bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 12299: Rejuvenation of the Bone Marrow-Derived Cardiac Resident Sca-1+ Stem Cell Subset Improved Healing of the Aged Heart
Authors: Li Shu-Hong , Sun Lu , Yang Lei , Shao Zhengbo , Yu Pan , Du Guo-Qing , Wu Jun , Weisel Richard D , Li Ren-Ke
Published: July 2021

Introduction:
We previously reported that bone marrow (BM) reconstitution with young BM cells into aged recipients restored progenitors in both the BM and the myocardium and improved functional recovery post-injury. Here, our goal was to identify the specific cell type responsible for the improved cardiac regeneration and to restore that capacity in aged individuals after myocardial infarction (MI).

Methods and Results:
We reconstituted old mice with BM cells from young or old GFP+ mice to generate young chimeras and old chimeras. The number of BM-derived Sca-1+ progenitors homing to the heart was significantly greater in young chimeras compared to old ones (7.14±0.32/field for young vs 2.48±0.78/field for old, P<0.01, 5 high-powered fields/section, 3 sections/heart, 3 animals/group). We then separated Sca-1+ from Sca-1- young donor BM cells using magnetic cell sorting and transplanted them into lethally-irradiated old recipients to generate Sca-1+ and Sca-1- chimeras. Quantification by flow cytometry of heart tissue revealed: 1) the Sca-1+ chimeras had more BM-derived cells that co-expressed PDGFRβ (1.65±0.13% for Sca-1+ vs 0.52±0.09% for Sca-1-, P<0.05, n=4/group) and 2) the number of GFP+ PDGFRβ+ cells was greater in the Sca-1+ chimeric hearts than the Sca-1- chimeric hearts after MI (3.77±0.55% for Sca-1+ vs 0.85±0.106% for Sca-1-, P<0.05, n=3/group). The BM-derived cells that homed to the heart in the Sca-1+ chimeras actively proliferated, stimulated proliferation of the host’s aged progenitors and improved ventricular function after MI. BM chimerism with Sca-1+ cells in aged mice restored the regenerative capability of cardiac resident progenitors and improved functional healing of the aged heart.

Conclusions:
BM Sca-1+ cells that homed to the heart in aged recipients proliferated and stimulated the propagation of host aged progenitor cells post-MI. This improved regeneration involved activation of the PDGFRβ/Akt/p27Kip1 signaling pathway. The number of BM-derived Sca-1+ progenitor cells in the aged myocardium was the major determinant for successful cardiac functional recovery. Restoration of the Sca-1 subset of stem cells by BM reconstitution improved cardiac repair and prevented heart failure.
Abstract 12320: Inhibition of DNA Methylation and Histone Acetylation Changes the Macrophage Polarization During Endotoxemia-induced Lung Injury
Authors: Samanta Saheli , Rajasingh Sheeja , Patel Urmi , Dawn Buddhadeb , Rajasingh Johnson
Published: July 2021

Introduction:
Acute lung injury (ALI) during sepsis is characterized by bilateral alveolar infiltrates, lung edema, and respiratory failure. The exact molecular mechanism for ALI is poorly understood. Although chemical epigenetic modifiers can potentially limit lung inflammation, to date no study has examined the efficacy of DNA methyl transferase inhibitor 5-Aza 2-deoxycytidine (Aza) and histone deacetylase inhibitor Trichostatin A (TSA) combination therapy (Aza+TSA) on the polarization of macrophages.

Hypothesis:
We hypothesized that therapy with Aza+TSA would reduce inflammation in ALI and will stimulate the production of M2 macrophages.

Methods and Results:
In LPS-induced mouse ALI, post-treatment with a single dose of Aza+TSA showed a substantial attenuation of adverse lung inflammation and histopathological changes. Flow cytometry data showed a significant decrease in expression of CD14 and CD40, and increased expression of CD23 and CD124 in Aza+TSA-treated cells compared with untreated LPS-induced primary bone marrow derived macrophages (BMDMs) or LPS-induced BMDMs treated with either drug alone (Fig panel A). This was further confirmed by Western analysis for M1 marker NOS2 and M2 marker CD206. Our data showed lesser expression of NOS2 (Fig panel B) and higher expression of CD206 (Fig panel C) in LPS-challenged BMDMs treated with Aza+TSA than in the BMDMs treated with either Aza or TSA alone. These data support that Aza+TSA treatment promotes an M2 phenotype in LPS-stimulated macrophages, which secrete anti-inflammatory cytokines.

Conclusions:
This novel treatment with combined epigenetic modifiers has therapeutic potential for patients with sepsis-induced ALI by reducing inflammation and generation of alternatively activated M2 macrophages with more abilities of pathogen clearance.
Abstract 12334: A Flavor of Metabolic Disease in Pulmonary Hypertension
Authors: Hautefort Aurelie , Chesne Julie , Preussner Jens , Tost Jorg , Looso Mario , Antigny Fabrice , Montani David , Deleuze Jean-François , Seeger Werner , Fadel Elie , Simonneau Gerald , Bonnet Sebastien , Humbert Marc , Perros Frederic
Published: July 2021

Introduction:
Pulmonary arterial hypertension (PAH) is a severe occlusive vascular disease of the lungs. One of the primary origin of PAH is pulmonary endothelial dysfunction driving vasoconstriction, aberrant angiogenesis and smooth muscle cell proliferation, endothelial-to-mesenchymal transition, thrombosis and inflammation. Interestingly, endothelial dysfunction is maintained in culture, out of fluid and hemodynamic stress, humoral/hormonal, and inflammatory environment.

Hypothesis:
This aberrant phenotype may be imprinted in pulmonary endothelial cells (PEC) DNA though a specific pattern of DNA methylations.

Methods:
Genomic DNA was extracted from cultured PEC (passage 3): idiopathic PAH (n=11), heritable PAH (BMPR2 mutation carriers, n=10), controls (n=18). DNA methylation was assessed at over 485 000 CpG sites using the Illumina Infinium HumanMethylation450 Bead Chip. We normalized all arrays against each other using functional normalization. Differentially methylated sites were clustered with Cluster3.0 and heatmap were obtained with Treeview.

Results:
We discriminated controls vs PAH into 2 clusters of hypermethylated loci (119 probes= 31 promoters) and hypomethylated loci (331 probes= 116 promoters). Interestingly, 46 promoters/147 (clusters 1+2) (31%) were related to metabolic diseases (Ingenuity pathway analysis), and top molecules (fold changes up- and down regulated) includes molecules highly involved in cellular lipid metabolic process (ABCA1, Q=0.002 and ABCB4, Q=0.003), regulation of glucogenesis (ACN9, Q=2.78.10-5), lipid and glucose metabolism (ADIPOQ, Q=10-4), and insulin sensitivity and metabolism of glucose and lipids (miR-26a, Q=0.005), among others.

Conclusions:
the methylation fingerprint of PAH highlighted a set of molecules involved in metabolic disease and metabolism regulation. This may have fundamental and clinical implications in PAH.
Abstract 12340: Risk Model of Aortic Valve Replacement After Cardiovascular Surgery based on 2,227 Cases From a National Japanese Database: The Japan Cardiovascular Surgery Database (JACVSD)
Authors: Ohira Suguru , Miyata Hiroaki , Doi Kiyoshi , Motomura Noboru , Takamoto Shinichi , Yaku Hitoshi
Published: July 2021

Objective:
To create a risk model to assess outcomes of aortic valve replacement after cardiovascular surgery (ReAVR) using a national Japanese database.

Methods:
The Japan Adult Cardiovascular Surgery Database is a web-based data system involving more than 500 hospitals. Between 2007 and 2012, 2,227 patients who underwent ReAVR for aortic stenosis were retrospectively analyzed. Patients with a previous history of AVR were also included.

Results:
The background of prior surgery (including overlapping cases) was: CABG, 30.9%; valve, 65.4%; and thoracic aorta, 14.7%. The mean age was 70.4. Types of prosthesis used were: bioprosthesis, 51.3%; and mechanical valve, 48.7%. The rate of isolated ReAVR was 59.5%. Concomitant procedures were: CABG, 14.6%; mitral valve surgery, 30.4%; and aortic surgery, 5.7%. The overall hospital mortality rate was 8.7%. Major complications (reoperation, prolonged ventilation, mediastinitis, stroke, and newly required dialysis) occurred in 26.0%. The incidence of stroke was 3.7%, and that of AV block was 3.5%. ORs for hospital mortality were as follows: age, 1.4 (reference ≦60, 5-year increments); male, 1.4; urgency, 1.7; EF ≦30%, 2.0; NYHA classification IV, 1.7; MR ≧2, 1.5; creatinine >2.0 mg/dL, 2.7; liver dysfunction (cirrhosis, AST or ALT >100 U/L, or bilirubin >1.5 mg/dL), 2.3; peripheral artery disease, 1.6; and recent stroke (<2 weeks), 4.8. The type of previous surgery was not a predictor for mortality. In addition to the above-mentioned risk factors, ORs for the composite outcome (mortality and major complications) were as follows: carotid stenosis, 2.5; respiratory dysfunction (FEV1.0 <75%, or bronchodilator use), 1.8; prior valve surgery, 1.3; preoperative inotropic agents, 2.0; endocarditis, 1.7; concomitant CABG, 1.4; and concomitant valve surgery, 1.5. As a performance metric model, C-indexes of hospital mortality and the composite outcome were 0.77 and 0.71, respectively.

Conclusions:
Based on a national Japanese database, early outcomes after ReAVR were satisfactory, despite these operations being associated with a higher risk than the primary operations. The type of previous surgery was not a risk for mortality after ReAVR.
Abstract 12358: Epidemiology of Acute Myocardial infarction in Systemic Sclerosis: Incidence and Outcomes
Authors: Khera Rohan , Jain Snigdha , Kumar Nilay , Singh Namrata , Derk Chris T , Girotra Saket
Published: July 2021

Introduction:
Risk of acute myocardial infarction (AMI) in inflammatory arthritides like rheumatoid arthritis (RA) is elevated. However, in autoimmune disorders with microvascular dysfunction, like systemic sclerosis (SS), the risk of AMI and its outcomes are not known.

Methods:
In the National Inpatient Sample (2003-2012), we used ICD9 codes to identify patients (≥18 years) with a primary diagnosis of AMI and a concurrent diagnosis of SS. We estimated population of SS at risk for AMI during each year by multiplying the previously reported stable SS prevalence of 276/million by the US adult population for the corresponding year. We used survey-analysis to generate national estimates for incident AMI and calculated incidence of AMI among SS patients by dividing the number of AMI patients during each year by the at-risk SS population. Characteristics and outcomes of AMI in SS were compared to those with RA and those without rheumatologic disease.

Results:
During 2003-2012, there were 4570 admissions for AMI in patients with SS in the US for an average of 63,121 at-risk SS patients each year. The incidence of AMI in patients with SS was 721/100,000 at-risk SS patients, which is 3-fold higher compared to incidence of AMI in the general population and remained elevated during 2003-12 (Figure). AMI patients with SS were younger, more likely to be female but were less likely to present as STEMI compared to RA or those with no rheumatologic disease (Table). They were also less likely to undergo PCI than either group. In-hospital AMI mortality in SS was higher than RA or those without rheumatologic disease (risk-adjusted odds ratio 1.65, 95%CI 1.28, 2.11, Table).

Conclusions:
There is a three-fold increase in risk of AMI in SS compared to the general population. Among AMI patients, in-hospital mortality is significantly higher in SS patients, compared to patients with RA or without rheumatologic disease. Further investigation is warranted to further assess measures to mitigate this risk.
Abstract 12362: Long-term Influence of Body Mass Index on Cardiovascular Events After Atrial Fibrillation Ablation
Authors: Bunch T J , May Heidi T , Bair Tami L , Jacobs Victoria , Crandall Brian G , Cutler Michael , Weiss J P , Mallender Charles , Osborn Jeffrey S , Anderson Jeffrey L , Day John D
Published: July 2021

Introduction:
Catheter ablation of atrial fibrillation (AF) is an established therapeutic rhythm approach in symptomatic patients. Obesity is a dominant driver of AF recurrence after ablation. However it is not known what weight status will lower AF risk and also minimize long-term cardiac events.

Hypothesis:
An increased body mass index (BMI) will negatively impact cardiovascular outcomes after AF ablation.

Methods:
All patients that underwent an index ablation with a BMI recorded and at least 3 years of follow-up were included (n=1558). The group was separated and compared by index ablation BMI status (≤20, 21-25, 26-30, >30 kg/m
2
). Long-term outcomes included AF recurrence, stroke/TIA, heart failure (HF) hospitalization, and death.

Results:
Patients increasing BMI strata were more likely to be male and have hypertension, a smoking history, diabetes, HF and a prior cardioversion. Patients with a BMI≤20 were more likely to have a moderate-high CHADS2 score. At 3 years, recurrence rates of AF increased significantly with increasing BMI status (p=0.02), but stroke rates were similar (p=0.06). Long-term death rates tended to increase inversely with BMI status and HF rates were greatest in the highest and lowest BMI groups (Figure).

Conclusion:
Lower weight at AF ablation, lowers arrhythmia recurrence risk. However, AF ablation patients that are underweight remain at high risk of other cardiovascular outcomes and the lower arrhythmia outcomes do not result in an observable stroke risk reduction.
Abstract 12374: Apparent Diffusion Coefficient Predictors of Outcome in Cardiac Arrest Survivors
Authors: Ha Cuhl-Min , Kim Joonghee , Kim Kyuseok , Suh Gil Joon , Kwon Woon Yong , Kim Kyung Su , Shin Jonghwan , Lee Huijai
Published: July 2021

Objective:
Various methods of quantitative apparent diffusion coefficient (ADC) analysis has been suggested as useful for prognostication of comatose cardiac arrest (CA) patients. We developed a new computerized prognostication method using relative volume of most dominant cluster of low-ADC voxels and tested its performance in multicenter setting.

Method:
Adult (>15 years) out-of-hospital CA patients from three different facilities with MRI taken after 12 hours after resuscitation were retrospectively analyzed. Patients with unknown long-term prognosis or poor baseline neurologic function were excluded. Average ADCs (mean and median), LADCV (relative volume of low-ADC voxels) and DC-LADCV (relative volume of most dominant cluster of low-ADC voxels) were extracted using different thresholds from 400 to 800х10–6 mm2/s at 10х10–6 mm2/s intervals. Area under the receiver operating characteristic curve (AUROC) and sensitivity for poor outcome (6-month cerebral performance category score > 2) while maintaining 100% specificity were measured.

Results:
110 patients were analyzed. Average ADCs showed fair performance with AUROC of 0.822 (95% confidence interval [CI], 0.744-0.900) for mean and 0.799 (95% CI, 0.716-0.882) for median ADC. LADCV showed better performance with higher AUROC (maximum, 0.925) in ADC threshold range from 400 to 690х10–6mm2/s. DC-LADCV showed the best performance with higher AUROC (maximum, 0.955) compared to LADCV in ADC threshold range of 600 to 680х10–6 mm2/s. It had high sensitivity for poor outcome (>80%) in wide threshold range from 400 to 580х10–6 mm2/s with maximum of 89.2%.

Interpretation:
Computerized quantitative analysis using DC-LADCV showed impressive performance in prognostication of out-of-hospital CA patients in multicenter setting.
Abstract 12384: Novel Approach to Residual Risk, K-877, a Potent and Selective PPAR-α Modulator (SPPARMα), Added-on to Pitavastatin in Japanese Patients With Dyslipidemia
Authors: Yokote Koutaro , Ishibashi Shun , Yamashita Shizuya , Arai Hidenori , Araki Eiichi , Suganami Hideki , Kodama Tatsuhiko
Published: July 2021

Background:
Residual cardiovascular risk remains despite intensive treatment with statins. K-877, a Selective PPAR-α Modulator (SPPARMα), has shown
significant
reductions in atherogenic lipids with fewer adverse effects than existing PPARα agonists. We hypothesized that combination with pitavastatin may provide further reduction in atherosclerotic risk, particularly in dyslipidemic patients with hypertriglyceridemia, than statin alone.

Methods:
This was a multi-center double-blind parallel-group study. A total of 188 patients with fasting high TG (≥200, <1000 mg/dL) and non-HDL-C (≥150 mg/dL), treated with pitavastatin (once daily, 2 mg/day) were randomized to 12-week treatment groups; placebo (n=46), twice-daily K-877 0.1 (n=45), 0.2 (n=49) and 0.4 mg/day (n=48). The primary endpoint was the percentage change in TG from baseline and incidence of adverse drug reactions (ADRs) and adverse events (AEs).

Results:
Fasting TG reduction was as follows; placebo: -6.9%, K-877 0.1, 0.2 and 0.4 mg: -46.1%, -53.4% and -52.0%. All K-877 groups had significant reductions compared with placebo (P<0.001). Fasting non-HDL-C reductions were -5.9% with placebo and -11.3, -14.1 and -13.3% with K-877 0.1, 0.2 and 0.4 mg, respectively. Significant increase in HDL-C, and reductions in VLDL-C, remnant lipoprotein cholesterol and apoCIII compared to placebo were found in all K-877 groups (P<0.01). Although K-877 had a neutral effect on total LDL-C, HPLC analysis revealed a significant reduction of very small LDL-C with K-877 compared to the placebo group (P<0.05). Moreover, the highest dose of K-877 (0.4 mg/day) showed significant reduction of fasting blood glucose and HOMA-R compared to placebo (P=0.003 and 0.019, respectively). The incidence of AEs and ADRs in the K-877 groups was similar to that in placebo group. The study discontinuation rates were similar across all groups.

Conclusions:
K-877 significantly improved plasma lipoprotein profiles in dyslipidemia patients on stable statin treatment without increasing the rates of AEs/ADRs. Thus K-877 may be a useful therapy to reduce residual cardiovascular risk in dyslipidemia.
Abstract 12413: Haemoglobin and Change in Haemoglobin Status Predict Mortality, Cardiovascular Events and Bleeding in Stable Coronary Artery Disease: A Clarify Registry Analysis of 21,829 Patients From 45 Countries
Authors: Kalra Paul R , Greenlaw Nicola , Ferrari Roberto , Ford Ian , Tardif Jean-Claude , Tendera Michal , Steg Philippe Gabriel , Fox Kim
Published: July 2021

Anaemia is a predictor of adverse outcome in patients with acute myocardial infarction and those undergoing revascularisation. Little is known regarding the relationship of hemoglobin (Hb) or its change over time on outcomes in patients with CAD. The CLARIFYregistry provides a unique contemporary opportunity to explore this relationship .

Methods:
33 283 patients from 45 countries were enrolled in the CLARIFY registry of stable CAD (Nov 2009 -July 2010). Hb values were available for 21,829 patients, who were divided into groups according to Hb quintiles and anaemia status (WHO criteria) at each of baseline and follow-up (anaemic[A]/normal[N]) (status at baseline/follow-up): (i) N/N (ii) A/N (iii) N/A, (iv) A/A.

Results:
(Table) Whilst patients with lower Hb were less commonly treated with aspirin and ACEIs, they more commonly received thienopyridines, anticoagulants and ARBs. Low Hb was a consistent predictor of mortality, adverse CV event and major bleeds after controlling for various factors at baseline. Anaemia at follow up was independently associated with higher all-cause mortality (p<0.001, HR 1.9 [1.5, 2.3] for A/A and 1.9 [1.5, 2.3] for N/A), non-CV mortality (p<0.001) and CV mortality (p = 0.001). Patients whose baseline anaemia normalised during follow-up (A/N) did not appear to be at increased risk of death (HR 1.0 [0.8, 1.3], although risk of major bleeding was greater (HR 2.1 [1.2, 3.4], p=0.01). Sensitivity analyses were performed after excluding patients with heart failure and chronic kidney disease at baseline and yielded qualitatively similar results.

Conclusions:
In this large contemporary stable CAD population, low Hb was an independent predictor of mortality, adverse CV event and major bleeds. Persisting or new onset anaemia is a powerful predictor of CV and non-CV mortality. Whilst low Hb may play a pathophysiological role in CV disease progression, the data suggest that it is also likely to be a marker of other co-morbid disease.
Abstract 12429: Reductions in Mean 24-Hour Ambulatory Blood Pressure After 6-Week Treatment of Canagliflozin in Patients With Type 2 Diabetes Mellitus and Hypertension
Authors: Townsend Raymond , Machin Israel , Ren Jimmy , Trujillo Angelina , Kawaguchi Masato , Vijapurkar Ujjwala , Pfeifer Michael
Published: July 2021

Background:
Canagliflozin (CANA), a sodium glucose co-transporter 2 inhibitor, decreases renal glucose reabsorption and increases urinary glucose excretion. In 26-wk clinical studies consistent and sustained reductions in BP have been observed. This study used ABPM to assess reduction of BP after the initiation of CANA.

Methods:
In this 6-wk, placebo (PBO)-controlled study, 169 pts (mean [SD] age 58.6 [8.4] y, A1C 8.1% [0.9], seated SBP 138.5 mmHg [9.6], seated DBP 82.7 mmHg [8.1]), on 1-3 antihyperglycemic agents (required metformin; excluded insulin) and 1-3 antihypertensive agents (required ACEi or ARB; excluded loop diuretics) received ≥1 dose of the study medication (CANA 100 mg [n = 57], CANA 300 mg [n = 56], or PBO [n = 56]). Primary endpoint was change from baseline to Wk 6 (LOCF) in mean 24-hr SBP between CANA 300 mg and PBO. Primary efficacy analysis was based on an ANCOVA model which included terms for treatment and beta-blocker use and baseline mean 24-hr SBP as a covariate. Key secondary endpoints included change from baseline in mean 24-hr DBP, and mean day- and nighttime SBP and DBP for CANA 100 and 300 mg.

Results:
At Wk 6, CANA 300 mg provided greater reductions in mean 24-hr SBP vs PBO (-4.9 mmHg, p = 0.006, Fig.). Reductions in mean 24-hr SBP were also observed with CANA 100 mg (-3.3 mmHg) vs PBO. Reductions in mean 24-hr DBP were observed for both CANA 100 mg (-1.94 mmHg) and CANA 300 mg (-2.92 mmHg*) vs PBO. CANA 100 and 300 mg resulted in greater reductions in mean daytime SBP (PBO-adjusted changes -4.0 mmHg* and -5.4 mmHg*) and DBP (PBO-adjusted changes -2.2 mmHg* and -3.0 mmHg*). Higher incidences of orthostasis, volume depletion and osmotic diuresis adverse events were observed with CANA 300 mg vs CANA 100 mg and PBO.

Conclusion:
At Wk 6, CANA 300 mg provided a rapid and significant reduction in mean 24-hr SBP. Both CANA doses reduced daytime SBP and DBP, and demonstrated an overall safety profile consistent with clinical studies.

*nominal p value (p < 0.05)
Abstract 12445: A Detailed Analysis of Peripheral Blood Cytokines 2-3 weeks After Acute Myocardial Infarction: IL-6-Related Impairment of Bone Marrow Function
Authors: Shahrivari Mahan , Wise Elizabeth , Taylor Doris A , Pepine Carl J , Henry Timothy D , Traverse Jay H , Cooke John P , Bolli Roberto , Cogle Christopher R
Published: July 2021

Background:
Intracoronary infusion of bone marrow (BM) mononuclear cells (BM-MNCs) late after acute myocardial infarction (AMI) has shown no improvement in global or regional left ventricular (LV) function (LateTIME and SWISS-AMI). Studies in experimental AMI models suggest a possible cytokine-related depression of progenitor cell function. Furthermore, BM cell content is correlated with the LV functional response. Accordingly, we hypothesize that inflammatory cytokines associated with the late phase of AMI may impair BM function and alter progenitor cell subsets.

Method:
Patients with previous AMI (n=87) were recruited in a multicenter cell therapy trial by the Cardiovascular Cell Therapy Research Network (CCTRN LateTIME, NCT00684060). BM and peripheral blood (PB) were collected 2-3 weeks after AMI and examined for cell phenotypes and progenitor capacities as well as PB inflammatory and angiogenic cytokines in a core laboratory. Multiple regression analyses were conducted and correlations between cytokine levels and cell phenotypes, cell functions, and post-MI cardiac function were determined. BM from healthy donors, handled in the same manner, was used as a reference.

Result:
Of 26 cytokines analyzed, IL-6 showed a negative correlation with ECFC colony maximum in BM (estimate±SE (SEE) -0.13±0.04 P=0.007, multivariableR2: 0.59) and Healthy BM showed decreased ECFC colony outgrowth in the presence of IL-6 (P <0.05), in a dose-dependent manner. PDGF-BB positively correlated with CFU-EC colony maximum in BM (SEE 0.006± 0.002, P=0.023, R2: 0.22), MSC colony maximum in BM (SEE 0.006±0.002, P=0.023, R2: 0.17) and MSC colony maximum in PB (SSE 0.018±0.005, P=0.00005, R2:0.24). No significant correlations were found between cardiac function after AMI and PB cytokine levels.

Conclusions:
At 2-3 weeks after AMI, PB levels of the angiogenic cytokine, PDGF-BB and the pro-inflammatory cytokine, IL-6, were associated with BM cell phenotype and function. IL-6 has the potential to impair endothelial progenitor cell capacity; inhibiting IL-6 may be a target for improving the regenerative capacity of BM cells after AMI.
Abstract 12446: Frequency and Practice Level Variation in Statin Use Among Patients With Diabetes: Insights From the NCDR® PINNACLE Registry
Authors: Pokharel Yashashwi , Gosch Kensey , Grodzinsky Anna , Nambi Vijay , Chan Paul , Kosiborod Mikhail , Spertus John , Ballantyne Christie , Petersen Laura , Virani Salim
Published: July 2021

Background:
Statins reduce major adverse cardiovascular events and mortality among patients with diabetes and routine use is endorsed by clinical practice guidelines. However, national trends and practice level variation in statin use are not known.

Methods:
From the American College of Cardiology’s Practice Innovation and Clinical Excellence (PINNACLE) registry, we identified 256,701 patients with diabetes 40-75 years of age from 187 practices with at least 30 diabetic patients between May 1, 2008 and September 31, 2014. Among patients without contraindication to statin therapy, we calculated the percentage of patients receiving statin therapy at each practice. We then examined variation in statin use across practices using multivariable hierarchical regression to determine median rate ratio (MRR), which quantifies the likelihood that 2 randomly chosen practices would differ in treating an identical patient.

Results:
Overall, 141,900 (55%) diabetic patients were on statins. Those prescribed statins were more likely to be men, of white race, have coexisting dyslipidemia or hypertension, be on non-statin lipid lowering medications and have lower LDL-C levels (91 vs. 103 mg/dL, P<0.001 for all). The median practice level use of statin was 57% (IQR, 48-63%), which remained similar throughout the study period. The adjusted MRR for statin use was 1.62 (95% CI: 1.57-1.67), indicating 62% differences in likelihood of statin treatment between 2 identical patients at 2 random practices (Figure).

Conclusion:
In a national outpatient registry, just over half of patients with diabetes 40-75 years old were treated with statins, with wide variation across cardiology practices. These results suggest that quality improvement initiatives are needed to support guideline recommended use of statins among patients with diabetes.
Abstract 12463: Apolipoprotein (Apo) AI Stability Determines High Density Lipoprotein Function
Authors: Yang Yaliu , Rosales Corina , Gillard Baiba , Gotto Antonio , Pownall Henry
Published: July 2021

Introduction
Atherosclerosis is characterized by the accumulation of free and esterified cholesterol in the subendothelial space of the arterial wall. Reverse cholesterol transport reduces the burden of cholesterol in the arterial wall in three steps including selective uptake by hepatic scavenger receptor class B member 1 (SR-BI). The mechanism for HDL-lipid uptake is distinct from that of low density lipoproteins, which are removed by endocytosis of the holo particle; in contrast, SR-BI selectively extracts lipids from HDL and leaves remnant HDL as an obligatory lipid-poor particle.

Hypothesis
HDL resides in a kinetic trap from which it escapes via perturbations that transfer apo AI into the surrounding aqueous phase as a lipid-free (LF) protein. Given that apo AI but not other HDL apos nor apo B-100 is labile and readily released by HDL, we hypothesized that apo AI lability is necessary or at least permitting for HDL function, including selective CE uptake.

Methods
HDL-protein lipophilicity was increased by lysine acylation. HDL stability was tested by chaotropic perturbation with guanidinium chloride (GdmCl), and with Streptococcal serum opacity factor (SOF) and phospholipid transfer protein (PLTP), which are functional perturbants of HDL structure. Production of LF apo AI was quantified by size exclusion chromatography; SOF reaction kinetics vs. HDL was determined turbidimetrically; selective [
3
H]CE HDL uptake was determined in human hepatoma Huh7 cells, and in SR-BI over expressing Chinese hamster ovary (CHO-SR-BI) and the parent CHO-ldlA7 cells.

Results
Hexanoylation of HDL profoundly reduces release of apo AI vs. the chemical perturbant–GdmCl, and biochemical perturbants–SOF and PLTP. The rate of [
3
H]CE uptake from polyhexanoylated HDL by Huh7 and CHO-SR-BI cells was respectively 32% and 38% lower than that of control HDL. The rate of [
3
H]CE uptake by the parent CHO-ldlA7 cells was 7% to 13% of that of CHO-SR-BI cells and similar for control and polyhexanoylated HDL.

Conclusions
We have developed and validated an HDL mechanism, reaction with hexanoic anhydride, which reduces the loss of LF apo AI. Our data support the hypothesis that apo AI lability in HDL is a permitting factor in multiple HDL functions, including selective hepatic CE uptake.
Abstract 12471: Optimal Prediction of Atrial Fibrillation Recurrence After Ablation: A Computational Anatomy Study
Authors: Varela Marta , Bisbal Felipe , Zacur Ernesto , Guiu Esther , Berruezo Antonio , Sitges Marta , Prat Susana , Aslanidi Oleg V , Mont Lluis , Lamata Pablo
Published: July 2021

Background:
Left atrial structural remodelling, assessed by left atrial (LA) sphericity or antero-posterior diameter, has been shown to predict recurrence after atrial fibrillation (AF) ablation. The study aimed to perform a computational shape analysis of the LA to quantitatively characterise the LA shape remodelling process and identify metrics that optimally predict recurrence.

Methods:
Pre-procedural bright-blood MRIs of the LA of patients undergoing AF ablation were segmented. Patient-specific smooth 3D meshes were fitted to the segmentations. A statistical shape model of the LA was created and the global features underpinning the observed shape variation extracted as principal components (PCs). PCs were optimally combined to create non-empirical atlas-based metrics using linear discriminant analysis. Meshes depicting mean and extreme recurrent and non-recurrent LA shapes were also synthetized. The capability of different metrics to predict recurrence was evaluated using the area under the ROC curve (AUC) of a leave 1 out cross validation test.

Results:
In total, 111 patients were included. At 12 months follow-up, LA sphericity was the best predictor of recurrence (AUC: 0.66) over novel atlas-based metrics (AUC: 0.65). At 24 months, atlas-based metrics were the best predictors of recurrence (AUC: 0.66), outperforming a combination of sphericity and volume (AUC: 0.64), sphericity alone (AUC: 0.63) and any other traditional metric.

Conclusions:
Novel atlas-based metrics improve the prediction of recurrence at 2 years post-AF ablation. They allow a more complete characterization of the LA shape remodelling process, for example by allowing the synthesis of recurrent and non-recurrent LA shapes, which may contribute to patient stratification for AF ablation.
Abstract 12540: High-Dose Statins Reduce the Risk of Contrast-Induced Nephropathy in Patients Undergoing Angiography: Meta-Analysis of 27 Randomized Controlled Trials
Authors: Rabbat Firas , Al Halabi Shadi , Shishehbor Mehdi H
Published: July 2021

Introduction:
Contrast-induced nephropathy (CIN) is a common complication of contrast administration during angiography. Short-term high-dose statins have been suggested for the prevention of CIN in patients undergoing coronary angiography (CAG) or percutaneous coronary intervention (PCI).

Hypothesis:
Multiple randomized controlled trials (RCT) have examined the role of statin in preventing CIN with conflicting results. We expanded on previous meta-analyses by including additional RCTs to provide a better outlook on the efficacy of statins in the prevention of CIN.

Methods:
We searched Pubmed, Medline, Embase, Cochrane, and conference abstracts for prospective RCTs that compared short-term high-dose statins to low-dose statins or placebo in patients undergoing CAG, PCI, computed tomography angiography, or peripheral angiography. High-dose statin was defined as Atorvastatin 40-80 mg, Simvastatin 40 mg, and Rosuvastatin 10-40 mg. Study quality was assessed using the Jadad score. Heterogeneity of the studies was analyzed by Cochran’s Q statistics. Mantel Haenszel relative risk was calculated using the random effect model.

Results:
Twenty seven trials (N=9559) were included in the analysis. Eight of the included trials enrolled patients with acute coronary syndrome (ACS) exclusively. High-dose statin was associated with statistically significant reduction in the incidence of CIN (RR=0.56; 95% CI 0.46, 0.69; P<001) compared to low-dose statin or placebo. This protective effect remained significant upon looking on trials that enrolled patients with ACS only (RR=0.40; 95% CI 0.29, 0.56; P<001). Subgroup analysis based on the type of statin showed no significant difference between simvastatin, atorvastatin, or rosuvastatin. No heterogeneity was detected among the studied outcomes (I2=0%).

Conclusions:
Peri-procedural Short-term high-dose statin administration significantly reduces the incidence of CIN in patients undergoing angiography.
Abstract 12550: Persistent Relative Hypochromia is Associated With Adverse Outcomes in Non-anemic Patients With Heart Failure
Authors: Hammadah Muhammad , Wu Yuping , Li Lin , Hazen Stanley , Tang W.H.Wilson
Published: July 2021

Background:
We previously reported that functional iron deficiency, assessed by low mean corpuscular hemoglobin concentration (MCHC), has been associated with adverse outcomes in non-anemic patients with HF. Yet, the effect of change in MCHC levels on outcomes has not been studied before.

Methods:
We prospectively enrolled 1,579 subjects with HF undergoing coronary angiography, with 5-year follow-up. Blood indices [hemoglobin (Hb), MCHC, MCV, RDW] were assessed on enrollment and after 6 months of follow up by reviewing medical records. Anemia was defined as Hb levels <12 g/dL in males, and <11 g/dL in females.

Results:
In our population (age 66 ± 10 years, male 65%, CAD 75%), most patients were non-anemic (n=1,161, 73.5%). In non-anemic patients, mean Hb and median (IQR) MCHC were 13.3±1.2 g/dL and 34.2 (33.43-34.9) g/dL, respectively. Non-anemic HF patients with lower MCHC had higher mortality risk [Q1 vs Q4 Hazard ratio (HR) (95%CI) of 2.5(1.9-3.2), p<0.001]. Total of 552 (35%) had follow up Hb levels with a mean time between baseline and follow up levels of 169.3 ± 41.6 days. HF severity (EF, BNP), outcomes and blood indices were similar in patients with and without follow up levels, suggesting good representation of the total population. Changes in MCHC levels was studied in non-anemic patients on baseline and follow up (n=318). Most patient with low MCHC at baseline (<Q1, n=79) continued to have low MCHC on follow up (n=61), while half of the patients with high baseline MCHC (≥Q1, n=239) developed low MCHC on follow up (n=120). In comparison to patient with persistently high MCHC, patients with persistently low MCHC had a significantly increased mortality risk [HR(95%CI) of 3.5(2.1-6.1), p<0.001]. All models remained significant even after adjusting for traditional CAD risk factors, EF and baseline blood indices.

Conclusion:
Relative hypochromia is an independent predictor of increase mortality in patients with HF, even in the setting of normal hemoglobin levels.
Abstract 12630: Cardiovascular Safety of Liraglutide: Pooled Analysis of Major Adverse Cardiovascular Events across Weight Management and Type 2 Diabetes Development Programs
Authors: Caterson Ian D , Bain Stephen C , Gross Jorge , House John , Salisbury Adam C , Baeres Florian M , Donsmark Morten , Marso Steven P
Published: July 2021

The cardiovascular safety of liraglutide in individuals with overweight/obesity and those with type 2 diabetes (T2D) is unknown. A meta-analysis of five phase II/III liraglutide (dose up to 3.0 mg) weight management (WM) trials was performed. Additional sensitivity meta-analyses of 21 liraglutide T2D trials (dose up to 1.8 mg) and a pre-specified pooled analysis of all WM and T2D trials (27 trials; WM+T2D) were also conducted.

The primary endpoint was first occurrence of adjudicated major adverse cardiovascular events (MACE) (non-fatal myocardial infarction, non-fatal stroke or cardiovascular death) with liraglutide (any dose) or pooled total comparator (placebo, active) and analysis was using a Cox proportional hazards model stratified by trial. Prospective adjudication (blinded, independent) was implemented in three of the WM trials; post-hoc adjudication was conducted for all other trials. For WM trials, the observation period was from the first drug dose to the last drug dose plus a 30-day follow-up; for the SCALE Obesity and Prediabetes trial, data to October 1, 2014 were included.

For WM trials (liraglutide: n=3,872; comparator: n=2,036), baseline characteristics were: 71% women; history of CV disease, 9%; mean age, 47 yrs; mean BMI, 38 kg/m
2
. For T2D trials (liraglutide: n=5,511; comparator: n=2,748): 43% women; history of CV disease, 13%; mean age, 56 yrs; mean BMI, 30 kg/m
2
.

In WM trials (n=20 events), the hazard ratio (HR) [95% confidence interval (CI)] for MACE (liraglutide/comparator) was 0.45 [0.18; 1.10] (Figure 1A). In T2D trials (n=49 events), the HR was 0.64 [0.35, 1.15] (Figure 1A). For the WM+T2D analysis (n=69 events), the HR was 0.57 [0.35, 0.94] (Figure 1B).

In a pooled analysis of WM+T2D trials, MACE was significantly lower in patients treated with liraglutide. The dedicated cardiovascular outcomes trial, LEADER, will provide further insights into the cardiovascular safety of liraglutide.
Abstract 12631: Peripheral Gamma-aminobutyric Acid(gaba) Signaling in Brown Adipose Tissue Induces Metabolic Dysfunction in Obesity
Authors: Ikegami Ryutaro , Shimizu Ippei , Sato Takeshi , Jiao Shuang , Yoshida Yohko , Suda Masayoshi , Hayashi Yuka , Katsuumi Goro , Kayamori Hiromi , Minamino Tohru
Published: July 2021

Accumulating evidence suggests that adult humans possess active brown adipose tissue (BAT) that may contribute significantly to systemic metabolism because of its high energy consumption capacity. Recently, we demonstrated that metabolic stress induced BAT hypoxia and impaired mitochondrial function, leading to the development of BAT “whitening” and systemic metabolic dysfunction in murine obese models. Various neurotransmitters are known to be involved in the maintenance of BAT homeostasis. Among them, the gamma-aminobutyric acid (GABA) signaling in the central nervous system is well accepted to have anti-obesity effects through the activation of the sympathetic nervous system. Here we show the previously unknown role of peripheral GABA signaling in the development of systemic metabolic dysfunction in obesity. We generated an obese model by imposing a high fat/high sucrose (HFHS) diet on C57BL/6NCr mice. Mass spectrometry analysis demonstrated a significant increase in GABA level in BAT of the dietary obese model. Addition of GABA into drinking water induced BAT whitening, reduced the thermogenic response upon cold tolerance test, and promoted systemic metabolic dysfunction in the obese mice. Mitochondrial calcium is important for the maintenance of mitochondrial homeostasis, whereas calcium overload is reported to inhibit mitochondrial function. Treatment of BAT cells with GABA markedly increased mitochondrial calcium level, promoted the production of reactive oxygen species (ROS), and inhibited mitochondrial respiration. These results indicate that peripheral GABA contributes to the development of systemic metabolic dysfunction by inhibiting BAT function in obesity. The inhibition of peripheral GABA signaling would become a new therapeutic target for obesity and diabetes.
Abstract 12635: Nationwide Long-term Follow-up of Pulmonary Atresia With Ventricular Septal Defect
Authors: Kaskinen Anu , Happonen Juha-Matti , Mattila Ilkka P , Pitkänen Olli M
Published: July 2021

Introduction:
The naturally poor survival of pulmonary atresia with ventricular septal defect (PA+VSD) has improved due to evolved perioperative and surgical treatment. Studies including PA+VSD patients, both with and without major aortopulmonary collateral arteries (MAPCAs), with extensive follow-up are scarce. This nationwide study aimed to investigate survival and surgical treatment in PA+VSD patients with and without MAPCAs.

Methods:
Study comprised 109 PA+VSD patients born in Finland between 1970 and 2007. We reviewed retrospectively medical records and operative reports through December 2011, as well as first available angiograms and preoperative angiograms prior to repair attempt.

Results:
The median follow-up time for the total study population, including also patients who died during the follow-up, was 11.4 years (IQR 0.8 - 21.1). The incidence of PA+VSD, which could be determined reliably from 1995 to 2007, was 6.1 per 100 000 live births.

Although the patients with (n = 43) or without MAPCAs (n = 66) showed no difference in survival (p = 0.74), the patients without MAPCAs had better probability to achieve repair (64% vs. 28%, p < 0.0001). The bigger size of true central pulmonary arteries assessed by McGoon index at first angiogram [HR 0.66 (CI95% 0.49 - 0.88) per 0.5 McGoon index units, p = 0.006] and achievement of repair [HR 0.07 (CI95% 0.03 - 0.17), p < 0.0001] improved the overall survival.

After successful repair survival was 93% at 1 year and 91% from 2 years on. Palliated patients, instead, had survival at 1, 5, 10, and 20 years of age of 55%, 42%, 34%, and 20% respectively. However, patients with right ventricle - pulmonary artery connection and septal fenestration had better survival than rest of the palliated patients (p = 0.001). Palliation with a systemic-pulmonary artery shunt increased McGoon index by 41% (p < 0.0001).

Conclusions:
The patients with MAPCAs had higher risk to remain palliated than patients without, although their survival was similar. Survival of PA+VSD was influenced by the initial size of true central pulmonary arteries and whether repair was achieved. Although palliative procedures may not improve the final outcome of PA+VSD, palliative surgery may have a role in its treatment.
Abstract 12656: Phosphodiesterase 4 (PDE4) Inhibition Induces Weight Loss and Improves Insulin Resistance via cAMP-EPAC-AMPK Mediated Reprogramming of Macrophages
Authors: Wu Chaoneng , Maiseyeu Andrei , Deiuliis Jeffrey A , Zhong Jixin , Rao Xiaoquan , Ying Zhekang , Bagalkot Vaishali , Rajagopalan Sanjay
Published: July 2021

Objective:
Recent evidence suggests an important role for cAMP-dependent pathways in modulation of innate immune function. Phosphodiesterase 4 (PDE4) is widely expressed in innate immune cells such as macrophages/dendritic cells with potent anti-inflammatory effects on pharmacologic inhibition of the enzyme. We investigated the importance of PDE4 in diet-induced obesity (DIO) and hypothesized that PDE4 inhibition will improve insulin sensitivity and reduce inflammation.

Methods and Results:
PDE4 was upregulated in both visceral and subcutaneous (SubQ) white adipose tissue (WAT) in DIO mice (12 weeks of high-fat diet, HFD, 60% fat) compared to normal-chow diet (NCD) mice (↑4∼10-folds, p<0.01). The degree of expression was correlated with macrophage infiltration in stromal vascular fraction from WAT (CD11b
+
F4/80
+
cells, r=0.56, p<0.05). Treatment with Roflumilast (3mg/kg/day), a high affinity inhibitor of PDE4 (IC
50
0.39 nM) versus vehicle control (n=6∼10 in each group) for 21 days concomitant with HFD, resulted in rapid and substantial weight loss (↓45.8% fat content), enhanced thermogenesis [(∼20% higher oxygen consumption and heat production, 0.7∼1.1°C higher core body temperature in a cold environment (4°C)], brown adipose reprogramming, improvement in insulin resistance (HOMA-IR ↓ from 0.69±0.04 to 0.44±0.01, p<0.01) and hepatic steatosis. These changes were paralleled by increased alternative macrophage activation (Altf), reduced inflammation in WAT [↑CD206 and CD301 by flow cytometry with ↓ TNF/IL-6 gene expression] and activation of thermogenic genes in brown adipose tissue.
In-vitro
treatment of mouse bone marrow-derived macrophages (BMDM) promoted Altf and increased expression of tyrosine hydroxylase (↑2.5 folds) and catecholamines secretion. Additional experiments with agents that augment/reduce intracellular cAMP/EPAC/AMPK revealed an essential role for this cascade in Altf activation and catecholamine release.

Conclusions:
PDE4 antagonism improves obese diabetic symptoms through convergent pathways involving Altf activation and enhancing thermogenesis via cAMP dependent modulation of macrophage catecholamine release.
Abstract 12713: Epidemiology and Mortality of Very and Extremely Preterm Infants With Congenital Heart Defects
Authors: Chu Patricia Y , Li Jennifer S , Kosinski Andrzej S , Hornik Christoph P , Hill Kevin D
Published: July 2021

Introduction:
Congenital heart disease (CHD) is estimated to occur in 6-10 per 1000 births. Although epidemiology and outcomes for term and near term infants with CHD are well described, data are limited for very and extremely preterm (VEP) infants. We used the Healthcare Cost and Utilization Project Kids’ Inpatient Database (KID), a nationally representative administrative database, to evaluate epidemiology and outcomes for VEP infants (25 to 32 weeks gestational age, GA) with CHD.

Methods:
Two separate cohorts were defined from the KID: an epidemiologic cohort including birth hospitalizations in ‘03, ’06, ’09 and ‘12; and an outcomes cohort including hospitalizations at a children’s hospital or pediatric unit for infants < 1 month of age in ‘06 and ‘09. CHD was defined by ICD-9-CM codes with severe CHD defined as those defects expected to be universally diagnosed during a preterm birth hospitalization. Weighted multivariate logistic regression analysis was used to calculate odds ratios (OR) for mortality, adjusted for race, sex, GA, year, small for gestational age and hospital teaching status.

Results:
Our epidemiologic and outcomes cohorts included 249,011 and 49,893 VEP infants, respectively. Incidence of CHD (116/1000 VEP births) and severe CHD (7/1000 VEP births) were both higher than previously reported in term infants. Relative risk of severe CHD in VEP vs term infants was 4.80 (95% CI 4.76, 4.84) and decreased with increasing GA (5.7 at 25 weeks GA to 4.3 at 31 weeks, p=0.005). Hospital mortality (Figure) was substantially higher for VEP infants with vs without severe CHD (26% vs 5%; adjusted OR 7.5 [95% CI: 5.9, 9.6]). Overall 16% of VEP infants with severe CHD underwent cardiac surgery during the neonatal hospitalization with mortality after surgery of 16%.

Conclusions:
CHD incidence is increased in very and extremely preterm infants and outcomes are poor. These data underscore the need for interventions to decrease preterm delivery when severe CHD is diagnosed in utero.