as development of targeted therapies. Comparative prognostic relevance of T1-mapping parameters in subjects with NICM for adverse outcome is unknown.

Methods:
an investigator-led multicenter observational longitudinal study in patients with NICM. We standardized imaging acquisition based on the modified Look-Locker sequence (MOLLI) (3(3)3(3)5) and post-processing approach of T1 mapping, and transferred the methodology to several other centres. We determined reference ranges for T1 mapping values and provided proof of concept studies in NICM in discrimination between health and disease. The primary endpoint was all-cause mortality.

Results:
805 consecutive patients (mean age (years) 50±16; males: n=499, 62%) with NICM underwent contrast-enhanced CMR with T1-mapping. During a median follow-up period of 17 months (range 36 months), we observed a total of 26 deaths (18 cardiac). Native T1, ECV and extent of LGE were strongly associated with an increased likelihood of all-cause mortality (p<0.001). In multivariate analyses, native T1 was the sole independent predictor of all-cause and cardiac mortality, over and above ECV and LGE. Native T1 was also superior in correctly classifying subjects and adverse events over a 17-months period. Conclusions. In patients with NICM, non-invasive measures of interstitial myocardial fibrosis are useful in prediction of outcome. Native T1 is an independent predictor over and above conventional markers of risk, providing a basis for a novel algorithm of risk stratification in NICM.
Abstract 15179: Prediction of Fluid Responsiveness Using Pressure Record Analytical Method in Infants After Cardiopulmonary Bypass
Authors: Li Jia , Han Ding , Luo Yi , Ma Jun , Liu Ya G , Jia Qing Y , Ou-Yang Chuan
Published: July 2021

Introduction:
Volume expansion therapy is considered the first-line treatment in infants after cardiopulmonary bypass (CPB), but excessive volume is harmful. Pulse pressure variance (PPV) is derived from analysis of the arterial waveform and based on lung-heart interaction during mechanical ventilation. It has been used to guide volume treatment mostly in closed chest patients. The degree of lung compression might be different in different body position, potentially affecting heart-lung interaction.

Hypothesis:
PPV by pressure record analytical method (PRAM) could predict fluid responsiveness in infants after CPB in open chest conditions with supine or left lateral decubitus.

Methods:
Infants during CPB for ventricular septal defect repair with supine decubitus (n=24) and left lateral decubitus (n=29) were enrolled. After CPB, mechanical ventilation was set with tidal volume 10 ml/kg. 5% albumin or blood plasma routinely was given (150 ml/min) over 15 minutes. PPV was recorded using PRAM along with heart rate (HR), dicrotic pressure (DicP), stroke volume index (SVI), cardiac index (CI) and cardiac cycle efficiency (CCE) before and after loading changes. Patients were considered as responders to fluid loading when CI increased ≥15%.

Results:
In children with supine decubitus, 12 were responders and 14 non-responders. PPV in responders was higher than that in non-responders (25.7±6.4% vs. 16.6±5.0%, P<0.05). Area under the curve (AUC) was 0.85 and cutoff value 19% with a sensitivity of 92% and a specificity of 64%. In children with left lateral decubitus, 16 were responders) and 13 non-responders. PPV in responders were higher than that in non-responders (25.0±6.8% vs. 18.2±5.3%, P<0.05), AUC was 0.83 and cutoff value 18% with a sensitivity of 88% and a specificity of 70%. Responders in both groups had increased DicP, SVI, CI and CCE after fluid loading (P<0.05).

Conclusions:
PPV by PRAM can predict fluid responsiveness in infants immediately after CPB in open chest conditions both with supine and left lateral decubitus.
Abstract 15296: Vernakalant Shows Superiority to Ibutilide in Recent-onset Atrial Fibrillation: A Randomized Controlled Trial at the Emergency Department
Authors: Simon Alexander , Niederdöckl Jan , Skyllouriotis Ekaterini , Schütz Nikola , Weiser Christoph , Herkner Harald , Laggner Anton N , Domanovits Hans , Spiel Alexander O
Published: July 2021

Introduction:
Ibutilide is a rapid-acting antiarrhythmic drug with worldwide use for conversion of recent-onset atrial fibrillation. Vernakalant is a novel drug, which is likewise used intravenously, with proven effectiveness and safety compared to placebo and amiodarone in randomized clinical trials.

Hypothesis:
We hypothesized that the time to sinus rhythm and the conversion rate within 90 minutes is different between vernakalant and ibutilide in patients with recent-onset atrial fibrillation.

Methods:
A randomized, controlled, open-label trial registered at clinicaltrials.gov (NCT01447862) was performed in one hundred patients with recent-onset atrial fibrillation treated at the emergency department of a tertiary care hospital. Patients received up to two short-infusions of vernakalant (n= 49; 3mg/kg, 2mg/kg) or ibutilide (n= 51; 1mg, 1mg) according to the manufacturer’s instructions. Clinical and laboratory variables, adverse events, conversion rates and time to conversion were recorded.

Results:
Time to conversion of AF to sinus rhythm was significantly shorter in the vernakalant group compared to the ibutilide group (median time: 10min vs. 26min, p=0.02), and likewise the conversion success within 90 minutes was significantly higher (69% vs. 43%, p=0.01) in the vernakalant group. In both groups no serious adverse events occurred.

Conclusion:
Vernakalant was significantly faster and more effective in converting recent-onset atrial fibrillation to sinus rhythm at the emergency department.
Abstract 15384: Laminar Flow Regulates Endothelial Cell Metabolism via Long Non-coding RNA lncflow2
(Best of Basic Science Abstract)
Authors: Pfisterer Larissa , Hartung Teresa , Michalik Katharina M , Chen Wei , Zeiher Andreas M , Boon Reinier A , Dimmeler Stefanie
Published: July 2021

Considering that the transcriptome consists largely of non-coding transcripts, we analysed the impact of atheroprotective laminar flow (20 dynes/cm2) on the expression of long non-coding RNAs (lncRNA) in human endothelial cells (EC) by RNA deep sequencing.

Among the significantly up-regulated lncRNAs, we specifically confirmed the up-regulation of lncflow2 upon laminar flow (3.4±1.5, p<0.05) and by overexpressing the flow-induced transcription factor KLF2 (1.95+0.2, p<0.05) by qRT-PCR. Lncflow2 is preferentially localized to the nucleus and RNA immunoprecipitation data indicate an association with the chromatin mark H3K27me3 suggesting that lncflow2 might epigenetically control gene expression.

Functionally, the reduction of lncflow2 using LNA-Gapmers suppressed spheroid sprout formation of ECs (34.7 % reduction, p<0.05) and increased expression of endothelial adhesion molecules suggesting that lncflow2 improves EC function and reduces endothelial inflammation. Furthermore, gene ontology analysis of exon microarray analysis with RNA of lncflow2-silenced ECs revealed a significant regulation of metabolic pathways, such as the mevalonate pathway, indicated by elevated acetyl-CoA-acetyltransferase-2, HMG-CoA-reductase and HMG-CoA-synthase-1 expression (confirmed by RT-PCR; all p<0.05). In this context, inhibition of the HMG-Co-reductase by atorvastatin rescued the diminished spheroid sprouting upon loss of lncflow2. To elucidate additional effects on endothelial metabolic function, a mass spectrometry metabolome screening revealed significant alterations in amino acid, glucose and lipid metabolism. Seahorse analysis confirmed these data showing an elevated respiration and fatty acid oxidation in lncflow2 silenced ECs.

Our data identify lncflow2 as a flow-regulated lncRNA that modifies EC metabolic responses by controlling metabolism-associated genes- particularly of the mevalonate pathway. Thereby, lncflow2 critically modifies EC functions and may play a regulating role in cellular metabolic adaption to stressors.
Abstract 15416: Impact of Acute Hyperglycemia on Microvascular Damage and Long-term Clinical Outcomes in Patients With ST-elevation Myocardial Infarction
Authors: Horimatsu Tetsuo , Fujii Kenichi , Fukunaga Masashi , Nishimura Machiko , Saita Ten , Sumiyoshi Akinori , Tamaru Hiroto , Kawai Kenji , Shibuya Masahiko , Ishihara Masaharu , Masuyama Tohru
Published: July 2021

Introduction:
We have recently reported the cause of microcirculatory damage after percutaneous coronary intervention (PCI) in ST-segment elevation myocardial infarction (STEMI) patients can be evaluated by analyzing the thermodilution-derived coronary blood flow pattern (CBFP), and only the capillary destruction pattern was associated with poor mid-term clinical outcomes. In this study, we extend our research on the contribution of acute hyperglycemia on microcirculatory damage and long-term clinical outcomes in STEMI patient.

Methods:
Ninety-seven consecutive STEMI patients undergoing primary PCI were prospectively enrolled. Using a pressure sensor/thermistor-tipped guidewire, CBFP was assessed from the thermodilution-curves immediately after successful PCI. All patients were classified into 3 groups according to the shape of thermodilution curve: no microvascular damaged group (n=47), arteriole microemboli group (n=33), or capillary destruction group (n=17). Blood glucose levels were measured on admission. Major adverse cardiac events (MACE) were defined as a composite of cardiac death, myocardial infarction, and heart failure rehospitalization within 3 years.

Results:
Mean admission glucose level was significantly higher in the capillary destruction group than in the microemboli and no microvascular damaged groups (259±134, 162±66, and 153±60 mg/dL, respectively, p<0.0001). These findings were similar when the analysis was limited to non-diabetic patients. The incidence of MACE was also higher in the capillary destruction group compared with the microemboli and no microvascular damaged groups (71, 19, and 16%, respectively, p<0.0001). On multivariate Cox regression analysis, the capillary destruction pattern was the independent predictor of MACE (hazard ratio, 9.41; 95%CI 2.28-38.8; p=0.001). In the multivariate logistic regression analysis, higher glucose level on admission remained as an independent risk factor of the capillary destruction pattern (per 10mg/dL increase, odds ratio, 1.10; 95%CI 1.10-1.22; p=0.002).

Conclusions:
Hyperglycemia on admission increases the risk of microvascular damage secondary to the capillary destruction and subsequent poor long-term clinical outcomes in STEMI patients.
Abstract 15487: The Systematic Evaluation of Identifying the Infarct Related Artery Utilizing Cardiac Magnetic Resonance in Patients Presenting With ST-Elevation Myocardial Infarction
Authors: Hamo Carine E , Klem Igor , Rao Sunil V , Songco Vincent , Najjar Samer S , Lakatta Edward G , Raman Subha V , Harrington Robert A , Heitner John F
Published: July 2021

Background:
Identification of the infarct-related artery (IRA) in patients with STEMI using angiography is often based on the ECG and can be challenging in some clinical situations. The current study aimed to determine how often percutaneous intervention (PCI) is performed in a coronary artery different from the artery supplying the territory of acute infarction on late gadolinium enhancement cardiac magnetic resonance imaging (LGE-CMR).

Methods:
Among patients enrolled in the Reduction of infarct Expansion and Ventricular remodeling with Erythropoetin After Large myocardial infarction (REVEAL) trial, 113 of 222 patients randomized who presented with a diagnosis of STEMI completed baseline CMR at 4 +/- 2 days post-PCI. Blinded reviewers interpreted the cardiac catheterization and the CMR, assigning acuity to the infarct region if microvascular obstruction or edema by T2-weighted imaging was present. For the determination of a match between the IRA by cardiac catheterization and the infarct territory on CMR, the segments affected by the IRA as coded according to the 17-segment model on angiography were compared to the segments of hyperenhancement noted on CMR.

Results:
A total of 5 (4%) patients were found to have a mismatch between the IRA identified on CMR and angiography. In 4 of the 5 cases, there were multiple infarcts noted on CMR. In addition, 13 patients (11.5%) had multiple infarcts in separate territories on CMR with 4 patients (3.5%) having multiple acute infarcts and 9 patients (8%) having both acute and chronic infarcts.

Conclusion:
This study found that the identification of the IRA by angiography did not match the coronary artery territory of MI as determined by CMR in 4% of patients presenting with STEMI. These data suggest a role for more sophisticated imaging prior to PCI in selected STEMI patients.
Abstract 15489: Altered Biomechanical Properties of PKP2-deficient Hl-1 Cardiac Cells
Authors: Puzzi Luca , Martinelli Valentina , Weiss Marek , Gurha Priyatansh , Marian Ali J , Sbaizero Orfeo
Published: July 2021

Arrhythmogenic cardiomyopathy (AC) is a genetic disease caused by mutations in genes encoding the intercalated disk (ID) proteins. ID is a multiprotein complex providing cell-cell junction and connecting the nucleus to the extracellular matrix, and playing a pivotal role for maintaining the structural integrity of the heart tissue. Mutations in PKP2 encoding plakophilin 2 (PKP2) are the most common causes of AC. The objective of this study was to investigate the biomechanical properties of the PKP2-knock down HL-1 mouse cardiac myocytes (PKP2-KD). PKP2 protein levels were reduced by 66 to 75% upon shRNA-targeting of the Pkp2 mRNA. Nuclear stiffness (Young’s modulus) and the force required to deform the nucleus were assessed by atomic force microscopy (AFM). Nuclear stiffness was decreased significantly (5 times) in PKP2-KD HL-1 myocytes as compared to wild-type (WT) myocytes, indicating an increased elasticity and/or susceptibility of the nucleus to be deformed (2 times). Interestingly, cell adhesion was also reduced (10 times) in the PKP2-KD myocytes, indicating a pivotal role of ID proteins in maintaining cell adhesion and mechanical integrity in cardiomyocytes. In the stress-relaxation test, while the decay time value was comparable between WT and PKP2-KD cells, relaxation force and cell deformation values were decreased 3 and 8 times, respectively, in PKP2-KD HL-1 myocytes, confirming the finding in the Young’s modulus. Moreover, the relaxation test revealed a reduced viscosity, highlighting a compromised cytoskeletal stability induced by the PKP2 deficiency. RNA-Sequencing and Ingenuity Canonical Pathway analysis identified integrin, tight junction, and the canonical Wnt signaling, among the most disturbed pathways in the PKP2-KD HL-1 myocytes. The findings indicate that the deficiency of a component of the ID protein markedly affects the whole-cellular biomechanics, which is expected to affect tissue stability, leading to activation of the mechano-transduction pathways.
Abstract 15589: Relationship Between Left Atrial Volume Index and Left Atrial Appendage Function in Patients With Non-Valvular Atrial Fibrillation and a Cha2ds2-vasc Score of 0-1
Authors: Minami Keisuke , Izumo Masaki , Yoneyama Kihei , Akashi Yoshihiro J
Published: July 2021

Introduction:
The management of patients with non-valvular atrial fibrillation (NVAF) and low CHA2DS2-VASc scores remains controversial. Left atrial appendage (LAA) function is a known risk factor for embolisms.

Hypothesis:
In this study, we aimed to investigate the value of the relationship between transthoracic echocardiography (TTE) parameters and LAA function in low-risk (CHA2DS2-VASc score, 0-1) patients with NVAF.

Methods:
This retrospective study included 370 consecutive patients with NVAF who underwent both TTE and transesophageal echocardiography (TEE). The LAA emptying flow velocity was assessed using TEE. We established that an LAA emptying flow velocity of <25 cm/s was associated with a high risk of thrombus formation.

Results:
Of the 370 patients, 146 (40%) had a CHA2DS2-VASc score of 0-1. These patients with low-risk NVAF were further stratified into the low-flow (LAA emptying flow velocity < 25 cm/s, n = 19) and normal-flow (LAA emptying flow velocity ≥ 25 cm/s, n = 127) groups according to LAA function (atrial fibrillation during TEE: n = 63). The age, gender, CHA2DS2-VASc score, and left ventricular ejection fraction did not differ between the two groups. The low-flow group had a significantly greater left atrial volume index (LAVI) than the normal-flow group (51.6 ± 19.8 vs. 32.3 ± 12.1 ml/m2, p < 0.01). A LAVI of 37.8 ml/m2 predicted a LAA emptying flow velocity of <25 cm/s with a sensitivity of 73% and specificity of 83% among patients with low-risk atrial fibrillation (area under the curve, 0.818, p < 0.001, Figure).

Conclusions:
Approximately 13% of patients with NVAF and CHA2DS2-VASc score of 0-1 had reduced LAA emptying flow velocity as well as left atrial enlargement. The use of LAVI may improve the current embolism risk stratification system among these patients.
Abstract 15653: Optimizing the Screening Algorithm for Critical Congenital Heart Disease: A Data-Driven Approach
Authors: Oster Matthew , Caglayan Caglar , Simeone Regina , Keskinocak Pinar , Ayer Turgay
Published: July 2021

Introduction:
Screening for critical congenital heart disease (CCHD) using pulse oximetry is performed with various algorithms in the United States, with none of these based on robust data, including the one endorsed by the AHA and other organizations.

Hypothesis:
Existing algorithms will have differing results for CCHD screening, and the test characteristics of these algorithms can be improved through modifications.

Methods:
After collecting de-identified, patient-level pulse oximetry values from existing national and international screening programs, we compared the commonly used algorithms in the US: the American Academy of Pediatrics (AAP) algorithm (endorsed by the AHA), the New Jersey (NJ) algorithm (slight modification of the AAP algorithm), and the Tennessee (TN) algorithm (screening first on the foot only). We then considered alternate algorithms by modifying the pulse oximetry values that would be considered a pass, fail, or retest result in the existing algorithms. We compared the algorithms according to sensitivity (Se), false positive rate (FP), and area under the curve (AUC).

Results:
There were 75,748 screenings, with 57 true positives. Performance characteristics of the 3 common algorithms are summarized in the Table. The NJ algorithm had the greatest Se but also the highest FP, and the TN algorithm had the lowest Se but also the lowest FP. Modifications of these algorithms yielded 2632 potential algorithms with Se ranging from 28% to 91%, FP from 0.05% to 60%, and AUC from 0.64 to 0.82. Of these, 224 algorithms met our optimal algorithm criteria of Se >50%, FP 0.75.

Conclusions:
Current algorithms for CCHD screening vary in their test performance characteristics, and there are opportunities to modify these algorithms to improve test performance. Before identifying an optimal algorithm, further work is needed to collect more data (including more robust data on false negatives) and to compare the cost and ease of use of potential algorithms.
Abstract 15706: Pregnancy Outcome After Preconcpetion Evaluation in Women With Heart Disease
Authors: Mendelson Marla A , Davis Lauren A , Andrei Adin-Christian
Published: July 2021

Background:
Cardiovascular disease is the leading cause of maternal mortality in pregnancy in western countries. The number of women with preexisting cardiac disease desiring pregnancy is increasing; therefore, preconception evaluation to assess maternal and fetal risks can determine necessary interventions prior to conception to improve outcome.

Objectives:
This observational pilot study sought to determine pregnancy outcomes in women with heart disease after preconception evaluation.

Methods:
Clinical records of women who had preconception evaluations at Bluhm Cardiovascular Institute between 1996 and 2012 were retrospectively reviewed.

Results:
Of the 400 women who had preconception evaluation, 276 had subsequent pregnancies. Maternal diagnoses and clinical outcomes are summarized in Table 1 and Table 2. Preconception procedures were required in 20 patients: atrial septal defect repair (7); arrhythmia ablation (6); valve replacement (3); pacemaker insertion (2) and coronary revascularization (2). Medication changes were recommended in 32% of women. The 276 pregnancies resulted in 178 live births (112 (64%) vaginal, 63 (36%) cesarean), 45 fetal deaths (85% spontaneous abortions or ectopic pregnancies), and 53 unknown outcomes. Congenital heart disease was diagnosed in 4 (2.3%) of the offspring. None of the women developed clinically significant cardiac complications.

Conclusion:
We describe pregnancy outcomes in women with varied heart disease diagnoses and disease severity who had preconception evaluation. Preconception evaluation may afford the opportunity to improve clinical outcome for mother and baby in women with preexisting heart disease.
Abstract 15771: Genetic and Pharmacological Regulation of Circadian Energy Metabolism
Authors: Jeong Kwon , He Baokun , Yoo Seung-Hee , Chen Zheng (Jake)
Published: July 2021

The circadian clock governs essential metabolic and physiological processes. For example, the sharp rise of blood pressure in the morning coincides with peak incidence rate for cardiovascular episodes such as heart attacks. The objective of the current studies is to elucidate novel mechanisms of genetic and pharmacological regulation of circadian clock and clock-related energy metabolism important for cardiovascular health. On the one hand, we investigated the functional mechanism of the Clockdelta19 mutation. Homozygous mutant mice (Clk/Clk) for this mutation have been shown to exhibit a wide spectrum of metabolic and cardiovascular disorders, correlated with a severe circadian misalignment or loss of rhythmicity in these mice. In comparison, Clockdelta19/+ heterozygous (Clk/+) mice showed sustained circadian rhythms, yet with significantly lengthened periodicity and dampened amplitude. We showed that Clk/+ mice exhibited improved glycemic control and resistance to circadian behavioral period lengthening under high-fat diet (HFD). Molecular analysis revealed that BMAL1 protein levels in Clk/+ mouse liver were upregulated compared with wild-type (WT) mice under HFD conditions. Mechanistic studies further demonstrated that CLOCKdelta19 stabilized BMAL1 proteins. Consistent with an important role of BMAL1 in glycemic control, enhanced activation of insulin signaling was observed in Clk/+ mice relative to WT. This study reveals an unforeseen plasticity of the circadian and metabolic networks, providing important insight into potential therapeutic intervention of clocks under disease conditions. On the other hand, we also identified small molecule modulators of the circadian clock. These small molecules, termed
C
lock amplitude-
E
nhancing small
M
olecules (CEMs), were able to enhance circadian amplitude of reporter rhythms in cardiomyocyte cells in vitro and improve energy expenditure and reduce cholesterol levels in vivo in a clock-dependent manner. Our studies together elucidate novel regulatory mechanisms for the circadian clock, and suggest novel therapeutic targets and drug candidates against clock-associated metabolic and cardiovascular diseases.
Abstract 15825: Inter-reader Concordance and Variations in Interpretation of Post Resuscitation ECG in Abnormal vs Normal Metabolic Milieus Following Out-of-hospital Cardiac Arrest
Authors: Shroff Gautam R , Miranda David F , Bart Bradley A , Sandoval Yader , Rodin Holly , Smith Stephen W
Published: July 2021

Background:
Among survivors of out of hospital cardiac arrest (OHCA), the post resuscitation 12-lead electrocardiogram (ECG) is a widely used tool to identify acute thrombotic coronary occlusion (ACTO) and for appropriate triage to the catheterization laboratory. It is unknown how a post-resuscitation abnormal metabolic milieu impacts ECG accuracy. We studied inter-reader concordance in ECG interpretation as well as same-patient variation in interpretation between abnormal (A) and normal (N) metabolic milieus (MM).

Methods:
We performed a retrospective analysis of 125 consecutive patients with OHCA with a shockable rhythm undergoing coronary angiography in a single institution. Patients with AMM were defined as pH <7.1, K <2.8 or >6 mEq/L, vasoactive drug use or lactate >2 ng/ml. All post resuscitation ECGs recorded in both AMM and NMM for each patient prior to any invasive intervention were blindly interpreted by 2 experienced readers, classified into two categories: diagnostic for ATCO (ATCO +) and not diagnostic for ATCO (ATCO -) and compared to angiographic ATCO. The Cohen’s kappa scale was used to measure concordance.

Results:
Concordance between readers was 0.69 (95% CI 0.56-0.84) in AMM and 0.82 (95% CI 0.64-0.99) in NMM. Of 35 ECGs interpreted as diagnostic for ATCO (+) in AMM, 27 (77%) were reclassified as ATCO (-) after metabolic correction. Among 90 ECGs initially diagnosed as ATCO (-) in AMM, 2 (2%) were reclassified as ATCO (+) whereas 88 (98%) remained as ATCO (-) in NMM. Most ATCO (-) ECGs were in the setting of angiographic ATCO; see table.

Conclusions:
Despite acceptable inter-reader concordance (moderate in AMM, high in NMM) between experienced ECG readers, a significant proportion of angiographic ATCO was missed on post resuscitation ECGs. A high percentage of patients with angiographic ATCO were reclassified on ECG from ATCO (+) in AMM to ATCO (-) in NMM, suggesting possible interim blunting/resolution of typical diagnostic ECG changes in NMM.
Abstract 15853: Identification of Novel Sites Required for PCSK9 Autocatalytic Cleavage
Authors: Huang Yongcheng , Palyha Oksana , Castro-Perez Jose , Lee Anita , Ai Xi , Ha Sookhee , Kavana Michael , Ogawa Anthony , Xiong Yusheng , Zhou Haihong , Pinto Shirly
Published: July 2021

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted protein that promotes degradation of cell surface LDL receptors (LDLRs). Decrease in circulating PCSK9 levels by monoclonal antibodies is correlated with improved lipid profiles in humans. In contrast to therapeutic antibodies, strategies to inhibit PCSK9 with a small molecule have proven to be challenging. Here we explored a potential strategy to decrease PCSK9 level by inhibiting its autocatalytic cleavage and subsequent secretion. We discovered a tool compound, which represents a highly reactive lactone series irreversible inhibitors, that can non-specifically bind to multiple sites on PCSK9 and prevent its autocatalytic cleavage and secretion. Mass spectrometry studies confirmed that serine residues 326 (S326) and 329 (S329) are the main binding sites. Structurally, S326 and S329 are far away from the PCSK9 autocatalytic cleavage site serine 386 (S386). Mutagenesis of S326/S329 reduced PCSK9 autocatalytic cleavage intracellularly. Through structural modeling, we identified additional residues serine 294 (S294) and asparagine 298 (N298) that interact with S326 and S329. Mutagenesis of S294 and N298 also reduced PCSK9 autocatalytic cleavage and secretion. In addition, by using the in-trans expression system of PCSK9, we determined that the effect of S326/S329 on PCSK9 secretion is not through their direct impact on PCSK9 autocatalytic cleavage. In conclusion, we have discovered a novel mechanism that regulates PCSK9 secretion, and we have determined the critical residues that are involved in this regulatory mechanism.
Abstract 15875: Waitlist Outcomes for Adults With Congenital Heart Disease Listed for Heart Transplantation in the United States
Authors: Alshawabkeh Laith , Hu Nan , Carter Knute D , Light-McGroary KellyAnn , Cavanaugh Joseph E , Bartlett Heather L
Published: July 2021

Background:
Heart failure represents a final common pathway for many adult survivors with congenital heart disease (ACHD). Data assessing severity and management of heart failure are limited, and often heart transplantation is the only viable treatment option. The criteria used to determine priority status at the time of transplant listing, however, does not account for ACHD physiology. We investigated the differences in death or delisting due to clinical worsening in ACHD vs. non-ACHD candidates for heart transplantation.

Methods:
We conducted a retrospective study of all patients listed for heart transplantation in the United States between 1999 and 2014 using the Scientific Registry of Transplant Recipients. Patients were censored at the time of transplant or delisting due to improvement.

Results:
Among the 1,290 ACHD and 35,559 non-ACHD patients listed for heart transplantation, median age was 35 vs. 56 years and 62% vs. 76% were male, respectively. Waitlist outcomes for the full follow up time per initial listing status are shown in Figure 1. Of the patients who died or worsened, 57% were initially listed at the lowest priority status for ACHD compared to 40% for non-ACHD. In patients initially listed at status 1A, the 180-day actuarial probability of death or delisting due to worsening was 41% for ACHD vs. 29% for non-ACHD, p < 0.01; and for death alone was 29% vs. 21%, p = 0.05; respectively, Figure 2.

Conclusion:
ACHD candidates for heart transplantation in the United States are more frequently listed at the lowest priority status, and when listed at the highest priority status are more likely to die or be delisted due to clinical worsening compared to other candidates.
Abstract 15925: Newt Exosomes are Bioactive on Mammalian Heart, Enhancing Proliferation of Rat Cardiomyocytes and Improving Recovery After Myocardial Infarction
Authors: Tseliou Eleni , Weixin Liu , Valle Jackelyn , Sun Baiming , Mirotsou Maria , Marbán Eduardo
Published: July 2021

Introduction:
Adult newts can regenerate amputated cardiac tissue (and whole limbs) without fibrosis, unlike adult mammals which lack such regenerative capacity. Exosomes are nanoparticles which mediate intercellular communication and play a critical role in therapeutic regeneration.

Hypothesis:
We isolated exosomes from a newt mesodermal cell line, and evaluated their bioactivity in rat models.

Methods:
A1 cells, derived from the amputated limb buds of Notopthalmus viridescense (Brockes JP, 1988), were expanded in culture. Exosomes were isolated by polyethylene glycol precipitation of A1-conditioned serum-free media (or media conditioned by human dermal fibroblasts [DF] as a control) followed by centrifugation. Bioactivity was tested in vitro on neonatal rat ventricular myocytes (NRVM), and in vivo on acute myocardial infarction in Wistar-Kyoto rats (250μg or 500μg of A1-exosomes or vehicle [placebo] injected intramyocardially). Functional and histological analyses were performed 3 weeks after therapy.

Results:
A1-conditioned media yielded ~2.8±1Billion particles/ml of 129±1.1 nm diameter. In vitro, A1-exosomes increased the proliferative capacity of NRVM compared to DF-exosomes (4.98±0.89% vs 0.77±0.33%, p=0.035). Priming of DFs with A1-exosomes increased SDF-1 secretion compared to DF-exosomes (755±117pg/ml vs.368±21pg/ml, p=0.03). In vivo, both A1-exosome doses increased cardiac function compared to placebo (EF= 46±1% in 250μg, 49±4% in 500μg vs 36±1% in placebo, p=0.045 by ANOVA). Scar size was markedly decreased (11±1% in 250μg, 9±2% in 500μg vs 18±2% in placebo, p=0.006 by ANOVA), and infarct wall thickness was increased after A1-exosome treatment (1.7±0.11mm in 250μg, 1.85±0.16mm in 500μg vs 1.17±0.11mm in Placebo, p=0.01 by ANOVA). Donor-specific antibodies were present at barely detectable levels in the serum of animals that had been injected with A1-exosomes.

Conclusions:
Newt exosomes stimulate rat cardiomyocyte proliferation and improve functional and structural outcomes in rats with myocardial infarction. Characterization of the RNA and protein content of newt exosomes, now in progress, may provide clues regarding conserved (or newt-unique) molecular mediators of therapeutic benefit.