bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 16483: Prognostic Value of Neurological Exam in Cardiac Arrest Patients Treated With Therapeutic Hypothermia in the Absence of Withdrawal of Life-sustaining Therapy
Authors: Matthews Elizabeth , Magid-Bernstein Jessica , Velazquez Angela , Falo Cristina , Park Soojin , Claassen Jan , Agarwal Sachin
Published: July 2021

Objectives:
Withdrawal of life-sustaining therapy (WLST) is the most common cause of death following cardiac arrest (CA). A well-described “self-fulfilling prophecy” exists, in which a poor exam often prompts WLST. The prognostic value of the neurological exam at various time points, in the absence of WLST, remains unknown.

Methods:
All patients (N=291) treated at Columbia University with therapeutic hypothermia (TH) following CA between May 2007 and February 2015 were identified. Neurological exams were documented at admission, 72 hours, five days and seven days after arrest. Glasgow coma motor scores (GCS-motor) no better than extensor posturing, bilaterally absent pupillary light response and bilaterally absent corneal reflexes were considered poor exams. Patients were excluded if the cause of death was WLST (n=125) or they died despite full support prior to 7 days (n=70). A cerebral performance score (CPC) at hospital discharge of 3-5 was considered a bad outcome. False positive rates (FPRs) in percentages were calculated.

Results:
A total of 96 patients were analyzed (average age 59±17 years, 40% female, 91% with pre-hospitalization CPC 1-2, bystander CPR in 69%, initial rhythm of VT/FT in 41%, mean ROSC 19±15 minutes). Sixty-one percent of patients had a poor outcome. GCS-motor was associated with a poor outcome, with FPRs of 36.3% (21-63.6), 29.4% (15.7-47.7), 11.8% (3.8-28.4) and 10.8% (3.5-26.4) at admission, 72 hours, five days and seven days respectively. Bilaterally absent corneal reflexes had FPRs of 29.2% (13.4-51.3), 26.3% (10.1-51.4), 5.3% (0.3-28.1) and 0% (0-18.5). Bilaterally absent pupillary response had the lowest FPRs at 8.3% (2.2-23.6), 0% (0-13.3), 0% (0-14.1), and 0% (0-13.7).

Conclusion:
A poor neurological exam remains a significant predictor of poor outcome following cardiac arrest. In the setting of TH, the pupillary exam reaches 100% specificity at 72 hours, while the GCS-motor and corneal reflex have unacceptably high rates of good outcomes despite poor exams. They become more specific over time, suggesting that patients may benefit from delaying prognostication until at least five days after arrest.
Abstract 16508: Effect of Disclosure of Genetic Risk for Coronary Heart Disease on Information Seeking and Information Sharing in a Randomized Clinical Trial (from the MI-GENES Investigators)
Authors: Brown Sherry-Ann , Jouni Hayan , Austin Erin , Marroush Tariq , Kullo Iftikhar ,   MI-GENES Investigators
Published: July 2021

Background:
Whether disclosing genetic risk for coronary heart disease (CHD) to individuals influences information seeking and information sharing is not known.

Methods:
The myocardial infarction genes (MI-GENES) trial randomized participants aged 45-65 years who were at intermediate risk for CHD based on conventional risk factors and not on statins, to receive their conventional risk score (CRS) or their CRS plus a genetic risk score (GRS) based on 28 susceptibility variants. CHD risk was disclosed by a genetic counselor and then discussed with a physician. Surveys to assess information seeking (including internet use and accessing electronic health records (EHR)) were completed before and three and six months after risk disclosure. Information sharing parameters were assessed after risk disclosure. We assessed whether these behaviors differed by GRS disclosure, or by high (≥1.1) or low (<1.1) GRS. Adjustments were made for age, sex, family history of CHD, baseline CRS and GRS, and education. Results were reported as the mean difference (and standard error) in the score for each survey response between the GRS and CRS participants, with significance determined by regression analysis.

Results:
GRS participants accessed their EHR to obtain information related to their CHD risk more than CRS participants (0.14 ± 0.06, p=0.03). Overall internet use (0.61 ± 0.23, p=0.01), as well as internet use to seek information about heart disease (0.14 ± 0.06, p=0.02) and how genetic factors affect risk of having a heart attack (0.23 ± 0.07, p=0.002), was significantly higher in the GRS participants. GRS participants shared information about heart attack risk with others (0.35 ± 0.13, p=0.007), particularly family members (0.1 ± 0.04, p=0.02), (V4: 0.10 ± 0.05, p=0.05), and their primary care provider (V4: 0.15 ± 0.07, p=0.03) more than CRS participants. Internet use, EHR access, and information sharing did not differ significantly between the high and low GRS groups.

Conclusions:
Disclosure of GRS for CHD resulted in greater information seeking (including internet use and EHR access) and information sharing by study participants. Disclosure of genetic risk for CHD may help advance patient engagement in precision medicine.
Abstract 16542: Predictors of Mortality in Patients With Light Chain (AL) Amyloidosis Heart Failure: A Multi-variate Analysis
Authors: Tahir Usman , Doros Georghe , Kim John S , Connors Lawreen H , Sam Flora
Published: July 2021

Background:
AL deposition in the heart occurs in about half of all patients affected by systemic AL amyloidosis, conferring an extremely poor prognosis. Cardiac involvement in AL amyloid (AL-CMP) may result in clinical heart failure (HF). Once HF occurs, the median survival is ~6 months if untreated. We thus sought to determine clinical characteristics and predictors of mortality in AL-CMP with HF.

Methods:
Between 2004-2014, patients with biopsy-proven AL-CMP, Stage C HF and
without
prior immunosuppressive therapy were enrolled at first visit to the Amyloid Clinic at Boston University Medical Center. Routine laboratory tests, physical examination and echocardiography were performed.

Results:
The AL-CMP cohort comprised of 165 patients. Mean age was 61.6±9.8 yrs., predominantly white (76.4%) and 60.6% were men. Median time to survival was 10.9 months (95% CI 6.2, 14.7) Figure 1. Age, atrial fibrillation, NYHA class, CRP, BNP, LV ejection fraction, relative wall thickness and intraventricular septum size were independent predictors of all cause mortality in univariate analysis. Only age [HR 1.04 (1.01-1.06)], log BNP [HR 1.45 (1.15-1.8)], CRP [HR 1.02 (1.00-1.04)], NYHA class [HR 1.50 (1.02-2.2)] and relative wall thickness [HR 6.70 (2.45-18.30)] were predictors of all cause mortality in multivariate analysis (P<0.05).

Conclusions:
In addition to using cardiac biomarkers such as BNP and troponin, which are predictors of prognosis and are used to guide staging and treatment in AL amyloidosis, we identified additional prognostic markers once patients with AL cardiac amyloid develop HF. Relative wall thickness is
the
strongest predictor of mortality. These markers can be used to help identify AL cardiac amyloid patients with HF at greatest risk for poor outcomes.
Abstract 16581: Pre-existing Venous Intimal Hyperplasia Explains Post-operatory Neointima Growth but Fails to Predict Arteriovenous Fistula Failure: The Matched-pair Cohort Study
Authors: Escobar Luis A , Tabbara Marwan , Duque Juan C , Martinez Laisel , Wu Wensong , Pan Yue , Fernandez Natasha , Velazquez Omaida , Salman Loay , Vazquez-Padron Roberto I
Published: July 2021

Introduction:
Arteriovenous fistulae (AVF) failure is the most common complication in hemodialysis patients. It compromises dialysis treatment, worsens patients’ quality of life and increases the medical costs associated with the maintenance of vascular accesses. There is a belief that AVF failure is mainly due to occlusive neointimal hyperplasia. This study assesses for the first time the impact of pre-existing venous intimal hyperplasia on post surgical neointima development and AVF function (patency).

Methods and Results:
Fifty one patients undergoing two-stage brachiobasilic AVF creation at the University of Miami Hospital and Jackson Memorial Health System were enrolled. Matched pair tissue samples were taken from each patient. The proximal basilic vein was procured during vascular access creation while the second biopsy was obtained at the time of AVF transposition for its superficialization. Tissues were rapidly formalin-fixed and cross-sectioned for histomorphometric measurements of the neointima and media areas. Pre-existing intima hyperplasia was persistent among most basilic veins with neointima to media ratios (N/M) ranging between 0.075 and 0.709 (mean: 0.289). The neointimal lesion size experienced a 2.26 fold increased during fistula maturation (p<0.0001, paired t-test). A general linear regression model controlled for multiple baseline covariates revealed the existing positive correlation between the venous intima hyperplasia and the later neointimal growth in the corresponding AVF (B=0.728, p=0.0311). Unexpectedly, the venous N/M ratio failed to predict primary AVF patency using a COX proportional hazard model that included 9 baseline-covariates (age, gender, time between surgeries, diabetes, previous AVF and catheter, statins, anti-platelet and anti-hypertensive drugs).

Conclusions:
While pre-existing intimal hyperplasia correlates with the size of the post-operatory neointima in the AVF as revealed in this matched-pair cohort study, it has no impact on the future AVF function and success.
Abstract 16623: Can We Predict Ventricular Arrhythmias in Familial Left Ventricular Non Compaction?
Authors: Morgagni Riccardo , Forleo Giovanni Battista , Romeo Francesco
Published: July 2021

Introduction:
Left Ventricular Non Compaction (LVNC) is an unclassified cardiomyopathy characterized by left ventricular hypertrabeculation and deep intertrabecular recesses in communication with the ventricular cavity. LVNC is often associated with other cardiomyopathies or with genetical disorders, and is familial at least in 25% of cases. The diagnosis is based on echocardiographic criteria (Chin et al. 1990; Jenni et al.2001; Stollberger et al. 1987-2002). Hypothesis: The aim of this study was to assess the value of echocardiographic parameters in predicting the occurrence of arrhythmic events in patients with familial LVNC.

Methods:
we studied 26 subjects, aged 39.9 ± 16.2 years, 11 males and 15 females, at a single institution, representing 7 families with LVNC. None had concomitant hypertension, diabetes mellitus or other significant cardiovascular disorder. Patients were evaluated at 3-month interval either clinically or with 12-Lead ECG, echocardiography and 24-hour Holter monitoring. The average duration of follow up was 36 ± 9 months. Echocardiographic parameters, ejection fraction (EF) and end-diastolic diameter (EDD), were matched with ventricular arrhythmias (VA) to assess their predictive value. The Kaplan-Meier method was used to calculate the probability of ventricular events.

Results:
Left Ventricular (LV) systolic function was depressed in 10 of 26 patients (38.5%), with a mean EF of 44 ± 3.2% at the first visit. Nine of 26 patients (34.6%) had LV dilatation (EDD ≥ 60 mm): among them only 5 patients (55.5%) had EF < 45%. Six of 26 patients (23.1%) underwent episodes of ventricular tachycardia (VT) during follow up. All 6 patients (100%) had LV dilatation, among them only 3 patients (50%) had depressed EF. By Chi square test and Kaplan Meier analysis, the only echocardiographic predictor of VA was LV dilatation (p < 0.001). Conclusions: In families with isolated LVNC, LV dilatation was the only echocardiographic predictor associated with subsequent development of ventricular arrhythmias. This finding might be helpful to optimally target preventive therapies in patients with familial LVNC.
Abstract 16651: Development of a Novel Cardiac Arrest Model in Aged Mice
Authors: Sheng Huaxin , Liu Huaqin , Xu Bin , Yu Zhui , Paschen Wulf , Warner David S , Yang Wei
Published: July 2021

Introduction:
Cardiac arrest (CA) occurs commonly in daily life, especially for elderly patients. However, most studies in CA and cardiopulmonary resuscitation (CPR) were performed in young animals. A relevant CA/CPR experimental model in aged animals is needed for better understanding the mechanisms of this disease and seeking advanced therapeutic approaches. In this study, we aimed to develop a novel mouse model that can be used to investigate CA/CPR in aged mice.

Hypothesis:
The aged mice subjected to CA/CPR would be resuscitated.

Methods:
Male C57Bl6 mice were subject to 8 min of KCl induced cardiac arrest and then resuscitated by epinephrine infusion and chest compression. The use of KCl was minimized by withdrawal of blood from jugular vein for better resuscitation and recovery. 22 months old mice were performed and 8-10 weeks old mice served as reference (n=10 per group). All mice had withdrawal of 0.5 ml of blood followed by infusing 30μl 0.5 M KCl to induce flat EKG. Blood was infused back at 3 min after onset of cardiac arrest. Epinephrine (32μL/mL) was slowly infused 30 seconds before resuscitation until regular EKG appeared. Resuscitation time and survival rate were recorded. Spontaneous activity was measured in smart cage at pre-injury and days 1, 2, and 3 post-injury. Neurological score (9 points ) was measured at day 3 after CA/CPR.

Results:
All mice were successfully resuscitated and survived for 24 hours. Young mice restored spontaneous heart activity within 1 min and however, most of aged mice took more than 1 min (p=0.014). Aged mice had a significantly decline of spontaneous activity including travel time and travel distance (travel time p=0.02 compared to young mice group, Fig 1). 3 days of survival rate was 40% in aged mice and 90% in young mice (p=0.03, Fig 2). Aged mice also had a worse neurological score at day 3 post-injury (p=0.026).

Conclusions:
This modified procedure ensured all mice resuscitated and survived for 24 hours. Declined spontaneous activity and neurological function represent the success of this disease model. Our on-going experiment is to define the age related stress responses and SUMO conjugation using this novel mouse model and seek new targets for treatment of this injury.
Abstract 16694: Transplantation of Bone Marrow Cells From miR150 Knockout Mice Attenuates Arterial Stiffness and Hypertension in Senescence-accelerated Mice P1 (SAMP1)
Authors: Fan Jun , Wang Shirley , Sun Zhongjie
Published: July 2021

Background & Objective.
Aging is associated with increased prevalence of arterial stiffness and hypertension. The senescence-accelerated mouse P1 (SAMP1) demonstrates early and spontaneous aging phenotypes around 6-8 months of age. In contrast, microRNA-150 knockout (miR15-KO) slows down the aging process and extends lifespan in mice by 20-30%. The objective of this study is to investigate if arterial stiffness and hypertension occur in SAMP1 mice and if transplantation of bone marrow cells (BMCs) from miR-150 KO mice affects arterial stiffening and hypertension in SAMP1 mice.

Method & Results.
The results showed that blood pressure (BP) and pulse wave velocity (PWV) were increased significantly in the SAMP1 mice
vs.
the age-matched control (AKR/J) mice (10 months). Therefore, SAMP1 mice developed arterial stiffening and hypertension. Western blot analysis showed that collagen 1 and TGFβ1 expression were increased but the elastin expression was decreased in aortas of SAMP1 mice, indicating arterial remodeling. Klotho is a recently-discovered aging-suppressor gene. Plasma levels klotho protein and renal expression of klotho protein were decreased in SAMP1 mice. Interestingly, transplantation of BMCs from miR150-KO mice decreased PWV and BP in SAMP1 mice to nearly control levels within 3 months, suggesting that BMC transplantation attenuates senescence-related arterial stiffening and hypertension. BMC transplantation from miR150-KO mice increased plasma levels of klotho and renal expression of klotho and abolished T cell and macrophage infiltration in aortas and kidneys in SAMP1 mice. BMC transplantation decreased expression of collagen 1 and TGFβ1 but increased expression of elastin in aortas in SAMP1 mice.

Conclusion.
Accelerated aging led to arterial stiffness and hypertension in SAMP1 mice. BMC transplantation from miR150-KO mice reversed arterial stiffness and hypertension in SAMP1 mice. This study demonstrates, for the first time, that BMC transplantation may be an effective therapeutic approach for aging-related arterial stiffness and hypertension. (supported by NIH R01 HL105302 & HL102074).
Abstract 16755: Association Between Achievement of Risk Factor Standard of Care Goals and Major Adverse Cardiovascular Events in Patients With Stable Coronary Artery Disease in the STABILITY Trial
Authors: White Harvey D , Stewart Ralph A , Dalby Anthony J , Stebbins Amanda , Cannon Christopher P , Budaj Andrzej , Linhart Ales , Husted Steen , Mohler Emile R , Pais Prem , Diaz Rafael , Steg Philippe Gabriel , Krug-Gourley Sue , Granger Christopher B , Hochman Judith S , Koenig Wolfgang , Harrington Robert A , Held Claes , Wallentin Lars
Published: July 2021

Introduction:
Clinical practice guidelines have recommended evidence based medicine (EBM) and treatment targets for optimal management of BP, LDL Cholesterol (LDLc) and of HbA1c in diabetic patients with stable coronary heart disease [CHD]. However the importance of achieving these goals is uncertain.

Hypothesis:
In patients with stable CHD achievement of goals for blood pressure, LDLc, and HbA1c in diabetics, and use of EBM are associated with a lower risk of major adverse cardiovascular events [MACE].

Methods:
In 13,624 patients with stable CHD, who participated in the STabilisation of Atherosclerotic plaque By Initiation of darapLadIb TherapY (STABILITY) trial, BP, LDLc and HbA1c in diabetes were assessed at baseline, and at 3, 6 and 12 month follow-up visits; BP and medication use were additionally assessed at 1 month. EBM; aspirin, beta blockers, ACE / ARB, and statins, were recommended for patients without contraindications. Standard of care (SOC) targets were BP<140/90 mmHg, LDLc <70mg/dl and <100mg/dl, and HbA1c<7% in 4711 diabetics. Achievement of each of these targets was defined as meeting the target on ≥4 of 5 visits for BP and EBM, and ≥3 of 4 biochemical measurements. A landmark analysis assessed the association between achievement of EBM and of each SOC target during the first year of the study and MACE, defined as cardiovascular death, MI, or stroke, during a further 2.7 years follow-up, after adjusting for baseline predictors of MACE in a Cox proportional hazards model.

Results:
See Table.

Conclusions:
High rates of evidence based medicine use were achieved. MACE was related to LDLc. After one year the risk of subsequent MACE was reduced for patients who met target LDLc levels and for diabetic patients who achieved target HbA1c.
Abstract 16761: Long Non-coding RNA Meg3 Controls Endothelial Cell Function: Implications for Endothelial Aging and Senescence
(Best of Basic Science Abstract)
Authors: Boon Reinier , Hofmann Patrick , Michalik Katharina , Knau Andrea , Ponomareva Yuliya , Zeiher Andreas , Uchida Shizuka , Dimmeler Stefanie
Published: July 2021

The majority of transcribed RNA does not encode proteins, but may function as regulatory RNA. Long non-coding RNAs (lncRNAs) have been described to play an important role in many biological processes, including epigenetic regulation of gene expression.

To determine the expression and functional role of lncRNAs in endothelial cells, we performed RNA deep sequencing of human umbilical venous endothelial cells (ECs). Among the highest expressed lncRNAs, we identified Meg3 (35.3±0.6 RPKM), which was increased in replicative senescent HUVECs in vitro (passage 16/17 vs 2/3, 2.9±0.99-fold). Interestingly, Meg3 is induced in the intima of aged mice and correlates with age in human hearts (p=0.016). In HUVECs, Meg3 localizes to the nucleus and is also induced by hypoxia (4.08±0.78-fold, p<0.05). Silencing of Meg3 using LNA-GapmeRs induced angiogenic sprouting and proliferation of endothelial cells in vitro (1.4±0.14-fold, P<0.05) and repressed SA-β-galactosidase activity. Conversely, lentiviral overexpression of Meg3 inhibited sprouting angiogenesis and cell cycle progression, although splicing isoforms of Meg3 show differential effects.

Mechanistically, RNA immunoprecipitation showed that Meg3 associates specifically to H3K27me3, a silencing chromatin mark, and interacts with EZH2, a histone methyl transferase. Silencing of Meg3 in HUVECs represses, and overexpression of Meg3 induces, global gene expression, as measured by exon array analysis. As Meg3 was described to recruit Jarid2 to chromatin, we determined whether Meg3 requires Jarid2. The Meg3 loss-of-function induced repression of proliferation was normalized after silencing Jarid2, indicating that Meg3 effects are at least partly Jarid2-dependent. Finally, silencing of Meg3 in aged mice in vivo using gapmeRs in combination with hind limb ischemia significantly repressed Meg3 levels in the hindlimb and induced recovery of perfusion compared to control mice. Capillary and arteriole density was also markedly induced after silencing Meg3.

These results demonstrate that silencing Meg3 may be a potential strategy to reduce endothelial senescence or increase regenerative angiogenesis.
Abstract 16780: Effects of Ethnicity on the Prevalence of Obstructive Sleep Apnea in Patients With Acute Coronary Syndrome: A Pooled Analysis of the ISAACC Trial and Sleep and Stent Study
Authors: Koo Chieh Yang ,   ISAACC and Sleep and Stent Study Investigators
Published: July 2021

Objective:
Obstructive sleep apnea (OSA) is an increasing yet under-recognized risk factor for acute coronary syndrome (ACS). We sought to determine the effects of ethnicity on the prevalence of OSA in patients presenting with ACS who participated in an overnight sleep study.

Methods:
A pooled analysis using patient-level data from the ISAACC Trial and Sleep and Stent Study was performed. In both of these studies, patients presenting with ACS were recruited to undergo an overnight sleep study. OSA was defined as an apnea-hypopnea index (AHI) of ≥15. A bivariate analysis of the factors affecting AHI and an age-adjusted analysis of the effect of BMI on sleep apnea according to ethnicity were conducted.

Results:
A total of 1961 patients were analyzed, including Spanish (53.6%, n=1050), Chinese (25.5%, n=500), Indian (12.0%, n=235), Malay (6.1%, n=119), Brazilian (1.7%, n=34) and Burmese (1.2%, n=23) populations. Significant differences in body mass index (BMI) were found among the various ethnic groups, averaging from 25.3 kg/m2 for Indians and 25.4 kg/m2 for Chinese to 28.6 kg/m2 for Spaniards. The prevalence of OSA was highest in the Spanish (63.1%), followed by the Chinese (50.2%), Malay (47.9%), Burmese (43.5%), Brazilian (41.2%), and Indian patients. Figure 1 shows the forest plot of the prevalence of OSA among the various ethnicities. A significant interaction between BMI and ethnicity to predict OSA was observed. The estimated odds ratio of BMI on OSA was highest in the Chinese population (1.17; 95% confidence interval: 1.10-1.24), but was not significant in the Spanish, Burmese or Brazilian populations. The area under the curve for the Asian patients (ranging from 0.6365 to 0.6692) was higher than that for the Spanish patients (0.5161).

Conclusion:
There was significant ethnic variation in the prevalence of OSA in patients with ACS, and the magnitude of the effect of BMI on OSA was greater in the Chinese population than in the Spanish patients.
Abstract 16817: Correlation of Right Heart Echocardiographic Quantitation With Cpet Parameters to Predict Clinical Outcomes in Patients With Congenital Right Heart Disease
Authors: Khan Asaad A , Bhatt Ami B , Capoulade Romain , Stefanescu Ada , Eisman Aaron , Youniss Mohamed A , Teoh Jonathan G , Teo Eliza , Lewis Gregory D , Defaria Yeh Doreen
Published: July 2021

Background:
Adults with congenital right heart disease (ACHD) patients have a diminished exercise tolerance compared to healthy population, and abnormal peak VO2 as assessed by cardiopulmonary exercise testing (CPET)significantly predicts outcomes of heart failure and death in this population. Despite this, CPET is not as widely available as echocardiography.

Aim:
We aim to correlate resting echocardiographic patterns of regional RV contractile function among ACHD patients with peak VO2 and major adverse cardiovascular events (MACE).

Methods:
We retrospectively recruited 160 ACHD patients who underwent CPET at our hospital . Out of these, 94 patients had complete echocardiographic data for analysis, in studies performed within 1 year of their CPET.RV quantitative parameters measured included: Tricuspid Annular Plane Systolic Excursion (TAPSE), Tissue doppler imaging TDI (S’), RA area, RV dimensions and RV fractional area change % (FAC).These variables were correlated with peak VO2,exercise RV function by ventriculography(RV score) and MACE(heart failure, arrhythmia,death or transplantation)after CPET.

Results:
The most frequent congenital pathology was Tetralogy of Fallot (35%).14% (n=13) patients had systemic right ventricles.There were 28 MACE during a median follow up of 1.3 years. FAC, TAPSE and S’ significantly correlated with peak VO2 in multivariate analysis.FAC also correlated with RV score. Decrease in FAC was associated with MACE in a continuous fashion while a cutoff value of S’< 9.5 cm/sec was also significantly associated with MACE (p=0.04,HR 2.48)(table)

Conclusion:
This is a heterogenous group of ACHD lesions and routinely acquired echo RV assessment was able to broadly correlate with exercise and outcome. This differentiates us from other papers which are all lesion specific or based on strain measurements (difficult to peform and reproduce).These findings can also help prioritize patients for more sophisticated testing like CPET.
Abstract 16898: Time Course and Associated Cardiac Conditions of Reduced Left Ventricular Ejection Fraction in Patients With Severe Aortic Stenosis
Authors: Ito Saki , Nkomo Vuyisile T , Pislaru Sorin V , Thaden Jeremy J , Greason Kevin L , Pellikka Patricia A , Oh Jae K
Published: July 2021

Objective:
In patients with aortic stenosis (AS), the development of left ventricular (LV) systolic dysfunction adversely affects the natural history and is associated with poor outcomes following aortic valve replacement. However, the timing and possible reasons for transition from preserved to impaired LV ejection fraction (LVEF) in patients with AS have not been described. The aim of this study was to describe the time course of development of LV dysfunction and associated conditions in patients with severe AS.

Methods & Results:
Between 1/1/2009 and 12/31/2012, 667 (19%) of 3528 patients with severe AS (aortic valve area (AVA) ≤1 cm2) identified from the Mayo Clinic, Rochester, MN Echocardiographic Laboratory database; had LVEF ≤50%. Of those 667 patients, 263 (39%) had previous echocardiograms (median: 71.6 months, 25 IQR: 36.3, 75:118.2) before the development of severe AS, allowing an assessment of change in LVEF over time. Among these 263 patients, 8 (3%) had dilated cardiomyopathy (DCM), 225 (86%) had ischemic heart disease (IHD), 5 (2%) had other significant valve disease, and 25 (10%) had no concomitant heart disease before the development of severe AS. The evolution of development of reduced LVEF at several time points is shown in the Figure. The initial LVEF was 34±12 % in DCM patients, 51±13% in IHD patients and 61±9 % in AS patients without other heart diseases (p<0.001, ANOVA). Patients with AS alone or AS+DCM/IHD showed a gradual decline in LVEF before AS became severe, and a more rapid decline in LVEF once the AVA reached ≤ 1 cm2.

Conclusion:
In patients with severe AS, a majority of the patients (86%) with reduced EF had ischemic heart disease. Although there was a gradual decline in LVEF before development of severe AS, the decline was more rapid after AS became severe in almost all patients regardless of associated cardiac condition. More frequent monitoring may be indicated in AS patients especially when AVA reaches 1cm2 and concomitant IHD.
Abstract 16924: Initial AMSA and Increased AMSA After CPR Predict Second Shock Success in Initially Shock-resistant VF During Out-of-hospital Cardiac Arrest
Authors: Herken Ulrich , Quan Weilun
Published: July 2021

Purpose:
Amplitude spectrum area (AMSA), which is calculated from the ventricular fibrillation (VF) waveform using fast Fourier transformation, has been recognized as a predictor of successful defibrillation (DF) and as an index of myocardial perfusion and viability during resuscitation. In this study, we investigated whether a change in AMSA occurring during CPR would predict DF outcome for subsequent DF attempts after a failed DF. We hypothesized that a patient responding to CPR with an increase in AMSA would have an increased likelihood of DF success.

Methods:
This was a retrospective analysis of out-of-hospital cardiac arrest patients who received a second DF due to initially shock-resistant VF. A total of 193 patients with an unsuccessful first DF were identified in a manufacturer database of electrocardiographic defibrillator records. AMSA was calculated for the first DF (AMSA1) and the second DF (AMSA2) during a 2.1 sec window ending 0.5 sec prior to DF. A successful DF attempt was defined as the presence of an organized rhythm with a rate ≥ 40 / min starting within 60 sec from the DF and lasting for > 30 sec. After the failed first DF, all patients received CPR for 2 to 3 minutes before delivery of the second DF. Change in AMSA (dAMSA) was calculated as dAMSA = AMSA2 - AMSA1.

Results:
The overall second DF success rate was 14.5%. Multivariable logistic regression showed that both AMSA1 and dAMSA were independent predictors of second DF success with odds ratios of 1.24 (95% CI 1.12 - 1.38, p<0.001) and 1.27 (95% CI 1.16 - 1.41, p<0.001) for each mVHz change in AMSA or dAMSA, respectively.

Conclusions:
In initially DF-resistant VF, a high initial AMSA value predicted an increased likelihood of second shock success. An increase of AMSA in response to CPR also predicted a higher second shock success rate. Monitoring of AMSA during resuscitation therefore may be useful to guide CPR efforts, possibly including timing of second shock delivery. These findings also further support the value of AMSA as indicator of myocardial viability.
Abstract 16948: Local Low Endothelial Shear Stress (ESS) Provides Incremental Prediction of Non-culprit MACE in Addition to Plaque Burden, Minimal Lumen Area, and Plaque Morphology: The PROSPECT Study
Authors: Stone Peter H , Maehara Akiko , Coskun Ahmet U , Maynard Charles C , Andreou Ioannis , Siasos Gerasimos , Zaromitidou Marina , Fotiadis Dimitris , Stefanou Kostas , Papafaklis Michail , Michalis Lampros , Lansky Alexandra J , Mintz Gary S , Serruys Patrick W , Feldman Charles L , Stone Gregg W
Published: July 2021

Introduction:
Low ESS, a pro-inflammatory stimulus, is an important predictor of coronary plaque development/progression. Whether low ESS adds incremental predictive value for future major adverse cardiac events (MACE) in untreated coronary lesions in high-risk patients with an acute coronary syndrome (ACS) is unknown.

Methods:
In the PROSPECT study, 697 patients with ACS underwent 3-vessel intracoronary imaging. Independent predictors of non-culprit (nc) lesion MACE from untreated coronary lesions in 3 year followup (f/u) were large plaque burden (PB), small minimum lumen area (MLA), and thin cap fibroatheroma (TCFA) morphology. In the present analysis, all nc-lesions leading to a new MACE in f/u (nc-MACE lesions, n=50) and ~4-fold randomly selected control nc-lesions without f/u MACE (nc-non-MACE lesions) were analyzed. Baseline ESS for each lesion was calculated using computational fluid dynamics. A propensity score for low ESS was determined accounting for PB, MLA, TCFA, artery and location in the artery. Local ESS (lowest ESS in 90
o
arc around the artery) was then examined for incremental association with MACE.

Results:
Imaging was sufficient for analysis in 32 nc-MACE lesions. Two nc-MACE lesions were excluded due to unreliable lesion morphology. Non-fibroatheromas were too few for analysis and excluded. Final dataset included 145 lesions: 13 nc-MACE TCFA, 10 nc-MACE thick cap fibroatheroma (ThCFA), and 122 non-nc-MACE lesions (63 TCFA, 59 ThCFA). Cumulative frequency distribution shows lesions responsible for future nc-MACE frequently exhibited low ESS (Figure). In a propensity-adjusted multivariable model, low ESS was strongly associated with nc-MACE in f/u (odds ratio 0.16 [95% CI 0.06-0.40], p<0.0001).

Conclusions:
After accounting for large PB, small MLA, TCFA, and lesion location, low local ESS adds significant and substantial incremental predictive value to identify high-risk untreated lesions likely to cause MACE during 3 year followup.
Abstract 16991: Cardiosphere-derived Cell Exosomes Confer Acute Cardioprotection Following Ischemia-reperfusion Injury Through Macrophage Polarization
(Best of Basic Science Abstract)
Authors: de Couto Geoffrey , Makkar Nupur , Marbán Eduardo
Published: July 2021

Introduction:
Cardiosphere-Derived Cells (CDCs) exert both regenerative and cardioprotective effects following ischemic insult to the myocardium. The regenerative effects are mimicked by human CDC exosomes (CDC
exo
), secreted nanovesicular entities that contain CDC-specific payloads of protein and noncoding RNA. Here we demonstrate that, CDC
exo
reduce infarct size and macrophage (Mf) infiltration when infused via the intracoronary route following ischemia/reperfusion (I/R) injury.

Methods & Results:
To examine the safety and efficacy of CDC
exo
, we performed a dose-finding study in Wistar-Kyoto rats (aged 8-12 weeks). Exosomes were precipitated from conditioned media collected from human CDCs or Fibroblasts [Fb, as a control] grown in serum-free media for 15 days. Exosome protein quantity, surface marker expression, and particle number were assessed prior to delivery. For
in vivo
analyses, rats underwent 45 minutes of ischemia followed by 20 minutes of reperfusion, then intracoronary infusion by random allocation of either Fb exosomes (Fb
exo
) or CDC
exo
. Two days later, histological analysis revealed that CDC
exo
reduced infarct mass (CDC
exo
: 6.38% vs. Fb
exo
: 13.32%; p<0.05) and CD68
+
Mf infiltration (CDC
exo
: 183.5/FOV vs. Fb
exo
: 302.1/FOV; p<0.05). In vitro, Mf uptake of exosomes and polarization based on gene expression profile (
Arg1, Vegfa, Il4ra
) occurred in a time-dependent manner. The phagocytic capacity of CDC
exo
-primed Mf was elevated relative to Fb
exo
-, M1-, or M2-polarized Mf (CDC
exo
: 76.8%; Fb
exo
: 38.3%; M1: 52.2%; M2: 33.9%; p<0.05).

Conclusions:
CDC
exo
are cardioprotective when delivered via the intracoronary route 20 min post-I/R. These data demonstrate that exosomes secreted by CDCs (but not by fibroblasts) recapitulate the cardioprotective effects of CDCs (cellular postconditioning; Kanazawa et al, Circ HF 2015; de Couto et al, JCI 2015). Like CDCs, CDC
exo
modulate the Mf infiltrate in the heart post-I/R and distinctively polarize Mf. The data support the conjecture that CDC
exo
mediate the cardioprotective effects of CDCs via effects on Mf.
Abstract 16994: RNA Editing Controls Gene Expression in Atherosclerotic Heart Disease by Enabling HuR-mediated Posttranscriptional Regulation
Authors: Stellos Konstantinos , Gatsiou Aikaterini , Boon Reinier , John David , Fürtig Boris , Lunella Federica F , Amrhein Carolin , Manavski Yosif , You Xintian , Uchida Shizuka , Keller Till , Boeckel Jes-Niels , Chen Wei , Schwalbe Harald , Zeiher Andreas M , Dimmeler Stefanie
Published: July 2021

Background:
Adenosine to inosine (A-to-I) RNA editing is catalysed by ADARs (adenosine deaminases acting on RNA) and is an important posttranscriptional regulator of RNA metabolism. Although RNA editing is essential for life, its role in cardiovascular disease is unknown.

Methods and Results:
Next generation RNA-sequencing (RNA-seq) of human endothelial cells revealed that ADAR1 edits almost 25% of endothelial transcriptome, regulates gene expression (135 transcripts were at least 2-fold regulated after ADAR1 knockdown) and controls endothelial cell function. Among the highest edited transcripts is cathepsin S (CTSS), an extracellular matrix degradation enzyme with an established role in cardiovascular and inflammatory diseases. The number of edited nucleotides in the 3’UTR of CTSS mRNA was increased under hypoxic conditions and was strongly associated with increased CTSS expression (r=0.971, P=0.029). Most importantly, absence of RNA editing resulted in a 3-fold decrease of CTSS mRNA expression under hypoxic conditions. RNA-seq analysis of 8 patients with coronary heart disease (CHD) and 4 healthy subjects revealed that A-to-I RNA editing of CTSS 3’UTR is significantly increased in patients with CHD compared to control healthy subjects (P<0.001). Most importantly, a strong association was observed between RNA editing in the CTSS 3’UTR and mRNA expression in our cohort (r>0.7, P<0.001). Mechanistically, RNA-immunoprecipitation, mRNA stability, luciferase reporter assays, mutagenesis experiments and NMR spectroscopy revealed that silencing of ADAR1 completely inhibited RNA editing of the 3’UTR of CTSS mRNA, which consequently affected CTSS RNA secondary structure, HuR binding to the CTSS 3’UTR and finally CTSS mRNA stability and protein expression (P<0.001 for all). Taken into consideration that 82% of edited genes in 3’UTR are enriched for HuR binding sites, RNA editing may critically regulate HuR-mediated posttranscriptional regulation and thus gene expression.

Conclusion:
This study suggests a novel primate-specific mechanism that may account for the increased cathepsin S expression in ischemic/inflammatory diseases and it may serve as a prototypical example for the evaluation of RNA-based mechanisms in health and disease.
Abstract 17015: When is a Pathological Q Wave Truly Pathological?
Authors: Prakash Keerthi , Malhotra Aneil , Dhutia Harshil , Siegenthaler Philippe , Nolan Grant , Roth Henry , Papadakis Michael , Sharma Sanjay
Published: July 2021

Introduction:
Pathological Q waves are considered harbingers of cardiac pathology and should instigate comprehensive evaluation of athletes. Several definitions of the depth or duration of a Q wave exist, with disagreement between scientific bodies as to the most useful.

Objectives:
1. Determine the prevalence of pathological Q waves in large cohorts of the general population, athletes and patients with hypertrophic cardiomyopathy (HCM).

2. Identify the most accurate Q wave criterion.

Methods:
ECGs were retrospectively analysed in consecutive cohorts of 10,008 healthy young athletes (14-35 years old), 2,994 healthy young non-athletes and 468 HCM patients.

Results:
Pathological Q waves that fulfilled at least one of the 4 individual definitions (Table 1) were identified in 0.7% athletes (n = 75), 1.2% non-athletes (n = 36) and 22.6% patients with HCM (n = 106). In the healthy athletic and non-athletic population, all pathological Q waves (n = 111) met the >3mm depth definition. In contrast, the majority of pathological Q waves in HCM patients met the ≥40msec duration definition (n = 75; 70.75%).

We tested the ability of all 4 criteria to distinguish between health and disease in the entire cohort. Seattle and Refined had the best sensitivity for detecting HCM. Refined criteria however, had a significantly higher positive predictive value and 7 times lower false positive rate compared to Seattle. (Table 2)

Conclusion:
Pathological Q waves are present in up to 1.2% of healthy young individuals and do not correlate with physical activity. Of the proposed criteria, the Refined criteria has the lowest false positive rate and should be utilised in the context of cardiac evaluation in young athletes.
Abstract 17063: Sleep Related Breathing Disorders and Heart Rate Variability in Young and Healthy Adults From the General Population
Authors: Aeschbacher Stefanie , Bossard Matthias , von Rotz Mirco , Schoen Tobias , Maseli Anna , Probst-Hensch Nicole , Schmidt-Trucksäss Arno , Leuppi Jörg , Risch Martin , Risch Lorenz , Conen David
Published: July 2021

Background:
The influence of sleep related breathing disorders on heart rate variability (HRV), a measure of autonomic nervous function, is not well studied. We therefore assessed the relationship of the Apnea-Hypopnea Index (AHI) and the Oxygen Desaturation Index (ODI) with 24-hour HRV in a large population of young and healthy adults.

Methods:
Individuals aged between 25-41 years with a body mass index ≤35km/kg2 and without known sleep apnea syndrome (SAS) or cardiovascular disease were included in the population-based GAPP-study. A 24-hour electrocardiogram (ECG) was obtained in every participant, and systematic post-processing performed with a dedicated software. The standard deviation of all normal RR intervals (SDNN) was used as main HRV marker. AHI and ODI were obtained from nighttime pulsoxymetry with nasal airflow measurements. Sleep apnea (SA) was defined as either an AHI ≥5 or an ODI ≥5. Multivariable regression models were constructed to assess the relationship of SDNN with either AHI or ODI and to adjust for a large number of confounders.

Results:
We included 1266 participants (47% men) with a median age of 35 years. Mean SDNN among men and women was 162 and 148ms (p<0.0001), respectively. The proportion of participants with SA using an AHI- or ODI-based definition was 10 and 11%, respectively. Compared to individuals without SA, the beta coefficient (95% confidence interval (CI)) for SDNN was -7.48 (-14.75; -0.23, p=0.04) among those with an AHI-based SA definition, and was -11.45 (-18.39; -4.52, p=0.001) among those with an ODI-based SA definition. A highly significant inverse trend across different categories of AHI and ODI was observed, as shown in the Table.

Conclusion:
Early stages of sleep related breathing disorders are strongly associated with decreasing HRV in young and healthy adults, without evidence of a threshold. These findings suggest a tight link between sleep related breathing disorders and autonomic dysfunction.
Abstract 17070: Efficacy and Safety of Alirocumab: Pooled Analyses of 1048 Individuals With Diabetes Mellitus From Five Placebo-controlled Phase 3 Studies of at Least 52 Weeks Duration
Authors: Ginsberg Henry N , Farnier Michel , Robinson Jennifer G , Cannon Christopher P , Sattar Naveed , Baccara-Dinet Marie T , Lorenzato Christelle , Bujas-Bobanovic Maja , Louie Michael J , Colhoun Helen M
Published: July 2021

Background:
Individuals with diabetes (DM) are at high risk for CVD and may not achieve adequate control of LDL-C levels with current lipid-lowering therapies.

Aim:
To assess alirocumab (ALI) efficacy and safety in individuals with and without baseline DM.

Methods:
Five placebo (PBO)-controlled Phase 3 studies of 52-78 weeks were analyzed, comprising 1048 individuals with DM at study entry and 2444 with no DM (safety population). All individuals had hypercholesterolemia, and were on maximally tolerated background statin therapy. Efficacy data were pooled by initial ALI dose; 3 studies (n=1043, ITT analysis) used PBO or ALI 75 mg every 2 weeks (Q2W), increasing to 150 mg Q2W at W12 if LDL-C at W8 ≥ 70 mg/dL; 2 studies (n=2416, ITT analysis) initiated treatment with PBO or ALI 150 mg Q2W. All doses were 1 mL SC injection. Safety data were pooled for all 5 studies. Efficacy data are reported to W24, safety for ≥52 weeks.

Results:
Individuals with DM had lower mean baseline LDL-C levels. At W12, ALI 75 mg Q2W significantly reduced LDL-C levels from baseline vs PBO with treatment effect consistent regardless of DM status (Table). A higher proportion of participants with no DM received a dose increase at W12, leading to a greater magnitude of reduction at W24 in that group.

For those initiating at ALI 150 mg Q2W, LDL-C reductions of 58.3% (DM) and 62.3% (no DM) vs PBO were achieved at W24 (Table).

Improvements were seen in other parameters, including TGs, HDL-C, and Lp(a), largely irrespective of baseline DM status.

Adverse event (AE) rates were generally comparable in both groups. AEs occurring in ≥5% of individuals in all subgroups were nasopharyngitis and URI. Injection site reactions (ISRs) were less frequent in those with DM: ALI 3.6% and PBO 2.8%, vs no DM: ALI 8.4% and PBO 6.1%.

Conclusions:
ALI demonstrated robust LDL-C reductions in individuals with and without DM. Safety observations were generally similar regardless of DM status, although those with DM reported fewer ISRs than those without.
Abstract 17116: Incidence and Outcomes of Out-of-hospital Maternal Cardiac Arrest and Compliance With Resuscitation Guidelines
Authors: Lipowicz Alan A , Cheskes Sheldon , Gray Sarah H , Jeejeebhoy Farida , Lee Janice , Scales Damon C , Zhan Cathy , Morrison Laurie J
Published: July 2021

Background:
Published survival rates after out-of-hospital cardiac arrests (OHCA) are lower than in-hospital cardiac arrest (IHCA). Current estimates for the incidence and rate of survival for maternal cardiac arrest are published only for IHCA. There are no studies that report the incidence and outcomes of maternal OHCA. Current cardiopulmonary resuscitation guidelines contain specific maternal recommendations, although compliance with recommended benchmarks has not been reported. The objective of this study was to report maternal OHCA incidence, outcomes, and compliance with resuscitation and maternal specific guidelines.

Methods:
This was a population-based cohort study of consecutive maternal OHCA between May 2010 and April 2014. The denominator was estimated from the total regional population of all women of childbearing age obtained from census and age-specific pregnancy rates provided by regional health authorities. Resuscitation performance was measured against the 2010 AHA Guidelines.

Results:
A total of 6 maternal OHCA occurred amongst 1,085 OHCA occurring in females of child bearing age (15-49) over 4yrs; Incidence-1.85:100,000 (95% CI 1.76 to 1.95) vs. 19.4 per 100,000 (95% CI, 19.37 to 19.43). Maternal and neonatal survival to discharge was 16.7% and 33.3%, respectively. Compliance with CPR quality metrics averaged 83% with a range from 75% to 100%. Compliance with maternal-specific resuscitation guidelines averaged 46.9%, with a range from 0% to 100%. The only performance metrics with 100% compliance was intravenous line insertion above the diaphragm and prehospital activation of the maternal cardiac arrest team. Uterine displacement compliance was low at 0%.

Conclusion:
The incidence of maternal OHCA was 1.85:100,000, which is lower than the published estimate for maternal IHCA. Survival after OHCA for mother and for child was higher than OHCA occurring in non-pregnant adult females of child bearing age; however, the number of survivors was small (<5). Compliance rates with recommended resuscitation guidelines were high, yet compliance with maternal-specific guidelines were low suggesting targeted training and implementation optimization at the point of care is required to prepare for this rare event involving two lives.