bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 16440: Cu Transporter ATP7A Protects Against Fibrosis Through Limiting Endothelial to Mesenchymal Transition
Authors: Youn Seock-Won , Varadarajan Sudhahar , Das Archita , McKinney Ronald D , Fukai Tohru , Ushio-Fukai Masuko
Published: July 2021

Background:
Endothelial to mesenchymal transition (EndMT) is induced by inflammation and contributes to fibrosis; however, underlying mechanism is poorly understood. Cu plays an important role in physiological processes and pathophysiologies associated with inflammatory diseases. Since excess Cu is toxic, bioavailability of Cu is tightly controlled by Cu exporter ATP7A, which obtains Cu via Cu chaperone, Atox1, and exclude Cu. We reported that Atox1 also functions as a Cu dependent transcription factor. However, role of Cu transport proteins in EndMT is entirely unknown.[[Unable to Display Character:  ]]

Results:
Here we show that TNFα stimulation for 24hr in HUVEC significantly decreased ATP7A protein (80%) and increased intracellular Cu and Atox1 in nucleus, which was associated with shape change forming EndMT. ATP7A depletion with shRNA in EC significantly reduced EC markers (VE-cadherin and VEGFR2) and increased mesenchymal markers (αSMA, Calponin, SM22α, Collagen I/II). ATP7A siRNA also increased intracellular Cu and nuclear Atox1. These ATP7A knockdown-induced phenotype changes were inhibited by Cu chelators BCS and TTM. Mechanistically, microarray and qPCR based screening revealed that ATP7A knockdown in EC significantly increased miR21 (2.5 fold) and miR125b (1.5 fold) which induce EndMT in a Cu-dependent manner. Of note, promoters of both miR21 and miR125b have Cu dependent transcription factor Atox1 binding sites. Consistent with this, overexpression of Atox1 increased miR21 and miR125b expression as well as promoted EndMT. In vivo, ATP7A mutant (ATP7Amut) mice with reduced Cu export function showed impaired blood flow recovery and reduced arteriogenesis while increased αSMA+ cells and fibrosis in capillary network after ischemic injury. Moreover, ATP7Amut mice crossed with ApoE-/- mice with high fat diet (HFD) induced robust fibrosis and enhanced atherosclerotic lesion vs ApoE-/-/HFD mice.[[Unable to Display Character:  ]]

Conclusions:
ATP7A protects against fibrosis by preventing EndMT via nuclear Atox1-mediated upregulation of miR21 and miR125b which induce EndMT, in Cu dependent manner. These findings provide the foundation for novel protective role of Cu transport proteins against EndMT- and fibrosis-mediated cardiovascular diseases.
Abstract 16468: Upcoding of Complication May Account for Declining Failure to Rescue Rates Following Major Cardiac Surgery
Authors: Gonzalez Andrew A , Ghaferi Amir A , Likosky Donald S
Published: July 2021

Introduction:
To guide public reporting and payment reform initiatives, payers are increasingly tying reimbursement to hospital performance on administratively-derived quality measures. This has created tension with the existing fee-for-service model where “upcoding” of post-operative complications may increase hospital revenue.

Hypothesis:
We hypothesized that current complication measures may inaccurately reflect hospital quality, due to increased upcoding.

Methods:
We used Medicare data (2000-8) for patients undergoing cardiac surgery. We compared rates of post-operative pulmonary complications and pulmonary-specific failure to rescue (FTR, ie mortality after a pulmonary complication) under one of two definitions: (1) allowing diagnostic codes solely for pulmonary failure to define a complication (unconditioned definition, UCD), or (2) conditioning the identification of a complication on having a treatment code for mechanical ventilation or intubation (procedure-conditioned definition, PCD). We considered PCD to be a better reflection of true hospital quality.

Results:
We studied 1,248,765 operations in 1027 hospitals. Over this time period, pulmonary complications decreased 0.3% under the PCD criteria but increased 14.3% under an UCD, p<0.001. Since the PCD rate remained essentially unchanged (6.2% vs 5.9%, p<0.001), this divergence was driven almost entirely by the prodigious increase in UCD complications (12.5% vs 20.3%, p<0.001), Figure. There was no change in PCD-FTR rate (15.4% vs 15.5%, p=0.876) but a sizable decline in UCD-FTR rate (18.9% vs 11.7%, p<0.001).

Conclusions:
Our findings suggest that current hospital surgical performance measures are sensitive to upcoding, and may provide qualitatively different reflections of quality depending on how they are derived. Measure developers should consider the implications of hospital upcoding, especially given its increasing incidence.
Abstract 16474: BP Reduction With the Sodium Glucose Co-Transporter 2 Inhibitor Empagliflozin in Type 2 Diabetes is Similar in Treatment Naïve as in Those on One or ≥ 2 Antihypertensive Agents - Further Insights From a Dedicated 24h ABPM Study
Authors: Mancia Guiseppe , Cannon Christopher P , Tikkanen Illka , Zeller Cordula , Ley Ludwin , Hach Thomas , Woerle Hans-Juergen , Broedl Uli C , Johansen Odd Erik
Published: July 2021

In patients with type 2 diabetes (T2D) hypertension is accompanied by an increase in CV risk which can be substantially attenuated if BP is lowered by drug treatment. Empagliflozin (EMPA) is a new glucose-lowering agent of the sodium glucose co-transporter 2 inhibitor (SGLT2i) class, which has been shown to reduce body weight and also lower BP. It is not known, however, whether the EMPA-related BP lowering effect is preserved in patients under background antihypertensive treatment. We investigated the effect of 12 weeks with EMPA on 24 hour (h) mean BP in 823 T2D patients (age 60.2 ± 9.0 years, HbA1c 7.9 ± 0.7%, office systolic (S)/diastolic (D) BP 142.1 ± 12.3/83.9 ± 7.0 mmHg, mean ± SD) in a study with a randomized design. EMPA was given at 10mg (n=276) or 25mg (n=276) daily; 271 patients were randomized to placebo. Patients were under no, 1 or ≥ 2 antihypertensive drugs (n= 62, 353 and 408, respectively) such as an ACE inhibitor (ACEI), an angiotensin receptor antagonist (ARB) or a diuretic (D). HbA1c and weight were significantly reduced with EMPA 10 mg (mean [SE] -0.62% [0.05], -1.5 kg [0.2]) and EMPA 25 mg (-0.65 [0.05], -2.0 [0.2]) relative to placebo (all p < 0.001). As shown in the Table, compared to placebo, EMPA at the lower or higher dose reduced 24h mean SBP and DBP in all groups. With the lower dose the BP reduction was somewhat less pronounced in patients with ≥ 2 antihypertensive drugs whereas with the higher dose the BP effect was similar irrespective of the presence and intensity of background antihypertensive treatment. The antihypertensive effect of EMPA was preserved also irrespective of the type of treatment (D and ACEIs or ARBs), especially at the higher dose. Thus, EMPA reduces BP in patients with T2D regardless of whether they are untreated or more or less intensively treated for hypertension.
Abstract 16491: Predictors of Incident Conduction System Disease in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)
Authors: Dewland Thomas A , Soliman Elsayed Z , Davis Barry R , Magnani Jared W , Yamal Jose-Miguel , Piller Linda B , Haywood L. Julian , Marcus Gregory M
Published: July 2021

Introduction:
Left and right bundle branch block (L and RBBB) have been associated with heightened morbidity and mortality, but risk factors for incident conduction disease remain unknown. Understanding factors that accelerate or delay conduction abnormalities could help identify therapies to treat or prevent this condition.

Hypothesis:
Clinical variables associated with myocardial fibrosis will increase conduction system disease risk while treatment with lisinopril (an anti-fibrotic) will reduce this risk.

Methods:
The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial was a double-blind clinical trial that randomized 33,357 hypertensive participants ≥ 55 years of age with at least one other cardiovascular risk factor to treatment with amlodipine, lisinopril, or chlorthalidone. An electrocardigram (ECG) was obtained at study enrollment and at every two years of follow up. Conduction system disease was defined as LBBB, RBBB, intraventricular conduction delay, or 1st degree AV block. Participants without a baseline or follow up ECG (n=4,510) or with baseline conduction disease (n=6,181) were excluded. Cox proportional hazards models were used to examine predictors of incident disease.

Results:
Among 21,129 participants without prevalent conduction disease, 444 developed LBBB, 608 developed RBBB, and 1,138 developed any conduction defect during a mean 5.0 ± 1.2 years of follow up. Several factors were significantly associated with incident disease (Figure). Compared to chlorthalidone, lisinopril was associated with a significant 19% reduction in conduction abnormalities (HR 0.81, 95% CI 0.69-0.95).

Conclusions:
Incident conduction system disease is independently associated with multiple clinical factors and is significantly reduced by lisinopril therapy. Further studies are warranted to determine if pharmacologic treatment can impact conduction abnormality outcomes, including pacemaker implantation.
Abstract 16514: Magnetic Resonance Imaging-Detected Carotid Plaque Characteristics Predict Systemic Cardiovascular Outcomes in Patients With Clinically Established Atherosclerosis in the AIH-HIGH Study
Authors: Sun Jie , Zhao Xue-Qiao , Balu Niranjan , Neradilek Moni B , Isquith Daniel A , Yamada Kiyofumi , Canton Gador , Crouse John R , Anderson Todd J , Huston John , O’Brien Kevin , Hippe Daniel S , Polissar Nayak L , Yuan Chun , Hatsukami Thomas S
Published: July 2021

Background:
Although vulnerable plaques are considered the pathological substrate for acute cardiovascular events, the pursuit of imaging surrogate markers for systemic atherothrombotic risk is currently focused on plaque burden. The prognostic value of vulnerable plaque characteristics as novel markers for systemic cardiovascular outcomes remains elusive. Advances in magnetic resonance imaging (MRI) have enabled characterization of the vulnerable carotid plaque. In a prospective study, we tested whether MRI-detected carotid plaque characteristics predict subsequent cardiovascular events.

Methods:
As part of an event-driven clinical trial, subjects with clinically established atherosclerotic disease were recruited. A multi-sequence protocol was used to measure the volumes of calcification and necrotic core (NC), and to identify the presence of intraplaque hemorrhage (IPH) and thin/ruptured fibrous cap (FC) using published criteria. The primary endpoint included fatal and non-fatal myocardial infarction or ischemic stroke, hospitalization for acute coronary syndrome, and symptom-driven revascularization. Cox regression analysis was used to present results as hazard ratio (HR) with 95% confidence interval (CI).

Results:
Of 232 subjects recruited, 214 (92.2%) with diagnostic image quality constituted the study population (mean age: 61±9 years; male: 82%; statin use: 94%). Calcification, NC, IPH, and thin/ruptured FC were detected in 48%, 52%, 8% and 14% of subjects, respectively. During a median follow-up of 35.1 months, 18 (8.4%) subjects reached the primary endpoint. MRI-detected plaque characteristics associated with the primary endpoint included larger NC (HR per 1 standard deviation increase in volume [1-SD]: 1.43 [1.16, 1.75], p<0.001), thin/ruptured FC (HR: 4.31 [1.67, 11.12], p=0.003), and marginally IPH (HR: 3.00 [0.99, 9.13], p=0.053). Although calcium deposition is traditionally pursued as a marker for atherosclerosis, subjects with larger calcification (HR per 1-SD: 0.60 [0.26, 1.41], p=0.20) did not show increased risk.

Conclusions:
Vulnerable plaque characteristics are prevalent in carotid arteries of patients with established atherosclerosis and are predictive of systemic cardiovascular outcomes.
Abstract 16620: The Prognostic Value of Mechanical Dyssynchrony Measured by GSPECT MPI versus Electrical Dyssnchrony Measured by QRS Duration Among Patients With an Ejection Fraction >35%
Authors: Hess Paul L , Shaw Linda K , Al-Khatib Sana M , Samad Zainab , Velazquez Eric J , O’Connor Christopher M , Borges-Neto Salvador
Published: July 2021

Background:
Whether mechanical dyssynchrony measured by phase analysis of gated single-photon emission computed tomography myocardial perfusion imaging (GSPECT MPI) adds prognostic information to electrical dyssynchrony or is is associated with death among patients with an EF >35% is incompletely understood.

Methods:
We identified consecutive patients with angiographically significant coronary disease who underwent GSPECT MPI in the Duke Databank for Cardiovascular Disease between July 2003 and May 2009. Serial Cox proportional hazards models consisting of clinical variables only, clinical variables plus electrical dyssynchrony as measured by QRS duration, clinical variables plus mechanical dyssynchrony according to the duration of the cardiac cycle during which 95% of the ventricle is initiating contraction (phase bandwidth),and a final model inclusive of all of these variables were fitted.

Results:
A total of 1,157 patients were identified. The median age was 64 (interquartile range (IQR) 55-72 years). Patients were predominantly white (73.8%), of male sex (67.7%), and had hypertension (76.7%). A minority had congestive heart failure (21.9%), peripheral vascular disease (10.5%), and cerebrovascular disease (12.2%). The median QRS duration was 92 (IQR 84-103) ms, while the median bandwidth was 58 (IQR 41-90)°. The median duration of follow-up was 4.3 (IQR 3.0-6.4) years. A total of 293 deaths were observed. Mechanical dyssynchrony added prognostic information independent of standard clinical variables and electrical dyssynchrony (Figure).

Conclusions:
Mechanical dyssynchrony measured by GSPECT MPI is independently associated with death and adds prognostic information above that provided by standard clinical covariates and electrical dyssynchrony among patients with an EF>35%. Whether cardiac resynchronization therapy improves outcomes among patients with mechanical dyssynchrony measured by GSPECT requires further study.
Abstract 16650: Role of Copper Transport Proteins in VSMC Phenotypic Modulation and Vascular Remodeling
Authors: Kamiya Tetsuro , Das Archita , Varadarajan Sudhahar , Clifford Rebecca , Mckinney Ronald D , Kaplan Jack , Ushio-Fukai Masuko , Fukai Tohru
Published: July 2021

Vascular smooth muscle cell (VSMC) phenotypic modulation plays a critical role in vascular repair and vascular remodeling after injury. This involves transition from quiescent contractile (C) to de-differentiated phenotype (S)(C to S) induced by PDGF, followed by re-differentiation to contractile phenotype (S to C). Copper (Cu), an essential micronutrient, is involved in vascular remodeling, and its bioavailability is controlled by Cu transport proteins (importer CTR1 and exporter ATP7A) and Cu chaperone (antioxidant-1, Atox1), which activates Cu enzymes such as amine oxidase, SSAO. However, role of Cu transport proteins in VSMC phenotypic modulation is entirely unknown. Here we show that PDGF stimulation in primary VSMC induced de-differentiation (C to S) by downregulating contractile SMC protein, which was accompanied by a robust increase in Cu uptake and CTR1, ATP7A and SSAO levels, and inhibited by Cu chelators. Knockdown of CTR1, ATP7A, SSAO, but not siAtox1, suppressed PDGF-induced VSMC de-differentiation (69%, 72% and 92%, respectively). Of note, ATP7A depletion inhibited PDGF-induced SSAO while SSAO siRNA suppressed ATP7A induction, suggesting that there is a positive feedback loop whereby ATP7A-SSAO pathway promotes de-differentiation. Mechanistically, PDGF-induced expression of KLF4, a repressor of SMC protein expression, was blocked by depletion of CTR1, ATP7A and SSAO. We reported that Atox1 also functions as a Cu-dependent transcription factor independent of ATP7A. Consistently, Atox1 siRNA suppressed serum starvation-induced VSMC re-differentiation, and overexpression of Atox1 increased SMC contractile gene expression. In vivo vascular injury model showed that SSAO and Atox1 were increased in neointimal SMCs at early de-differentiation phase and at later re-differentiation phase, respectively, in response to injury.

Summary and Conclusion:
CTR1-ATP7A-SSAO pathway is involved in PDGF-induced VSMC de-differentiation via regulating KLF4 while Cu dependent transcription factor function of Atox1 promotes VSMC re-differentiation via regulating SMC contractile gene transcription. Cu transport proteins and SSAO are potential therapeutic targets for modulating VSMC phenotype switching and vascular remodeling.
Abstract 16682: No Increased Risk of Early or Late Adjudicated Cardiovascular Events With Dapagliflozin
Authors: List James , Sonesson Christian , Gause-Nilsson Ingrid , Ptaszynska Agata , Johnsson Eva , Johansson Peter A , Frederich Bob
Published: July 2021

Dapagliflozin (DAPA), a sodium-glucose cotransporter 2 inhibitor, reduces plasma glucose in patients (pts) with type 2 diabetes by inhibiting renal glucose reuptake leading to glucosuria. DAPA has diuretic and longterm weight loss effects, and is associated with blood pressure (BP) reduction. Diuresis and BP reduction are evident soon after commencement of therapy, raising the question of whether there could be time dependent effects on cardiovascular safety. Data were pooled from 21 double blind phase 2b and phase 3 studies of DAPA with duration of treatment of up to 4 years and analyzed for prospectively adjudicated composite CV event end points, both for major adverse cardiac events ([MACE]; CV death, myocardial infarction, and stroke) and for the prespecified primary end point of MACE plus unstable angina (UA). The pt cohort (n=5936 for DAPA; n=3403 for controls) included 3214 pts with a history of CV disease. As previously reported, the overall hazard ratio for the primary end point between DAPA and control cohorts was 0.79 (95% CI 0.58-1.07). For MACE it was 0.77 (95% CI 0.54-1.10). Although the hazard rates (HR) per month demonstrated large variation, the HR for the primary end point and for MACE in the DAPA group in the first 30 days were similar to later time points, showing no evidence of an early increase in risk (Figure). Kaplan-Meier estimates of both end points showed no notable separation between DAPA and control in the first 30 days of treatment; however, a separation favoring DAPA started at approximately 250 days that was not statistically significant. Baseline characteristics for pts who had events in the first 30 days were similar to those of the general population and did not suggest a population with early risk for MACE events. Results were consistent across composite end points and pt subgroups with respect to history of a CV event.

In conclusion, there was no increase in early CV events with DAPA, and no evidence for a population susceptible to early CV events with DAPA.
Abstract 16692: MicroRNA 1825 Acts as a Master Regulator Inducing Proliferation of Adult Cardiomyocytes and Regenerates Ischemic Myocardium
Authors: Pandey Raghav , Durrani Shazia , Jiang Shujia , Savani Umeirra , Ahmed Rafeeq P
Published: July 2021

Background:
While cardiomyocytes (CMs) in zebrafish and neonatal mice are known to proliferate and regenerate the infarcted heart, this capacity is lost in adult mammals. From our unpublished RNA sequencing data using rat neonatal CMs (NCM) transfected with miR-1825 we identified miR-99a and miR-199a to be downstream effectors of miR-1825. In this study we aim to elucidate the mechanism and relative contribution of each of these miRs in inducing adult CM (ACM) proliferation.

Methods and Results:
CMs were isolated from 8-12 week old adult rat hearts and transfected with miR-cel-67 (control), miR-1825, miR-99a, and miR-199a. To label proliferating CMs EDU was added daily. On day 5 cells were fixed and stained for EDU, and Troponin I (TnI) (CM marker). MiR-1825 transfected CMs showed 50±5% increase in proliferation compared to control 11.2±3%, while miR-99a and miR-199a showed an increase of 14±3% and 16±2%, respectively. To identify the relative contribution of these downstream miRs additional experiments using respective miRNA inhibitors were carried out revealing proliferation of 40±4% with miR-1825+anti-miR-99a and 22±3% with miR-1825+anti-miR-199a, which were lower than miR-1825 alone. These results indicate that miR-1825 works both independently as well as through miR-99a and miR-199a. To elucidate a mechanism for miR-1825 mediated proliferation of ACM, we performed protein analysis and found a significant reduction in expression of p16, while cyclin-D1 was significantly increased in miR-1825 transfected ACMs. To further identify in-vivo proliferative potential, following LAD ligation we transduced 12 week old (C57BL/6) mice hearts with miR-1825 and miR-cel-67(control). EDU was administered IP up to day 12 post surgery. Four weeks after LAD ligation mice were euthanized and hearts were perfused and harvested for histochemical studies. A significant increase in proliferating ACMs was seen in heart receiving miR-1825 (11.4±3.6% ) vs miR-cel-67 control (1.35± 0.5%).

Conclusion:
We determine that miR-1825 acts as a master regulator of downstream miRs, and induces proliferation of ACMs through regulation of cyclin-D1 and p16. Overall, this project determines a hierarchical role of miR-1825 and elucidates a novel mechanism of ACM proliferation.
Abstract 16772: Discovery of a Novel Approach for Modulating Angiogenesis: The Interaction Between Heat Shock Protein 27 and ATP5A1 Promotes Endothelial Cell Dynamics
Authors: Li Yumei , Shi Chunhua , Chen Yongxiang , Koumbadinga Geremy , Adijiang Ayinuer , O’Brien Edward R
Published: July 2021

Introduction:
ATP5A1 is the alpha subunit of the soluble F1 catalytic core of mitochondrial ATP synthase that catalyzes ATP synthesis. Previous studies identified ATP synthase as the receptor for the anti-angiogenic factor, angiostatin. We demonstrated that Heat Shock Protein 27 (HSP27) functions in the extracellular space to accelerate re-endothelialization (FASEB 2014) and more recently using mass spectrometry identified ATP5A1 as a potential cell membrane client protein of HSP27.

Hypothesis:
HSP27 interacts with ATP5A1 to promote endothelial dynamics.

Methods / Results:
(1) The binding of HSP27 to ATP5A1 was quantified using an ELISA by coating plates with an anti-ATP5A1 antibody. While a negative control truncated C-terminus form of HSP27 did not bind ATP5A1, full length HSP27 showed an abundant binding pattern to HSP27 that was further enhanced by the presence of auto-antibodies to HSP27.

(2) As detected by immunofluorescence imaging and use of a fluorescent activated cell sorter, ATP5A1 expression was up-regulated in endothelial cells that over-express HSP27.

(3) ATP production in endothelial cells was increased after exposure to HSP27 (p<0.01 vs. control; detected using a Luciferin-Luciferase ATP detection assay).

(4) Endothelial cell migration in vitro was increased with the addition of HSP27. Indeed, HSP27 in combination with anti-HSP27 auto-antibodies potentiated the interaction with ATP5A1.

Conclusions:
The interaction of HSP27 with cell membrane localized ATP5A1 appears to be a key mechanism of enhancing endothelial cell dynamics. Interestingly, the presence of auto-antibodies to HSP27 potentiates this effect and is explained in separately described data regarding anti-HSP27 immune phenomena in cell signaling. These data provide for the first time impetus for the development of angiogenesis modulating strategies that either promote or antagonize the interaction between HSP27 and ATP5A1 in order to enhance or suppress angiogenesis, respectively.
Abstract 16796: β2-Adrenergic Receptor Expression on Hematopoietic Cells is Critical for Survival Following Myocardial Infarction
Authors: Grisanti Laurel A , Repas Ashley A , Gao Erhe , Gumpert Anna M , Carter Rhonda L , Koch Walter J , Tilley Douglas G
Published: July 2021

β-adrenergic receptors (βAR) are critical regulators of cardiac function normally and during (HF). The importance of βAR on cardiomyocyte contractility and survival is well defined however, following myocardial infarction (MI), inflammatory responses occur, which are critical for healing and scar formation. Catecholamines acting through βAR, particularly the β2AR subtype, are known to modulate immune responses, however, the influence of β2AR in regulating the inflammatory response following MI is unknown. To investigate the contribution of β2AR on immune cells following myocardial infarction (MI), wild-type (WT) mice were irradiated and then received β2ARKO or WT control BM transplants to create immune cell specific knockout (KO) animals. Following bone marrow reconstitution, mice were subjected to MI and cardiac function and survival were monitored. Cardiac function, as assessed by echocardiography, did not differ between WT and β2ARKO chimeric mice. However, mice lacking β2ARKO in their BM resulted in 100% mortality from cardiac rupture within two weeks of receiving MI in contrast to their WT counterparts that had ~20% death. Masson trichrome staining demonstrated infarct expansion in β2ARKO chimeric mice occurred more rapidly than their WT counterparts. Flow cytometric analysis showed decreased mobilization of granulocytes from bone marrow in β2ARKO mice. Additionally, β2ARKO chimeric mice reductions in infiltrating monocyte/macrophage, neutrophil and mast cell populations in the heart with no change in total cell infiltration suggesting a disruption in the ratio of infiltrating immune cells. Alterations in chemokine receptor levels, particularly CCR2, on BM resulted in decreased cellular migration. These results demonstrate the critical role of β2AR in mounting an immune response and promoting healing following MI.
Abstract 16821: Impact of Patient Transfers on Outcome Evaluations Following Acute Myocardial Infarction
Authors: Pak Melissa , Izadnegahdar Mona , Lee May K , Gao Min , Humphries Karin H
Published: July 2021

Introduction:
Patients hospitalized for an AMI are commonly transferred to tertiary care facilities to receive advanced procedures. In the United States, transferred patients are often excluded from outcome evaluations due to limitations in ascertaining outcomes. In Canada, centralized administrative and clinical databases allow for linkage of outcomes across institutions. This study evaluated the influence of excluding transferred AMI patients on estimates of age and sex-specific 30-day mortality rates over a 10-year period.

Methods:
All incident AMI hospitalizations (ICD-9: 410 and ICD-10: I21, I22) to acute care hospitals in British Columbia from 2000 to 2009 were identified through the Discharge Abstract Database and linked to mortality through the Vital Statistics registry. A transfer was identified as a discharge from the index AMI admission hospital to another hospital. Thirty-day mortality was defined as any death within 30 days of the index hospitalization. A logistic regression model was used to compare transfer rate by age (20-55, 56-64, 65-74 and ≥ 75 years), sex and admission year. Thirty-day mortality rates by sex and age were calculated with and without transferred patients.

Results:
Of the 67,444 AMI hospitalizations identified, 38.6% involved at least one transfer. Overall, younger patients were more likely to be transferred. Transfer rates increased over time in all age groups but with different slopes (p = 0.02) regardless of sex, and differed significantly between sexes only in those ≥ 75 (p < 0.001; Fig. A). Thirty-day mortality rates were overestimated in each age-sex category when transferred patients were excluded, compared to rates that included all patients, irrespective of transfer status (Fig. B).

Conclusions:
The rate of patient transfers post AMI has increased over time. Excluding transferred patients results in overestimates of 30-day mortality, and thus impacts outcome assessments. This impact is expected to increase over time.
Abstract 16882: Over Expression of
Scn5a
in Mouse Heart Mimics Human Syndrome of Enhanced Atrioventricular Nodal Conduction
Authors: Liu Gongxin , Belardinelli Luiz , Rajamani Sridharan , Remme Carol Ann , Boukens Bastiaan J.D.
Published: July 2021

Introduction:
The mechanism of enhanced atrioventricular nodal conduction (EAVNC), including Lown-Ganong-Levine (LGL) syndrome, is not well described. Transgenic mice with the over-expression
SCN5A
results in a shorter P-R interval; hence, we tested the hypothesis that overexpression of
SCN5A
may provide an animal model mimicking EAVNC.

Methods:
Electrocardiogram (ECG), atrial, His-bundle and ventricular electrograms were recorded from wild type (WT) and transgenic mice over-expressing
SCN5A
(TG). Peak Na
+
current (I
Na
) and Nav1.5 expression were measured using patch-clamp technique and immunohistochemistry method, respectively.

Results:
P-R interval in TG was much shorter than in WT mice (13.6±1.20 vs. 40.2±0.59 ms, n=20 and 35). In TG isolated hearts the A-V conduction during right atrial pacing remains shorter than that of WT isolated hearts (14.4±0.81 vs. 39.5±0.62 ms, n=28 each). His-bundle electrogram (HBE) revealed a short A-H and H-V intervals in TG, compared to WT mice (Figure 1A-D). In addition, TG mice had a short Wenckebach cycle length (CL) and atrioventricular effective refractory period (AVERP). Peak I
Na
was 2-fold greater in TG compared to WT ventricular myocytes (198.2±16.22 vs. 89.6±5.35 pA/pF, n=12). Flecainide (6 μM, n=6) led to prolongation of A-V conduction time in TG to a value close to that of WT hearts. Nifedipine (1 μM, n=) prolonged A-H interval in WT but not in TG hearts. Immunohistochemistry studies revealed increased Nav1.5 labeling in TG atrial and ventricular tissue, and Nav1.5 expression in A-V junction and A-V ring regions of TG compared to WT hearts.

Conclusion:
SCN5A over expression in TG mice enhanced the A-V conduction mimicking EAVNC. Thus, higher level of sodium channel expression in the A-V nodal region may be an electrophysiological substrate responsible for the syndrome of EAVNC.
Figure 1
Abstract 16936: Implications of the 2013 ACC/AHA Cholesterol Guidelines for Adults in Contemporary Cardiovascular Practice: Insights from the NCDR® PINNACLE Registry®
Authors: Maddox Thomas , Borden William , Tang Fengming , Virani Salim , Oetgen William , Mullen Brenden , Chan Paul , Casale Paul , Douglas Pamela , Masoudi Frederick , Farmer Steve , Rumsfeld John
Published: July 2021

Background:
In a significant update, the 2013 ACC/AHA cholesterol guidelines recommend fixed-dose statin therapy for those at risk and do not recommend non-statin therapies or treatment to target LDL-C levels, limiting the need for repeated LDL-C testing. We examined the implications of these updated guidelines on current lipid treatment and testing patterns in a national registry of cardiology practices.

Methods:
Using NCDR® PINNACLE Registry® data from 2008 to 2012, we assessed current practice patterns as a function of the 2013 cholesterol guidelines. Lipid-lowering therapies and LDL-C testing patterns by patient risk group (atherosclerotic cardiovascular disease (ASCVD), diabetes, off-treatment LDL-C ≥190mg/dL, or an estimated 10-year ASCVD risk ≥7.5%) were described.

Results:
Among a cohort of 1,174,545 patients, 1,129,205 (96.1%) were statin-eligible (91.2% ASCVD, 6.6% diabetes, 0.3% off-treatment LDL-C ≥190mg/dL, 1.9% estimated 10-year ASCVD risk ≥7.5%). 377,311 (32.4%) patients were not receiving statin therapy and 259,143 (22.6%) were receiving non-statin therapies. 20.8% patients had 2 or more LDL-C assessments during the study period, and 7.0% had more than 4 assessments.

Conclusions:
In U.S. cardiovascular practices, 32.4% of statin-eligible patients, as defined by the 2013 ACC/AHA cholesterol guidelines, were not currently receiving them. In addition, 22.6% were receiving non-statin lipid-lowering therapies and 20.8% had repeated LDL-C testing. Achieving concordance with the new cholesterol guidelines would result in significant increases in statin use, as well as significant reductions in non-statin therapies and laboratory testing.
Abstract 16941: Questioning the efficacy of Proliferation Signal Inhibitors for established Coronary Artery Disease after Heart Transplant
Authors: Kornblit Adva , Patel Jignesh , Kittleson Michelle , Yu Zhe , Liou Frank , Yabuno Jamie , Azarbal Babak , Chang David H , Czer Lawrence , Kobashigawa Jon
Published: July 2021

Purpose:
Cardiac Allograft Vasculopathy (CAV) is one of the major factors limiting long term survival after heart transplantat (HTx). The use of proliferation signal inhibitors (PSIs) such as everolimus and sirolimus has been found to be effective in the prevention of CAV in multicenter studies. There has been 1 study (Mancini et al) that has suggested the use of Sirolimus can decrease the progression of CAV in patients (Pts) long term after Htx. It is not been evaluated in the current era of Tacrolimus (TAC)/Mycophenolate Mofetil (MMF) whether a switch from MMF to PSIs has such an advantage.

Methods:
Between 1998 and 2010, we evaluated 26 HTx Pts who had developed CAV according to the new ISHLT CAV nomenclature (CAV1, CAV2, CAV3) and were subsequently switched from TAC/MMF to TAC/PSIs. Pts who were maintained on TAC/MMF were served as 1:1 controls. Outcomes for these Pts included worsening of CAV by category at 3 year, subsequent 3-year survival and subsequent 3-year freedom from non-fatal major adverse cardiac events (NF-MACE: Myocardial Infarction, Congestive Heart Failure, angioplasty, pacemaker/ICD and stroke).

Results:
There were 26 patients in the switched to PSIs group and 23 patients in the maintained on MMF group. All patients were either CAV 1 or CAV 2 at baseline. The average time to switch to PSIs was 5.3 ± 3.3 years. At 3 year follow up, the percentage of patients who had worsened CAV by category were comparable among the two groups. Subsequent 3-year survival and 3-year freedom from NF-MACE were also comparable among the two groups (see Table).

Conclusions:
In the current era of TAC/MMF, switch from MMF to PSI for patients with established CAV does not appear to be beneficial in preventing progression of disease. A larger number of patients are needed to confirm this finding.
Abstract 16942: Alternatively Spliced Tissue Factor promotes plaque progression, inflammation and angiogenesis in experimental atherosclerosis
Authors: Alicea Daniel , Chudnovskiy Aleksey , Rodriguez David T , Yang Dong Kwon , Jeong Dongtak , Kovacic Jason C , Badimon Juan J , Weber Thomas , Merad Miriam , Hajjar Roger J , Fuster Valentin , Giannarelli Chiara
Published: July 2021

Introduction:
Alternatively Spliced Tissue Factor (asTF) is novel isoform of tissue factor with angiogenic activity mediated via HIF-1α signaling (Giannarelli, AHA 13). asTF is highly expressed in human complicated atherosclerotic plaques (Giannarelli, ACC 13); however, it is unknown whether asTF has a functional role in atherogenesis.

Hypothesis:
asTF promotes atherosclerotic plaque progression, inflammation and angiogenesis.

Methods:
ApoE-/- mice (8-weeks old; n=15) were fed a Western-type diet from 2 weeks before surgery continuing through the experiment. Immediately after transluminal wire injury of the left common carotid artery (LCCA), LCCA was incubated with lentivirus encoding asTF-GFP (asTF+ group; n=10) or GFP (asTF- control group; n=5). Four weeks after, blood and spleen were collected for flow cytometry analysis of neutrophils and monocytes. LCCA was removed and processed for H&E, Oil-Red O staining and immunostaining for macrophages (MOMA-2 and MAC-3), vascular smooth muscle cells (VSMC, α-actin), endothelial cells (CD31) and HIF-1α.

Results:
Neointimal thickness and plaque lipid accumulation were significantly greater in asTF+ vs asTF- mice (Fig 1, A-C). An increase in plaque macrophages, neovessels and HIF-1α was observed in asTF+ vs asTF- (Fig 1, D-F). Medial thickness and VSMC density were similar between groups. Increased circulating neutrophils and Ly6C
high
(classical/inflammatory) monocytes were observed in asTF+ vs asTF- mice (Fig 1, G,H). In contrast, circulating Ly6C
low
(patrolling) monocytes were significantly reduced (Fig 1, I). Similar findings were observed in the spleen (Fig 1, J-L).

Conclusions:
Our results demonstrate that asTF expressed within atherosclerotic lesions promotes plaque progression towards a more advanced phenotype and is associated with systemic proinflammatory status. These data makes asTF an attractive marker of plaque vulnerability and a potential therapeutic target for plaque stabilization.
Abstract 16958: ADHERE Risk Levels Predict 60-day Death and Re-hospitalization in Clinical Trial Patients with Acute Decompensated Heart Failure
Authors: Hebl Virginia B , Stevens Susanna R , Takahama Hiroyuki , Bart Bradley A , Chen Horng H , Felker G. M , Goldsmith Steven R , Redfield Margaret M
Published: July 2021

Background:
The Acute Decompensated Heart Failure National Registry (ADHERE) risk levels are a validated tool to assess the risk of in-hospital mortality in patients with acute decompensated heart failure (ADHF). The objective of this study is to determine if the risk levels predict 60-day outcomes in well-defined ADHF patients from NIH Heart Failure Clinical Research Network (HFCRN) trials.

Methods:
Our study cohort included 835 unique patients with ADHF enrolled in 3 NIH HFCRN trials: Diuretic Optimization Strategies Evaluation (DOSE), CARdiorenal REScue Study in Acute Decompensated Heart Failure (CARRESS-HF), and Renal Optimization Strategies Evaluation (ROSE). ADHERE risk level was assigned, as previously described, by baseline BUN (<43 vs. ≥43 mg/dL), Cr (<2.2 vs. ≥2.2, a modification from 2.75 mg/dL used in ADHERE due the Cr distribution in our study population), and systolic BP (≥ 115 vs < 115 mmHg). Baseline characteristics and outcomes were compared between risk levels.

Results:
Of the 835 patients enrolled in DOSE (308), CARRESS-HF (188), and ROSE (360), an ADHERE risk level could be assigned to 830, with 62 (8%) high, 521 (63%) intermediate, 247 (30%) low risk. Baseline characteristics (Table 1) and outcomes (Table 2), including combined 60-day death and re-hospitalization (hazard ratio 1.94, high risk versus low risk, p<0.01), varied by ADHERE risk level.

Conclusion:
ADHERE risk levels predict 60-day death and re-hospitalization rates in patients with ADHF. These results extend the utility of the ADHERE risk levels, by informing longer-term clinical decisions regarding advanced heart failure treatment, care transition strategies and clinical trial design.
Abstract 16963: A Novel Rehabilitation Intervention for Older Patients with Acute Decompensated Heart Failure: the REHAB-HF Pilot Study
Authors: Reeves Gordon R , Patel Mahesh J , Whellan David J , O’Connor Christopher , Eggebeen Joel D , Duncan Pamela , Morgan Timothy M , Hewston Leigh A , Pastva Amy , Adams Patricia A , Adams Suzanne , Kitzman Dalane W
Published: July 2021

Introduction:
Exercise training improves outcomes in patients with chronic, stable heart failure (HF). However, little is known regarding patients with acute decompensated HF (ADHF) who are typically elderly, frail, with multiple co-morbidities and frequent rehospitalizations.

Hypothesis:
A novel rehabilitation intervention in older patients hospitalized for ADHF will be feasible and safe, improve physical function and reduce rehospitalizations.

Methods:
This was a 3-site, randomized, attention-controlled pilot study of a tailored, progressive, multi-domain (strength, balance, mobility and endurance) rehabilitation intervention beginning in the hospital and continuing for 12 weeks post-discharge. The primary outcome was the Short Physical Performance Battery (SPPB) score, a standardized measure of physical function in frail elderly, assessed by a blinded observer; the secondary outcome was rehospitalizations.

Results:
We enrolled 27 patients aged 60-98 years: 59% women, 56% African-American, 41% preserved EF. Patients had ~ 5 co-morbidities and markedly impaired physical function; > 50% were frail. Characteristics were similar between groups. Study retention (89%) and intervention adherence (93%) were excellent. Figure 1 shows change in SPPB score and 6-minute walk distance. All-cause rehospitalizations were reduced by 29% (1.16±0.35 vs. 1.64±0.39) and all-cause rehospitalization days were reduced by 47% (6.0± 2.5 vs. 11.4±2.8) at 6 month follow-up. The change in SPPB score explained 90% of the reduction in all-cause rehospitalizations. There were no adverse events related to the intervention.

Conclusions:
These findings support the feasibility, safety and potential efficacy of a novel multi-domain rehabilitation intervention to improve physical function and reduce rehospitalizations in older, frail ADHF patients with multiple comorbidities. An NIH-funded multi-center trial is being launched to confirm these findings.
Abstract 17007: Does Age Modify Gender-based Differences in Clinical Outcomes Following Percutaneous Coronary Intervention (PCI)
Authors: Theodoropoulos Kleanthis , Yu Jennifer , Aquino Melisssa , Baber Usman , Roy Swathi , Kovacic Jason , Sweeny Joseph , Mehran Roxana , Sharma Samin , Kini Annapoorna
Published: July 2021

Introduction:
Women experience higher complication rates and mortality after PCI than men but it remains unknown whether these differences are sustained among younger and older patients.

Hypothesis/Objectives:
To investigate if previously reported gender-based disparities in outcome following percutaneous coronary intervention (PCI) are modified by age in a large and racially-diverse cohort in the drug eluting stent (DES) era.

Methods:
A total of 23,400 patients (7942 female, 34%) underwent PCI of de novo lesion(s) from 01/2005 to 12/2012 at Mount Sinai Hospital. We compared demographics, procedural characteristics, and 1-year rates of death, myocardial infarction, and major adverse cardiovascular events (MACE), by sex in younger (≤65 years old, n=11,381) and older (>65 years old, n= 12,019) patients.

Results:
Regardless of age, compared to males, females had higher body mass index (BMI), better renal function, smoked less, but were more hypertensive and diabetic. Women had higher HDL and LDL cholesterol levels. More women presented with an unstable coronary syndrome and required left anterior descending artery PCI. Women had more vascular and bleeding complications post-PCI but the 30-day readmission rate did not differ between genders within age groups. At 1 year women, in both age categories, were at higher risk for death or myocardial infarction than men. Among younger patients, women had more MACE than men, but formal interaction testing was negative (Figure).

Conclusion:
Females undergoing PCI have more comorbidities and are at higher risk for unfavorable outcomes than males. The substantial gender-based differences in clinical outcomes following PCI were independent of age suggesting that preventive strategies should be promoted amongst women.
Abstract 17011: Gender Differences in the Cardiovascular Risk Factors in First acute myocardial infarction in a Middle Eastern Country over a 20-year period
Authors: Ahmed Emad , El-Menyar Ayman , Al Suwaidi Jassim , AlBinAli Hajar AH , Singh Rajvir , Gehani Abdurrazzak A
Published: July 2021

Introduction:
Coronary artery disease (CAD) is a global health problem and a leading cause of death worldwide.

Hypothesis:
In Middle East, the rate of CAD is expected to rise in parallel with the increase in per capita income and cardiovascular risk factors (CVRFs) burden. The present study evaluates temporal trends in CVRFs stratified by gender over a 20-year period in Qatar.

Methods:
All patients hospitalized with first acute myocardial infarction (AMI) during the study period were analyzed and compared in 2 groups: group 1 (1991-2000) and group 2 (2001-2010).

Results:
Among 10,915 patients who were admitted with first AMI, 9610 (88%) were men and 1305 (12%) were women. The overall mean age was 52.7±11.8 years. The overall rate of

hospitalization increased from 34% to 66% (p<0.001), representing a relative increase by 48%.The proportion of men to women remained relatively constant.During the study period. most of the measured CVRFs have shown a steady upward trend in both sexes. Compared to men, women were older, had a higher burden of CVRFs and presented mainly with non-ST-elevation MI. However, in comparison to group 1, women in group 2 had significant increases in the prevalence of dyslipidemia and obesity. Multivariate logistic regression analysis showed that female gender was independent predictor of in-hospital mortality (odd ratio 1.92, 95% CI 1.60-2.77).

Conclusions:
Over the study period, the rate hospitalization increased by nearly half, this potentially could be explained by the unfavorable alteration in the major modifiable CVRFs. Furthermore, women with acute myocardial infarction represent a higher risk group.
Abstract 17013: Post-traumatic Stress Disorder is Associated with Adverse Non-Linear Heart Rate Variability in Veteran Twins
Authors: Kella Danesh K , Lampert Rachel , Lee Forrester , Goldberg Jack , Bremner Douglas , Vaccarino Viola , Shah Amit J
Published: July 2021

BACKGROUND:
Veterans with post-traumatic stress disorder (PTSD) have higher risk of coronary heart disease (CHD) incidence and mortality. Psychological conditions may have an adverse effect on the autonomic nervous system, and may in part have genetic origins. Novel non-linear measures of heart rate variability (HRV), such as fractal dimension (FD) and power law slope have been associated with mortality and may signify autonomic dysfunction. We hypothesized that PTSD is associated with reduced FD and increased power law slope, suggesting higher mortality risk.

METHODS:
FD and power law slope were measured from 24-hour Holter recordings in 416 predominantly healthy middle-aged male twins from the Vietnam Era Twin Registry. Current (symptoms within the past month) and remitted (past history of) PTSD were measured using the Structured Clinical Interview for Psychiatry Disorders. Mixed-effect regression models were used to adjust for twin clustering and account for genetic/familial influences.

RESULTS:
The mean age was 56 ± 3 years, 35 had current PTSD, and 46 had remitted PTSD. In models that analyzed twins as individuals, current PTSD was significantly associated with 22% reduced FD and 18% increased power law slope. This association persisted for power law slope after adjustment for traditional risk factors, lifestyle factors, depression, and anti-depressant medication use (table). After controlling for genetic/familial factors by comparing twin brothers discordant for current PTSD within pairs (20 pairs), both measures remained significantly associated with current PTSD. Remitted PTSD did not influence HRV measures. No interaction by zygosity was found.

CONCLUSIONS:
Vietnam era veterans with PTSD have reduced FD and increased power law slope persisting after multivariable adjustment. This suggests that autonomic mechanisms, independent of genetic and familial effects, may contribute to increased CHD and mortality in veterans with PTSD.