bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 16039: CX3CR1 And CCR2 Synergistically Modulate Inflammatory but Not Metabolic Effects of High-fat Feeding
Authors: Zhang Hanrui , Hinkle Christine C , O’Neill Sean , Caughey Jennifer , Lynch Emma , Lynch Gina , Shah Rachana , Ahima Rexford S , Reilly Muredach P
Published: July 2021

Introduction:
Obesity is associated with a systemic inflammatory reaction that has been associated with the development of type 2 diabetes and atherosclerosis. Substantial evidence points towards the C-C motif chemokine receptor-2 (CCR2) and fractalkine receptor (CX3CR1) as important modulators of metabolic and inflammatory phenotypes in high fat diet (HFD)-induced obesity, but the synergistic effects of dual targeting of CX3CR1 and CCR2 have not been studied.

Hypothesis:
CX3CR1 and CCR2 exert synergistic effects in HFD-induced obesity.

Methods:
C57BL/6J wild type mice (WT), Cx3cr1
-/-
, Ccr2
-/-
and Cx3cr1
-/-
Ccr2
-/-
double knockout mice were fed a 45% HFD (D124551, Research Diets), which is known to promote hypertriglyceridemia and insulin resistance, for up to 6 months starting at 12-wks old (n=10-16 male mice per group).

Results:
WT, Cx3cr1
-/-
, Ccr2
-/-
, and Cx3cr1
-/-
Ccr2
-/-
gained weight at a similar rate and developed similar degrees of adiposity and hyperglycemia in response to 45% HFD. All groups demonstrated progressive impairment in glucose tolerance, insulin sensitivity (by Insulin Tolerance Test), and glucose-evoked insulin secretion. A complete blood cell count with differential suggested reduced monocyte count in Ccr2
-/-
(22.2 ± 10.1 % of WT, mean±SEM, P<0.05) and Cx3cr1
-/-
Ccr2
-/-
(10.6 ± 1.9% of WT, P<0.05), but not in Cx3cr1
-/-
(82.8 ± 16.3 % of WT, P=0.45), consistent with the impaired
monocytosis due to Ccr2 deficiency.
FACS analysis showed that in stromal vascular cells from epididymal adipose, % of CD45(+)F4/80(+)CD11c(+)MGL1(-) M1-like macrophage was lower while CD45(+)F4/80(+)MGL1(+)CD11c(-) M2-like macrophage was higher in the Cx3cr1
-/-
Ccr2
-/-
mice vs. WT mice. In contrast, a single knockout of Cx3cr1 or Ccr2 did not affect macrophage phenotypic switching.

Conclusion:
A single knockout or double knockout of Cx3cr1 and Ccr2 did not affect weight gain, glucose levels and insulin sensitivity in response to HFD. However, the Cx3cr1
-/-
Ccr2
-/-
but not the single knockout of Cx3cr1 or Ccr2 mice, showed reduced adipose macrophage activation. The results indicate that CX3CR1 and CCR2 synergistically modulate inflammatory but not metabolic effects of HFD.
Abstract 16045: Is Low Dose Beta Blocker Equivalent to High Dose for Reducing Major Adverse Cardiovascular Events?
Authors: Allen Jason E , Knight Stacey , McCubrey Raymond O , Muhlestein Joseph B , Lappé Donald L , Goldberger Jeffrey J , Anderson Jeffrey L
Published: July 2021

Introduction:
Beta-blockers (BB) are a fundamental component of care for patients (pts) with coronary artery disease (CAD) and acute coronary syndromes (ACS). BB therapy based on decades-old trials generally targets high doses (HD). Yet, whether better-tolerated low-dose (LD) BB is as effective in the current era of medical and interventional therapy has not been tested.

Hypothesis:
LD BB is equivalent to HD BB for major adverse cardiovascular events (MACE), i.e., all-cause death, myocardial infarction, and stroke, in patients (pts) with symptomatic CAD.

Methods:
Intermountain Healthcare pts with CAD documented at coronary angiography (n=12,882; 60.9% with ACS) were studied. BB use and dose were determined at discharge and 6 mo. LD was defined as ≤25% and HD as ≥50% of the equivalent of 200 mg metoprolol. Univariate testing of associations between BB usage and clinical characteristics was performed using chi-square and Wilcoxon tests. Significant factors were entered into logistic regressions to calculate propensity scores. Equivalence testing was done using time until MACE for 0 to 6 mo, 7 to 24 mo, and combined periods using the Wellek method based on Cox proportional hazards and an assumed risk function within 0.15.

Results:
7158 (55.6%) of pts were discharged on BB: 6078 (85.0%) on LD and 974 (13.6%) on HD. Within 6 mo, 263 (4.3%) of LD compared to 47 (4.8%) of HD pts had a MACE. After adjusting for propensity score, MACE on LD versus HD BB was equivalent (p=0.036) but not superior (HR= 0.92; 95% CI: 0.67, 1.28). For 7 to 24 mo, of the 7090 pts without a prior MACE, 5868 (82.8%) were on LD and 1145 (16.1%) on HD BB, and 433 (7.4%) of LD versus 109 (9.5%) of HD pts had a MACE. After adjusting for propensity score, LD again was equivalent to HD (p<0.005) but not superior (HR=0.98; CI: 0.76, 1.26). Outcome for pts on LD versus HD over the entire 0-24 mo period was equivalent (p=0.002) and nearly superior (HR=0.86; CI: 0.71-1.05). ACS pts also showed dose equivalence (p=0.02) and near LD superiority (HR=0.82; CI: 0.64-1.04).

Conclusions:
In the modern era of advanced medical and interventional therapy for symptomatic CAD and ACS, LD BB is associated with at least equivalent cardiovascular protection as HD and should be encouraged when HD BB is not tolerated or contraindicated.
Abstract 16071: Electroanatomical Voltage and Morphology Characteristics in Post-infarction Patients Undergoing Ventricular Tachycardia Ablation
Authors: Tsiachris Dimitris , Silberbauer John , Oloriz Teresa , Mizuno Hiroya , Baratto Francesca , Della Bella Paolo , Stefanadis Christodoulos
Published: July 2021

Introduction:
We analyzed the endo-epicardial electroanatomical mapping (EAM) characteristics, their association with clinical data and their prognostic value in a large cohort of post-myocardial infarction (MI) patients.

Methods:
We performed analysis of voltage (bipolar dense scar-DS and low voltage-LV areas, unipolar LV and penumbra areas) and morphology characteristics (presence of abnormal late-LPs and early potentials-EPs) in 100 post-MI patients undergoing EAM-based ventricular tachycardia (VT) ablation (26 endo-epicardial procedures). We defined as unipolar LV areas those with voltage <8 mV and unipolar penumbra area the unipolar LV area beyond the bipolar LV area. The ratio of bipolar DS to LV area reflected the fibrosis density within the infarct region.

Results:
Mean endocardial surface area was 236.1 cm2. Of that, 10.2% was bipolar DS, 21.8% was bipolar LV and 46.7% was unipolar LV. Endocardial penumbra was present in all but one patients and mean area was 51.6 cm2 (24.9%). There was no endocardial bipolar DS in 18% of the patients. Endocardial bipolar DS area >22.5 cm2 (sensitivity 61.1% and specificity 87.5%) best predicted scar transmurality.

Endocardial LPs were recorded in 66% of the patients and epicardially in 17/26 (65.4%). Endocardial bipolar DS area >7 cm2 (sensitivity 88.2% and specificity 66.7%) and endocardial bipolar scar density >0.35 (sensitivity 52.9% and specificity 100%) predicted epicardial LPs. Abolition of endocardial LPs was achieved in 51/66 (77.3%) and of epicardial LPs in 10/17 (58.8%) patients.

As a primary strategy, LPs and VT-mapping ablation occurred in 48%, only VT-mapping ablation in 27%, only LPs ablation in 17% and EPs ablation (in the absence of LPs) in 6%. After a median follow-up time of 628 days, endocardial LP abolition was associated (HR 0.274, p=0.01) with reduced VT recurrence (32%). Endocardial LP presence (HR 0.177, p=0.041) acted as a prophylactic predictor while increased endocardial penumbra area (HR=1.028, p=0.044) as an adverse predictor of cardiac death (7%).

Conclusions:
Endocardial scar extension and density predicted scar transmurality and endo-epicardial presence of LPs, although DS is not always identified in post-MI patients. LPs were abolished in 51% resulting in improved outcome.
Abstract 16078: Pulmonary Vasculopathy Assessed By Intravascular Ultrasound in Persistent Pulmonary Hypertension After Mitral Valve Replacement, Comparation to Idiopathic Pulmonary Arterial Hypertension and Healthy Controls
Authors: Grignola Juan Carlos J , Fernandez-Lopez Leticia L , Domingo-Ribas Enric E , Aguilar Rio R , Arredondo Cristian Humberto C , Zavala German G , Roman Antonio A
Published: July 2021

Purpose:
The aim of the study is to assess pulmonary vasculopathy (wall fibrosis, pulmonary arterial pulsatility and elastic modulus ) in patients with persistent pulmonary hypertension (pulmonary systolic pressure by ECHO > 50 mmhg ) at least 1 year after mitral valve replacement with normal function of the valve. The evaluation was carried out by intravascular ultrasound (IVUS) in medium sized pulmonary arteries. We compared three groups: Group 1 ( persistent pulmonary hypertension after mitral valve replacement), Group 2 (pulmonary hypertension belonging to the group 1 of the Dana Point classification) and Group 3 (healthy controls).

Methods:
We studied 43 patients, 15 in Group 1 , 18 Group 2 and 10 in Group 3. Group 1: 13 females, the mean age of this group was 74+-7 years; Group 2: 14 females, 53+-14 years and Group 3: 6 females, 51+-5 years. All patients were submitted to left and right heart catheterization, and IVUS in medium sized elastic PA ( 2-3 mm diameter ) of the inferior lobes. Studied variables were: mean pulmonary artery pressure (PAP, mm Hg), pulmonary wedge pressure, aortic pressure, cardiac output (CO,l/min), pulmonary vascular resistance (PVR, Wood Units), IVUS pulsatility and elastic modulus (EM,mm Hg).

Local pulsatility was estimated by IVUS: (systolic- diastolic lumen area/ diastolic lumen area) X 100. PA stiffness was assessed by the elastic modulus (EM= pulse pressure/ IVUSp).

Results:
In Group 3 all variables were statistically different from the other 2 groups (p<0.01). Variables are shown in table.

Conclusions:
Group 1, even with a lower mean PAP than Group 2 (p<0.05) showed a similar anatomical ( wall fibrosis ) and similar functional wall remodeling ( EM ).
Abstract 16117: Nonresponders to Cardiac Rehabilitation and Outcomes
Authors: De Schutter Alban , Lavie Carl , Jahangir Eiman , Menezes Arthur , Dinshaw Homeyar , Shum Kelly , Arena Ross , Milani Richard
Published: July 2021

Introduction:
Studies of coronary heart disease (CHD) and cardiac rehabilitation (CR) have traditionally focused on increasing enrollment in CR. We examine here the prognosis of patients who enrolled and completed CR, but saw no significant improvement in exercise capacity [nonresponders (NR)].

Hypothesis:
Nonresponders have a poor prognosis.

Methods:
780 CHD patients who completed CR with cardiopulmonary exercise testing (CPX) before and after the intervention were divided according to improvement in exercise tolerance (ET; no change or decline vs improvement in metabolic equivalent). Mortality was tracked post CR for all patients; 1 to 161 months of follow-up (mean 6.4 years).

Results:
243 (31%) subjects were NR. After adjustment for body mass index, age, gender, ejection fraction and baseline ET, lack of improvement in exercise capacity was associated with a statistically significant 55% increase in mortality (p=0.03; Figure 1). Higher age (OR 1.02; p 0.05) and baseline ET (OR 1.07; p 0.001) was significantly associated with being a NR, but depression, gender and ejection fraction were not significant risk factors.

Conclusions:
A substantial proportion of subjects referred to CR have no improvement in ET and comparatively demonstrate a poor prognosis. Further investigation into the identifying characteristics of this population is needed to examine if their prognosis can be altered.
Abstract 16187: Validation of Novel Algorithm to Automate Detection of Fractionated Electrograms During Ventricular Tachycardia (VT) Ablation
Authors: Alipour Pouria , Khaykin Yaariv , Pirbaglou Meysam , Ritvo Paul , Hayam Gal , Pantano Alfredo , Kochhaeuser Simon , Healey Jeffrey , Nault Isabelle , Sarrazin Jean-Francois , Deyell Marc W , Verma Atul
Published: July 2021

Introduction:
Ablation of ventricular tachycardia (VT) substrate in patient at risk for VT in the setting of ischemic heart disease is a technically challenging procedure. We thought to evaluate a novel algorithm used to automatically identify target electrograms.

Methods:
16 consecutive patients (70±10 years of age, 90% male, 34±18% LV EF) had 20 ablations for ischemic VT using CARTO 3 mapping system over 2 years. Left ventricular (LV) substrate was mapped during right ventricular (RV) apical stimulation. Navistar Thermocool 3.5 mm irrigated tip catheters were used in all patients. A novel algorithm counting the number of electrogram deflections (NOD) crossing the 0.05mV noise threshold and duration of time from first to last such deflection during the window of interest (total fractionation time, TFT) was applied to all acquired maps after ablation was complete. Snapshots of 200 electrograms representing the high and low end of TFT and NOD values were presented to a group of 8 electrophysiologists experienced in VT ablation who were asked to select electrograms they would target for substrate ablation. The diagnostic accuracy of TFT and NOD values was then analysed.

Results:
Across the range of TFT values (0.0-281.0 ms), a cut-off value of 49.0 ms (81.6% sensitivity, 57% specificity) was established as an optimal indicator of an ablation target. Area under the curve for TFT was 0.675 (95% CI: 0.59-0.75, p=0.001). For NOD values (0.0-70.0 deflections), a cut off of 4.5 deflections (88.0% Sensitivity, 57 % specificity) was established as an optimal indicator of an ablation target. The area under the curve for NOD yielded an area of 0.75 (95% CI: 0.68-0.82, P=0.001). For TFT-NOD product as a variable, a cut-off value of 64 (91.0% Sensitivity, 52.4 % specificity) an optimal indicator of an ablation target. The Area under the curve for NOD and TFT multiple was 0.72 (95% CI: 0.65-0.80, P=0.001).

Conclusion:
A novel algorithm may be able to automatically classify LV substrate during mapping and ablation of ischemic VT with high sensitivity and acceptable specificity.
Abstract 16194: Prognostic Value of Cardiac Magnetic Resonance T2 Quantification in Heart Transplant Patients: A 5-year Outcome Study
Authors: Chowdhary Varun , Barfuss Spencer B , Gao Yi , Blaisdell Julie A , Ackerman Mary A , Ragin Ann , Markl Michael , Carr James
Published: July 2021

Background:
Endomyocardial biopsy (EMB) is the current gold standard to monitor patients for heart transplant rejection. Quantification of myocardial T2 relaxation time using cardiac magnetic resonance (CMR) has been shown to have high sensitivity and specificity to detect rejection episodes. In this study, we evaluated the prognostic value of myocardial T2 to predict adverse cardiovascular outcomes during 5-year follow-up after initial CMR.

Methods:
49 cardiac transplant patients (mean age, 48 ± 14 years; 65% male) were recruited from a single institution. CMR at 1.5T was performed in all patients, with subsequent quantifications of regional and global myocardial T2. Clinical data was gathered post-CMR over a 5-year period. EMBs were graded according to the International Society of Heart & Lung Transplantation criteria. Rejection episodes were defined by EMB ≥ 2R, new onset heart failure (HF), LV ejection fraction < 40%, or death. Adverse cardiovascular events gathered included coronary artery disease, cardiomyopathies, arrhythmias, and different types of HFs. Multivariable logistic regression and Kaplan-Meier analysis was performed to measure the prognostic value of myocardial T2.

Results:
Myocardial T2 was found to increase with worsening EMB grade from 53.0 ms (0R, no rejection) to 59.9 ms (3R, severe rejection). ROC analysis using two groups (EMBs ≤ 1R and ≥ 2R) showed T2 = 55.0 ms to have the highest specificity and sensitivity. In multivariable analysis that considered T2 measures, age, length of surgery, donor ischemic time, and BMI, both peak T2 (p = 0.038) and septal T2 (p = 0.035) were significant predictors of EMB grade ≥ 2R. Kaplan-Meier analysis showed a significant higher probability of developing EMB ≥ 2R, new onset HF, or death with a global T2 ≥ 55 (p = 0.02). Adverse cardiovascular outcomes of systolic HF, acute systolic HF, and chronic diastolic HF had a higher probability of developing in patients with global T2 ≥ 55 (p = 0.01, p = 0.01, and p < 0.01, respectively).

Conclusions:
CMR T2 quantification demonstrated prognostic value for all-cause rejection and various types of HFs in cardiac transplant patients. These findings suggest that CMR may be a suitable modality to non-invasively monitor cardiac transplant patients for rejection.
Abstract 16198: Modifying Heparan Suflate Glycoasminoglycan Content and Chemokine Binding in Transplanted Donor Organs Improves Vascular Inflammation and Rejection
Authors: Ambadapadi Sriram , Chen Hao , Bartee Meeyong , Zheng Donghang , Morshed Sufi , Wakefield Dara , Clapp William , Lucas Alexandra
Published: July 2021

Background:
Transplant allograft vasculopathy (TAV) is the leading cause for late transplant organ loss. TAV is induced by activation and invasion of inflammatory monocytes and T cells in response to chemokine binding to glycosaminolycans (GAGs) in the endothelial glycocalyx. We investigated the effect of inhibiting heparin sulfate (HS-GAG) / chemokine interactions on rejection in a renal transplant model with (a) heparin sulfate HS-GAG deficient (Ndst1
-/-
) donor mice and (b) a virus-derived chemokine modulating protein M-T7, that is blocks C, CC and CXC interaction with GAGs.

Methods:
BALB/c renal allograft recipients receiving either Ndst1
-/-
(C57BL/6 background) or C57Bl/6 wild type (WT) donor kidneys (n = 48 each) were treated for 10 days with either Saline, M-T7 or one of three M-T7 point mutations (100 ng/gm) with differing inhibitory actions for HS-GAG / chemokine interaction. No other immunosuppressants were added.

Results:
Ndst1
-/-
kidneys had 10X reduced HS content and markedly reduced sulfation compared to WT kidneys. Overall acute rejection and vasculitis scores were significantly reduced in Ndst1
-/-
donor kidneys (P < 0.0001). In WT donors, M-T7 significantly reduced rejection and vasculitis (P < 0.0001), but interestingly, lost activity in Ndst1
-/-
allografts. CD3+ cells were significantly reduced (P < 0.0001) in Ndst1
-/-
donor grafts and with M-T7 treatment in WT transplants and TH17+ cells were significantly reduced in spleen cell isolates. M-T7 point mutation E
209
I retained activity in both Ndst1
-/-
and WT donors while but R
171
E was active only in WT. The third mutant F
137
D was inactive. PCR array analysis detected significant decreases in IL-4, NOS2 and CC chemokine 20, in Ndst1
-/-
donor transplants or in WT transplants with M-T7 or M-T7 mutant treatments with significant reductions in TAV.

Conclusions:
A critical role played by HS-GAG / chemokine interactions in the DONOR allograft transplant is demonstrated by these studies. Significant decreases in acute rejection and inflammatory vasculitis are seen in Ndst1
-/-
donors with saline treatment and after treatment of C57Bl/6 WT donor grafts with M-T7. HS-GAG composition of donor organs has a potential decisive effect on transplant viability.
Abstract 16267: NADPH Oxidase Nox4 Up-regulation Contributes to the Worsening of Pressure Overload-induced Cardiac Dysfunction in Angiopoeitin-like 2 Knockdown Mice
Authors: Martel Cécile , Raignault Adeline , Yu Carol , Gillis Marc-Antoine , Mamarbachi Maya , Bousette Nicolas , Duquette Natacha , Thorin-Trescases Nathalie , Des Rosiers Christine , Thorin Eric
Published: July 2021

Background:
Angiopoietin-like 2 (angptl2) is a circulating protein promoting vascular inflammation and endothelial dysfunction in mice, but little is known on its impact on cardiac function. Our previous results suggest that knocking down angptl2 in mice (KD) worsens pressure overload-induced cardiac dysfunction while preserving cerebral artery structure and endothelial function. As NADPH oxidase NOX4 is known to produce H2O2, a deleterious hypertrophic stimulus in cardiomyocytes but also a vasodilatory factor, we hypothesized that increased expression of NOX4 contributes to the aggravated cardiac dysfunction observed in KD mice.

Methods/Results:
Cardiac function was measured in vivo by Millar catheter in KD mice versus their wild-type (WT) littermates in response to a 6-week pressure overload induced by transverse aortic constriction (TAC). Concomitantly to a worsened cardiac remodeling and an aggravated cardiac dysfunction compared to WT-TAC mice, only KD-TAC mice displayed an increase in cardiac mRNA and protein expression of NOX4 (p<0.05 vs. WT, n=8). To specifically decrease cardiac NOX4 expression, we performed, two weeks after TAC surgery, a single i.v. injection of cardiac specific associated adenovirus AAV9 expressing a NOX4-targeted shRNA or a scrambled shRNA. In KD-TAC mice, the AAV9-shNOX4 limited cardiac hypertrophy as evidenced by a smaller heart/tibia ratio (Table, * p<0.05). Moreover, cardiac function in KD-TAC-AAV9-shNOX4 mice was partly prevented by maintaining contraction and relaxation maximal velocities and by limiting the abnormal rise of minimal pressure and end diastolic pressure caused by TAC (Table, * p<0.05).

Conclusion:
Angptl2 knockdown worsens cardiac hypertrophy and contractile dysfunction induced by pressure overload: cardiac up-regulation of NOX4 could contribute to these deleterious effects in angptl2 KD mice.
Abstract 16401: Cardiovascular Clinical Effects of Testosterone Supplementation Among Healthy Hypo-androgenic Men: Information From the Intermountain Healthcare Health Plans Database
Authors: Bair Tami L , May Heidi T , Le Viet T , Lappé Donald L , Anderson Jeffrey L , Muhlestein Joseph B
Published: July 2021

Introduction:
Epidemiologic studies have identified low serum testosterone (T) levels as an independent risk factor for cardiovascular (CV) and total mortality. However, the cardiovascular safety of T therapy among healthy men with low T levels is unknown.

Hypothesis:
We hypothesized that T supplementation among healthy men over the age of 50 yrs with low T levels is not associated with an increased risk of major adverse cardiovascular events (MACE).

Methods:
All men in the Intermountain Healthcare Health Plans Database >50 years of age, with no prior history of CV disease, a documented low (<212 ng/dL) baseline T level, at least 1 follow-up (f/u) T level and 3 years of clinical f/u were stratified by whether or not they received at least 90 days of T supplementation (topical gel or injection) or not. Cox hazard regression analysis, adjusting for 17 baseline variables, was performed to determine any association between T supplementation and 3 year MACE (death [D], non-fatal MI, and stroke).

Results:
A total of 1,472 men (age 57.0 ± 5.5 y, diabetes: 20%, hypertension: 41%, hyperlipidemia: 43%, smokers: 13%) were studied. Event rates at 1 and 3-y by supplementation status, and adjusted HRs, are shown in the Table. Overall 3-y rates of MACE, D, MI and stroke were low consistent with the baseline age and health of the population. After adjustment, subjects supplemented with T had statistically reduced 1 and 3 year rates of D and total MACE, including numerically reduced rates of MI and stroke compared to those receiving no supplementation.

Conclusions:
Among a generally healthy and relatively young population of hypo-androgenic men, T therapy was associated with reduced MACE and D over 3-y compared to no T supplementation. These findings provide further observational evidence of the CV safety associated with T supplementation in this population.
Abstract 16416: Wide QRS-T Angle on the 12-lead ECG as a Predictor of Sudden Death Beyond the LV Ejection Fraction
Authors: Chua Kelvin C , Teodorescu Carmen , Uy-Evanado Audrey , Reinier Kyndaron , Narayanan Kumar , Chugh Harpriya , Gunson Karen , Jui Jonathan , Chugh Sumeet S
Published: July 2021

Introduction:
If we are to improve risk stratification for sudden cardiac death (SCD) we should extend beyond the LV ejection fraction (LVEF). The frontal QRS-T angle has been shown to predict risk of SCD but its value independent of LVEF has not been investigated.

Hypothesis:
We hypothesize that a wide frontal QRS-T angle predicts SCD independent of LVEF.

Methods:
Cases of adult sudden cardiac arrest with an available electrocardiogram before the event were identified from a large ongoing population based study of SCD in the Northwest US (population approx. one million). Subjects with a computable frontal QRS-T angle were included. A total of 686 SCD cases (mean age 67.4 years; 95% CI, 52.5 to 82.3 years; 68.2% males; 83.5% whites) met criteria, and were compared to 871 controls with and without coronary artery disease (mean age 66.8 years, 55.3 to 78.3 years; 67.7% males; 90.6% whites) from the same geographical region.

Results:
The mean frontal QRS-T angle was higher in SCD cases (73.9 degrees; 95% CI, 17.5 to 130.3 degrees, p<0.0001) compared to controls (51.1 degrees; 95% CI 5.0 to 97.2 degrees). Using a cut-off of more than 90 degrees, the frontal QRS-T angle was predictive of SCD, and remained predictive, after adjusting for age, sex, left ventricular ejection fraction (LVEF), prolonged QTc, prolonged QRS duration and baseline comorbidities (OR 1.80; 95% CI, 1.27 to 2.55, p=0.001). On the receiver operating characteristic (ROC) curve, the QRS-T angle demonstrated an area-under-curve (AUC) value of 0.614. Compared to the lowest quartile of QRS-T angle, the highest quartile had nearly a triple increase in the risk of SCD (OR 2.71; 95% CI; 2.03 to 3.60; p<0.0001).

Conclusion:
A wide QRS-T angle greater than 90 degrees is associated with increased risk of sudden cardiac death independent of left ventricular ejection fraction.
Abstract 16434: IL-6 Signaling is Crucial for Cardiomyocyte Hypertrophy and Left Ventricular Dysfunction Induced by Pressure Overload
Authors: Zhao Lin , Cheng Guangming , Yang Yanjuan , Samanta Anweshan , Afzal Rizwan R , Girgis Magdy , Chen Xing , Ye Sheng , Asante Samuel , McEnulty Patrick , Vincent Robert J , Hauptman Jeryl , Jin Runming , Dawn Buddhadeb
Published: July 2021

Introduction:
Interleukin-6 (IL-6), a proinflammatory cytokine, has been implicated in ischemic cardiac pathologies. Very little is currently known regarding the role of IL-6 signaling in pathological cardiomyocyte hypertrophy and LV dysfunction.

Hypothesis:
We hypothesized that IL-6 signaling plays a central role in cardiomyocyte hypertrophy and exerts a deleterious impact on LV remodeling induced by pressure overload.

Methods:
In vitro, adult cardiomyocytes from C57BL/6 (WT, control) and IL-6 knockout (KO) mice were stimulated by IL-6 and pro-hypertrophic agent angiotensin II (Ang II). The expression of hypertrophy markers and related signaling molecules were examined by real-time quantitative RT-PCR. In vivo, weight-matched male WT and IL-6 KO mice underwent transverse aortic constriction (TAC) or a sham procedure. Serial echocardiograms and a terminal hemodynamic study were performed.

Results:
After exposure to IL-6 and hypertrophic agonists, the expression of hypertrophy related genes, BNP, GATA-4, αSK actin, and β-MHC increased significantly in WT cardiomyocytes (Fig). These effects were significantly attenuated in IL-6 knockout cardiomyocytes (Fig), indicating an essential role of IL-6 in cardiomyocyte hypertrophy. In vivo, the worsening in LV contraction as well as relaxation after TAC was significantly attenuated in IL-6 KO mice, indicating superior preservation of LV function in the setting of pressure overload in the absence of IL-6 signaling.

Conclusions:
The protection against Ang II-induced hypertrophy observed in IL-6 KO adult cardiomyocytes in vitro, and in hearts of IL-6 KO mice after TAC in vivo illustrates a crucial role played by IL-6 in pathogenesis of pressure overload-induced LV hypertrophy. Modulation of IL-6 signaling may have preventive therapeutic potential for countless hypertensive patients at risk for LV hypertrophy and failure.
Abstract 16445: Anticoagulation Control, Risk of Overanticoagulation and Major Hemorrhage Among Warfarin Users is Influenced by Race
Authors: Limdi Nita A , Shendre Aditi , Yan Qi , Thigpen Jonathan , Liu Nianjun , Brown Todd M , Hill Charles E , Beasley T M
Published: July 2021

Objective:
Racial differences in warfarin response have been of significant interest. Differences in dose requirements have been extensively studied. Herein, we assess whether anticoagulation control [percent time in target range (PTTR; INR range 2-3)], risk of overanticoagulation (INR>4) and major hemorrhage differ by race among warfarin users.

Methods:
The analysis included 1357 participants [595 African Americans (AA); 762 European Americans (EA)]. The Rosendaal interpolation method was used to compute the PTTR, percent time above range (PTAR) and percent time below range (PTBR). Major hemorrhages included serious, life threatening and fatal bleeding events. The influence of race (AA vs. EA) on PTTR, PTBR, and PBAR was evaluated using linear regression; overanticoagulation and hemorrhage by Cox proportional hazards analysis adjusting for clinical and genetic factors.

Results:
Over 1912 person-years (pyrs) accrued (average per patient 1.4 (± 0.9) years), after adjusting for covariates, compared to EAs, AAs had lower PTTR (56.3% vs. 50.8% p<0.001), higher PTBR (26.5% vs. 31.2%; p=0.001) and were also more likely to experience overanticoagulation (HR: 1.31, 95% CI 1.10-1.56, p=0.003).

A total of 156 major hemorrhagic events were encountered (incidence 8.2/100 pyrs, 95% CI: 7.0 – 9.5/100 pyrs). AAs had higher incidence of hemorrhage compared to EAs (IRR: 1.38, 95% CI 1.00-1.89, p=0.046). After adjusting for clinical and genetic factors, AAs remained at a higher risk for hemorrhage (HR: 1.60, 95% CI: 1.10-2.34, p=0.016).

Older age, antiplatelet therapy, renal impairment, and possession of
CYP2C9
variants increased the risk of hemorrhage. Higher PTTR was associated with a lower risk of hemorrhage in both race groups. Compared to patients with PTTR<50%; those with PTTR 50-60% had a 37% lower risk (HR=0.63; 95%CI0.4-0.97; p=0.04), those with PTTR 60-70% had a 43% lower risk (HR=0.57; 95%CI 0.35-0.92; p=0.02), and those with PTTR >70 had a 75% lower risk (HR=0.25; 95%CI0.14-0.43; p<0.0001).

Conclusion and Relevance:
Among warfarin users, African Americans spent less time in target INR range, and had a higher risk of overanticoagulation and hemorrhage. Strategies to improve anticoagulation control among African Americans can lower risk of hemorrhage.
Abstract 16449: miR-195 Regulates Myocardial SIRT3 Expression and Mitochondrial Enzyme Acetylation
Authors: Zhang Xiaokan , Ji Ruiping , Liao Xianghai , Brunjes Danielle , Castillero Estibaliz , George Isaac , Hirano Michio , Kennel Peter , Schulze Paul Christian
Published: July 2021

Background:
Unique cardiac and systemic miRNAs play an important role in cardiac remodeling and the associated response to injury by modulating key signaling elements. Through deep-sequencing of cardiac and circulating non-coding miRNAs, we identified miR-195 as the only miRNA up-regulated in plasma, serum and myocardium of patients with advanced heart failure (HF). Further, binding elements for miR-195 were found in the 3’UTR region of sirtuin3 (SIRT3), the major mitochondrial deacetylase. We hypothesized that miR-195 regulates myocardial SIRT3 expression and mitochondrial protein acetylation levels with subsequent changes in cardiac metabolism.

Methods:
Cellular signaling was analyzed in human cardiomyocyte-like AC16 cells and acetylation levels in a rodent model of transgenic miR-195 overexpression were compared to WT. Luciferase assays, Western blotting and immunoprecipitation (Co-IP) assays were performed. Enzymatic activities of pyruvate dehydrogenase (PDH) and ATP synthase were measured.

Results:
We observed suppression of SIRT3 and increased total protein acetylation in failing human myocardium. Luciferase assays confirmed that miR-195 directly targets the SIRT3 mRNA 3’UTR and negatively regulates SIRT3 expression. Transfection of miR-195 into AC16 cells resulted in a pronounced decrease in SIRT3 expression levels and induction of total protein acetylation levels. Myocardium of miR-195 transgenic animals was showed a global increase in total protein acetylation compared to WT. Co-IP assays revealed increased acetylation of 3 subunits of PDH (2.1-, 1.6-, 2.2-fold) and ATP synthase α subunit (2.3-fold), two key regulators of mitochondrial energy metabolism. Enhanced acetylation of these proteins correlated with a 24% decrease in PDH activity and a 30% decrease in ATP synthase activity.

Conclusions:
Altogether, these data demonstrate a crucial role of miR-195 in HF and identified SIRT3 as a direct target of miR-195. Our findings suggest a new pathway of abnormal cardiac energy metabolism in the failing myocardium through miR-195-mediated SIRT3 suppression and increased protein acetylation. These changes result in specific inhibition of PDH and ATP synthase activity leading to impaired energy metabolism and ATP deprivation.
Abstract 16459: Myocardial Replenishment of Tissue Inhibitor of Metalloproteinase (TIMP)-3 and TIMP4 Following Myocardial Infarction Result in Differential Protective Effects
Authors: Takawale Abhijit , Basu Ratnadeep , Wang Xiuhua , Kassiri Zamaneh
Published: July 2021

Introduction:
The cardiomyopathy ensuing myocardial infarction (MI) results from the ischemic loss of the myocardium, impaired left ventricular (LV) dilation, eventually leading to heart failure. This is accompanied with adverse remodeling of the extracellular matrix (ECM) and disrupted balance of its regulatory proteins, particularly TIMP3 and TIMP4 that are reduced shortly after MI induction.

Hypothesis:
Replenishment of TIMP3 and/or TIMP4 post-MI will hinder adverse remodeling of the ECM and may also promote beneficial cellular response to limit tissue injury and cardiac dysfunction.

Methods:
MI was induced in adult male wildtype (C57BL/6) mice by ligation of the left anterior descending artery. Adenoviral constructs expressing human TIMP3 (Ad-hTIMP3), human TIMP4 (Ad-hTIMP4) or no-TIMP control (Ad-Null) were injected in the peri-infarct zone (5 injections/heart; 5.4x107 pfu/heart). Cardiac function was assessed by Vevo2100 ultrasound imaging system. Cellular and molecular analyses (inflammation, cell viability, angiogenesis, ECM composition) were assessed at 3 and 7 days post-MI.

Results:
Injection of Ad-Null had minimal effects in the post-MI dysfunction and remodeling. Ad-hTIMP3 injection exerted more beneficial effects compared to Ad-hTIMP4. Ad-TIMP3 group showed significantly better cardiac function (EF=35.49±2.52%, p<0.05), and to a lesser extent Ad-TIMP4 group (EF=28.79±1.79%) compared to Ad-Null group (EF=25.46±2.29%). Similarly, LV dilation was markedly attenuated in Ad-TIMP3 (LVEDV=77.08±6.05μL) but not in Ad-TIMP4 group (LVED=112.98±5.68 μL) compared to Ad-Null (LVEDV=112.98±7.0 μL). Inflammatory response (macrophage/neutrophil density) was not altered with Ad-TIMP treatment. Interestingly, the infarct size was smaller in Ad-TIMP3 group and even after 1wk post-MI, viable myocytes were detected in these hearts. Assessment of coronary density in the infarct and peri-infarct regions (intra-jugular fluoro-tagged lectin injection) revealed that Ad-TIMP3 promoted angiogenesis in the infarcted myocardium.

Conclusions:
This novel pro-angiogenic function of TIMP3 post-MI, in addition to its MMP inhibitory function, could provide additional beneficial effects in post-MI treatment.
Abstract 16461: Genetic Basis of Severe Pulmonary Arterial Hypertension in a Colony of SU5416 “Hyper-responsive” Sprague-dawley Rats
Authors: Chaudhary Ketul R , Deng Yupu , Yang Anli , Cuppen Edwin , Stewart Duncan J
Published: July 2021

Introduction:
Our lab has identified a unique sub-strain of Sprague Dawley (SD) rats obtained from a colony of Charles River labs (Montreal, Canada) exhibiting hyper-responsiveness (HR) to the VEGFR2 antagonist, SU5416 (SU). These rats developed severe progressive PAH in response to single injection of SU in absence of CH. In the present study, we investigated genetic basis of hyper-responsive (HR) phenotype in the sub-strain of SD rats.

Hypothesis:
We hypothesized that hyper-responsiveness to SU was conferred by as yet unknown genetic modifiers that modulate the response to VEFR2 blockade.

Methods and Results:
Male and female rats were injected with SU (20mg/kg, sc) or vehicle (control). Right ventricular systolic pressure (RVSP) was measured at 7 weeks after SU injection. In absence of CH, 72% (13 of 18) male SD rats demonstrated HR-phenotype and developed severe PAH in response to SU with mean RVSP of 97±18 mmHg; whereas only 27% (7 of 26) of the female rats showed HR-phenotype. Furthermore, crossing non-responsive male and female animals markedly decreased the proportion of HR animals in the F1-generation (HR 15% and 0%. male vs. female, respectively), supporting a possible genetic basis for the HR phenotype. Therefore, we undertook whole genome-wide exome sequencing to identify mutations related to the HR phenotype. This resulted in the identification of a number of mutations unique to the HR SD colony (not found in 40 other background strains) and predicted to have a “high effect” on gene function. Preliminary analysis has identified several candidate genes exhibiting mutations tightly associated with the HR phenotype, including the protein C receptor, hypoxia inducible factor 1α and SP110. These and other potential modifier genes identified by a bioinformatics analysis are currently being validated in a larger population of rats from this SD colony, with and without the HR phenotype.

Conclusion:
For the first time, we have identified modifier genes that play a critical role in determining susceptibility to development of severe PAH in response to SU alone. These data may provide insight into the nature of potential genetic determinants that may influence the penetrance of the PAH phenotype in humans harboring mutations BMPR2 or in other PAH causing genes.
Abstract 16574: Heart Failure Biomarkers (NT-proBNP, Gal-3, sST2) Correlate With Right Ventricular Systolic Pressure and Provide Insight to Poor CRT Response: A BIOCRT Substudy
Authors: Deaño Roderick C , Szymonifka Jackie , Zhou Qing , Contractor Jigar H , Lavender Zachary , Januzzi James L , Singh Jagmeet P , Truong Quynh A
Published: July 2021

Objective:
Patients with heart failure (HF) and pulmonary hypertension (PH) have worse outcomes after cardiac resynchronization therapy (CRT). The relationship of circulating HF biomarkers and right ventricular systolic pressure (RVSP) may provide insight to the mechanism between PH and poor CRT response.

Methods:
In 90 patients (age 65 ± 13, 78% male, EF 26 ± 8%, RVSP 44 ± 12 mmHg) undergoing CRT, we measured baseline RVSP by echocardiography and obtained peripheral blood samples drawn at the time of device implantation. We measured levels of established and emerging HF biomarkers (Table 1). CRT non-response was defined as no improvement of adjudicated HF Clinical Composite Score at 6 months. Major adverse cardiac event (MACE) was defined as composite endpoint of death, cardiac transplant, left ventricular assist device, and HF hospitalization within 2 years.

Results:
There were 34% CRT non-responders and 27% had MACE. Per 1 unit increase in log-transformed RVSP, there was an 11-fold increase risk of having CRT non-response (odd ratio [OR] 11.0, p=0.01) and over 5-fold increase of developing 2-year MACE (hazard ratio [HR] 5.8, p=0.02). When comparing patients with severe PH (RVSP>60 mmHg) to those without PH (RVSP < 35 mmHg), there was an 8-fold increase in CRT nonresponse (OR 8.4, p=0.03) but no difference in MACE (p=NS). RVSP was correlated with increased biomarker levels of myocardial stretch and fibrosis, but not myocardial necrosis (Table 1).

Conclusions:
Higher RVSP is associated with greater rates of CRT non-response and adverse clinical outcomes. The mechanistic association between severe PH and CRT nonresponse may be explained by the biomarker profile reflective of myocardial wall stretch and fibrosis.
Abstract 16606: 30-day and 2-year Prognostic Information of Total Atheroma Volume, Segment Stenosis Score, and Traditional Coronary Artery Stenosis Assessment by CT Angiography - Results From the CORE320 International Study
Authors: Arbab-Zadeh Armin , Magalhaes Tiago , Kishi Satoru , Rochitte Carlos , Chen Marcus Y , Kofoed Klaus F , Dewey Marc , George Richard T , Niinuma Hiroyuki , Kitagawa Kakuya , Matheson Matthew , Vavere Andrea , Miller Julie M , Rybicki Frank , Cox Christopher , Di Carli Marcelo , Clouse Melvin E , Brinker Jeffrey , Lima Joao
Published: July 2021

Introduction:
Among abundant information on coronary artery disease (CAD) features by CT angiography (CTA), total atheroma volume and segment stenosis score (SSS) have recently shown promise for clinical utility.

Methods:
We followed 379 patients with suspected or known CAD enrolled in the CORE320 study for 2 years after 320-detector row CT coronary angiography. CT images were analyzed for semi-automatically derived total % atheroma volume (total atherosclerotic burden/vessel volume analyzed) and SSS in addition to traditional stenosis assessment (≥50%). Outcome variables were 1) 30-day revascularization and 2) major adverse cardiac events (MACE) after 2 years follow up. Events included cardiac death, myocardial infarction, hospitalization for acute chest pain or heart failure, arrhythmia, and revascularization. Area under the curve (AUC) and Kaplan-Meyer analysis were used to compare risk prediction and survival analysis according to CT CAD characteristics.

Results:
Thirty-day revascularization was most accurately predicted by CT stenosis assessment (AUC 75, confidence interval [CI] 71-80) vs. % atheroma volume (70 [65-74] and CTA SSS (67 [62-72]) (p=0.007). Prediction of MACE (45 late revascularizations, 5 myocardial infarctions, 1 cardiac death, 8 hospitalizations for chest pain or congestive heart failure, and 1 arrhythmia) was similar for % atheroma volume (64 [71 for patients without history of CAD]) and CTA stenosis assessment (65 [70]) but risk discrimination using common criteria trended favorably for % atheroma volume (FIGURE). Accuracy was low for CTA SSS (58 [62]).

Conclusions:
Semi-automated assessment of % total atheroma volume by CTA performs similarly to standard stenosis assessment for predicting short and long term event rates, especially revascularization, in patients with suspected CAD and holds promise for more nuanced risk discrimination. In contrast, CTA segment stenosis score performed only modestly in our analysis.
Abstract 16615: Reconstitution of CD4 T Cells Causes Cardiac Fibrosis and Myocardial Dysfunction in T Cell Specific S1P Receptor 1 Deficient Diabetic Mice
Authors: Abdullah Chowdhury S , Jin Zhu-Qiu
Published: July 2021

Involvement of T cells in fibrosis has been reported but modulation of their role in context of diabetic fibrogenesis has yet to be determined. Our previous studies indicated that T cell S1P receptor 1 (S1P1) genetic depletion ensues sustained lymphopenia in circulation and reduced fibrosis in streptozotocin-induced type 1 murine diabetic model. We hypothesized that adoptive transfer of T cells to T-cell S1P1 receptor knock-out (TS1P1KO) mice would abolish cardioprotection and antifibrotic effect as observed earlier. TS1P1KO and littermate wild-type (WT) mice were divided into vehicle and streptozotocin (STZ) (50 mg/kg body weight for five days, i.p.) groups. Naïve CD4 T cells were isolated by positive selection through MS column from CD4 magnetic microbeads-labeled WT mice splenocytes. Isolated CD4 T cells (purity >95%) were adoptively transferred (i.v.) into the mice of above groups at dose of one million cells. Body weight (g) and blood glucose level (mg/dl) were monitored. CD4 and CD8 T cells in blood were counted by flow cytometry. Heart histology was studied in H&E stained sections and pathological grading was given. Masson Trichrome stained heart sections were digitally imaged at 16x magnification and percent of fibrotic area was quantified by using NIH ImageJ. Cardiac contractility was measured in ex-vivo Langendorff’s heart perfusion system at the end of 11 weeks. TS1P1KO mice had ~90% reduced T cells (CD4 cells: 1.15±0.30% vs 25.06±0.64%, CD8 cells: 2.09±0.42% vs 14.72±0.38% in WT, **P<0.01, n=4-5) in blood. KO diabetic mice without adoptive transfer of CD4 T cells exhibited about 70% less fibrotic area (11.86±4.34% vs 46.48±8.06% in WT STZ, *P<0.05, n=7-9) and improved cardiac structure and function. Adoptively CD4 T cells recipient KO diabetic mice presented cardiac structural disorganization (histological score: 9.25±0.95 vs. 1.29±0.52 in KO STZ without transfer, *P<0.05, n=4-7) and increased myocardial fibrosis (37.11±3.22% vs. 11.86±4.34% in KO STZ without transfer, *P<0.05, n=4-7) with reduced cardiac contractile force compared with KO diabetic mice without CD4 T cells transfer. In conclusion, reconstitution of CD4 T cells increases cardiac fibrosis and attenuates cardiac function in lymphopenic T cell S1P1 knock-out diabetic mice.
Abstract 16621: Clinical Results of Scar Related Ventricular Tachycardia Ablation Performed in a South America School Hospital
Authors: Pisani Cristiano , Hardy Carina , Lara Sissy , Chokr Muhieddine , Bellotti Hugo , Hachul Denise , Darrieux Francisco , Sosa Eduardo , Scanavacca Mauricio
Published: July 2021

Introduction:
Ventricular Tachycardia (VT) ablation is indicated in patients with recurrent episodes of VT or ICD shocks despite the use of AAD.

Hypothesis:
to evaluate the clinical characteristics and follow-up of patients that underwent scar related VT ablation in a school hospital in south america.

Methods:
We collected and analyzed data of all VT ablation performed in our institution between 2013 and 2014.

Results:
During the 2-year period we performed 107 scar related VT ablation procedures in 86 patients with an age of 56.7±14 years-old, most were male (70,9%). Sixty (56%) presented Chagas disease, 17 (16%) ischemic, 13 (12%) dilated, 12 (11%) RVAD and 5 (5%) other cardiomyopathies and the mean LV EF was 36.9±12.4%. The ablation was performed with CARTO in 60 (56,1%), Ensite 3 (2,8%) and EP only mapping in 44 (41,1%) procedures. Epicardial mapping was performed in 65 procedures (60,7%), most frequent in Chagas patients (81,7%;P<0.001). There was complications in 6 (5,6%) procedures: one hemopericardium that open-chest surgery was necessary; two iliac artery dissection, both with conservative treatment; one complete AV block; one patient with refractory hypotension with the need of IABP and procedure interruption and one patient with late cardiac tamponade with the need of surgical drainage. In a median follow-up of 261 (Q1: 93 Q3: 479) days, 42 (40%) procedures presented recurrence in a median time of 40 (Q1: 7.5 Q3: 125) days. After the VT recurrence the ablation was repeated, and one patient underwent 4 ablation, 2 three ablations and 13 underwent two ablations. Following the last ablation, 61 (72.6%) patients remained free of VT recurrence (figure). Sixteen (19%) patients died in a median time of 34 (Q1: 14.75 Q3: 93) days following last ablation.

Conclusion:
Chagas disease was the most common cardiopathy in this population, where epicardial approach was frequently performed. After the last procedure, the majority of patients remained free of VT recurrence