bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 15569: Video-Only Cardiopulmonary Resuscitation Education for Families Before Hospital Discharge: A Multicenter Pragmatic Clinical Trial
Authors: Blewer Audrey L , Li Jiaqi , Leary Marion , Becker Lance B , Riegel Barbara J , Putt Mary E , Shea Judy A , Kirkpatrick James N , Berg Robert A , Nadkarni Vinay M , Groeneveld Peter W , Abella Benjamin S
Published: July 2021

Background:
The need for improved dissemination of public cardiopulmonary resuscitation (CPR) education is highlighted by the fact that bystander CPR is delivered in less than 40% of cardiac arrests in the US. Studies have suggested that simplified methods for CPR training can promote broader dissemination. The minimum CPR training curriculum to encourage broad implementation but ensure long-term retention remains poorly characterized.

Objectives:
To compare video-only CPR training without a manikin to training with a video self-instruction (VSI) kit including a practice manikin. We hypothesized that laypersons who receive video-only training will perform comparable chest compressions (CC) as those taught with a VSI kit six months after initial training.

Methods:
We performed a pragmatic, randomized trial of CPR training for family members of cardiac patients on inpatient wards at eight hospitals. Hospitals were block randomized to offer either video-only training or the VSI kit to high-risk families before patient discharge. At six months post-training, CPR skills were assessed quantitatively. We analyzed the mean difference in chest compression rate and depth between cohorts and used multivariate regression modeling to control for confounding.

Results:
From 2/2012 to 5/2015, 1610 subjects were enrolled and 571 subjects consented to a 6-month skills check. Enrollees’ mean age was 52±15 years, 73% were female and 81% were immediate patient’s family. The unadjusted mean CC rate in the video-only cohort was 88 (95% CI: 85, 90) compressions per min (cpm) and 89 (95% CI: 87, 91) cpm in the VSI cohort (p=0.56), while the mean CC depth was 40 (95% CI: 39, 42) mm in the video-only cohort and 45 (95% CI: 44, 47) mm in the VSI cohort (p<0.01). The statistical relationship remained the same after adjustment for confounding.

Conclusions:
To our knowledge, this represents the largest prospective trial of CPR training and long-term retention among lay providers. Video-only training yielded a statistically indistinguishable difference in CC rate compared to VSI training. While the CC depth was statistically different, the clinical impact of these differences may be small given recent clinical research suggesting maximum survival benefit at depths between 40-55 mm.
Abstract 15579: Multivessel Coronary Artery Revascularization During Index Hospitalization Has Favorable Outcomes Compared to Infarct Related Artery Only Revascularization in STEMI Patients- Meta-Analysis of Randomized Control Trials
Authors: Gaddam Sainath , Anugu Viswajit Reddy , Asti Deepak , Raza Muhammad , Pandya Bhavi , Kandov Ruben , McCord Donald , Lafferty James
Published: July 2021

Introduction:
Multivessel coronary artery disease is present in about half of the patients presenting with STEMI. Timing of revascularization for the non-culprit vessels has been a long debate, with few trials suggesting benefit at index hospitalization rather than staging them at a later time. Current ACCF/AHA 2013 STEMI guidelines do not recommend PCI of non-infarct artery at the time of primary PCI but recommend it at a later time if patients are symptomatic. We hypothesized, complete revascularization during primary PCI or index hospitalization would have favorable outcomes compared to culprit vessel only revascularization.

Aim:
We performed meta-analysis of randomized control trials comparing multivessel vs. infarct artery only revascularization during primary PCI or index hospitalization.

Methods and Results:
Pubmed, Embace and Google scholar databases were searched for randomized control trials comparing multivessel vs. culprit vessel only revascularization during primary PCI or index hospitalization. We compared deaths, non-fatal MI and repeat revascularization events for the groups.

Total number of patients in our study was 1819, with 919 patients in multivessel revascularization and 900 patients in infarct artery only revascularization groups. Mean follow up period was 28 months. Pooled analysis showed significant favorability for multivessel coronary revascularization comparing events of repeat revascularization (OR= 0.39, p<0.0001). There was also non-significant decrease in mortality (OR=0.92, p=0.7) and non-fatal MI (OR=0.68, p=0.09) with complete revascularization.

Conclusions:
In our study of STEMI patients, complete revascularization during primary PCI or index hospitalization has significantly decreased need for repeat revascularization and there was also non-significant decrease in mortality and non-fatal MI. Studies with larger sample size and longer follow up are needed for stronger evidence.
Abstract 15633: Inaccuracy of Friedewald-Estimation at Clinically Relevant Very Low Levels of LDL-Cholesterol: The Very Large Database of Lipids Study 1C
Authors: Quispe Renato , Hendrani Aditya , Elshazly Mohamed B , Michos Erin D , McEvoy John W , Blaha Michael J , Toth Peter P , Coresh Josef , Blumenthal Roger S , Jones Steven R , Martin Seth S
Published: July 2021

Background:
Appropriate classification of low-density lipoprotein cholesterol (LDL-C) in the very low range has direct relevance to patient care and clinical trials. Some guidelines recommend targeting an LDL-C <70 mg/dL for high-risk patients or consideration of statin down-titration at levels <40 mg/dL. Moreover, recent lipid-lowering trials have classified many participants with an LDL-C <50 and even <25 mg/dL.

Objectives:
Previously, we showed significant underestimation of Friedewald-estimated LDL-C (LDLf-C) compared with directly-measured LDL-C (LDLd-C) at low LDL-C and high triglycerides (TG). We now seek to extend these findings to persons with very low LDLf-C levels.

Methods:
We analyzed 191,333 US adults from the Very Large Database of Lipids with LDLf-C <70 mg/dL and TG <400 mg/dL. We calculated the median difference by subtracting LDLd-C from LDLf-C. Upward reclassification by LDLd-C vs LDLf-C was calculated based on several cutpoints: 25, 40, 50, and 70 mg/dL (0.2th, 1.3th, 3.6th, 14.7th percentile, respectively).

Results:
Patients were 65±15 years old and 60% men. Greater underestimation was found at lower LDLf-C and higher TG levels. The median difference (25th to 75th percentile) increased from -2 (-7 to 1) at LDLf-C 60-69 mg/dL to -30 (-37 to -22) at LDLf-C <10 mg/dL in the overall population, and from -16 (-22 to -12) to -32 (-39 to -26), respectively, in patients with TG 200-399 mg/dL. Among individuals with LDLf-C lower than 25, 40, 50, and 70 mg/dL cutpoints, 82%, 57%, 43%, and 23% had LDLd-C higher than those levels. Reclassification occurred most commonly in those with high TG (Table).

Conclusion:
Extending our prior work on Friedewald LDL-C underestimation at levels <70 mg/dL, we now show even more substantial misclassification at very low LDL-C levels (<25, 40, 50 mg/dL), particularly at high TG. These findings likely have relevance for personalized clinical decision-making and for clinical trial design using more potent lipid lowering agents.
Abstract 15647: Mental Stress-Induced Reductions in Left Ventricular Ejection Fraction Predict Future Heart Failure Exacerbation
Authors: Newhouse Amy , Boyle Stephen H , Sun Julia , Zainab Samad , Babyak Michael A , Wilson Jennifer , Kuhn Cynthia , Becker Richard C , Ortel Thomas L , Williams Redford , Rogers Joseph G , O'Connor Christoper M , Velazquez Eric J , Jiang Wei
Published: July 2021

Background:
Mental stress-induced myocardial ischemia (MSIMI) is common in patients with ischemic heart disease (IHD) and has been associated with an elevated risk of mortality and adverse cardiac events. Microcirculation dysfunction may have a critical mechanistic role as MSIMI has been associated with microvascular constriction but not epicardial coronary stenotic burden. This may also play a role in the etiology of heart failure and other cardiovascular (CV) events. We explored the relationship of MSIMI to heart failure exacerbations and other categories of CV events using data from the REMIT trial.

Methods:
Patients with stable IHD (N=310) underwent mental and exercise tress testing; 44% had mental stress induced myocardial ischemia (by echocardiographic wall motion abnormality, left ventricular ejection fraction (LVEF) reduction of > 8%, and/or ischemic ST-change on ECG). Patients were followed for up to 6 years (median 4 yrs) for all-cause mortality and CV events resulting in hospitalization. Cox proportional hazard models, controlling for age, sex, and resting LVEF, were used to examine the associations of MSIMI indices with each CV category.

Results:
MSIMI, as a dichotomous variable, was not significantly associated with any CV category. Continuous mental stress-induced LVEF change scores were linearly associated with risk of being hospitalized for a heart failure exacerbation (HR = 2.35, 95%CI = 1.30 - 4.25,p=.005) (Table). This association did not significantly change after controlling for exercise-induced LVEF changes (HR = 2.35, 95%CI = 1.24 - 4.47,p=.009).

Conclusion:
In patients with stable IHD, every incremental 5% reduction in LVEF change induced by mental stress was associated with a 2.35 times greater risk of experiencing a hospitalization for heart failure exacerbation over an average 4-year period. This is independent of the risk conferred by traditional exercise testing.
Abstract 15779: Quality of Life in a Cohort of Familial Hypercholesterolemia Patients Undergoing Molecular Cascade Screening in Brazil
Authors: Souto Ana Cristina , Pereira Alexandre , Jannes Cinthia E , Fukushima Julia , Krieger Jose E , Santos Raul D
Published: July 2021

Introduction::
Familial hypercholesterolemia (FH) is an underdiagnosed and undertreated disease associated with elevated risk of early cardiovascular disease (CVD) and thus can reduce quality of life. The present health related quality of life (HRQL) investigation, evaluated patients personal interpretation of morbidity burden in daily life.

Methods:
The study included a total of 1,032 adult individuals participating in a FH molecular cascade-screening program. The involved individuals were index cases (IC n=363), with genetic diagnosis or FH and their first-degree relatives (FDR, n=669). All patients were evaluated at the first session of the molecular diagnosis process. HRQL measurements, mental (MCS) and physical (PCS) component scores, was carried out with the Medical Outcomes Study (MOS) 12-Item Short-Form Health Survey (SF-12) questionnaire.

Results:
IC were older (52±13.1 vs. 46±16.2 years, P<0.05) and presented lower PCS than FDR (44.7±9.3 vs. 49.2±8.4, P<0.05). No differences were seen on the MCS component. Overall, generalized linear models showed that smoking habit (11.9% prevalence, P=0.006), previous diagnosis of hyperlipidemia (78.6%, P=0.020) and depression (13.5% prevalence, P<0.000) were significant predictors of MCS. The presence of heart failure (6.5%, P=0.018), angina pectoris (12.9%, P=0.005), previous myocardial infarction (12.3%, P=0.012), hypertension (33.9%, P=0.018) and obesity (12.8%, P<0.000) were all predictors of PCS. The presence of arrhythmias (10.7% prevalence) predicted both MCS and PCS (P=0.042 and P=0.00, respectively). Male gender (42.4%, P<0.000) and education level (< 9 years of background, 28% P<0.000) were social-demographic aspects predictive of differences in MCS and PCS, respectively.

Conclusions:
Reductions in the individuals’ reported quality of life were explained by differences in social-demographic characteristics but mainly by inadequate health/disease status, such as risk factors and previous CVD. Active FH genetic cascade diagnosis by promoting early and adequate medical care and thus preventing early CVD, may improve substantially the subjective appraisal of HRQL.
Abstract 15794: Changes in Patient and Caregiver Depression and Anxiety Post-implantation of a Ventricular Assist Device
Authors: Bidwell Julie T , Mudd James O , Gelow Jill M , Lyons Karen S , Hiatt Shirin O , Chien Christopher V , Grady Kathleen L , Lee Christopher S
Published: July 2021

Introduction:
The impact of ventricular assist device (VAD) therapy on affective symptoms among patients with advanced heart failure (HF) and their informal caregivers is not well understood.

Hypothesis:
We hypothesized that patients’ affective symptoms would improve post-implant, while caregivers’ affective symptoms would worsen.

Methods:
Prospective, longitudinal data was collected on patients and their caregivers (n=25 dyads) prior to and at 30 and 90 days after VAD implantation. Depression was measured using the Patient Health Questionnaire-8 (PHQ-8; range 0-24, higher scores indicate worse depressive symptoms), and anxiety was measured using the Anxiety Scale of the Brief Symptom Inventory (BSI-ANX; range 0-4; higher scores indicate worse anxiety) in patients and their caregivers. Pre vs. post VAD comparisons in affective symptoms were examined using paired t-tests.

Results:
Patients requiring VAD implantation were 54.9±12.5 years of age and mostly male (84.0%), while caregivers were 53.9±11.1 years of age and mostly female (80.0%); a majority (72.0%) of dyads were spouses. Patient depression decreased significantly from pre-implant (9.3±5.6) to 30 days (6.9±5.4; t=2.2, p=0.04) and 90 days post-implant (3.6±3.6; t=5.3, p<0.01); patient anxiety also decreased from pre-implant (1.0±0.9) to 30 days (0.5±0.7; t=2.9, p<0.01) and 90 days post-implant (0.3±0.4; t=4.5, p<0.01). In contrast, there were no significant changes in caregiver depression from pre-implant (6.0±5.2) to 30 days (5.2±4.4; t=0.5, p=0.6) and 90 days post-implant (6.6±5.7; t=-0.4, p=0.7) or in caregiver anxiety from pre-implant (0.8±0.6) to 30 days (0.5±0.4; t=1.5, p=0.2) and 90 days post-implant (0.6±0.7; t=0.9, p=0.4).

Conclusions:
Although depression and anxiety improved dramatically for patients after VAD implantation, the pre-implant affective symptom burden of caregivers was substantially higher than national norms at baseline and was not ameliorated over time. As patient symptoms improve with VAD therapy, their caregivers may benefit from psychosocial interventions to address protracted symptoms of depression and anxiety.
Abstract 15837: Circulating Proneurotensin Concentrations Predict Cardiovascular Disease Events in the Community: The Framingham Heart Study
Authors: Januzzi James , Lyass Asya , Liu Yuyin , Gaggin Hanna K , Trebnick April , D'Agostino Ralph B , Wang Thomas J , Massaro Joseph , Ramachandran Vasan
Published: July 2021

Introduction:
Neurotensin is a 13-amino acid peptide whose receptor (SORT1) is strongly linked to cardiovascular disease (CVD) development through several mechanisms, including a role in hepatic low density lipoprotein (LDL) metabolism. We measured concentrations of proneurotensin (PNT; the stable pro-fragment of neurotensin) in subjects from the Framingham Heart Study (FHS) Offspring cohort.

Hypothesis:
Concentrations of PNT provide incremental information for incident CV events, possibly through interactions with LDL.

Methods:
Blood samples from 3439 fasting subjects (mean age 59.2 years, 47.1% male) were tested for PNT (Sphingotec, Hennigsdorf, GE). The primary outcome of interest was incident hard CVD (composite of myocardial infarction [MI], stroke, and CV death). Incident hard CHD (MI and CV death) was also examined.

Results:
Compared to subjects in PNT quartiles 1-3, those in the highest quartile were more likely to be younger and heavier, more likely to smoke (all P <0.007), and across PNT quartiles more likely to have prevalent CVD (from 24.4% to 31.1%; P =0.003) and diabetes mellitus (from 5.5% to 13.4%; P<0.001). No association between PNT and LDL concentrations was observed. In age and sex-adjusted Cox proportional hazards models, log-PNT concentrations predicted incident hard CVD (hazard ratio [HR] = 1.24 per one standard deviation [SD] change in log-PNT; 95% confidence intervals [CI] = 1.11-1.39; P <0.001). Greatest risk for incident hard CVD was observed in log-PNT quartile 4 (HR = 1.53 per one SD change in log-PNT vs quartile 1; P =0.005). In models adjusted for standard risk factors, log-PNT remained significantly associated with incident hard CVD (HR = 1.13 per one SD change in log-PNT; 95% CI = 1.01-1.27; P = 0.03). Addition of log-PNT to the FHS Risk Score resulted in modest risk reclassification (NRI = 0.024; 95% CI=-0.0008-0.048), and in Kaplan Meier analyses, shorter time to first event was seen in higher log-PNT values (log rank P = 0.02). Similar results were found for hard CHD. We did not observe effect modification by LDL.

Conclusions:
Higher concentrations of PNT are associated with a greater risk of incident hard CVD and CHD in the community independent of LDL concentrations and other risk factors.
Abstract 15890: Spatiotemporal Analysis of Phase and Frequency Dynamics in Human Persistent Atrial Fibrillation
Authors: Dastagir Nawshin , Vanheusden Frederique J , Chu Gavin S , Salinet João L , Li Xin , Almeida Tiago P , Stafford Peter J , Schlindwein Fernando S , Ng G A
Published: July 2021

There is increasing focus on understanding the substrates that maintain persistent atrial fibrillation (persAF) based on dominant frequency (DF) sources and phase singularity points (PS). In this study we aimed to combine these two parameters and study the relationship between them to depict the complex spatiotemporal patterns of fibrillation.

For 9 patients with longstanding persAF (duration: 34 ± 25 months) undergoing left atrial (LA) ablation, noncontact array catheter (EnSite Array, St. Jude Medical) was used to collect virtual unipolar electrograms (EGMs) simultaneously from 2048 nodes on the LA. After QRST subtraction, 3D DF maps were obtained through the fast Fourier Transform applied simultaneously to each individual EGM. DF was defined within the range of 4-10Hz (4s time window; 87.5% overlap; 30s/patient). Highest DF (HDF) regions for each individual window were defined as any LA geometry nodes where the calculated DF was within 0.25 Hz of the maximum DF value registered in the window. In order to correlate these HDF locations with PS, phase maps were constructed using the Hilbert transform approach and the locations of PS and its respective chirality (+ clockwise; - anticlockwise) were identified applying an automatic PS detection algorithm.

A statistical majority of PSs (92.5%, p<0.001) were distributed outside the HDF regions. There was a relationship between PSs and the HDF regions such that PSs of opposite chirality influence the propagation of HDF. This was observed for all patients and in 72.1 (± 10.5) % of the total windows. The influence of direction of HDF movement by PSs of opposite chirality was observed 12 (±9) times for each window. A case illustration is presented on Figure 1.

Our analysis suggests an organised behaviour of PS of opposite chirality and HDF regions travelling between them. Once an electrophysiological relationship is established, the spatiotemporal behaviour of PS and HDF could provide alternative ablation strategies for AF.
Abstract 15911: Reduced Senescence and Enhanced Proliferation of Human Cardiac Progenitor Cells Isolated and Expanded Under Reduced Oxygen Tension
Authors: He Huamei , Xiong Hui , O’Malley Thomas , Ji Beisi , Favre Elizabeth G , McGowan Francis X
Published: July 2021

Background:
Oxygen availability at the cellular level in vivo is significantly lower (~1-7%) than that used for typical ambient cell culture conditions (21%). Here we investigated whether prolonged culture at reduced O2 concentrations affected proliferation, senescence and oxidative stress of human cardiac progenitor cells (hCPCs).

Methods:
hCPCs positive for c-kit and negative for lineage markers (ckit+/Lin-) were isolated from right atrial tissues obtained from five infants during repair of congenital heart defects and expanded for a maximum of 10 passages in varying O2 concentrations (1, 5, and 21%); all manipulations were performed at the target O2 in a hypoxic chamber. Cellular phenotype was confirmed by ICC staining and flow cytometry. Doubling time, oxidative stress (8-OH-deoxyguanosine [8OHdG], protein carbonyl formation) and senescence markers (telomere length, telomerase activity, P16ink4a staining) were measured.

Results:
Reducing ambient O2 from 21% to 1% did not alter cell surface marker expression. Culture and expansion at 21% O2 markedly accelerated hCPC senescence compared to 1% or 5% O2, as indicated by increased P16ink4a positive hCPCs and greater loss of telomere length and telomerase activity; much of this damage appeared to occur during early passage and expansion. Both protein carbonyl and 8OHdG formation progressively increased in 21% O2, whereas these oxidative injury markers showed little change at 1 and 5% O2 concentrations. hCPCs that were cultured at either 5% or 1% O2 demonstrated shorter doubling times with resultant higher cell yields during in vitro expansion.

Conclusion:
Culturing ckit+/Lin- hCPCs at lower oxygen tension minimizes oxidative damage, reduces senescence, and enhances proliferative potential during long-term culture; expansion at 1% ambient O2 appeared to be most effective. This relatively straightforward modification may further understanding of the biology of CPCs and their regenerative potential.
Abstract 16000: Impaired Fasting Glucose Increases Risk for an Unrecognized Myocardial Infarction: The Cardiovascular Health Study
Authors: Stacey Richard B , Leaverton Paul E , Schocken Douglas D , Peregoy Jennifer , Lyles Mary , Bertoni Alain G , Burke Gregory
Published: July 2021

Background:
Almost 25% of initial myocardial infarctions (MI) are unrecognized or clinically-silent (UMI). The prognostic implications of a UMI parallel those of symptomatic MIs. With diabetes mellitus (DM) being a known risk factor for UMI, further investigation is warranted regarding impaired fasting glucose (IFG) as a risk factor for UMI. Up to one-third of Americans have IFG . Therefore the relationship between UMI and IFG may have significant public health and clinical ramifications.

Methods:
The relationship between IFG and UMI was examined in the Cardiovascular Health Study: a cohort of individuals aged ≥ 65 years old. At year 2, there were 5,018 participants who had an initial 12-lead electrocardiogram (ECG). Of these participants, those with prior coronary heart disease (CHD), incident CHD, or a UMI on initial ECG were excluded. Our study population consisted of 1,714 participants without exclusions with measured fasting glucose (normal fasting glucose, NFG; n = 844), IFG (n=679), and DM (n=191) who underwent a baseline 12-lead electrocardiogram (ECG). Using Minnesota code, an UMI was identified by the presence of pathological Q waves or minor Q waves with ST-T abnormalities. Crude and adjusted hazard ratios (HRs) were calculated. Cox proportional hazard models were used to adjust for age, gender, body mass index, hypertension, anti-hypertensive medication use, total cholesterol, HDL cholesterol, lipid-lowering medication use, and cigarette use.

Results:
The sample was 36% male, 95% white, and had a mean age of 72.4 ± 5.6 years. Over a mean follow-up of 8.1 years, there were 94 UMIs identified among NFG subjects, 110 among IFG subjects, and 35 among DM subjects. Relative to NFG, the crude risk ratio estimates for UMI with IFG and DM were 1.53 (95% CI: 1.16-2.01) and 1.85 (1.24-2.70), respectively. With adjustment, the HR for UMI in IFG compared with NFG was 1.37 (95% CI: 1.03-1.83; p=0.032), and the HR for UMI in DM compared with NFG was 1.59 (95% CI: 1.24-2.70; p=0.035).

Conclusion:
Impaired fasting glucose increased the risk for a subsequent unrecognized myocardial infarction. Considering the enormous number of individuals at risk, these findings suggest the need for more aggressive CVD prevention activities.
Abstract 16015: Exosome-mediated Reversal of Duchenne Cardiomyopathy
Authors: Aminzadeh Mark A , Durvasula Prasanthi , Tobin Rachel , Guan Xuan , Andres Allen , Taylor David , Ibrahim Ahmed , Sun Baiming , Torrente Angelo , Goldhaber Joshua , Victor Ronald , Gottlieb Roberta , Childers Martin , Marbán Eduardo
Published: July 2021

Duchenne muscular dystrophy, a crippling genetic disease leading to premature death, affects the heart as well as skeletal muscle. Indeed, cardiomyopathy is the leading cause of death in Duchenne patients. There are no approved treatments for the cardiomyopathy, and novel Duchenne-specific experimental approaches such as exon skipping do not benefit the heart. Here we demonstrate that cardiosphere-derived cells (CDCs), which are in advanced clinical testing for therapeutic regeneration after myocardial infarction, reverse the key pathophysiological hallmarks of Duchenne cardiomyopathy (oxidative stress, inflammation, fibrosis and mitochondrial dysfunction) in mdx mice. Exosomes secreted by human CDCs reproduce the benefits of CDCs in mdx mice, and reverse mitochondrial dysfunction in human Duchenne cardiomyocytes. Both CDCs and their exosomes improve heart function in mdx mice (P<0.05); a single injection of CDCs suffices to increase maximal exercise capacity and improve survival (P<0.005). Delivery of a microRNA enriched in CDC exosomes, miR 148a, mimics key effects of CDCs and CDC exosomes. Thus, CDCs effectively treat Duchenne cardiomyopathy, via exosome-mediated transfer of signaling molecules including miR 148a. The present findings motivate clinical testing of CDCs in patients with Duchenne cardiomyopathy.
Abstract 16017: Mid-term Outcomes in Persistent and Long-standing Persistent Atrial Fibrillation Patients Undergoing Rotor Ablation
Authors: Gianni Carola , Metz Tamara , Di Biase Luigi , Mohanty Sanghamitra , Trivedi Chintan , Gökoglan Yalçin , Günes Mahmut F , Bai Rong , Al-Ahmad Amin , Burkhardt J D , Gallinghouse Joseph G , Horton Rodney , Hranitzky Patrick M , Sanchez Javier E , Tomassoni Gery , Halbfaβ Philipp , Müller Patrick , Schade Anja , Deneke Thomas , Natale Andrea
Published: July 2021

Introduction:
Focal impulse and rotor modulation (FIRM)-guided ablation targets localized sources that are thought to sustain AF. We sought to evaluate if acute success of FIRM-guided ablation in patients with non-paroxysmal AF influenced the mid-term ablation outcomes.

Methods:
This was a multicenter prospective observational study of persistent and LSP AF patients undergoing FIRM ablation in 3 centers. Patients with at least 2 months follow-up were included in the analysis.

FIRM was performed alone or in addition to conventional ablation and rotors were ablated as confirmed by their absence during remapping. Acute success was defined as AF termination, organization or slowing 10%. Mid-term success was defined as freedom from AT/AF off antiarrhythmic drugs (AADs) and after a single procedure during the initial follow-up (excluding the 2-month blanking period).

Results:
A total of 43 patients were enrolled (mean age 62 ± 10; 91% persistent, 9% LSP). Rotors-only ablation was performed in 65% of patients, and in addition to conventional ablation in the remaining 35%. Overall, acute success was achieved in 33% of patients.

During a mean follow-up of 5.5 ± 2.4 months, 35% of patients were free of AT/AF off AADs after a single procedure. When comparing patients who underwent rotors-only ablation with those who received additional conventional ablation, mid-term success rates were respectively 25% vs. 53% (P = NS).

There was no statistical difference in SR maintenance between patients with and without acute success during FIRM ablation (29% vs. 38%, P = NS).

Conclusion:
FIRM-guided ablation in persistent and LSP AF was not effective in obtaining AF slowing/organization/termination during the procedure and in preventing mid-term AT/AF recurrences. Acute success did not impact the mid-term success rate.
Abstract 16082: Plin2 Attenuates Cardiomyocyte Lipotoxicity
Authors: Berube-Simard Felix-Antoine , Haffar Taha , Bousette Nicolas
Published: July 2021

Diabetic cardiomyopathy is associated with excess lipid accumulation in the heart. We previously showed that oleate, a non-toxic mono-unsaturated fatty acid causes the formation of abundant lipid droplets in cardiomyocytes that were lined with Plin2, an important lipid droplet binding protein. In contrast, palmitate, a toxic saturated fatty acid, led to the formation of aberrant lipid droplets which lacked Plin2 immunoreactivity.

Hypothesis:
We hypothesized that Plin2 overexpression may protect against palmitate mediated lipotoxicity.

Methods:
We overexpressed and silenced Plin2 in rat neonatal cardiomyocytes (NCMs) by LentiVector mediated overexpression of Plin2 cDNA and shRNAs, respectively. We treated these NCMs with bovine serum albumin (51μM, vehicle control), 100-300μM oleate, or 100-300μM palmitate for 4-24 hours. We evaluated viability with the propidium iodide exclusion assay and measured gene expression by qRT-PCR.

Results:
Plin2 overexpression protected NCMs from the lipotoxic effects of palmitate. Conversely, silencing of Plin2 sensitized NCMs to the effects of palmitate and caused oleate, which is normally non-toxic, to induce cell death in NCMs. Interestingly, we found that Plin2 overexpression had a marked stimulatory effect on several PPAR target genes including Carnitine palmitoyl transferase 1b (Cpt1b), the rate limiting enzyme in β-oxidation. In contrast, Plin2 silencing led to a significant decrease in oleate induced expression of PPAR target genes, including Cpt1b.

Conclusion:
Here we showed that overexpression of Plin2, a key lipid droplet binding protein protected against lipotoxicity, while silencing it caused lipotoxicity. We show that this may be due to alterations in lipid metabolism, since Plin2 overexpression led to increased expression of key β-oxidation genes. This is important because we have previously shown that palmitate impairs β-oxidation capacity in cardiomyocytes. Therefore enhancing β-oxidation may attenuate lipotoxicity by limiting the build-up of lipid metabolites. The mechanism of Plin2 mediated effects on PPAR target gene expression, as well as the effect on lipid droplet formation are the subject of on-going studies.
Abstract 16191: Phospholamban Regulates Perinuclear/nuclear Calcium Dynamics in Cardiomyocytes
Authors: Wu Adonis Z , Chan Yi-Hsin , Lin Shien-Fong , Chen Peng-Sheng , Chen Zhenhui
Published: July 2021

Introduction:
Phospholamban (PLB) regulates cardiac sarcoplasmic reticulum (SR) Ca
2+
-ATPase (SERCA2a), thus modulating SR Ca
2+
dynamics. Recent studies demonstrated that SERCA is involved in Ca
2+
uptake into the lumen of nuclear envelope (NE) of cardiomyocytes (CMs). However, the regulatory role of PLB on Ca
2+
uptake into NE remains unknown.

Hypothesis:
We hypothesize that PLB is also responsible for modulating nuclear Ca
2+
dynamics.

Methods:
Confocal immunofluorescence microscopy was used to determine subcellular expression of PLB. By using fluo-4 based confocal line-scan Ca
2+
imaging, we measured spontaneous Ca
2+
waves (SCWs) across both cytoplasmic and nuclear regions in isolated permeabilized mouse CMs.

Results:
Several anti-PLB antibodies strongly stained PLB at both SR and the perinuclear membranes in CMs. A PLB peptide (residues 1-31) eliminated all these anti-PLB antibody stains. To identify the functional role of PLB expressed in the perinuclear membranes, we took advantage of our recently established method that a Fab fragment of anti-PLB monoclonal antibody (Fab) reversed PLB inhibition specifically and increased SR Ca
2+
uptake and release. SCWs through the nuclear regions had typically relative low fluorescent amplitude (F/F
0
) and slow decay time (t
1/2
) compared to that in the cytoplasmic region. At the free intracellular Ca
2+
concentration ([Ca
2+
]
i
) of 400 nM, Fab (100 μg/mL) significantly enhanced F/F
0
and decreased t
1/2
of SCWs in both cytoplasmic and nuclear regions. After addition of Fab, F/F
0
of SCWs through the nuclear regions increased from 0.91±0.16 to 1.27±0.19 (n=9, p<.05) while t
1/2
decreased from 137.6±18.5 ms to 105.0±11.3 ms, (p<.05). Similar effects were also observed after phosphorylation of PLB by addition of 20 μM cAMP (F/F
0
=1.43±0.11 vs. 1.04±0.14 in control, p<.05; t
1/2
=107.82±10.9 ms vs. 139.21±20.1 ms in control, n=6, p<.05). At high [Ca
2+
]
i
of 1000 nM where PLB does not inhibit SERCA2a, addition of cAMP or Fab had no significant effect on SCWs in both cytoplasmic and nuclear regions.

Conclusions:
We demonstrated that PLB is expressed in and around NE. Acute removal of PLB inhibition increased perinuclear/nuclear Ca
2+
uptake and release. PLB is critically involved in nuclear Ca
2+
signaling modulation.
Abstract 16357: Identification of Circulating Proteins that Predict the Presence of Obstructive Coronary Artery Disease in Symptomatic, Non-Diabetic Patients Referred for Invasive Coronary Angiography
Authors: Wingrove James , Fitch Karen , Beineke Phil , Rosenberg Steven
Published: July 2021

Background:
The diagnosis of patients presenting for the first time with typical or atypical symptoms consistent with obstructive coronary artery disease (CAD) remains challenging; despite the existence of a number of non-invasive modalities for the assessment of CAD, the yield of obstructive CAD in patients who undergo invasive coronary angiography remains low. We sought to identify circulating protein biomarkers that might aid in the diagnosis of obstructive CAD in non-diabetic patients.

Methods:
386 non-diabetic patients from the PREDICT study (NCT00500617) were divided into two independent case:control sets for initial marker discovery (Set 1, n=187) and preliminary model validation (Set 2, n=199). Cases were defined as patients with ≥50% stenosis in ≥1 major coronary artery; controls had < 50% stenosis in any major coronary artery as determined by quantitative coronary angiography (QCA). In 11% of the patients QCA was not available and 70% stenosis by clinical read was used as a case threshold. 135 protein markers were evaluated in plasma from Set 1 patients using an electrochemoluminescence-based platform (MesoScale); the top markers were analyzed in Set 2 and used to develop predictive models using penalized logistic regression (LASSO). Model performance was estimated via 2500 iteration of cross validation on random holdout sets of 14 patients.

Results:
In a sex and age adjusted analysis, nine protein markers obtained nominal significance (p < 0.05) in Set 1, with 9 additional markers trending towards significance (p 0.7); the average of these pairs was used for subsequent analysis. Top markers were evaluated in Set 2 and a five marker (Adiponectin, ApoA1, NT-proBNP, S100A8-MPO, PlGF) model was fitted via LASSO, resulting in a mean cross-validated AUC of 0.64.

Conclusion:
We have identified a set of plasma protein markers in subjects referred for invasive angiography, which in age and sex adjusted analysis are responsive to the presence of obstructive CAD. Use of such protein markers alone, or in combination with other genomic markers or clinical risk factors may aid in the identification of obstructive CAD in non-acute, symptomatic patients.
Abstract 16381: Novel Thiol-activated H2S Donors Attenuate Myocardial Ischemia/Reperfusion Injury
Authors: Organ Chelsea , Li Zhen , Zhao Yu , Yang Chuntao , Bhushan Shashi , Otsuka Hiro , Xian Ming , Lefer David J
Published: July 2021

Background:
Hydrogen sulfide (H2S) protects against acute myocardial ischemia/reperfusion (MI/R) injury and heart failure by ameliorating oxidative stress, improving mitochondrial function, and attenuating apoptosis. One of the major limitations of currently available H2S donors is poor pharmacokinetics profiles that result in very rapid and uncontrolled H2S release. NSHD-1 and NSHD-2 are recently developed thiol-activated H2S donors designed for sustained release of H2S upon activation by molecules containing thiol groups such as cysteine and glutathione. We hypothesized that these novel H2S donors would generate H2S for extended periods and ameliorate myocardial cell death following MI/R in an in vivo murine model.

Methods and Results:
C57BL6/J male mice (10-12 weeks of age) were subjected to 45 minutes of MI followed by 24 hours of R. At the time of reperfusion, animals received Vehicle (0.5% THF), NSHD-1 (50 μg/kg and 100 μg/kg), or NSHD-2 (50 μg/kg) by direct intracardiac (i.c.) injection. In addition, at 4 hours of R, plasma was collected for troponin-I measurements. In preliminary studies we observed sustained release of H2S with both of these H2S donors. Myocardial infarct size was reduced by 35% (p < 0.01 vs. Vehicle) in mice treated with NSHD-1 (100 μg/kg), 43% (p < 0.05 vs. Vehicle) in mice treated with NSHD-2 (50 μg/kg), and 54% (p < 0.01 vs. Vehicle) in mice treated with NSHD-2 (100 μg/kg).

Conclusions:
NSHD-1 and NSHD-2 significantly attenuate MI/R injury in a murine model. Experiments are currently underway to further define the in vivo pharmacokinetics of H2S release from these agents, mechanisms of action, and safety profile.
Abstract 16428: Characteristics and Impact of Bystander Cardiopulmonary Resuscitation Following Pediatric Out of Hospital Cardiac Arrest in the United States: A Study From the Cardiac Arrest Registry to Enhance Survival (CARES)
Authors: Naim Maryam Y , Burke Rita V , McNally Bryan F , Berg Robert A , Vellano Kimberly , Markenson David , Bradley Richard N , Rossano Joseph W
Published: July 2021

Introduction:
Bystander cardiopulmonary resuscitation (BCPR) is associated with improved outcome in adult out-of-hospital cardiac arrest (OHCA). There are few data on the prevalence and impact of BCPR on children.

Hypothesis:
We aimed to characterize BCPR in pediatric OHCA and test the hypothesis that BCPR would occur infrequently and would be associated with neurologically favorable survival at hospital discharge from a large cardiac arrest registry in the United States.

Methods:
We conducted an analysis of the Cardiac Arrest Registry to Enhance Survival database. Inclusion criteria were age ≤ 18 years of age and non-traumatic OHCA from January 1, 2013 through December 31, 2014. Neurologically favorable survival was defined as a Cerebral Performance Category Scale of 1 or 2.

Results:
A total of 2,176 cardiac arrests were evaluated. Most patients were infants (62%) or adolescents (19%). Most arrests occurred at home (86%), were unwitnessed (75%), and had a non-shockable rhythm (93%). BCPR was provided in 49%, most commonly by a family member (71%). BCPR was more common for white (60%) compared to black (42%) and Hispanic children (44%) (p<0.001). Overall, BCPR was associated with a higher rate of neurologically favorable survival (11% vs. 7%, odds ratio [OR]1.6 95% confidence interval [CI] 1.2-2.3). In sub-group analyses, BCPR was associated with a higher rate of neurologically favorable survival for out of home arrests (34% vs. 15%, OR 2.9, 95% CI 1.6-5.3), and arrests presenting in a shockable rhythm (48% vs. 32%, OR 2.0 95% CI 1.0-4.0). For infants BCPR was not associated with survival (6.4% vs. 6.0%, OR 1.1 95% CI 0.7-1.7) or neurologically favorable survival (5.2% vs. 5.0%, OR 1.1 95% CI 0.6-1.8).

Conclusion:
BCPR was provided in just under 50% of pediatric OHCAs and was more common for white compared to black and Hispanic children. BCPR was associated with improved survival that was most notable in out of home arrests, with over twice as many patients having neurologically favorable survival. Though infants comprised the largest age group, no effect of BCPR outcome was observed. This impact of BCPR suggests the need for a public health strategy to improve the provision of BCPR, and the need for an alternative strategy for some groups including infants.
Abstract 16456: Regulation of Vascular Smooth Muscle Phenotypic Switch and Suppression of Atherosclerosis by c-Kit/SCF Expression in Hyperlipidemic Mice
Authors: Song Lei , Mesa Annia , Fernandez Natasha , Selman Guillermo , Santos Nieves , Webster Keith A , Vazquez-Padron Roberto I
Published: July 2021

Introduction:
This study provides our novel evidence that stem cell factor (SCF) receptor c-Kit regulates vascular smooth muscle cell (SMC) phenotype and is potently anti-atherogenic.

Methods and Results:
Atherosclerotic plaque was quantified in transgenic mice deficient for c-Kit (c-Kit
W/Wv
ApoE
-/-
) or SCF (c-Kitl
sl
/+
ApoE
-/-
) after 16 weeks of high fat diet (HFD). Both mutant strains displayed substantially greater atherosclerosis compared with control (ApoE
-/-
) littermates (
p
<0.01 and <0.05 respectively). Transplantation of c-Kit positive bone marrow into c-Kit
W/Wv
ApoE
-/-
mice failed to rescue the atherogenic phenotype indicating that increased atherosclerosis was associated with reduced arterial c-Kit. To investigate the mechanism, SMC organization and morphology were analyzed in aorta by histopathology and electron microscopy. Remarkably, SMCs were more abundant, disorganized and vacuolated in aortas of c-Kit mutant mice compared with controls (
p
<0.05). Markers of the “contractile” SMC phenotype (Calponin, SM22α) were downregulated in parallel with decreased c-Kit (
p
<0.05). Reconstitution of c-Kit in synthetic cultured SMCs conferred increased spindle-shaped morphology, reduced proliferation and elevated levels of contractile markers Calponin and SM22α, each characteristic of a resumed contractile phenotype (
p
<0.05). Conversely, aortas of c-Kit
W/Wv
ApoE
-/-
accumulated more pro-inflammatory cytokines (MCP-1, RANTES, MIP-1β, G-CSF,
p
<0.01) and elevated monocytes compared with control mice treated equivalently. Additionally, quantitative mRNA screening and western blot analysis revealed elevated levels of atherosclerotic and inflammatory biomarkers Toll Like Receptors (TLR4, 6, 9) and TNF-α in cultures of c-Kit
W/Wv
VS c-Kit
+/+
SMC.

Conclusion:
c-Kit/SCF expression prevents phenotypic switching of contractile SMC to the pro-inflammatory, synthetic phenotype and markedly suppresses atherosclerosis in this murine model.
Abstract 16457: Markers of Diabetes and Renal Function Extend Sudden Death Risk Assessment Beyond the Ejection Fraction
Authors: Narayanan Kumar , Uy-Evanado Audrey , Teodorescu Carmen , Reinier Kyndaron , Gunson Karen , Jui Jonathan , Chugh Sumeet S
Published: July 2021

Introduction:
Although diabetes and renal dysfunction are known to be associated with SCD risk, the cumulative risk of objective laboratory markers in combination with left ventricular ejection fraction (LVEF) has not been previously evaluated.

Hypothesis:
Addition of glycosylated hemoglobin (HbA1C) and serum creatinine levels to LVEF can improve the SCD risk stratification model.

Methods:
As part of a large, prospective, ongoing study of SCD in a Northwestern US metropolitan region (catchment population about 1 million), SCD cases were compared with controls with coronary artery disease (CAD) and no SCD from the same geographic location. HbA1C, serum creatinine levels and LVEF (all prior and unrelated to the SCD event for cases) were obtained for all subjects. Odds ratios for SCD associated with abnormal HbA1C (≥ 7%) and creatinine (≥ 1.5 mg/dL) levels was calculated. Cumulative odds and improvement in model performance on addition of elevated lab markers to low LVEF (≤ 35%) was assessed.

Results:
243 SCD cases (68.7 ± 13.2 yrs; 62.1% male) and 159 CAD controls (66.2 ± 9.9 yrs; 65.6% male) with appropriate lab values and LVEF information were evaluated. The mean HbA1C (7.3 ± 2.3 vs. 6.6 ± 1.5%) and creatinine (1.8 ± 1.7 vs. 1.2 ± 0.7 mg/dL) levels were significantly higher in cases. Cases were significantly more likely to have HbA1C ≥ 7% (49.4 vs. 27.7%; p<0.0001) or creatinine ≥ 1.5 mg/dL (39.1% vs. 13.8%) (all p<0.0001). After adjustment for age, sex and low LVEF, high HbA1C (OR 2.3, 95% CI 1.4-3.6; p=0.001) and high creatinine (OR 3.3, 95% CI 1.9-5.7; p<0.0001) were independently associated with SCD; LVEF ≤ 35% was associated as well (OR 1.8, 95% CI 1.1-3.2; p=0.05). As compared to neither lab marker being high, elevation of one marker (OR 2.4, 95% CI 1.5-3.9) or both markers (OR 7.9, 95% CI 3.5-17.6) was associated with progressive increase in SCD odds. Addition of lab markers to a risk stratification model with only LVEF improved model discrimination significantly (AUC 0.613 vs. 0.709; p=0.01).

Conclusions:
HbA1C and serum creatinine improved the SCD risk stratification model when added to LVEF. Further investigation is warranted before clinical use, including consideration of competing risks that influence overall mortality.
Abstract 16479: Remote Ischemic Preconditioning: Do Exosomes Play a Requisite Role in Evoking Cardioprotection?
Authors: Wider Joseph , Kulek Andrew R , Undyala Vishnu V , Przyklenk Karin
Published: July 2021

Remote ischemic preconditioning (RIPC) is the phenomenon whereby brief episodes of ischemia-reperfusion applied in distant tissues or organs render the heart resistant to a subsequent sustained ischemic insult. The hallmark of RIPC is inter-organ communication, with recent evidence suggesting that exosomes may serve as the vector for the transport of protective factor(s) from the site of the distant trigger to the cardiomyocytes. To test this hypothesis, rats underwent a standard RIPC stimulus: i.e., 4 5-min episodes of bilateral femoral artery occlusion. Serum (~3 mL per rat) was harvested immediately after RIPC; 1 mL was stored at -80°C, and 2 mL was processed for exosome isolation by prolonged ultracentrifugation (12 hours at 300,000
xg
). Aliquots of the pellet and supernatant were probed (by immunoblotting) for expression of exosome markers including HSP60 and flotillin. Most importantly, the cardioprotective efficacy of: 1) RIPC serum, 2) the pellet, reconstituted in buffer, 3) supernatant-bottom layer, 4) supernatant-top layer and 5) buffer alone was assessed by transfer of volume-matched aliquots to cultured HL-1 cardiomyocytes. After 1 hour of pretreatment, cells were subjected to 2.5 hours simulated ischemia + 24 hours reoxygenation and % cell death was quantified by Trypan blue staining. As expected, RIPC serum was protective: mean cell death was 34
+
5%*
vs
48
+
5% in buffer-controls (*p<0.05). As further expected, the exosome-depleted top layer of supernatant failed to confer protection. However, in contrast to the ‘exosome hypothesis’, RIPC with exosome-rich aliquots did not yield consistent cardioprotection: both the pellet and the supernatant-bottom layer had robust expression of HSP60 and flotillin, yet only the supernatant-bottom attenuated cell death (32
+
3%*; Figure). Thus, while transport of protective factor(s) via exosomes may play a role in RIPC, our results reveal that exosomes
per se
are not sufficient to evoke remote cardioprotection.