bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 20361: Statin-Induced Myopathy in Patients With Familial Hypercholesterolemia
Authors: Ahmad Zahid , Song Li , Wosik Jedrek , Mani Preethi , Petr Elisabeth , McLeod George , Murad Shatha , Garg Abhimanyu
Published: July 2021

Introduction:
Patients with familial hypercholesterolemia (FH) suffer from premature coronary heart disease (CHD) due to extreme elevations in low-density lipoprotein cholesterol (LDL-C). As such, they require high doses of potent statins, a major risk factor for developing statin-induced myopathy. Little is known, though, about other underlying factors predisposing them to statin-induced myopathy.

Methods:
We studied 272 genetically screened FH patients - ascertained from Dallas, TX, lipid specialty clinics - with and without a documented history of statin-induced myopathy (defined as developing muscle symptoms or elevated serum creatine kinase (CK) levels while taking a statin).

Results:
Statin-induced myopathy was diagnosed in 35% of FH patients; however, at the time of participation in our study, 73% of myopathy patients were taking statins (vs 79% of statin-tolerant patients; p = 0.37). Statin dosages were similar in the two groups except for rosuvastatin (20 mg/day in myopathy patients vs 40 mg/day in statin-tolerant patients; p < 0.001). Myopathy patients were older (57 ± 11 vs 51 ± 14 years; p = 0.001), had lower BMI (29 ± 6 vs 31 ± 7 kg/m2; p = 0.01), suffered from less premature CHD (22% vs 34%; p = 0.006), and had less hypertension (57% vs 67%; p = 0.05). On-treatment LDL-C was higher in myopathy patients (141 ± 37, n = 63, vs 128 ±40 mg/dL, n= 148; p < 0.01). No differences were identified in pretreatment LDL-C (253 ± 53 vs 263 ± 83 mg/dL; p = 0.57), gender (63% vs 57 % female; p = 0.3), % with diabetes (23% vs 29%; p = 0.38), % with LDL-receptor or apolipoprotein B mutations (26% vs 36%; p = 0.09), or baseline CK levels (median 103 vs 115; p = 0.10).

Conclusions:
Despite a history of statin-induced myalgia, most FH patients eventually tolerated statins and achieved up to 44% reduction in LDL-C levels. FH patients with increased age and lower BMI were more likely to be diagnosed with myopathy, consistent with prior reports that age and smaller body frame are risk factors. Also, FH patients lacking hypertension or premature CHD were diagnosed more often with myopathy, suggesting that patients without CHD risk factors complain more about muscle symptoms. In conclusion, statin-induced myopathy adds an additional - but manageable - challenge to the treatment of FH patients.
Abstract 20364: Successful Ablation of Ventricular Fibrillation in Malignant Bileaflet Mitral Valve Prolapse Syndrome
Authors: Syed Faisal F , Noseworthy Peter , McLeod Christopher , Kapa Suraj , Mulpuru Siva , Sriram Chenni , Cannon Bryan , Asirvatham Samuel , Ackerman Michael
Published: July 2021

Introduction:
Although the vast majority of mitral valve prolapse (MVP) is benign, women with bileaflet MVP (biMVP), complex ventricular ectopy (VE), and abnormal T waves may comprise the recently described malignant biMVP syndrome. The mechanism of ventricular arrhythmia is unknown. To further characterize the arrhythmic substrate, we reviewed our center’s ablation experience in 6 biMVP patients with prior cardiac arrest and recurrent ICD shocks for drug refractory ventricular fibrillation (VF).

Methods and Results:
Six women with biMVP (median age 31.5 [range 24.2 - 58.7] years, EF 65 [45 - 67]%, all ≤moderate mitral regurgitation) experienced 6 (3 - 25) appropriate ICD shocks over 4.8 (2.8 - 10.7) years and underwent index ablation between 2/2007 - 10/2013. All had multiple VE morphologies (median 7 [3 - 24]) with variable coupling intervals but with a predominant VE trigger for the VF. A median 2 (1 - 4) VE foci were ablated. Sites of successful ablation of VF-triggering and other dominant VE were left ventricular papillary muscles [PM] (1 anterior, 1 posterior, 1 both), fascicles (1 anterior, 1 posterior), or both (1 both PM and posterior fascicle). Outflow tract VE was also present and targeted (1 left, 1 right)i. Two underwent repeat ablation (288 and 312 days) for recurrent complex VE without shocks, with different foci to the index ablation (1 posterior fascicle, 1 both fascicles). The VF-triggering VE in all patients was confirmed as originating from within the left fascicular system, which in 3/6 was at a papillary muscle. Acute procedural success was seen in all with no complications to date. A VF storm occurred within 24 hours of ablation in a single patient. At follow-up of a mean 662 (47 - 2099) days, 1 patient received a single shock (p=0.03 vs. preablation). Symptomatic VE was reduced in all; while 3/6 continue Class 1c antiarrhythmics and 5/6 have beta blockade.

Conclusion:
Malignant biMVP syndrome is characterized by fascicular and papillary muscle PVCs that trigger ventricular fibrillation, yet in all patients, the VE is multifocal. Ablation of at least one focus appears to improve symptoms and reduce shocks.
Abstract 20395: Racial/Ethnic and Gender Disparities in Use of Drug-Eluting vs. Bare Metal Stents in ST-Elevation Myocardial Infarction Patients, 2006-2012
Authors: Salemi Jason L , Pathak Amit P , Pathak Elizabeth B
Published: July 2021

Background:
Recent evidence continues to show the benefit of drug-eluting stents (DES) over bare metal stents (BMS) in patient outcomes following ST-elevation myocardial infarction (STEMI), although the use of DES may be contraindicated in patients with specific comorbidities. In this study, we investigated racial/ethnic and gender disparities in the use of DES, after controlling for the effects of age, insurance status, secular trends, and comorbidities.

Methods:
The study population included all STEMI patients (n=60,218) who received PCI and at least one stent in any Florida acute-care hospital during 2006-2012. Hospital discharge data were analyzed. Procedure codes identified DES (ICD-9-CM 36.07) and BMS (ICD-9-CM 36.06). We used logistic regression to model the odds of receiving a DES. Potential predictors included in the model were patient age, racial/ethnic-gender group (referent=White men), year, payer (referent=commercial), diabetes, atrial fibrillation (AFIB), chronic kidney disease (CKD), and end-stage renal disease (ESRD).

Results:
Among all STEMI patients, Hispanic women were most likely to receive a DES (61.2%) and Black men were least likely (46.8%). Furthermore, the % of patients who received no stent also varied from 6.7% among Hispanic men to 12.8% among Black women. Multivariable logistic regression results were highly significant, with included independent variables significantly predictive of the odds of receiving a DES in the expected directions. After adjustment and compared with White men, Hispanic women were 24% more likely to receive a DES (OR 1.24, 95%CI 1.13-1.37), White women were 8% more likely to receive a DES (p=0.001), and Black women were 15% less likely to receive a DES (OR 0.85, 95% CI 0.76-0.95). There were no significant differences in DES usage for Hispanic men or for men or women or “other” race/ethnicity. The strongest disparity was observed for Black men, who were 32% less likely to receive a DES than White men (OR 0.68, 95% CI 0.63-0.74, p<0.0001).

Conclusions:
In this real-world analysis of unselected and recent STEMI patients, a significant disparity in use of DES for Black men and women was observed. This disparity was not explained by patient age, payer or comorbidities, nor by the secular trend.
Abstract 20414: Cardiac Resynchronization Therapy Reduces Septal Contribution to Right Ventricular Work
Authors: Storsten Petter , Remme Espen W , Boe Espen , Eriksen Morten , Kongsgaard Erik , Smiseth Otto A , Skulstad Helge
Published: July 2021

Introduction:
During left bundle branch block (LBBB) there is abnormal motion of the interventricular septum (IVS) with early systolic beaking into the left ventricle (LV), followed by rebound stretch into the right ventricle (RV).

Hypothesis:
We hypothesize that septal rebound stretch contributes to RV function, and therefore cardiac resynchronization therapy (CRT) which removes rebound stretch, may have a negative effect on RV systolic performance.

Methods:
In 6 anesthetized dogs, LBBB was induced by radio frequency ablation. CRT was applied with electrodes on the IVS and the LV lateral wall. RV pressure (RVP) was measured by a micromanometer, and septum-to-RV free wall diameter and RV free wall long axis segment length by sonomicrometry. RV short-axis work was calculated as the area of RVP-diameter loop and long-axis work as area of the RVP-segment length loop.

Results:
Induction of LBBB increased RV short axis work from 36 ± 20 to 62 ± 18 mmHg*mm (± SD, p<0.05), but decreased RV long-axis work from 40 ± 13 to 30 ± 14 mmHg*mm (p<0.05). With CRT these changes were reversed; RV short-axis work decreased to 35 ± 21 (p<0.05) and long-axis work increased to 41 ± 15 mmHg*mm (p<0.05). This was associated with an increase in RV dP/dt max (p<0.05).

Conclusions:
Application of CRT during LBBB caused a marked reduction in RV short-axis work, indicating reduced septal contribution to RV work. This was compensated by an increase in RV free wall long-axis work, and RV dP/dt max increased. Thus, a non-failing RV has the ability to compensate and even increase its function during CRT, but emphases the importance of RV function to achieve response of CRT treatment.
Abstract 20440: Cardiovascular Events in a Physical Activity Intervention as Compared to a Successful Aging Intervention: The LIFE Study Randomized Trial
Authors: Newman Anne B , Dodson John A , Church Timothy , Bonds Denise , Buford Thomas , Fielding Roger , Kritchevsky Stephen , Beavers Daniel P , Pahor Marco , Stafford Randall S , Szady Anita D , McDermott Mary M
Published: July 2021

Background:
There is little clinical trial evidence that sustained physical activity can prevent cardiovascular disease (CVD) in older adults. The LIFE Study was a multi-center randomized trial comparing sustained, structured physical activity (PA) to health education/successful aging (SA) to prevent mobility disability in older sedentary men and women. Cardiovascular morbidity and mortality was a secondary endpoint.

Methods:
Eligible participants (N=1635, 67% women, aged 70-89 years) were randomized to PA vs. SA. Eligibility criteria included being sedentary with a score <10/12 on a short physical performance battery (SPPB), indicating higher risk for disability. Prevalent CVD was 30% at baseline. The PA intervention was a structured moderate intensity program, predominantly aerobic (walking), with resistance and flexibility exercises, at least five days weekly, 2x per week on site for 2.6 years on average. The SA intervention consisted of weekly health education sessions for six months, then monthly. CVD was assessed every 6 months, including fatal and non-fatal MI, angina, stroke and transient ischemic attack, peripheral artery disease including abdominal aortic aneurysm and all revascularizations. Hospital records were reviewed and adjudicated for CVD events by committee. Silent MI was assessed by ECG at 18 and 36 months.

Results:
Incident CVD occurred in 14.4% (n=118/818) of PA and 13.8% (113/817) of SA participants (HR=1.07, 95%CI=0.82-1.38. Using a narrower endpoint of MI, stroke or cardiovascular death, rates were 8.9% in PA and 8.7% in PA groups respectively with HR = 1.04 (95% CI=0.75-1.45). There were no significant differences in rates of incident vs. recurrent CVD. Among participants with SPPB <8, CVD rates were 13.8% in PA vs 17.7% in SA with HR = 0.74 (95%CI=0.51-1.08), compared to 14.8% vs.10.5% (HR = 1.54 (95%CI=1.06-2.24) among those with SPPB of 8 or 9 (p for interaction = 0.007).

Conclusions:
Among participants in the LIFE Study, an aerobically-based, moderately intensive PA program did not reduce cardiovascular events overall. However, the intervention was more protective in lower functioning participants. Hypotheses to explain differences by functional status could be addressed with continued follow-up.
Abstract 20452: Microrna-200b Induces Endothelial Progenitor Cell Apoptosis and Senescence by Targeting Cjun Expression
Authors: Zhu Shoukang , Deng Shanming , Jia Chunling , Ma Qi , Chen Emily , Zhu Wei , Goldschmidt-Clermont Pascal J , Dong Chunming
Published: July 2021

Introduction:
Lineage negative bone marrow cells (Lin
-
BMCs) mediate vascular repair. Aging-associated apoptosis and senescence result in reduced number and impair Lin
-
BMCs’s pro-repair capacity. Molecular mechanisms underlying lin
-
BMCs apoptosis and senescence remain poorly understood. MicroRNAs (miRNAs) regulate many important biological processes. The identification of miRNA-mRNA networks that modulate the health and functionality of lin
-
BMCs is a critical step in understanding the process of vascular repair.

Hypothesis:
miR-200b-cJun network plays a vital role in regulating Lin
-
BMCs apoptosis, senescence and self renewal in angiogenesis.

Methods:
Lin
-
BMCs were isolated from young (3-week-old) wild type (WT), young apoE
-/-
, aged WT (29-month-old) and aged apoE
-/-
(12 month-old) C57BL/6 mice. Global miRNA and gene expression profiling were analyzed.

Results:
Transcriptome analysis in Lin
-
BMCs isolated from young and aged WT and apoE
-/-
mice showed a significant aging-associated increase in miR-200b expression. We found that C-Jun was predicted to be a miR-200b target and c-Jun expression was reversely correlated with miR-200b levels. Luciferase reporter assays confirmed c-Jun as a direct target of miR-200b. MiR-200b overexpression in young lin-BMCs inhibited c-Jun expression, resulting in increased senescence and apoptosis in vitro and impaired angiogenic capacity
in vivo
. In contrast, suppression of miR-200b or overexpression of c-Jun in aged lin
-
BMCs increased c-Jun expression rejuvenated Lin
-
BMCs with decreased senescence and apoptosis, leading to improved angiogenesis
in vitro
and
in vivo
.

Conclusions:
Using genomic and functional studies, we discovered that miR-200b regulates apoptosis and senescence of age-associated lin
-
BMCs by suppressing c-Jun expression, thus negatively affecting vascular repair capacity of those cells in atherogenesis. Modulation of miR-200b and/or its target c-Jun may suggest a potential therapeutic intervention to improve Lin
-
BMCs-mediated angiogenesis and vascular repair.
Abstract 20470: Lower Mortality and Stent Thrombosis Rates Associated With Introduction of Potent P2Y12 Inhibitors in Patients With Acute Coronary Syndromes
Authors: Iqbal Javaid , Rowe Rebecca , Zhang Yao-Jun , Parviz Yasir , Morton Allison C , Grech Ever , Gunn Julian P , Storey Robert F
Published: July 2021

Aims:
We investigated the impact of new platelet P2Y12 inhibitors, prasugrel and ticagrelor, compared with clopidogrel, upon mortality and stent thrombosis (ST) in patients with acute coronary syndromes (ACS) in a large, single-centre, ‘all-comers’ population.

Methods:
Data were collected for 6742 consecutive patients attending the cardiac catheterization lab at Sheffield, UK (2009-2013) with ACS. Differences in outcomes among patients receiving different P2Y12 inhibitors were evaluated at 12 months by Kaplan-Meier curves and log-rank test in the overall and a propensity-matched population.

Results:
Of 6742 patients with ACS (36% STEMI, 64% NSTE-ACS), 67% (4525) received clopidogrel, 15% (1007) prasugrel and 18% (1210) ticagrelor, with aspirin for all. In the overall group, prasugrel (HR 0.78, 95% CI 0.59-1.02, p=0.07) and ticagrelor (HR 0.77, 95% CI 0.60-0.99, p=0.04) were associated with lower all-cause mortality compared with clopidogrel (Fig 1A). There was no difference in mortality between prasugrel- and ticagrelor-treated groups (HR 1.01, 95% CI 1.00-1.67, p=0.96). The incidence of definite/probable ST was 4.2% (1.5% definite, 2.7% probable) at 12 months. ST rates were nearly 2-fold higher in patients treated with either clopidogrel or prasugrel compared with ticagrelor (Fig 1B). In the STEMI subgroup, lower mortality and ST rates were observed with new P2Y12 inhibitors but no significant differences between prasugrel and ticagrelor (Fig 1C and 1D). The results for all ACS population or STEMI subgroup remained similar after adjustment for confounding variables or analysing propensity-matched cohorts.

Conclusions:
Both prasugrel and ticagrelor appear superior to clopidogrel for reduction in mortality in ACS in the ‘real world’. Ticagrelor was associated with the lowest mortality and ST rates in all ACS patients, whereas either prasugrel or ticagrelor appear suitable in STEMI patients without contraindications.
Abstract 20478: Circulating Inflammatory Potential Measured by an Endothelial Biosensor Assay in Coronary Artery Disease Patients
Authors: Cung Heidi , Anderson Joe , Nawarskas James , Campen Matthew
Published: July 2021

Introduction:
Vascular disease is driven by systemic inflammation that can arise from sites distal to the affected coronary or cerebral vessels. The objective of this study is to characterize the inflammatory potential of serum from patients with coronary artery disease (CAD) using cultured endothelial cells as a biosensor of the circulating milieu.

Methods:
Serum samples from CAD patients (N=48) and healthy control subjects (N=50) were incubated with primary human coronary artery endothelial cells at a 1:10 dilution for 4h, following by isolation of the cellular RNA. Alteration of inflammation-responsive elements (adhesion molecules and cytokines) was assessed on a gene expression level. Specific indicators included intercellular adhesion molecule-1 (ICAM), vascular cell adhesion molecule-1 (VCAM), and interleukin-8 (IL-8). Additionally, the serum samples from the CAD patients and healthy individuals were quantitatively analyzed for IL-1β, IL-6, IL-8, and TNF-α using an electrochemical luminescence platform.

Results:
For the CAD subjects’ serum, the mean values of ICAM, VCAM, and IL-8 expression were all elevated compared to healthy control subjects (p<0.001 for each by Students T-test). Correlational analysis revealed the three indicators (ICAM, VCAM, and IL-8) to be independent of each other and also other inflammatory markers such as C-reactive protein. IL-8 expression was negatively correlated with serum HDL levels but positively correlated with body fat composition. Interestingly, serum levels of IL-1β, IL-6, IL-8, and TNF-α in CAD patients were not statistically different from healthy control subjects.

Conclusions:
As yet uncharacterized circulating factors in the serum of CAD patients appear to activate endothelial cells. This assay paradigm performed well in terms of discriminating patients with CAD compared to healthy subjects, with greater range and specificity than specific inflammatory markers.
Abstract 20514: Adults With Hypoplastic Left Heart Syndrome: Outcomes in a New Cohort of Patients
Authors: Wilson William M , Silversides Candice , Valente Anne , Oechslin Erwin , Roche S. Lucy , Burchill Luke , Broberg Craig , Hickey Edward , Grigg Leeanne , Teo Eliza , Von Der Muhll Isabelle , Gibson Patrick , Grewal Jasmine , Khairy Paul , Greutmann Matthias , Hickey Kelsey , Emmanuel Yaso , Clift Paul , Wald Rachel
Published: July 2021

Background:
Surgical palliation of hypoplastic left heart syndrome (HLHS) has only been possible for the past few decades. Prior to this, without heart transplantation, HLHS was universally fatal in infancy. The oldest survivors of palliated HLHS are only now entering adulthood and limited data are available regarding their welfare.

Methods:
For this multi-center, cross-sectional, observational study, 6 adult congenital heart disease (ACHD) centers contributed data regarding all HLHS patients aged >18 years followed at their institution. HLHS was defined as a dominant right ventricle (RV) and diminutive left ventricle with a combination of mitral valve disease (stenosis [MS] or atresia [MA]) and aortic valve disease (stenosis [AS] or atresia [AA]). Patients with single RV physiology without hypoplasia of left heart inlet and outlet structures were excluded. All available clinical data, including cardiac imaging, cardiac catheterization results and exercise tests were reviewed.

Results:
The study included 53 HLHS adults (65% male) with mean age 21.8±3.6 years. Underlying cardiac anatomy was AA&MA (n=21, 41%), AS&MS (n=19, 37%), AS&MA (n=10, 20%), and AA&MS (n=1, 2%). Stage 1 Norwood was completed at age 6.0±4.4 days, Glenn shunt at age 10.8±8.7 months and Fontan at age 3.3±2 years. Stage 1 cardiopulmonary bypass and circulatory arrest times were 94±46 and 59±2 minutes respectively. The mean duration of follow-up in an ACHD center was 3.4±2.5 years. After age 18 years, major adverse events had occurred in 15/53 patients (28%). These mutually exclusive events were: death (n=3, 6%), transplant (n=1, 2%), protein losing enteropathy (n=2, 4%), stroke (n=2, 4%), symptomatic ventricular tachycardia (n=1, 2%), heart failure requiring admission for intravenous therapy (n=3, 6%) and major cardiac surgery (n=3, 6% [aortic valve replacement n=1, tricuspid valve replacement n=2]).

Conclusions:
Young adults with a Fontan palliation for HLHS are at high risk of major adverse cardiac events. It is essential that close attention is paid to successful transition of this vulnerable population into adult care and that these patients remain under vigilant specialist follow-up through adult life.
Abstract 20556: Safety and Efficacy of Intracoronary Hypoxia-PrecondItioned Bone Marrow Mononuclear Cells Administration for Acute Myocardial Infarction Patients
Authors: Hu Xin Yang , Huang Xin , Yang Qian , Wang Lihan , Sun Jianzhong , Zhan Hongwei , Lin Jianjing , Pu Zhaoxia , Jiang Jun , Sun Yong , Liu Xianbao , Xie Xialjie , Yu Xia , Chen Zexin , Tse Hung-Fat
Published: July 2021

IMPORTANCE:
Cell therapy has been a potential approach for ST-segment elevation acute myocardial infarction (STEMI). To improve the therapeutic oucome, the safety and efficacy of hypoxia-preconditioned (H-) bone marrow mononuclear cells (BMCs) in AMI patients need further evaluation.

OBJECTIVE:
To investigate the safety and efficacy of H-BMCs therapy in AMI patients.

DESIGN:
A phase 1, randomized and blinded study (February, 2011~ March, 2012) with one-year of follow-up.

SETTING:
A single center for hospitalized care.

PARTICIPANTS:
22 Patients with an acute ST elevation myocardial infarction were recruited and randomized to two groups: normoxia BMCs (N-, n=11) and H-BMCs (n=11).

INTERVENTIONS:
Intracoronary infusion of H-BMCs or N-BMCs within 5-7 days after treatment with percutaneous transluminal coronary intervention (PCI). Patients were similarly treated by a stop-flow technique through an over-the-wire balloon catheter.

MAIN OUTCOMES AND MEASURES:
Primary endpoint was Treatment-emergent 30-day serious adverse event rate defined as a composite of death, MI, sustained ventricular tachycardia, stroke, hospitalization for worsening heart failure and revascularization. Secondary endpoints were change of myocardium perfusion, global left ventricular ejection fraction and left ventricular volumes.

RESULTS:
The primary endpoint events was none for N-BMCs and 9.1% (95% CI, 0.2%-41.3%) for H-BMCs. There was significant increase in the change of LVEF of H-BMCs group at 6 month. The change of end diastolic volume (EDV) and end systolic volume (ESV) in H-BMCs at 12 month were significantly decreased. Ratio of myocardium perfusion defect by Single-Photon Emission Computed Tomography (SPECT) was significantly reduced in H-BMCs group at 6 months, and score of myocardium perfusion defect by SPECT was significantly reduced than that of baseline in H-BMCs group at 6 and 12 months, unlike N- group.

CONCLUSIONS AND RELEVANCE:
Intracoronary infusion with H-BMCs appeared to be safe and effective for patients with AMI. Although the sample size precludes a definitive statement about safety and efficacy, these results provide the basis for larger studies to provide definitive evidence about safety and to assess efficacy of this new therapeutic approach.
Abstract 20579: Chronic Kidney Disease is Associated With Increased Mortality and Major Adverse Cardiovascular Events in Patients With Peripheral Arterial Disease
Authors: Westin Gregory G , Armstrong Ehrin J , Chen Debbie C , Laird John R
Published: July 2021

Introduction:
Chronic kidney disease (CKD) is common in patients with peripheral arterial disease (PAD), but patients with severe CKD have been excluded from many trials and no objective performance goals exist for patients with PAD and CKD. We sought to analyze the association between severity of CKD and cardiovascular and limb-related outcomes among patients with PAD.

Methods:
We reviewed records of all patients at our institution who underwent lower extremity angiography between 2006 and 2013. We analyzed outcomes including mortality, major adverse cardiovascular event (MACE) rate, and major adverse limb event (MALE) rate according to clinical stage of CKD, determined by calculating each patient’s glomerular filtration rate using the Cockcroft-Gault equation. We used Cox proportional hazard modeling to account for covariates, along with Bonferroni correction for multiple comparisons.

Results:
Of 773 patients, 45% had CKD stage 3-5. The patients had a median age of 67, were 58% male, 51% diabetic, and 57% presented with critical limb ischemia (CLI). During a median follow-up time of 3.2 years, patients with higher stages of CKD had an increased rate of death (Figure 1, p<0.001). CKD stages 4 and 5 were significant predictors of mortality in a multivariate model (HR 3.2 and 2.4 vs. CKD 1, P<0.001 and P<0.01, respectively). An analysis of MACE by CKD stage demonstrated similar results (CKD 4 HR 2.2, p<0.01; CKD 5 HR 2.0, p<0.01). CKD stage also predicted MALE in a univariate analysis (p<0.01), driven by increased limb events among patients with CKD stage 5 (p<0.01). However, CKD stage did not demonstrate a significantly increased hazard of MALE in a multivariate Cox model.

Conclusions:
Patients with PAD who also have CKD have increased rates of adverse outcomes. This relationship seems to be more robust for major cardiovascular events and overall mortality than for major limb events. Future studies should investigate how management of PAD should differ for patients with CKD.
Abstract 20589: Exercise and Mitochondrial Respiration in Mice with Arrhythmogenic Cardiomyopathy
Authors: Chelko Stephen , Asimaki Angeliki , Wei An-Chi , DeMazumder Deeptankar , Bedja Djahida , Wagle Rohan , Amat Nuria , O’Rourke Brian , Saffitz Jeff , Judge Daniel
Published: July 2021

Incomplete penetrance of Arrhythmogenic Cardiomyopathy (AC) suggests environmental factors, such as exercise, influence disease progression. We have previously demonstrated that increased PPARγ contributes to apoptosis and fat deposition in a cellular model of AC. Therefore, we examined the effects of exercise training in a mouse model of AC (knock-in desmoglein-2 mutant). Desmoglein-2 homozygous (Dsg2mut/mut, n=12), heterozygous (Dsg2mut/+, n=11) and WT (n=9) mice were forced to swim train at 5 weeks of age (10min/day increments) and by 7 weeks mice swam 90min/day, 5 days/week. At 16 weeks of age echo- and electrocardiographic, mitochondrial, histological, gene expression and protein analysis were performed. Non-exercised Dsg2mut/mut mice showed redistribution of Cx43, Dsg2, GSK3β and nuclear PKG, increased apoptosis and reduced ejection fraction (EF, p<0.001) and fractional shortening (FS, p<0.01) compared to WT controls by 16 weeks of age. Additionally, by 6 weeks of age Dsg2mut/mut mice (n=3/group) demonstrated reduced carnitine-palmitoyltransferase-1 (p=0.029), increased PPARα (p=0.05), FABP4 (p=0.05) and CEBPα (p=0.04) gene expression and decreased State 3 respiration with Complex I substrates (p=0.01) compared to WT mice. In exercise studies, 50% (6/12) of Dsg2mut/mut mice survived to 16 weeks of age, whereas 6 died suddenly while swimming (mean time of death 19.5 ± 3.88 days post-swimming, p=0.03). Exercised Dsg2mut/mut mice (n=6) showed reduced EF and FS compared to Dsg2mut/+ (n=10) and WT mice (n=8, p<0.001 for all comparisons). Dsg2mut/mut mice had longer mean QRS complex duration (23.9 ± 0.03 ms, p=0.05) and isovolumetric relaxation time (IVRT: 31.3 ± 3.5 ms, p=0.02) compared to Dsg2mut/+ and WT mice (n=3/group; QRS: 23.4 ± 0.03 ms, 19.4 ± 0.02 ms; IVRT: 23.8 ± 0.8 ms, 23.3 ± 1.9 ms, respectively). Furthermore, Dsg2mut/mut mice exhibit higher mitochondrial membrane potential (n=3/group, p=0.03) compared to Dsg2mut/+ and WT mice, and a trend towards increased pyruvate oxidation rate and decreased beta-oxidation rate. These data show that Dsg2mut/mut mice are at risk of arrhythmic fatality and demonstrate glycolytic-dominant respiration during exercise.
Abstract 20627: Modulation of Cardiac Sodium Channel by Palmitoylation and Its Association With Cardiac Disease Mutations
Authors: Pei Zifan , Hudmon Andy , Cummins Theodore R
Published: July 2021

Cardiac sodium channel (Nav1.5) is responsible for the generation and propagation of the cardiac action potential, which underlies cardiac excitability. It can be modified by a variety of post-translational modifications. Palmitoylation is one of the most common post-translational lipid modifications that can dynamically regulate protein life cycle and functional activity. In our study, we identified palmitoylation on Nav1.5 and its alteration in channel biophysical properties. Nav1.5 palmitoylation was identified in both HEK 293 cells stably expressing Nav1.5 and cardiac tissues using acyl-biotin exchange assay. Nav1.5 palmitoylation was inhibited by pre-incubating the cells with the inhibitor 2-Br-Palmitate (2BP, 25uM, 24hrs). Biophysically, 2BP treatment drastically shifted the channel steady-state inactivation to more hyperpolarized voltages, suggesting palmitoylation altering channel functional activity. In addition, four predicted endogenous palmitoylation sites were identified using CSS-Palm 3.0. Site-directed mutagenesis method was used to generate a cysteine removing background of wt Nav1.5 to study the role of predicted sites. Patch clamp analysis of wt and cysteine-removed Nav1.5 revealed a significant change in channel biophysics. 2BP treatment significantly shifted steady-state inactivation of wt Nav1.5 while not affecting cysteine-removed Nav1.5 significantly, indicating the important role of these four cysteine sites in modulating channel palmitoylation. Moreover, several LQT disease mutations were identified to potentially add or remove palmitoylation sites. Further analysis of these disease mutations revealed a significant shift in channel steady-state inactivation and this alteration cannot be seen with the substitution of other residues on the same site, suggesting the specific role of cysteine residue in causing the functional alteration. For the LQT mutation that removes potential palmitoylation site, 2BP treatment did not affect channel biophysical properties, indicating the essential role of this cysteine in channel palmitoylation. These results suggest that palmitoylation on Nav1.5 regulates channel functional activity and its modulation may contribute to new cardiac channelopathies.
Abstract 20662: Variations in Local Calcium Signaling in Adjacent Cardiomyocytes of the Intact Mouse Heart Detected With Two-Dimensional Confocal Microscopy
Authors: Hammer Karin P , Pieske Burkert M , Heinzel Frank R
Published: July 2021

Coordinated Ca release in the heart ensures efficient myocardial contraction and electrical stability. Dyssynchronous Ca release within individual cardiomyocytes has been linked to cellular contractile dysfunction. Differences in Ca kinetics in adjacent cells may also provide a substrate for inefficient contraction and arrhythmias. We present an approach to quantify local Ca signals related to the geometry of adjacent cardiomyocytes within the intact heart using 2D confocal microscopy. We observe significant differences in Ca kinetics between adjacent cardiomyocytes.

Methods:
Ca transients (CaT, Fluo-8 AM) and cell membranes (Di-4 ANEPPS) were visualized in an epicardial area of 465 μm by 315 μm (12 to 20 cells) in Langendorff-perfused mouse hearts. Images (55/second) from a series of CaT at steady state stimulation (250 ms cycle length) were registered to their relative timepoint in the cardiac cycle to restore local CaT with a temporal resolution of 2 ms. Variation of local CaT within a cardiomyocyte (INTRA) and between adjacent cardiomyocytes (INTER) were compared with regard to amplitude, time to peak (TTP) and time constant of decay (TAU).

Results:
Temporal registration of images from successive CaT yielded local signals with good signal/noise ratio (N= 4 hearts, n= 8 regions). Along the long axis but not along the short axis of cardiomyocyte orientation the variation of CaT amplitude was significantly larger between that within cells (INTER 51.49 ±23.57% vs. INTRA <0.01 ±0.001% of global Ca amplitude). Variation in TTP Ca was comparable in all directions, but TAU also tended to vary more along the long axis (INTER 68.50 ±27.03% vs. INTRA 37.74 ±13.17%). Isoproterenol (10 μM) significantly increased the differences in TAU between adjacent cardiomyocytes along the short axis but not along the long axis.

Summary:
We present an approach to detect and analyze local Ca signals in Langendorff-perfused intact mouse hearts with high temporal and spatial resolution, taking into account 2D orientation of the cells. We observed significant differences in the synchrony of Ca signals along the long and short axis of adjacent cardioymyocytes. Alterations in synchrony of Ca signals in neighboring cells may contribute to the substrate in cardiac remodeling.
Abstract 21: Remote Limb Ischemic Postconditioning Improves Postresuscitation Cerebrovascular Circulation and Survival/Neurological Prognoses via In Situ and Remote Activation of Akt-eNOS-NO Signaling Pathway
Authors: Chang Wei-Tien , Wang Woan-Yi , Lee Chun-Pei , Wei Hsiao-Ching , Tang Sung-Chun , Huang Chien-Hua , Tsai Min-Shan , Wang Chih-Hung , Wang An-Yi , Cheng Hsiao-Ju , Ma Matthew Huei-Ming , Fang Cheng-Chung , Chen Shyr-Chyr , Chien Chiang-Ting , Chen Wen-Jone
Published: July 2021

Introduction:
Cerebrovascular circulation is usually compromised after cardiac arrest and CPR. Remote limb ischemic post-conditioning (RLIP) is clinically feasible and can potentially mitigate post-resuscitation neurological deficits. Since nitric oxide (NO) is implicated in post-conditioning protection, we aim to investigate if RLIP impacts post-resuscitation cerebral perfusion and prognosis via NO-related mechanism.

Hypothesis:
RLIP improves post-CPR cerebral perfusion and prognosis through
in situ
and remote activation of Akt-eNOS-NO signaling.

Methods:
Using an established rat model of asphyxia cardiac arrest and CPR, we randomized the rats to the following groups: (1) sham, (2) standard CPR, (3) RLIP 5 min after return of spontaneous circulation (ROSC). RLIP was done by 3 cycles of 5 min of left hind limb ischemia followed by 5 min of reperfusion. Arterial blood was sampled for colorimetric determination of nitrate/nitrite. The cerebral perfusion was continuously recorded by OxyFLO probe. Two hours after ROSC, the brain and left femoral artery were harvested for measuring phosphorylated endothelial NO synthase (p-eNOS at Ser1177) and protein kinase B (p-Akt at Ser473). In a subgroup the survival and neurological outcomes were monitored up to 3 days.

Results:
The cerebral perfusion was significantly decreased (0.6-0.8 folds that of baseline) after ROSC in standard CPR group. If RLIP was employed, the cerebral perfusion was significantly augmented (up to 1.6 folds,
P
< 0.001) in the post-resuscitation phase. This was associated with improved survival (log-rank
P
< 0.05) and neurological scores at 6, 24, 48 and 72 h (all
P
< 0.05). Plasma NO as indicated by nitrate/nitrite was significantly increased in the RLIP group (
P
< 0.05). Most of all, p-eNOS and p-Akt were significantly increased not only in left femoral artery but also in brain. If NOS inhibitor

N
ω

-nitro-L-arginine methyl ester (10 mg/kg) was used, not only the NO increase was reversed, the improvement in survival and neurological outcomes were also abrogated.

Conclusions:
RLIP enhances post-resuscitation cerebral perfusion and improves survival and neurological prognoses not only via
in situ
limb artery derived NO but remote activation of Akt-eNOS signaling in the brain.
Abstract 22: Experienced Impact and Post-Traumatic Stress Symptoms of Dispatched Local Lay Rescuers Performing Basic Life Support
Authors: Zijlstra Jolande , Beesems Stefanie , de Haan Rob , Koster Rudolph
Published: July 2021

Aim:
A text message (TM) alert system for OHCA has been implemented in part of the Netherlands. This system uses TM from EMS dispatch to alert local lay rescuers (TM-responders [TMRs]) living <1000m radius of the OHCA victim, to either go directly to the victim and perform CPR, or to a nearby AED first. Over 14 000 TMRs and >1500 AEDs were registered in a database residing with the dispatch center. We studied the level of experienced impact shortly after performing BLS and compared it with the Impact of Event Scale (IES) score 4-6 wks afterwards.

Methods:
With each TM-alert an email was sent to the TMRs with a link to an online questionnaire. We analyzed all questionnaires from 15-02-2013 to 21-04-2014 which were filled out median 5h after EMS call. We counted the experienced impact level (no, little, bearable, much, unbearable). All firstly arrived TMRs who provided BLS±AED use prior to EMS arrival, participated in a semi-structured interview by telephone median 4 days after resuscitation. To assess if TMRs had post-traumatic stress symptoms (PTSS), the IES was sent to all interviewees 4-6 wks after the resuscitation. Scores 0-8 indicated subclinical, 9-25 mild, 26-43 moderate, and ≥44 severe stress. A score >25 indicated PTSS.

Results:
The dispatcher activated the TM-alert system 697 times, alerting 18 742 TMRs. 4799 completed the questionnaire. Of these, 1639 responded to the call and 353 arrived on scene, participating in the resuscitation. We interviewed 148 first arriving TMRs of whom 137 also completed the IES. Comparison between level of experienced impact and IES score is shown in the figure. None showed PTSS (median: 1, 25th-75th percentile: 0-8, max. 25). Of all TMRs experiencing no/little impact, 13% was grouped as mild. Of all TMRs experiencing bearable impact, 22% scored mild and of all TMRs experiencing much impact, 44% scored mild.

Conclusion:
TMRs do not show PTSS 4-6 wks after performing BLS, even if their experienced level of impact is considerable shortly after the event.
Abstract 231: Preliminary Experience with Prehospital Pupillometry: A Prospective, Observational Study in Out-of-Hospital Cardiac Arrest
Authors: Reynolds Joshua C , Chassee Todd , Fankhauser Mark D , Uber Amy
Published: July 2021

Objective:
Physiologic monitoring & neuroprognostication during resuscitation are relatively crude. Real time assessment of neurophysiology could be useful to guide resuscitative efforts. Objective assessment of the pupillary light reflex [PLR] is feasible during IHCA with a portable pupillometer, & PLR is associated with survival & neurologic outcome. We are conducting a prospective, observational study to assess the translational potential of pupillometry in the prehospital setting for OHCA.

Hypotheses: Prehospital pupillometry is feasible & qualitative assessment of PLR is associated with patient outcomes.

Methods:
Portable pupillometers (NeurOptics, Inc) were deployed for subjects with EMS treated OHCA. Serial recordings were obtained during routine pulse checks until ROSC, termination, or hospital arrival. We qualified PLR as normal/abnormal/absent with Neurologic Pupillary Index (NPiTM), a continuous scale that combines facets of PLR (e.g. % change, velocity, latency). We reviewed prehospital & hospital records to identify patient characteristics & outcomes, tabulated data as means/medians/proportions, & estimated test performance characteristics.

Results:
From 2/14 - 6/14, a pupillometer was deployed to 38/58 (66%) patients with EMS treated OHCA (63 ± 16 years, 66% male, 33% witnessed, 54% bystander CPR, 11% shockable rhythm). Of 38 subjects, 21 (56%) were transported (19 ROSC & 2 CPR). At the time of submission, follow-up data were available on 27 (71%) patients (6 survived to admission, 4 had therapeutic hypothermia, 3 had cardiac catheterization, 1 survived to discharge with excellent neurologic recovery). In total, 385 readings were attempted (median 8.5 attempts/patient; IQR 6-12). Median 47% (IQR 25%, 67%) readings had usable data. Most (92%) patients had ≥1 usable reading and 9/38 (24%) had any PLR during resuscitation.

Conclusion:
Prehospital pupillometry is feasible & may yield prognostic information during resuscitation.
Abstract 243: Bystander CPR May Not Improve Survival from Cardiac Arrest in Patients with Epilepsy
Authors: Stecker Eric , Uy-Evanado Audrey , Reinier Kyndaron , Teodorescu Carmen , Gunson Karen , Jui Jonathan , Chugh Sumeet
Published: July 2021

Introduction:
Sudden cardiac arrest (SCA) is the major cause of death among patients with epilepsy and occurs in the absence of a terminal seizure in approximately two-thirds. We aimed to evaluate the effectiveness of conventional cardiac arrest resuscitation factors (Utstein elements) in predicting survival among patients with epilepsy.

Methods:
This analysis was conducted as part of a large, ongoing, population-based study of SCA in the Northwest US (the Oregon Sudden Unexpected Death Study, community pop. approx. 1 million). Data were obtained from multiple sources (first responders, medical practitioners and medical examiner) between 2002 and 2011 for adult patients with attempted resuscitation. Those with non-cardiac causes of arrest (e.g. severe COPD or metastatic cancer) were excluded. Those with a history of infantile febrile seizures or alcoholic withdrawal seizures were considered non-epileptic. The impact of Utstein resuscitation factors on survival to hospital discharge among patients with epilepsy was evaluated, as were differences in survival for each Utstein factor among patients with and without epilepsy.

Results:
There were 63 patients with epilepsy and 1403 patients without epilepsy who underwent resuscitation for SCA. The overall survival rate among patients with epilepsy was lower (3% vs 12%, p=0.014) despite identical rates of ROSC (36%, p=0.91). Survival was unaffected by any Utstein variable (age, gender, initial arrhythmia, witnessed status, location, bystander CPR, response time) and was lower for epilepsy patients receiving bystander CPR than for non-epilepsy patients (table).

Conclusions:
SCA survival rates for patients with epilepsy are low and are not appreciably improved by conventional resuscitation techniques. It is important to explore the basis for these observations and consider modifications to EMS activation, response and post-resuscitation hospital care in order to improve survival for patients with epilepsy.
Abstract 249: Sodium Nitroprusside Combined with Intrathoracic Pressure Regulation Increases Neurologically Favorable 24-Hour Survival in a Porcine Model of Prolonged Ventricular Fibrillation
Authors: Debaty Guillaume , Metzger Anja , Rees Jennifer , McKnite Scott , Matsuura Timothy , Bartos Jason , Lick Michael , Yannopoulos Demetris , Lurie Keith G
Published: July 2021

Introduction:
Use of epinephrine and standard (S) CPR has not been shown to improve neurologically-sound survival after cardiac arrest. Treatment with the potent vasodilator sodium nitroprusside (SNP) improves neurologically intact survival rates in animals when combined with abdominal compression, active compression decompression (ACD) CPR, and an impedance threshold device (ITD). We recently observed that SNP combined with ACD-CPR and a new intrathoracic pressure regulator (IPR), which provides continuous negative intrathoracic pressure after each positive pressure ventilation, increases blood flow to the heart and brain in the absence of epinephrine or abdominal compression. We hypothesized that this combination of SNP plus ACD CPR plus IPR (S-A-I) would improve 24h survival with favorable neurologic function compared with S-CPR.

Method:
After 12 minutes of untreated ventricular fibrillation (VF), 14 pigs received 3 minutes of S-CPR and were then randomized to a) a bolus of epinephrine (0.05mcg/kg), 2 more minutes of S-CPR and up to 3 defibrillation shocks or b) S-A-I and up to 3 shocks 2 minutes later. All resuscitated animals received therapeutic hypothermia for 4 hours. The primary endpoint was favorable neurologic outcome 24h after resuscitation defined by a Cerebral Performance Category score ≤ 2 (CPC with 1 for no deficit and 5 as dead or unable to resuscitate) as determined by a blinded veterinarian. Hemodynamic parameters and left ventricular ejection fraction were recorded. Data are presented as mean±SEM.

Results:
At 24 hours, 0/7 pigs in the S-CPR group vs. 5/7 pigs in S-A-I had favorable outcome (p=0.02). One pig survived 24 hours in the S-CPR group with a CPC of 4 vs. 5 in the S-A-I group with a CPC of 1.4±0.2. Carotid blood flow and ETCO2 were higher with S-A-I_vs. S-CPR and epinephrine (127±32 vs. 22±4 ml/min, p=0.005, and 46±5 vs. 22±3 mmHg, respectively, p=0.001).

Conclusion:
After prolonged VF in pigs, treatment with the combination of ACD CPR, an intrathoracic pressure regulator and SNP, in the absence of epinephrine, significantly increased carotid flow, ETCO2 levels, and neurologically-favorable 24 hour survival rates compared with S-CPR and epinephrine. This novel and promising approach should be considered for a Phase 1 human trial.
Abstract 251: Association Between Early Arterial Blood Gas Levels and Neurological Outcome in Adult Patients Following In-Hospital Cardiac Arrest
Authors: Wang Chih-Hung , Huang Chien-Hua , Chang Wei-Tien , Tsai Min-Shan , Yu Ping-Hsun , Wang An-Yi , Chen Nai-Chuan , Chen Wen-Jone
Published: July 2021

Background:
The early partial pressures of arterial O2 (PaO2) and CO2 (PaCO2) have been found in animal studies to be correlated with neurological outcome after brain injury. Recent guidelines for the management of cardiac arrest recommend maintaining the arterial oxyhemoglobin saturation at ≥ 94% and PaCO2 at 40-45 mm Hg after successful resuscitation of patients sustaining cardiac arrest. However, there are few clinical studies that have investigated the relationship of early PaO2 and PaCO2 to the neurological outcomes of resuscitated patients or determined the optimal values for PaO2 and PaCO2.

Methods and Results:
This was a retrospective observational study from a single medical center of adult patients who had in-hospital cardiac arrest and achieved sustained return of spontaneous circulation (ROSC) between 2006 and 2012. Multivariable logistic regression analysis was used to identify factors associated with favorable neurologic outcome at hospital discharge. A general additive model was used to detect nonlinear relationships between independent and dependent variables. The first PaO2 and PaCO2 values measured after first sustained ROSC were used for analysis.

Of the 550 study patients, 154 (28%) survived to hospital discharge and 74 (13.5%) achieved favorable neurologic outcome. The mean time from sustained ROSC to the measurement of PaO2 and PaCO2 was 136.8 minutes. The mean PaO2 and PaCO2 were 167.4 mm Hg and 40.3 mm Hg, respectively. PaO2 between 70 and 240 mmHg (odds ratio [OR] 1.96, 95% confidence interval [CI] 1.08-3.64) and PaCO2 levels (OR 0.98, 95% CI 0.95-0.99) were positively and inversely associated with favorable neurological outcome, respectively.

Conclusions:
The early PaO2 and PaCO2 levels obtained after ROSC were correlated with neurological outcome of patients with in-hospital cardiac arrest. PaO2 levels between 70 and 240 mm Hg were associated with favorable neurological function at hospital discharge, while higher PaCO2 levels might be associated with adverse outcomes.