bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 15951: Palmitate, Not Oleate, is the Preferred Fatty Acid for Cardiac Triacylglycerol Synthesis
Authors: Kolwicz Stephen C , Tian Rong
Published: July 2021

Introduction:
Previous studies using cell culture models identified cyto-toxic effects of palmitate and that supplementation with oleate was protective by redirecting palmitate into triacylglycerol (TAG) stores. However, other cull culture studies reported that diacylglycerol transferase 1 (DGAT1), the last enzyme in TAG synthesis, demonstrated a preference for oleate. At present, it is not clear whether the supply of exogenous fatty acids (FA) to the heart is differentially allocated into the endogenous TAG pool. Therefore, the purpose of the present study is to examine the influence of palmitate and/or oleate on cardiac TAG incorporation.

METHODS/RESULTS:
Hearts were isolated from DGAT1-transgenic (DGAT) and control littermates (CON) and perfused in Langendorff mode with a mixed substrate buffer consisting of glucose, lactate, insulin, and FAs. The FA supply was varied with 0.2mM of both labeled (13C) and unlabeled (12C) FAs in 4 different experiments: 1) 13C/12C palmitate; 2) 13C/12C oleate; 3) 13C palmitate/12C oleate; 4) 13C oleate/12C palmitate. The incorporation of 13C palmitate or 13C oleate into the TAG pool was monitored by 13C NMR spectroscopy. In CON hearts (n=3), the incorporation of palmitate was ~65% higher than oleate when the perfusate contained a homogenous supply of FA. This was also observed in DGAT hearts (n=4) although the incorporation of both palmitate and oleate was ~75% higher compared to CON (P <0.05). In the presence of oleate, palmitate incorporation decreased 25-30% in both CON and DGAT hearts. In contrast, oleate incorporation was diminished by ~50% and ~100% in CON and DGAT hearts, respectively, in the presence of palmitate.

CONCLUSIONS:
These data suggest that when palmitate and oleate are provided in equal concentrations, palmitate is more readily utilized in the synthesis of endogenous TAG stores in the heart. Furthermore, although overexpression of DGAT increases both oleate and palmitate incorporation, the DGAT1 enzyme demonstrates a preference for palmitate. These findings provide insight into the relationship between exogenous FA supply and endogenous TAG dynamics in the contracting heart.
Abstract 15955: Widely Varying Prevalence of Diastolic Dysfunction by Different Classification Criteria: The Cardia Study
Authors: Rasmussen-Torvik Laura , Colangelo Laura , Lima Joao , Jacobs Daivd , Rodrigez Carlos , Lloyd-Jones Donald , Shah Sanjiv
Published: July 2021

Background:
Diastolic dysfunction is an important target for investigations attempting to understand heart failure with preserved ejection fraction. The many existing classification criteria for diastolic dysfunction could identify widely different case mixes in large cohort studies with research echocardiographic data. We compared prevalence of diastolic dysfunction at the Y25 exam in CARDIA using definitions of diastolic dysfunction proposed by the American Society of Echocardiography (ASE), Rochester County Epidemiology Project (Redfield), and the VALIDD trial.

Methods:
3474 CARDIA participants had echocardiographic data at Y25. Echocardiographic exams were performed at the CARDIA Y25 exam. At each center, trained echo techs obtained images by a standardized protocol and scans were read centrally. Standard 2D and M-mode assessments were obtained. Published binary definitions of diastolic dysfunction were applied; pulmonary venous flow and mitral inflow at peak Valsalva maneuver measures were not available in CARDIA, so the (modified) Redfield definition of diastolic dysfunction was based on two of the four variables included in the definition. Logistic regression was used to determine demographic predictors of diastolic dysfunction.

Results:
The mean age in the sample was 50.2 years, mean BMI was 30.2 kg/m2, 46.7% of the sample was African American and 53.3% was white. The prevalence of diastolic dysfunction according to different definitions was as follows: 1.6 % according to the ASE definition, 24.3% according to the VALIDD definition, and 32.0% according to the (modified) Redfield definition. Using the ASE definition, 38.9% of individuals were unclassifiable for diastolic dysfunction. After adjustment for age, sex, and BMI, African Americans had 7.0 (95% C.I.: 3.4-14.4) times the odds of having diastolic dysfunction compared to whites according to the ASE definition. The comparable OR was 1.9 (95% C.I.: 1.6-2.2) for the Redfield Definition and 1.9 (95% C.I.: 1.6-2.2) for the VALIDD definition.

Discussion:
Existing definitions for diastolic dysfunction are difficult to implement in cohort studies and provide widely varying estimates for the prevalence of diastolic dysfunction as well as for predictors of diastolic dysfunction.
Abstract 15957: A Simple Ablation Strategy Targeting Exclusively AF Triggers is Equally Effective for Paroxysmal and Persistent Atrial Fibrillation: Single Center Large Series
Authors: Otomo Kiyoshi , Takizawa Kaname , Inoue Naoto , Meguro Taiichiro
Published: July 2021

Backgrounds:
Recent studies reported that the ablation strategies including ganglionated plexi ablation, linear ablation and ablation of complex and fractionated electrograms and atrial fibrillation (AF) rotors in conjunction with pulmonary vein isolation (PVI) were superior to the conventional ablation strategy aimed to eliminate AF triggers in terms of post-ablation clinical outcomes. It is controversial whether addition of above-mentioned supplementary ablation to PVI improves post-ablation clinical outcomes in persistent AF (PeAF).

Purposes:
To test the post-ablation clinical outcomes of our ablation strategy exclusively targeting AF triggers in paroxysmal (PAF) and PeAF, and to compare the post-ablation clinical outcomes between PAF and PeAF in a single center large series.

Methods:
Consecutive 1183 patients (pts) (age: 64±11 years, LA diameter: 40±6mm) with PAF (988 pts (84%)) or PeAF (195 pts (16%), AF duration: 5±3 months (range: 1-11)) who received ablation procedures in our institution were included. Irrespective of AF types, the procedure consisted of encircling PVI (EPVI) and SVC isolation (SVCI) in all pts, and additional ablation targeting non-PV, non-SVC AF triggers if spontaneous AF initiation was observed by high dose (100-400μg/hr) isoproterenol (ISP) infusion and bolus administration of 40mg of adenosine triphosphate (ATP) during ISP infusion. Procedure end point was complete elimination of spontaneous AF initiation on by ISP infusion and ATP boluses.

Results:
Total of 1949 procedures were performed in all 1183 pts (1.3±0.5/pt, range: 1-4). EPVI and SVCI were successful in all pts. Non-PV, non-SVC AF triggers were identified in 50 pts (4%) and eliminated by focal ablation in 42 (84%). Kaplan-Meier analysis revealed similarly favorable recurrence-free survivals after the last ablation procedure without antiarrhythmic drugs (blanking period of 1 month) in both PAF and PeAF groups (945 (96%)/988 vs. 190 (97%)/195; p>0.05, follow-up period: 414±245 days (median: 395)).

Conclusions:
This study exhibited that post-ablation recurrence-free survivals were similar between PAF and PeAF, even if only AF triggers were targeted. An ablation strategy targeting only AF triggers may be sufficient in both PAF and PeAF.
Abstract 15972: Fibronectin is Essential for Mesendoderm Induction During Cardiac Differentiation of Human Pluripotent Stem Cells
Authors: Zhang Jianhua , Tao Ran , Annis Douglas S , Mosher Deane F , Kamp Timothy J
Published: July 2021

Extracellular matrix (ECM) plays important roles in development, and we have previously demonstrated a matrix sandwich protocol for efficient cardiac differentiation of human pluripotent stem cells (hPSCs). The purpose of the present study was to identify the key ECM proteins required to initiate cardiogenic differentiation of hPSCs and define their mechanism of action. We tested purified ECM proteins including human laminin (LN111, LN521), fibronectin (FN) and collagen IV in the matrix sandwich protocol, and found FN promoted efficient cardiac differentiation. To determine if FN is essential for the early stages of cardiogenesis we tested three FN blockers: FUD peptide that binds the N-terminal 70-kDa fragment of FN, anti-human FN antibody clone10 which recognizes FN domain III2, and anti-human FN antibody clone 3E3 that binds on the cell attachment domain. All three blockers showed concentration-dependent inhibition of cardiac differentiation of hPSCs when added at day 0 for 24 hours, measured by flow cytometry for cTnT+ cells in the Matrigel/Matrigel (bottom/overlay) and FN/FN sandwich culture as well as in the small molecule GiWi protocol. Furthermore, clone10 showed significant inhibition of cardiac differentiation even in the absence of adding exogenous FN due to the robust endogenous expression of FN by the hPSCs. Gene expression analysis with qRT-PCR demonstrated that blocking FN by clone10 caused a significant suppression of gene expression related to: 1) epithelial to mesenchymal transition, e.g. SNAIL1, SNAIL2, GSC, VIM, CDH2 and FN1; 2) Mesendoderm e.g. T, MIXL1, SOX17 and precardiac mesoderm of MESP1; 3) Cardiac transcription factors ISL1 and NKX2.5. To investigate the cellular signaling activated by FN, we tested a blocking antibody (clone P5D2) to the major FN receptor, integrin β1, and found that P5D2 produced a concentration-dependent inhibition of cardiogenesis in multiple hPSC lines. Furthermore, the integrin-linked kinase (ILK) inhibitor, Cpd22, inhibited cardiac differentiation in a concentration-dependent fashion as well when added on day 0. We conclude that FN, acting via integrin β1-activated ILK signaling, is essential to mesendoderm formation enabling cardiogenesis of hPSCs.
Abstract 15973: miRNA-Hippo Pathway Plays a Critical Role in the Cardiac Conduction System
Authors: Wang Jun , Evans Sylvia , Martin James
Published: July 2021

The cardiac conduction system (CCS) is required for initiating and maintaining regular rhythmic heartbeats and the CCS defects can give rise to cardiac arrhythmia, a leading cause for morbidity worldwide. Given the poor self-repair potential in the adult human CCS, it is critical to elucidate the molecular mechanisms limiting the CCS regeneration to facilitate developing efficient cardiovascular therapies. MicroRNAs (miRs) are small non-coding RNAs that repress gene expression post-transcriptionally. The miR-17-92 cluster can induce cardiomyocyte proliferation and regeneration. Hippo signaling, an ancient organ size control pathway, represses cardiomyocyte proliferation and regeneration. Here we found that both miR-17-92 and Hippo signaling were active in the CCS. Specific disruption of either miR-17-92 or Hippo signaling in the CCS gave rise to cardiac arrhythmias in mice. Notably, miR-17-92 regulates Hippo signaling through directly repressing Lats2, a core Hippo pathway component. In miR-17-92 null mutant hearts, up-regulated Lats2 led to increased Hippo pathway activity. Moreover, we performed chromatin immunoprecipitation deep sequencing (ChIP-Seq) using Yap antibody, the Hippo signaling effector, which data suggested that Hippo signaling regulates genes involved in the CCS homeostasis. Together, our data indicate a novel miR-Hippo genetic pathway plays critical function in the CCS.
Abstract 15975: Atrial Fibrillation Triggers From Non-PV, Non-SVC Foci: Assessment of Incidence, Characteristics and Efficacy of Catheter Ablation in a Single Center, High Volume Series
Authors: Otomo Kiyoshi , Takizawa Kaname , Inoue Naoto , Meguro Taiichiro
Published: July 2021

Backgrounds:
The electrical isolation of the thoracic veins to eliminate triggers of atrial fibrillation (AF) is the mainstay of catheter ablation (CA) for AF. AF is sometimes triggered by repetitive firings from the non-PV, non-SVC (nPVnSVC) foci, and their characteristics have not been fully elucidated.

Purposes:
To elucidate the incidence, characteristics and efficacy of CA of the nPVnSVC foci in AF patients (pts).

Methods:
Consecutive 1491 pts who received CA for AF (1080 males, age: 64±10 years, paroxysmal: 995, non-paroxysmal: 496) were included in this study. In index procedures, PV and SVC isolation were performed in all pts without subsequent provocation of nPVnSVC triggers. In repeat procedures, high dose isoproterenol (up to 400μg/hr) and boluses of adenosine triphosphate were given to provoke AF initiation by nPVnSVC triggers and focal ablation of all AF triggers was performed.

Results:
Among 2097 procedures in all 1491 pts, 58 AF triggers from nPVnSVC foci were provoked in 55 pts (3.7%; 30 paroxysmal and 25 non-paroxysmal AF pts) during 57 procedures (12 index and 45 repeat procedures). The pts with nPVnSVC triggers were significantly more likely to be females (42 vs 28%; P=0.03). The trigger foci were localized in the RA (20 foci; CS os in 8, crista terminalis in 7, IVC os in 3 and tricuspid annulus in 2), LA (24 foci; anterior (6), inferior (3) and posterior wall (3), roof in 3, mitral annulus in 3, Marshall vein in 5 and appendage in 1) and septum (14 foci; left (7) and right side (2) of fossa ovalis, high right septum in 4 and non-coronary cusp of the aortic sinus in 1). All AF triggers were eliminated in 46 pts (84%), while in the others they were not. During follow-up after the last procedure (284±218 days), recurrence-free survival was similar in those with and without nPVnSVC triggers (91 vs 95%; P=0.05), although mean procedure number was significantly larger in those with nPVnSVC triggers than in those without (2.1±0.6 vs 1.4±0.6 times/pt; P<0.0001).

Conclusions:
The nPVnSVC triggers were observed in 3.7% of all AF pts. The location of the triggers could be clustered to the several anatomical regions. Successful elimination of nPVnSVC triggers contributed to high post-ablation recurrence-free survival that was similar to that in those without nPVnSVC triggers.
Abstract 15983: Increased Mitochondrial Reactive Oxygen Species Lead to Deleterious JNK Signaling and Ischemia-Reperfusion Injury in AMPK-Inactivated Hearts
Authors: Zaha Vlad G , Qi Dake , Lee Hui-Young , Hu Xiaoyue , Wu Xiaohong , Shulman Gerald I , Rabinovitch Peter S , Young Lawrence H
Published: July 2021

AMP-activated kinase (AMPK) is a key stress responsive kinase that regulates cellular adaptation to metabolic stress. Inactivation of AMPK in “kinase-dead” (KD) mice increases myocardial damage following ischemia-reperfusion (IR). We have also shown decreased mitochondrial respiration and increased mitochondrial reactive oxygen species (ROS) production and susceptibility to mitochondrial transition pore opening in KD hearts following IR. The aim of this study was to establish the importance of mitochondrial ROS production and downstream deleterious signaling to mediate tissue damage in absence of active AMPK in the heart. Detoxification of mitochondrial ROS requires conversion of hydrogen peroxide to water, therefore, we studied the effect of transgenic expression of mitochondrial catalase (MCAT) in wild type (WT) and KD mice. MCAT prevents mitochondrial hydrogen peroxide production independent of mitochondrial energy production. Myocardial necrosis was assessed in vitro after global ischemia-reperfusion and in vivo after LAD ligation and reperfusion. Mitogen activated protein kinase kinase 4 (MKK4) and downstream c-Jun terminal kinase (JNK) expression and phosphorylation was assessed in vivo. Increased necrosis in KD hearts following mild global ischemia (15 minutes) - reperfusion (10 minutes) in vitro, was prevented by expression of MCAT (WT vs. KD 17.8±4.1 vs. 50±4.1%, p<0.05 and MCAT-WT vs. MCAT-KD 16.9±4.8 vs. 29.3±4.4%, n.s., and factorial p<0.05). Total JNK protein was not increased in WT and KD hearts with or without expression of MCAT. After coronary occlusion in vivo, KD mice showed increased cardiac activation of MKK4/JNK pathway (p<0.05) as well as greater myocardial necrosis (p<0.05). MCAT expression prevented the excessive cardiac JNK activation observed during IR in KD mice in vivo. Inhibition of JNK with SP600125 (10μM) during in vivo IR also resulted in a significant decrease in necrosis in KD hearts (WT vs. KD 9.1±0.7 vs. 28.2±2.9%, p<0.05 and WT vs. KD with SP600125 8.5±0.5 vs. 10.2±1.1%, n.s. and factorial p<0.05, percentage of equivalent area at risk). Thus, AMPK activation during IR prevents excess mitochondrial reactive oxygen production and consequent JNK signaling, thus protecting against myocardial injury.
Abstract 16008: Improved Safety and Efficacy of a Novel Dual cRGD- and Everolimus-Coated Coronary Stent Compared to Everolimus-Eluting Stents in the Porcine Coronary Model
Authors: Vogt Felix , Mause Sebastian , Schröder Jörg , Liehn Elisa , Krott Nicole , Marx Nikolaus , Blindt Rüdiger
Published: July 2021

Background:
Re-endothelialization after drug-eluting stent implantation is delayed. Integrin-binding cyclic Arg-Gly-As p (cRGD) peptide-loaded stents offer potential for enhanced early and late endothelial recovery by endothelial progenitor cell (EPC) anchorage. Here, a novel dual cRGD and everolimus-eluting stent was compared to an everolimus-eluting stent.

Methods:
The porcine coronary overstretch model was employed for analysis of Multi-Link Tetra bare metal stents with or without a specific conformal, mechanically robust polymer coating based on an aromatic polyetherurethaneurea with a soft segment of polytetramethyleneoxide and a hard segment of diphenylmethane diisocyanate and mixed diamines covered by a control-release layer. Stents were coated with immobilized cRGD, everolimus or cRGD+everolimus on the biostable PEA-40 polymer surface coating. Isolated porcine EPCs were labeled with cell tracker and infused into coronary arteries immediately after stent implantation. cRGD or everolimus recovered mass was quantified, re-endothelialization was assessed by scanning electron microscopy and area stenosis was quantified.

Results:
cRGD and everolimus recovered mass from PEA-40 cRGD/everolimus stents possessed a slow release profile. Marked EPC recruitment to stents was evidenced after intracoronary infusion of fluorescence-labeled EPCs. In cRGD+everolimus loaded stents, in-stent cross sectional stenosis was reduced and re-endothelialization above stent struts was accelerated (p<0.05 for both) while re-endothelialization between struts was similar (p>0.05) as compared to both everolimus-loaded and bare-metal stents.

Conclusions:
PEA-40 is a reliable carrier for cRGD and everolimus; the novel PEA-40 dual cRGD and everolimus stent coating both everolimus-dependently decreases coronary stenosis as well as integrin-dependently accelerates stent strut re-endothelialization as compared to everolimus-eluting stents in the porcine coronary overstretch model. Therefore, the concerted acceleration of vascular healing by facilitated homing of circulating EPCs and distinct antiproliferatory properties of everolimus might transfer to an improvement of stent safety while stent efficacy is maintained.
Abstract 16059: Racial and Ethnic Differences in Preserved Ejection Fraction and Reduced Ejection Fraction Incident Heart Failure in a Multiracial Cohort of Post-Menopausal Women
Authors: Quddus Abdullah , Klein Liviu , Rossouw Jacques E , Wu Wen-Chih , Liu Simin , Wampler Nina S , Martin Lisa W , Margolis Karen , Johnson Karen , Foraker Randi , Corbie-Smith Giselle , Breathett Khadijah , Allison Matthew , Manson Joanne E , Eaton Charles B
Published: July 2021

Introduction:
We compared the incidence of Heart Failure with preserved (HFpEF) and reduced ejection fraction (HFrEF) in African-Americans (AA), Hispanic (H) and Caucasian (C) women in the Women Health Initiative (WHI) and evaluated risk factors to explain differences in rates of incident hospitalized HFpEF and HFrEF .

METHODS:
A multi-racial cohort of 42,272 post-menopausal women that oversampled for H and AA were followed for mean of 11.3 years and evaluated for incident HFpEF or HFrEF. Risk factors for incident HFpEF and HFrEF were tested using Cox proportional hazards regression models for AA, H and C with appropriate sample weighting.

RESULTS:
There were a total of 1497 incident cases of HF, of which, 632 were HFpEF, 545 HFrEF, and 320 with an unknown ejection fraction. Age, SES, hypertension, diabetes, tobacco use, CHD were risk factors for both HFpEF and HFrEF whereas obesity, number of co-morbid conditions, and anemia were risk factors for HFpEF only (p <0.001). After adjusting for age, and compared to C, HFpEF and HFrEF were more common in AA (HR 1.12 and 1.43) and less common in H (HR 0.60 and 0.70). For HFpEF, the differences between AA and C were explained by income as the HR is no longer significant after adjusting for income (HR = 0.99; CI 0.73 - 1.33) and clinical risk factors such as hypertension, diabetes, and obesity (HR 0.74; CI 0.53 - 1.02). For HFrEF, the differences between AA and C were only partially explained by income disparities (HR 1.17, CI 0.85 - 1.60) while hypertension, diabetes, dyslipidemia and coronary heart disease played a more important role (HR 0.75; CI 0.52 - 1.07). For Hispanics, the inverse association for HFpEF and HFrEF were accentuated after accounting for income disparities (HR=0.51 and 0.47), and similarly clinical risk factors such as hypertension, diabetes, obesity and dyslipidemia (HR=0.46 and 0.45).

CONCLUSION:
In post-menopausal women, incident HFpEF and HFrEF are more common in AA than C, while the incidence is lower in H women. Differences in clinical risk factors and income explain the differences in AA compare to C, but not the inverse associations in H.
Abstract 16081: A Familial Hypertrophic Cardiomyopathy is Caused by a Mutation in Elp2, Encoding One of Subunits of Elongator Acetyltransferase Complex
Authors: Okamoto Ryuji , Goto Itaru , Kobayashi Issei , Hashizume Ryotaro , Shimojo Naoshi , Dohi Kaoru , Nakamura Mashio , Ito Masaaki
Published: July 2021

Introduction:
Elongator protein 2 (ELP2) is known as a STAT3-interacting protein and one of subunits of elongator, which can regulate RNA elongation via its histone acetyltransferase activity. It remains unknown whether ELP2 plays an important role in cardiac hypertrophy.

Aim:
Our aim is to identify new gene mutations that cause familial HCM, which can progresses into dilated-phase HCM (d-HCM).

Methods:
We examined a patient and her elder brother who both presented with complicated severe HCM and whose parents are married cousins. The elder brother had died suddenly as a child; the autopsy revealed that he had developed HCM. The patient was diagnosed with HCM, and HCM progressed to d-HCM during the 20-year follow-up. The patient received a left ventricular-assist device implant, and the patient is currently on a waiting list for cardiac transplantation. The parents are healthy. We hypothesized that a causative allele was transmitted to both the patient and the elder brother as an autosomal recessive mutation that caused familial HCM. The genome analysis and whole-exome sequencing was performed with samples from each of the three participants. Sarcomere organization in H9C2 cells overexpressed with ELP2 and localization of ELP2 in biopsy samples were examined.

Results:
The gene exome analysis showed 340 single nucleotide polymorphisms (SNPs) that caused amino acid change for which the patient was homozygous and both parents were heterozygous. After excluding all known common (>10%) SNP gene mutations in the SNP Database (dbSNP), ELP2 was the only identified gene that is possibly associated with cardiac muscle. The identified missense mutation was a 2385 G>A nucleotide transition in ELP2 isoform 2. The resultant E795G substitution replaces a polar carboxylic glutamate with a nonpolar glycine. The H9C2 overexpressed with mutant ELP2 showed a distinct sarcomere organization compared with cells overexpressed with intact ELP2. Immunohistochemistry studies showed the localization of ELP2 in the patient’s endomyocardial biopsy sample was different from in control samples.

Conclusions:
These results indicate both that mutations in ELP2 can cause a familial form of HCM and that ELP2 may be a new target for treatment of cardiac hypertrophy.
Abstract 16107: Combined HbA1c and Systolic Blood Pressure Reduction With Dapagliflozin in Patients With Both Inadequately Controlled Type 2 Diabetes Mellitus and Hypertension
Authors: Weber Michael A , List James , Mansfield Traci A , Parikh Shamik J , Ptaszynska Agata
Published: July 2021

Background:
Hypertension is a common comorbidity in patients with type 2 diabetes mellitus (T2DM). Initial treatment is usually with an angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin receptor blocker (ARB), with other antihypertensive therapies (AHTs) added if needed. Dapagliflozin (DAPA) increases urinary glucose excretion accompanied by diuresis and weight loss, which contributes to blood pressure (BP) reduction. Here we evaluate the proportions of patients achieving combined HbA1c and systolic blood pressure (SBP) reduction with DAPA in two studies of patients with both inadequately controlled T2DM and hypertension.

Methods:
Patients with both inadequately controlled T2DM (HbA1c 7.0-10.5%) and hypertension (seated SBP / diastolic BP: 140-164 / 85-104 mmHg) despite receiving glucose-lowering drugs and an ACEi or ARB (Study 1) plus a 2nd AHT agent (Study 2) were randomized to receive double-blind DAPA 10 mg or placebo for 12 weeks. Primary results have been presented previously; here we present proportions of patients achieving combined changes from baseline (Δ) in HbA1c and SBP.

Results:
In Study 2, additional AHT drugs were thiazide/thiazide-like diuretics (~44%), calcium channel blockers (~27%), and beta blockers (~27%). Across both studies, 520 and 522 patients had available paired ΔHbA1c and ΔSBP values in the DAPA and placebo groups, respectively. More patients achieved combined ΔHbA1c and ΔSBP reduction with DAPA (n=325; 62.5%) vs placebo (n=190; 36.4%) (Figure - dotted boxes). Considering more stringent thresholds, more patients achieved combined reductions in ΔHbA1c of ≥0.5% and ΔSBP of ≥5 mmHg with DAPA (n=194; 37.3%) vs placebo (n=86; 16.5%) (Figure - solid boxes).

Conclusions:
In T2DM patients with hypertension on glucose-lowering therapies and an ACEi or ARB ± 1 additional AHT, adding dapagliflozin achieved clinically significant combined HbA1c and SBP reductions over 12 weeks in greater numbers of patients than placebo.
Abstract 16151: Acute Kidney Injury is a Powerful and an Independent Determinant of In-Hospital Mortality in Patients Undergoing Percutaneous Coronary Interventions
Authors: Kooiman Judith , Seth Milan , Nallamothu Brahmajee K , Heung Michael , Humes David , Gurm Hitinder S
Published: July 2021

Introduction:
Acute kidney injury (AKI) is a common complication of percutaneous coronary intervention (PCI) and is associated with increased mortality. Previous studies analysing mortality risk in patients with AKI were hampered by common risk factors for both outcomes. The aim of our study was to analyse the association between AKI and in-hospital mortality post PCI after adjustment for confounding by common risk factors.

Methods:
This study was performed using data from a regional registry of patients undergoing PCI in the state of Michigan. The primary endpoints were AKI and all-cause in-hospital mortality. Propensity matching was performed, with each AKI patient matched to four controls. Attributive risk (AR) and the exposed impact number of AKI for mortality were calculated in the propensity-matched cohort.

Results:
Between January 2009 and June 2013, 92,317 patients were included, of whom 2,141(2.3%) developed AKI. We matched 1,371/2,141 patients with AKI to 5,484 controls. AKI was strongly associated with mortality (OR = 12.52, 95% CI 9.29 - 16.86, p < 0.0001) after adjustment for baseline covariates in the propensity-matched cohort. The association between AKI and mortality was present in all subgroups and strata of baseline AKI-risk (Figure 1). The estimated AR for mortality of AKI was 31.4% (95% CI 26.8% - 37.5%). Among matched patients with AKI, one death could be prevented for every 9 cases of AKI successfully eliminated.

Conclusion:
Our results indicate that AKI attributes to nearly one-third of the in-hospital mortality post PCI. Preventing nine cases of AKI could potentially prevent one death. These study findings stress the need for highly effective AKI preventive strategies.
Abstract 16161: Bone Marrow Characteristics are Associated With Changes in Infarct Size Following STEMI: A Biorepository Evaluation From the CCTRN TIME Trial
Authors: Schutt Robert C , Trachtenberg Barry H , Cooke John P , Traverse Jay H , Henry Timothy D , Pepine Carl J , Willerson James T , Perin Emerson C , Ellis Stephen G , Zhao David X , Bhatnagar Aruni , Johnstone Brian H , Lai Dejian , Resende Micheline , Ebert Ray F , Wu Joseph C , Sayre Shelly L , Simari Robert D , Moye' Lem , Cogle Christopher R , Taylor Doris A
Published: July 2021

OBJECTIVE:
Despite significant interest in bone marrow cell mononuclear cell (BMC) therapy for ischemic heart disease, current techniques have shown only modest benefit. However, select patients show improvements after autologous BMC therapy for unknown reasons. The purpose of this study was to identify BMC characteristics associated with infarct size reduction following STEMI.

METHODS:
This study evaluated prospectively the cohort of patients enrolled in the CCTRN TIME trial who agreed to their BMCs being stored and used for further analyses at the CCTRN Biorepository. Analyses were pre-specified and the core laboratories were blinded to clinical data and treatment assignments. The changes in infarct size between baseline (three days after PCI) and 6 months was measured by cMRI. BMC product underwent phenotype analysis using FACS identifying cells expressing CD45, CD34, CD31, CD133, CXCR4, CD3, CD11, CD14, and CD19 and functional analysis with the CFU-Hill, ECFC and CFU-F assays.

RESULTS:
Quantification of BMC characteristics and infarct size was available in 101 patients. The patients’ mean age was 56.5 years, with a mean screening ejection fraction of 37% and mean baseline cMRI ejection fraction of 45%. At 6 months, 75 (74.3%) patients had reductions in infarct size (mean -21.0% ± 17.6%). Multiple regression analysis revealed that, regardless of treatment allocation, an increased percentage of BMC that expressed CD31 (p=0.046) was associated with greater reductions in infarct size. Greater reductions in infarct size also were associated with more rapid growth rates for BMC functional assays (CFU-Hill, ECFC) (p=0.033, p=0.032, respectively).

CONCLUSIONS:
This study demonstrates a correlation between characteristics of BMCs in the acute STEMI phase and subsequent changes in infarct size. These data suggest that resident BMCs (specifically, endothelial precursors) play an important role in regenerating infarcted myocardium irrespective of treatment with autologous BMC transplantation.
Abstract 16172: Predicting the Presence of a Mutation Resulting in Familial Hypercholesterolemia - Development of a Prediction Model in a Cohort of 64,000 Subjects
Authors: Besseling Joost , Reitsma Johannes B , Hovingh Gerard K , Hutten Barbara A
Published: July 2021

Introduction:
Familial hypercholesterolemia (FH) is a hereditary disease that warrants early diagnosis to prevent premature cardiovascular disease (CVD) by initiating therapy. A definitive diagnosis is made by demonstrating a causal mutation. This might not only increase therapy adherence, but is also an important requirement for cascade screening. However, DNA analysis is costly and careful selection of subjects is important. Unfortunately, the accuracy of current selection criteria is poor.

Hypothesis:
We set out to develop a model to predict the presence of an FH causing mutation in persons referred by general practitioners.

Methods:
All participants in the Dutch FH screening program from January 1994 till January 2014 were included. Cross-sectional data was available on medical history, lipid profile and DNA analysis. The primary outcome was the presence of a deleterious FH mutation. We developed a prediction model using multivariable logistic regression analysis.

Results:
Our study population consisted of 25,809 FH patients and 38,297 unaffected relatives. Our final model included age, gender, levels of LDL-cholesterol, HDL-cholesterol and triglycerides, history of CVD, use of statins and other lipid lowering therapy, smoking and alcohol. The performance was good: the area under the receiver operating characteristic curve (AUC) was 85.2% (95% CI: 84.9 - 85.5). The model was well calibrated with a slope of 1.02 (1 is optimal). Internal validation was excellent: the AUC was unaltered in 100 bootstrap samples. The performance of the model can be illustrated by selecting subjects with a predicted probability of 30% or lower. This would identify 87.0% of all unaffected subjects, and avoid testing in 46.1% of the population.

Conclusions:
We developed a model to predict the presence of a deleterious FH mutation in subjects referred by general practitioners. Our model showed good discrimination and calibration, with no signs of overfitting during internal validation. After external validation, we will develop an interactive web-based calculator or smart phone application that can be used to calculate the probability of the presence of an FH mutation in individual subjects and will facilitate the use of our prediction model in daily clinical practice.
Abstract 16185: Medicare Budget Implications of Left Atrial Appendage Closure for Stroke Risk Reduction in Non-Valvular Atrial Fibrillation
Authors: Armstrong Shannon O , Amorosi Stacey L , Garfield Susan S , Stein Ken
Published: July 2021

Introduction:
Strokes associated with atrial fibrillation (AF) are estimated to cost Medicare $8 billion annually. Advancements in stroke prevention are aimed at improving clinical outcomes and reducing healthcare costs. This analysis quantifies the budget impact to Medicare and Medicare beneficiaries of left atrial appendage closure (LAAC) with the Watchman Device compared to warfarin, the standard of care, and rivaroxaban, the most commonly prescribed new oral anticoagulant in the US, for stroke risk reduction in non-valvular AF.

Methods:
A budget impact model was developed from a Medicare perspective using 2.3-year data from PROTECT AF and relative risks from ROCKET AF. The model captured all costs of treatment and associated complications. Costs for stroke included acute, direct costs as well as long-term disability costs. Cost data were from 2014 US DRGs. Medicare deductibles and co-insurance rates were used in the patient analysis.

Results:
In addition to better net clinical outcomes (table), LAAC is cost neutral to Medicare relative to warfarin and rivaroxaban by year 5, and one third less costly than both by year 10. Treatment-related complications comprised 33% of LAAC total costs compared to 65% for rivaroxaban and 87% for warfarin at year 5. Patient out-of-pocket costs for LAAC were lower than warfarin and rivaroxaban at 2 and 3 years, respectively.

Conclusions:
Upfront LAAC procedural costs are offset by ongoing therapy and complication costs associated with warfarin and rivaroxaban. LAAC with Watchman represents an opportunity for improved clinical outcomes and substantial savings to both Medicare and Medicare beneficiaries.
Abstract 16195: Inverse Relationship Between Inflammation and Cardiorespiratory Fitness: The Henry Ford Hospital ExercIse Testing Project (FIT Project)
Authors: Qureshi Waqas , Blaha Michael J , Brawner Clinton , Keteyian Steven , Al-Mallah Mouaz
Published: July 2021

Introduction:
High sensitivity-C reactive protein (hs-CRP) is a measure of the degree of inflammation and has been associated with risk of coronary artery disease.

Hypothesis:
Hs-CRP is independently inversely associated with cardiorespiratory fitness (CRF).

Methods:
This is a cross sectional study of patients without heart failure or known coronary artery disease underwent graded exercise stress test in Henry Ford Health System (Detroit) according to Bruce protocol and CRF was estimated as peak metabolic equivalents (METs). Hs-CRP was dichotomized by 75th percentile and the relationship between CRF and hs-CRP was assessed by unadjusted and adjusted logistic regression model for age, sex, race, hypertension, diabetes, hyperlipidemia, smoking, total cholesterol, HDL, aspirin use, statin use and obesity.

Results:
A total of 4381 patients (mean age 54±11 years, 58% male, 79% whites) were analyzed. The 75th percentile of hs-CRP was 4.2 mg/L. Mean hs-CRP was higher in women, blacks, hypertensives, diabetics, smokers, and obese patients. In unadjusted analysis, CRF was inversely associated with highest quartile of hs-CRP (OR per 1 MET increase in CRF 0.82; 95% CI 0.81 - 0.84, p <0.0001). In multiple logistic regression model, CRF remained inversely associated with hs-CRP (OR per 1 MET increase in CRF 0.83; 95% CI 0.80 - 0.86, p 12 METS) compared to individuals with poor exercise capacity (<6 METS) had a 47% lower risk of having highest quartile of hs-CRP (OR 0.53; 95% CI 0.46 - 0.62, p <0.0001). Mean hs-CRP level decreased with increasing category of CRF (figure). There was a negative linear relationship between log transformed hs-CRP and peak METs achieved (r = -0.32, p<0.0001).

Conclusions:
In conclusion, exercise capacity, as measured by estimated Mets, was associated with reduced inflammation as measured by hs-CRP. The underlying pathophysiology between hs-CRP and CRF warrants further investigation.
Abstract 16196: Impact of Baseline PCSK9 Levels on the Efficacy of Evolocumab, a Monoclonal Antibody Against PCSK9
Authors: Desai Nihar , Giugliano Robert , Wasserman Scott , Gibbs John , Liu Thomas , Scott Robert , Sabatine Marc
Published: July 2021

Introduction:
Evolocumab (AMG 145), a fully human monoclonal antibody against proprotein convertase subtilisin kexin type 9 (PCSK9), significantly reduces low-density lipoprotein-cholesterol (LDL-C) by ~65%. Whether baseline PCSK9 levels impact the efficacy of evolocumab remains undefined.

Methods:
The mean placebo-controlled percent change from baseline in LDL-C measured by ultracentrifugation at week 10 & 12 was calculated for evolocumab 140 mg Q2W and 420 mg QM in 2293 patients from the pooled phase 3 trials. Median PCSK9 levels were measured in 138 patients from a substudy of the pooled phase 2 trials. For both analyses, patients were stratified into quartiles based upon baseline PCSK9 levels. Interaction tests were performed to evaluate for heterogeneity across quartiles.

Results:
At baseline in the pooled phase 3 trials, the median PCSK9 level was 323 ng/mL (25
th
%ile 258 ng/mL; 75
th
%ile 406 ng/mL). Demographics were similar across quartiles of baseline PCSK9, but, as expected, patients with higher levels of baseline PCSK9 were more likely to be receiving more intensive background statin therapy and had lower levels of LDL-C at baseline. Evolocumab 140 mg Q2W reduced PCSK9 levels by >90% 1 week after dosing and levels remained low (~100 ng/mL), regardless of baseline PCSK9 level (Figure top left). Evolocumab 420 mg QM rendered PCSK9 levels undetectable 1 week after dosing and reduced by >90% 2 weeks after dosing, regardless of baseline PCSK9 levels (Figure top right); 3 weeks after dosing PCSK9 levels remained low (~100 ng/mL) and by 4 weeks levels remained proportionately reduced by nearly half. Evolocumab significantly (P<0.001) reduced LDL-C at week 10 and 12 and to a similar extent regardless of baseline PCSK9 (Figure bottom).

Conclusion:
Evolocumab, a PCSK9 inhibitor, when administered 140 mg biweekly or 420 mg monthly, consistently and substantially reduces PCSK9 and LDL-C regardless of a patient’s baseline level of PCSK9.
Abstract 16216: Emergency Department Crowding Does Not Predict Door-In-Door-Out Time for Acute Myocardial Infarction Patients Transferred for Acute Coronary Intervention
Authors: Ward Michael J , Baker Olesya , Schuur Jeremiah
Published: July 2021

Introduction:
Emergency department (ED) crowding and prolonged length of stay (LOS) are associated with lower quality care. Patients with acute myocardial infarction (AMI) should be transferred to percutaneous coronary intervention capable facilities within 45 minutes of arrival.

Hypothesis:
Increased ED crowding, as measured by ED LOS, is correlated with longer AMI door-in-door-out (DIDO) times at transferring EDs.

Methods:
We analyzed the Centers for Medicare and Medicaid Services (CMS) quality data. The outcome, DIDO, was CMS measure OP-3b,
ED Median Time to Transfer a Patient with AMI for Acute Coronary Intervention
. OP-3b data included hospitals with ≥10 AMI cases annually. To measure ED crowding, we used the CMS ED timeliness measures: discharged LOS, admitted LOS, boarding, and waiting time to be seen by a provider. Our primary measure of interest was ED-1:
Median ED LOS for Admitted Patients
. We analyzed bivariate associations between DIDO and ED timeliness measures. We used linear regression to evaluate the contribution of hospital characteristics from the American Hospital Association survey (academic, trauma, rural, ED volume) to DIDO.

Results:
Data were available for 405 out of 4,129 hospitals for the CMS DIDO measure (934 had <10 cases). These facilities were primarily non-academic (99%), non-trauma centers (65%), in metro locations (68.6%). Median DIDO was 54 minutes (IQR 42, 68). Increased DIDO time was associated with longer admitted LOS, and boarding times, but not waiting time or discharged LOS. Mean ED admitted LOS was different between hospitals with average DIDO <45 versus those ≥45 minutes (259 vs. 283 minutes; p=0.008). After adjusting for hospital characteristics, longer ED admitted LOS at referring facilities [coefficient, 0.078 (95% CI 0.042, 0.113); p<0.001] was associated with DIDO. A 13 minute increase in ED admitted LOS was associated with a 1 minute increase in DIDO. Among hospital characteristics only rural status was associated with longer DIDO.

Conclusions:
Among AMI patients presenting to U.S. EDs, we found that ED crowding has a small but operationally insignificant effect on AMI DIDO times. EDs have found ways to facilitate timely transfer of AMI patients despite crowding.
Abstract 16260: Aspirin-Responsive Platelet Genes Are Associated With Platelet Function and Cardiovascular Events
Authors: Suchindran Sunil , Himmel Tiffany , Ortel Thomas L , Becker Richard C , Kraus William E , Newby L K , Ginsburg Geoffrey S , Voora Deepak
Published: July 2021

Background:
Aspirin prevents myocardial infarction (MI); the pathways with which aspirin interacts are not fully described. We hypothesized that genes that changed in response to aspirin exposure would be associated with platelet function and death/MI.

Methods:
Discovery (healthy volunteers; n=53) and Validation (diabetic patients; n=45) cohorts were exposed to aspirin 325mg/day. Before and after aspirin exposure, we measured platelet function by aggregometry and gene/platelet protein expression by whole blood RNA microarray analysis and unbiased proteomics of purified platelet protein, respectively. Gene Set Enrichment Analysis (GSEA) identified gene sets that changed in response to aspirin. Paired t-tests and regression were used to test individual genes and proteins for changes in expression with aspirin or association with platelet function, respectively. Cox regression models tested gene sets in aggregate using the 1st principal component of gene expression for association with death/MI in patients (n =638) using RNA collected at cardiac catheterization.

Results:
In the discovery cohort we identified 25 gene sets that changed in response to aspirin (family wise error rate [FWER] < 0.05). Of these, we chose to follow up on one set of 43 genes because it represented abundant platelet genes. This gene set was down regulated in the discovery and validation cohorts (FWER p = 0.01 and 0.04, respectively). We identified 4 of 43 genes in the platelet protein dataset; the expression of 3 changed (p < 0.03) in response to aspirin and was associated (p < 0.01) with platelet function after accounting for aspirin. The aggregate expression of this platelet gene set was associated with death/MI (p = 0.03) with the majority of genes associated with increased risk. Analysis of individual genes in this gene set identified several (HLA-E, H3F3A, GNAS, FTH1, TUBA4A, OAZ1, FLNA) that were significantly (p < 0.05) down-regulated by aspirin and also associated with an increased risk of death/MI.

Conclusion:
By using aspirin as a probe to uncover novel biology we identified a set of aspirin-responsive platelet genes associated with an increased risk of cardiovascular events. These findings may help to explain the effects of aspirin on preventing MI.
Abstract 16305: Incidence and Timing of High-Risk Arrhythmias With Long-Term Continuous Ambulatory Electrocardiographic Monitoring
Authors: Solomon Matthew D , Yang Jingrong , Lenane Judy , Sung Sue Hee , Go Alan S
Published: July 2021

Background:
Ambulatory electrocardiographic (ECG) monitoring is the standard of care to screen patients for arrhythmias. However, there is marked variation in the technological features and patient adherence among different ECG monitoring systems. We evaluated a novel adhesive, wireless, single-lead, full-disclosure, up to 14-day ECG monitoring system to measure the burden and timing of high-risk arrhythmias.

Methods:
We examined data from 122,815 long term continuous ambulatory ECG Monitors. (ZIO® Patch Service, iRhythm Technologies, San Francisco, CA) from 2011-2013 and categorized high-risk arrhythmias into two types: (1) ventricular arrhythmias including non-sustained and sustained ventricular tachycardia and (2) high risk bradyarrhythmias including sinus pauses >3 seconds, atrial fibrillation pauses >5 seconds, and high grade heart block including Mobitz Type II or third-degree heart block. We calculated the proportion of patients with each arrhythmia and the elapsed wear time until each arrhythmia.

Results:
Of 122,815 Ziopatch recordings, median wear time was 9.9 (IQR 6.8-13.8) days and median analyzable time was 9.1 (IQR 6.4-13.1) days. There were 22,443 (18.3%) with at least one episode of non-sustained ventricular tachycardia (NSVT), 238 (0.2%) with sustained VT, 1,766 (1.4%) with a sinus pause >3 seconds (SP), 520 (0.4%) with a pause during atrial fibrillation >5 seconds (AFP), and 1,486 (1.2%) with high-grade heart block. Median time to first arrhythmia was 74 hours (IQR 26 -149 hours) for NSVT, 22 hours (IQR 5-73 hours) for sustained VT, 22 hours (IQR 7-64 hours) for SP, 31 hours (IQR 11-82 hours) for AFP, and 40 hours (SD 10-118 hours) for high-grade heart block. The yield over time is shown in the Figure 1.

Conclusions:
A significant percentage of high-risk arrhythmias can be identified by long term continuous monitoring for longer than 24 to 48 hours. The clinical impact from better identification of high-risk arrhythmias warrants further study.