bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 18462: Hickam's Dictum Revisited: A Multifactorial Etiology of Stroke in a Patient With Rheumatic Mitral Stenosis and Atrial Septal Aneurysm
Authors: Sinha Shashank S , Hagan Peter G , Eitzman Daniel T
Published: March 2022

A 64-year-old gentleman with rheumatic mitral stenosis (MS), coronary artery disease, and active tobacco abuse was admitted with a left posterior cerebral artery (PCA) territory ischemic cerebrovascular accident (CVA). He presented with confusion, headaches, and alexia with stable vital signs. He denied rest or exertional dyspnea. Physical exam revealed right homonymous hemianopia, mild right upper extremity dysmetria, decreased right facial sensation, and mild prosopagnosia. Initial neuroimaging confirmed an evolving left hemispheric infarct. Laboratory testing showed unremarkable inflammatory markers. Computed tomographic (CTA) and magnetic resonance angiography (MRA) of the head and neck confirmed left PCA territory acute or subacute infarction with occlusion of the left P2 segment. 12-lead electrocardiogram demonstrated normal sinus rhythm. Occult atrial fibrillation was not seen. Transthoracic echocardiogram (TTE) showed no evidence of right-to-left interatrial shunt. Moderate left atrial (LA) dilation, posterior mitral leaflet tip calcification, and a resting mean mitral gradient of 20 millimeters of mercury (mmHg) suggested severe mitral stenosis. Given the discrepancy between the patient’s symptoms and the TTE findings, transesophageal echocardiogram (TEE) was performed (Figure). The patient’s left PCA territory infarct was ascribed to multifactorial cardioembolic etiologies: 1) Atrial septal aneurysm (ASA) 2) Rheumatic MS and 3) Aortic arch atheroma. Anticoagulation was recommended and initiated 14 days after his CVA to minimize risk of hemorrhagic transformation. High-dose atorvastatin and aspirin were instituted. He progressed well through rehabilitation, demonstrating steady neurological improvement. The case underscores the importance of pursuing further investigation when discrepancies exist between clinical and objective data. ASA is an uncommon but under-recognized risk factor for cardioembolic stroke.
Abstract 18537: Aortic Valve Repair Improves Mid-term Outcomes versus Replacement for Aortic Insufficiency: A Propensity Matched Study
Authors: Kapralik Jessica , McLean Kathryn , Chan Vincent , Sohmer Benjamin , Ruel Marc , Mesana Thierry , Boodhwani Munir
Published: March 2022

Objectives:
Aortic valve (AV) repair has emerged as a feasible and attractive alternative to AV replacement in patients with aortic insufficiency (AI). However, little data exists comparing outcomes following repair versus replacement. We performed a single-center comparative study in patients undergoing AV repair or replacement for AI.

Methods:
Patients undergoing AV replacement (n=263) or repair (n=153) for AI between 2000 and 2014 were included. Patients ineligible for both repair and replacement surgeries and patients lacking perioperative data were excluded (n=155). To adjust for baseline differences, non-parsimonious logistic regression models were used to generate propensity scores. A 1:1 greedy matching algorithm was used to create 70 propensity matched pairs. Peri-operative and long-term clinical and echocardiographic outcomes were assessed, focusing on survival and valve-related events, and analyzed using Kaplan-Meier techniques. Primary endpoints included late mortality, myocardial infarction, stroke, and AV reoperation. Total follow-up exceeded 1100 patient-years in the entire cohort and 800 patient-years in the matched cohort.

Results:
The matched pairs were similar in baseline attributes including age (57±14 vs. 56±15, p=0.75), sex (Female: 17% vs. 25%, p=0.22), incidence of LV dysfunction (27% vs. 24%, p=0.38), severe AI (67% vs. 74%, p=0.42) and presence of cardiac risk factors. Replacements consisted of 53% mechanical, 41% bioprosthetic, and 6% homograft valves. Repairs included 61% valve-sparing root replacements, 70% cusp repairs with 43% bicuspid AVs. In hospital mortality (1% vs. 4%, repair vs. replacement, p=0.62) and perioperative outcomes were similar between groups. Four-year survival was 97±2% and 87±4% in repair vs. replacement groups (p=0.11). A total of 5 vs. 17 valve-related events occurred in repair vs. replacement groups. Freedom from primary endpoints at 4 years was 97±2% and 82±8% in the repair vs. replacement groups (p=0.03).

Conclusions:
In a propensity matched cohort, AV repair for AI was associated with a mid-term reduction in death and serious valve related complications compared to AV replacement. AV repair should be considered, when technically feasible, as the preferred treatment of AI.
Abstract 18621: Self-care Confidence is Important in Self-care in Emerging Adults With Congenital Heart Disease
Authors: Fleck Desiree , Deatrick Janet , Dickson Victoria V , Lipman Terri , Webb Gary , Riegel Barbara
Published: March 2022

Background:
Emerging adults (ages 18-25 years) with congenital heart disease (CHD) are expected to perform self-care, behaviors that maintain physiologic stability and the response to symptoms as they occur. In spite of the seriousness of CHD, some emerging adults forego self-care. Identifying those unlikely to perform self-care is essential.Objective: The purpose of this study was to describe self-care and to identify the correlates of self-care in emerging adults with CHD. We hypothesized that knowledge and beliefs would be the primary determinants of self-care.

Methods:
In this descriptive, cross-sectional study, we enrolled a convenience sample (n=57) of emerging adults from two outpatient CHD centers (adult, n=37; pediatric, n=20) in the Northeastern US. All participants completed neuropsychological testing (PMR, DSST, Trail-Making Tests and the Letter Number Sequencing Tests) and scales measuring developmental stage (Course of Life), mood, knowledge of CHD (Leuven Knowledge Questionnaire), self-efficacy (the NGSES), family functioning (FAD), and a demographic survey. Disease severity was determined by the diagnosis and the number of repairs. Variables were tested as correlates of self-care measured using the Self-Care in CHD Scale (SC-CHD). Scores are standardized 0-100; higher scores indicate higher self-care. Multivariate regression was conducted in two blocks. First age, disease severity, developmental stage, mood, family functioning, cognition, and self-care confidence were entered. Second, knowledge and beliefs were entered for hypothesis testing.

Results:
Participants (42% female, mean age 21 years, SD 2.32) had predominantly moderate (42%) to severely (45.6%) complex CHD. Self-care was low (SC-CHD=mean 57, SD 11.23). More CHD repairs, higher levels of self-care confidence, and older age explained 41% of the variance in self-care (Block 2: F=3.785, df=3, 46, p=0.17). The higher the level of self-care confidence, the more likely the performance of self-care.

Conclusions:
These results can be used to identify a subset of CHD patients at risk for poor self-care. Self-care confidence is the only modifiable determinant, suggesting that interventions designed to increase self-care confidence may be useful in this population.
Abstract 18720: HDL Particle Subclasses, Rosuvastatin Therapy, and Risk of Vascular Events: An Analysis From the JUPITER Trial
Authors: Akinkuolie Akintunde O , Lawler Patrick R , Glynn Robert J , Ridker Paul M , Mora Samia
Published: March 2022

Background:
In the JUPITER trial, total HDL particle concentration (HDL-P) performed better that HDL-cholesterol (HDL-C) in predicting residual vascular risk. It is uncertain whether biological heterogeneity of HDL particle subclasses relates to differential vascular risk in the setting of statin therapy.

Methods:
We analyzed data from JUPITER (NCT00239681) in which participants with LDL-C <130 mg/dL and hsCRP ≥2 mg/L were randomized to 20mg/day of rosuvastatin vs placebo. HDL subclass concentrations were measured and categorized into 5 groups (very large, large, medium, small, and very small) by NMR spectroscopy (LipoScience, NC [now LapCorp]) in 12,487 participants before and 1 year after randomization.

Results:
A total of 308 first vascular events (MI, stroke, revascularization, unstable angina, CVD death) occurred during maximum follow-up of 5.0 (median, 1.9) years. For baseline risk, multivariable adjusted Cox regression models demonstrated that the baseline concentrations of all HDL subclasses were inversely associated with incident vascular events (Table), with statistically significant associations for large HDL (adjusted HR per SD: 0.85, 95% CI, 0.76-0.95) and medium HDL (HR 0.89, 95% CI 0.80-0.98) even after mutually adjusting for the other HDL subclasses. By contrast, among rosuvastatin-allocated participants, on-treatment concentrations of very large HDL subclasses were associated with an increased risk of residual risk of vascular events (adjusted HR per SD: 1.65, 95% CI, 1.02-2.66).

Conclusion:
In JUPITER participants, baseline levels of HDL subclasses were inversely associated with the risk of incident vascular events with significant associations for the large and medium particles. However, on-statin levels of very large HDL particles were significantly associated with an increased risk of vascular events.
Abstract 18743: Lack of Evidence of Higher 30-day All-cause Readmission Among Older African American (vs. White) Medicare Beneficiaries Hospitalized for Heart Failure
Authors: Ahmed Ali , AhmadBeygi Shervin , Sheriff Helen , Morgan Charity , Zhang Sijian , Fletcher Ross D , Blackman Marc , Wu Wen-Chih , Butler Javed , Fonarow Gregg C , Deedwania Prakash , White Michel , Aronow Wilbert S , Allman Richard M
Published: March 2022

Background:
A recent study using administrative data suggested that older African American heart failure (HF) patients may have higher 30-day readmissions than whites do (PMC3332042). However, to what extent these associations are intrinsic remains unclear.

Methods:
Of the 8042 Medicare beneficiaries hospitalized for HF and discharged alive from 106 U.S. hospitals (1998-2001), 1994 were African American and 6048 were white. Using propensity scores for being an African American, we assembled a matched cohort of 1799 pairs of African American and white patients balanced on 33 baseline characteristics.

Results:
Matched patients (N=3598) had a mean age of 74 (±11) years with no racial difference (p=0.599). 30-day all-cause readmission occurred in 20% and 22% of matched African Americans and whites, respectively (HR, 0.89; 95% CI, 0.77-1.03; p=0.110; Figure, left panel). In the pre-match cohort (N=8042), African Americans were younger (77 v 72 years for whites; p<0.001) and had similar unadjusted 30-day all-cause readmission (20% v. 20% for whites; p=0.075), but had significantly lower risk when adjusted for age and sex (HR, 0.87; 95% CI, 0.77-0.98; p=0.018; Figure, right panel) but not for propensity scores (HR, 0.90; 95% CI, 0.80-1.02; p=0.101). Among matched patients, race had no association with 30-day HF readmission or all-cause mortality.

Conclusions:
Findings from our propensity-matched study suggest that in a cohort of hospitalized African American and white HF patients who were balanced on 33 baseline characteristics, race had no independent association with 30-day all-cause or HF readmissions or all-cause mortality.
Abstract 18748: What is the Resilience of Out-of-hospital Cardiac Arrest Patients Who Do Not Receive Bystander Resuscitation?
Authors: Grunau Brian E , Scheuermeyer Frank X , Stenstrom Robert , Pennington Sarah , Straight Ron , Barbic David , Christenson Jim
Published: March 2022

Background:
Many patients with witnessed out-of-hospital cardiac arrest (OHCA) will not have CPR attempted until emergency medical services (EMS) personnel arrive. The potential for favourable outcomes in patients with increasing no-flow durations is unclear. While some extra-corporeal CPR programs have excluded patients without bystander CPR, others have treated these patients provided short durations to EMS arrival. We sought to describe the outcomes of patients with increasing no-flow durations to determine the potential viability of these patients.

Methods:
This study examined consecutive non-traumatic OHCA’s collected by a prospective registry in British Columbia (2007 and 2011). We included adult patients with bystander-witnessed OHCA but no attempt at bystander chest compressions. The primary variable of interest was the duration from the bystander 9-1-1 call to the time of CPR commencement by EMS. The primary endpoint was survival at hospital discharge. Multivariable logistic regression, with adjustment for sex, age, public location of arrest, and initial shockable rhythm, was used to assess the association of time to CPR and survival to hospital discharge.

Results:
Of 6571 EMS-treated OHCA’s, 1062 were included. The median age was 73 (IQR 58-82), 69% were male, and 35% had initial shockable rhythms. Overall survival was 13%. The median time to CPR commencement was 8.5 minutes (IQR 6.9 - 10.5). Time to CPR was independently associated with survival to hospital discharge (adjusted OR 0.85 per minute increase; 95% CI 0.78-0.92). Among survivors, the 90th percentile of time from 9-1-1 call to CPR was 10.3 minutes.

Conclusion:
In adult OHCA patients, no-flow durations were negatively correlated with outcome, however survival was observed with prolonged durations without CPR extending to 16 minutes. Patients with witnessed OHCA and no bystander CPR include survivors and aggressive resuscitation strategies are warranted.
Abstract 18759: Safety and Cost Effectiveness of Same Day Discharge After Elective Percutaneous Coronary Interventions: A Large Rural Single Center Experience
Authors: Htun Wah Wah , Vijayakrishnan Rajakrishnan , Awdisho Alan , Syed Ibrahim , Kaur Sanjeet , Verma Beni , Ferrari Ashley M , Henry Yvette M , Blankenship James C , Berger Peter B
Published: March 2022

Background:
Stable patients (pts) undergoing an uncomplicated elective percutaneous coronary intervention (PCI) typically stay in the hospital overnight after their procedure. Many studies suggest that in carefully selected pts, discharge within hours after the PCI appears to be safe. There are no studies, however, comparing the economic impact of same day versus next day discharge.

Objective:
We sought to evaluate the safety and economic impact of same day discharge after an uncomplicated PCI compared with those after an overnight observation stay..

Methods:
We performed a retrospective review of pts who underwent elective PCI and were discharged the same day vs. next day (from observation status) at Geisinger Medical Center between 1/1/2008 to 9/15/2013. The same-day discharge program for selected pts (“outpatient PCI”) was initiated in 2010. Guidelines for same day discharge included negative troponins at 4 hours; readiness for discharge before 8:00 pm; freedom from CHF; LVEF >40%; live within <60 miles; no impediment to obtaining immediate medical attention after discharge if needed; BMI <40, and no severe aortic regurgitation. Thirty-day outcomes were analyzed.

Results:
A total of 1164 elective PCI pts were identified; 280 (24%) were discharged the same day (Group 1) and 884 (76%) stayed overnight (Group 2), by physician preference. The radial route was used in 47% of pts, and increased over time. No same day discharge pts were readmitted within 24 hours. At 30 days, there were no differences between Group 1 vs. 2 in frequency of access site complications (0% vs. 0.01%), peri-procedural MI (0 % vs. 0.006%), urgent care/ED visit or readmission (0.05% vs. 0.08%) (P=NS all comparisons). Stent thrombosis and death did not occur in either group in the first 24 hr post PCI. The average charges were $67,471 for pts discharged the same day, 17% less than the $81,175 for those who spent a night being observed in the hospital (P < 0.0001).

Conclusions:
Same day discharge after an uncomplicated PCI and 4 hour observation period was safe and resulted in significantly reduced charges.
Abstract 18786: Real Time Gene Knock Out in Human Induced Pluripotent Stem Cell Derived Cardiomyocytes Allows Rapid Evaluation of Gene Function in Cellular Electrophysiology
Authors: Xiao Ling , Wang Gang , Jang Megan , Leyton-Mange Jordan , Pu William , Ellinor Patrick T , Milan David J
Published: March 2022

Background and objective:
Modeling of human physiologic traits using pluripotent stem cell derived cardiomyocytes has been hampered in part by variability between cardiomyocytes derived from different stem cell lines. While the advent of genome editing affords unprecedented opportunities to evaluate gene function, the variation between cell lines creates challenges in distinguishing signal from noise. We recently developed a genetically encoded voltage sensing fluorescent protein, Arclight, that enables serial recording of cellular electrical activity. Using an inducible CRISPR-CAS9 nuclease we have developed a method to knockout genes of interest in differentiated cardiomyocytes. The use of the Arclight voltage reporter allows monitoring of the loss of gene function over time. This real-time knockout method is demonstrated for the KCNH2 gene and compared to shRNA mediated knockdown.

Methods and Results:
Human iPSCs that were genetically engineered to contain a doxycycline (DOX) inducible Cas9 allele were differentiated into cardiomyocytes and transduced with lentiviral vector carrying the genetically encoded fluorescent voltage indicator, A242-Arclight. These human Cas9 iPSC-CMs expressing Arclight were further transduced with lentiviral vector containing a guide RNA (gRNA) targeting KCNH2 to achieve knockout upon DOX treatment. Arclight fluorescence was repeatedly recorded in these cardiomyocytes at day 0, 3, 5, 7, and 9 after DOX treatment. APDs at 90% repolarization (APD90) were analyzed and compared to APD90 from CMs without DOX treatment. APD90 in DOX treated iPSC-CMs gradually prolonged from day 3 to day 5 and remained relatively stable between days 5 and 9. At day 7, APD90 was significantly prolonged in DOX treated iPSC-CMS (321 ± 21 ms) compared to untreated cardiomyocytes (231 ±15 ms). RNAi-mediated knockdown of KCNH2 using short hairpin RNA (shRNA) on the iPSC-CMs expressing Arclight did not significantly alter APD90 throughout the study time course.

Conclusion:
In this in vitro human cell model, Crispr/Cas9 knockout of KCNH2 results in APD prolongation in iPSC-CMs in a real-time manner, which provides a powerful cellular platform to evaluate gene function in cellular electrophysiology.
Abstract 18794: Systemic Heparin Use and Outcomes in Cardiac Arrest Patients Treated With Therapeutic Hypothermia Without Coronary Intervention
Authors: Young Michael N , Holmes Benjamin B , Xu Meng , Borges Nyal , Zern Emily K , Armstrong William C , McPherson John A
Published: March 2022

Introduction:
The effects of hypothermia on hemostatic function are complex and poorly understood. While cardiac arrest and CPR can elicit a pro-inflammatory, pro-coagulant state, hypothermia may alter platelet count, activation and aggregation. Hypothesis: We hypothesized that treatment with systemic heparin during therapeutic hypothermia (TH) is associated with improved neurologic outcomes.

Methods:
We conducted a retrospective study of 157 cardiac arrest survivors treated with TH at our institution from 2007-2014. A priori, we excluded TH patients (pts) presenting with an acute coronary syndrome requiring percutaneous coronary intervention, pulmonary embolus, venous thrombosis or need for mechanical circulatory support. We used a multivariable logistic regression model to examine the relationship between systemic heparin and neurologic outcome (Cerebral Performance Category score 1-2=good; 3-5=poor) as well as inpatient survival. We also performed a chi-square analysis for the secondary endpoint of major bleeding.

Results:
Mean age was 57.0 (+/- 16.2) years; 86 (54%) pts were male; and 75 (47.8%) pts had an initial rhythm of ventricular tachycardia or ventricular fibrillation. At discharge, 48 (30.6%) pts had a good neurologic outcome and 23 (14.7%) pts suffered from a major bleed. Systemic heparin was administered to 48 (30.6%) pts, and was neither associated with favorable neurologic outcome (OR 0.99, CI 0.39-2.56, p=0.991) nor inpatient survival (OR 1.28, CI 0.54-3.05, p=0.574). The risk of bleeding with heparin was 2.08 (CI 0.99-4.38, p=0.052). Conclusions: In our cohort, indiscriminate use of systemic heparin during TH post-cardiac arrest was not associated with improved neurologic outcomes. Conversely, a trend towards increased risk of major bleeding was noted.
Abstract 18826: Cardiac Myosin Binding Protein C Mutants Interact With and Cause Mislocalization of the Hsp70 Family Chaperones
Authors: Glazier Amelia A , Helms Adam , Yob Jaime M , Mellacheruvu Dattatreya , Tang Vi , Bartolone Sarah , Basrur Venkatesha , Nesvizhskii Alexey I , Day Sharlene
Published: March 2022

Introduction:
Myosin binding protein C (MYBPC3) is the most frequently mutated gene in hypertrophic cardiomyopathy (HCM) and >90% of MYBPC3 mutations produce truncated proteins. Ubiquitin proteasome dysfunction has been observed in human HCM hearts with MYBPC3 mutations and in experimental models, but the mechanisms responsible are unknown. We hypothesize that interactions between truncated MYBPC3 and molecular chaperones could underlie proteasome dysfunction by exhausting a critical chaperone pool required to sustain normal cellular protein quality control.

Methods and Results:
FLAG-tagged wild-type and two mutant truncated MYBPC3 proteins of different lengths were expressed in neonatal rat cardiomyocytes via adenovirus. Spontaneous contractions per minute were markedly reduced in myocytes expressing mutant compared to wild-type MYBPC3 (non-transduced 49±8; WT 57±7; W1098* 25±3; I154Lfs*5 4±1; n=6, p<0.05). Mutant MYBPC3 expression also caused proteasome dysfunction as evidenced by increased expression of the GFPμ degron reporter (% non-transduced myocytes: WT 55.3±17.6%; W1098* 324.4±117.5%; I154Lfs*5 307.4±52.8%; n=3, p<0.05). Affinity purification mass spectroscopy identified heat shock protein 70kDa (Hsp70) and heat shock cognate 70kDa (Hsc70) as highly abundant interacting proteins with wild-type and W1098* MYBPC3 but not I154Lfs*5. Interaction confidence scores as determined by SAINT analysis were ~3 fold higher for W1098* than for wild-type MYBPC3 (23.5 vs 8.0 for Hsc70 and 77.7 vs. 12.3 for Hsp70). These interactions were confirmed by Western blot and co-localization experiments. In non-transduced myocytes, and in myocytes expressing wild type MYBPC3, Hsc70 showed distinct M-line and Z-disc banding, while in myocytes expressing either mutant MYBPC3, Hsc70 was relocalized from the sarcomere to cytosolic, nuclear, and perinuclear aggregates, similar to non-transduced myocytes that were subjected to heat shock.

Conclusions:
These results suggest MYBPC3 is a client of Hsp70 chaperones and that mutant proteins may interfere with regular functions and localization of Hsp70 and Hsc70. Further experiments will determine if these interactions are important for maintaining cellular proteostasis in MYBPC3-mutant HCM.
Abstract 18846: Heart Rate Reserve, a Prognostic Marker for Heart Failure Hospitalizations and Adverse Outcomes
Authors: Madan Shivank A , Nahumi Nadav , Garcia Luis , Gentile Kevin , Duong Jimmy , Algodi Mohammed , Sweet David , Mignatti Andrea , Sayer Gabriel , Colombo Paolo C , Thomas Sunu S , Uriel Nir , Jorde Ulrich
Published: March 2022

Introduction:
Heart Failure hospitalization (HFH) is a major clinical event and economic burden. Heart Rate Reserve (HRR), a marker of chronotropic incompetence is associated with mortality, but its prognostic value in HF progression is unknown.

Methods:
In this multi-center study, HF patients with NYHA class 2-3, in sinus rhythm, on stable medical therapy underwent a cardiopulmonary exercise test (CPET) from 2008-2013 at Columbia University Medical Center and were prospectively followed for 3 endpoints: HFH, inotrope dependence or worse, and heart replacement therapy or death (HRT-D). Various clinical variables including HRR were evaluated and included in risk score models. The models with highest significance were validated in an independent cohort from Montefiore Medical Center

Results:
In the derivative cohort of 135 patients, low pVO2, HRR, and LVEF were significantly associated with all 3 endpoints. Using ROC analysis, HRR<45% was equivalent to pVO2<14 ml/kg/min in predicting all outcomes. The model using LVEF<30%, pVO2<14 ml/kg/min and HRR<45% as binary cut-offs (total score: 0-3) was able to stratify patients into different risk strata for freedom from HFH (p<0.001, Fig-1), freedom from inotrope dependence or worse (p<0.001) and from HRT-D (p<0.001, Fig-2) at 1 year. A simpler model using LVEF<30% and HRR<45% (total score: 0-2) was also able to risk stratify patients (p<0.001). These results were validated in an independent cohort of 294 patients.

Conclusions:
HRR is a strong predictor of outcomes in advanced HF. If a metabolic cart is unavailable, a simple risk score using HRR<45% and LVEF<30% alone can help clinicians identify patients at highest risk for HFH.
Abstract 18848: Carotid Artery Remodeling is Segment Specific: An in Vivo Study by Cardiovascular Magnetic Resonance Imaging
Authors: Watase Hiroko , Sun Jie , Hippe Daniel S , Balu Niranjan , Li Feiyu , Zhao Xihai , Fayad Zhai , Fuster Valentine , Hatsukami Thomas S , Yuan Chun
Published: March 2022

Introduction:
Coronary atherosclerosis can be accompanied by coincident change in lumen and total vessel area, described as arterial remodeling. Early-stage atherosclerosis is believed to be associated with enlarged outer wall and preserved lumen (outward remodeling). However, direct in vivo evidence in the carotid artery is scarce. Magnetic resonance imaging provides a non-invasive means to characterize remodeling patterns in the carotid arterial wall.

Hypothesis:
We tested the hypothesis that carotid arteries exhibit expansive remodeling in a large cohort of asymptomatic subjects with multiple cardiovascular risk factors. We further examined whether remodeling is carotid segment specific.

Methods:
From the BioImage Study (NCT00738725), 525 subjects were evaluated with magnetic resonance imaging. Axial images of bilateral carotid arteries were acquired and categorized into common carotid artery (CCA), carotid bulb, and internal carotid artery (ICA) segments based on their distance to the flow divider. Lumen area (LA), total vessel area (TVA), and mean wall thickness (MWT) were measured on all slices and averaged for each CCA, carotid bulb, and ICA segments per subject. General linear models were used to examine cross-sectional associations of MWT with LA and TVA after adjustment for age, sex and body surface area. The regression slopes are presented as the cross-sectional area change per 1 mm MWT increase and were interpreted as indicators of the remodeling pattern.

Results:
A total of 489 subjects (mean age: 68 years; 49% female) with sufficient image quality were enrolled in this study. In the CCA, both TVA (Slope: 44.6 mm2, p<0.001) and LA (Slope: 11.9 mm2, p=0.009) tended to be larger with increased MWT, suggesting outward remodeling. In the ICA, TVA also increased with MWT (Slope: 17.0 mm2, p<0.001), while the LA tended to decrease (Slope: -6.8 mm2, p=0.07). In contrast, the TVA changed less in the carotid bulb with MWT (Slope: -8.2 mm2, p=0.29) while the LA distinctly decreased with increasing MWT (Slope: -35 mm2, p<0.001), consistent with inward remodeling.

Conclusions:
In this asymptomatic cohort with multiple risk factors, carotid artery atherosclerosis is accompanied by arterial remodeling which appears to be segment specific.
Abstract 18897: Extracellular Signal-related Kinase Signaling and Smooth Muscle Cell Contractile Gene Expression are Uniformly Enhanced in the Aortic Root and Ascending Aorta in Marfan Syndrome
Authors: Pedroza Albert J , Koyano Tiffany K , Trojan Jeffrey , Palmon Itai , Arakawa Mamoru , Penov Kiril , Fischbein Michael P
Published: March 2022

Introduction:
Enhanced TGF-β signaling drives aortic root aneurysm development in Marfan syndrome (MFS) via the non-canonical (ERK) pathway in murine models, but ERK not been studied in human tissue. Conversely, blockade of canonical (Smad) TGF-β signaling is detrimental in MFS mice. Recently, TGF-β-induced increases in smooth muscle cell (SMC) contractile genes and collagen I (COL1) expression have been proposed to lead to aortic stiffness and dilatation in MFS.

Hypothesis:
We hypothesized that ERK signaling is enhanced in human MFS tissue and dictates the predilection of the aortic root to develop aneurysm by altering SMC gene expression.

Methods and Results:
Western blot of aortic root tissue from MFS patients with root aneurysms (4.67±0.09 cm) revealed 3.1-fold increased ERK activation relative to control aortic root (p=0.03, n=8). When compared to non-dilated MFS ascending (ASC) aorta (2.94±0.14 cm), there was no difference in ERK activation between the two regions. While RT-PCR of MFS root showed increased expression of the contractile gene regulator myocardin (2.4±0.07 fold, p=0.01), and of MYH11 (3.05±0.13 fold, p=0.03) ACTA2 (2.93±0.10 fold, p<0.01), and SM22-α (1.88±0.13 fold, p=0.02) versus controls, these genes were not differentially expressed between MFS root and ASC. COL1 expression was increased in MFS root relative to controls (5.57±0.06 fold, p<0.01) and MFS ASC (2.25±0.06 p<0.01). In vitro treatment of cultured MFS aortic root SMCs (n=5 patients) with TGF-β and Smad-specific inhibitor (SB431542) failed to increase expression of MYOCD, MYH11, ACTA2, SM22-α or COL1, while co-treatment with TGF-β and ERK inhibitor (PD98059) induced significant increases in expression of these genes (5.4-, 2.6-, 2.7-, 1.4-, and 1.4- fold, respectively p<0.05).

Conclusions:
ERK signaling is uniformly enhanced in MFS aortic root and ASC tissue, indicating that further study into aortic region-specific responses to cellular signals is needed to assess the development of focal aortic root aneurysm in MFS. Increased contractile gene expression is Smad-dependent and non-focal and thus does not clarify focal root aneurysm. COL1, while focally enhanced in the MFS root, is Smad-driven and suppressed by ERK, and may represent a compensatory response.
Abstract 18904: VARSITY Study (VA Retrospective study of Statin IntensiTY): Utilizing a Large VA Cohort to Determine the Actual Clinical Response of LDL Reduction After Initiating Statin Therapy in Newly Diagnosed ASCVD
Authors: Garcia Mark , Murata Allison , Charlton Gerald
Published: March 2022

Background:
According to the 2013 ACC/AHA Blood Cholesterol Guideline (BCGL), high-intensity statin therapy (HIST) is recommended in individuals with newly diagnosed atherosclerotic cardiovascular disease (ASCVD) and this therapy is expected to lower LDL by >50%. These recommendations come from multiple studies which demonstrated that the reduction in major vascular events was proportional to the absolute LDL reduction. This retrospective study utilized a large VA cohort to report the LDL reduction with the initiation of statin therapy after an initial diagnosis of ASCVD.

Methods:
A national cohort of VA patients with a new diagnosis of ASCVD and subsequent initiation of statin therapy was constructed. The most proximate LDL measured within 12 weeks before (PreLDL) and 4-12 weeks after (PostLDL) initiation of statin therapy were recorded. Patients with a prior diagnosis of ASCVD, a prior prescription for any lipid lowering drug, or a prior prescription for immunosuppressant agents were excluded. The statin doses were categorized as high-, moderate- or low-intensity as defined in the 2013 BCGL.

Results:
This cohort consisted of 92,755 VA patients with an initial ASCVD diagnosis from 5/1992 to 7/2014. The cohort was 97% male, 19% ethnic minority, and the average age was 66.7 (± 10.9) years. The average PreLDL was 129.8 (±35.1), the average PostLDL was 94.2 (±31.7) mg/dl, and only 2.5% were prescribed HIST. The results are summarized in Table 1.

Conclusion:
This cohort study examined statin intensity and LDL reduction after the initial diagnosis of ASCVD. HIST was rarely prescribed as initial therapy and in a majority of these patients the expected >50% LDL reduction was not achieved. This study suggests the need for additional research to explore the factors contributing to a >50% reduction in LDL following the initiation of statin therapy in patients with ASCVD, and that the monitoring of response to HIST may be clinically important.
Abstract 18925: The Serum Level of Mir-30a-3p And Mir-31-5p Can Discriminate Responders From Non-responders to CD34 + Cell Therapy in Patients With Dilated Cardiomyopathy
Authors: Pajic Tadej , Klinec Nika , Sever Matjaz , Cernelc Peter , Poglajen Gregor , Haddad Francois , Vrtovec Bojan
Published: March 2022

Introduction:
The potential predictive value of specific, circulating miRNAs in blood in patiens with non-ischemic dilated cardiomyopathy (DCM) undergoind CD34+ cell therapy remains undefined.

Hypothesis:
We assessed the hypothesis that the relative level of specific miRNAs in serum obtained at baseline will discriminate responders from non-responders to stem cell therapy in patients with DCM.

Methods:
We enrolled 10 consecutive patients with DCM who underwent transendocardial CD34+ cell transplantation between January and December 2013. All patients received 5-day stimulation with G-CSF; CD34+ cells were selected with apheresis and injected transendocardially guided by electroantomical mapping. Patients were followed for 6 months and good clinical response was defined as an increase of left ventricular ejection fraction (LVEF) ≥5%. Before cell therapy, total RNA was isolated from serum with the miRCURY RNA Isolation Biofluids Kit. cDNA synthesis and real-time qPCR were performed using the miRCURY Locked Nucleic Acid and Universal RT microRNA PCR system with The qPCRs were run on a ViiA7 thermocycler.

Results:
At 6 months after therapy, good clinical response was found in 5 patients (Group A), and 5 patients failed to respond to cell therapy (Group B). The two groups did not differ with regards to age (55±9 years in Group A vs. 57±3 years in Group B; P=0.58), male gender (87% vs. 100%; P=0.34), baseline LVEF (33±5% vs. 28±8%; P=0,28), LVEDD (6.6±0.4 cm vs. 6.9±0.7 cm; P=0.33) or NTproBNP levels (1460±932 pg/mL vs. 4540±3808 pg/mL; P=0.15). When analyzing the pool of miRNAs we found the serum level of miR-30a-3p and miR- 31-5p to be significantly different between two study groups (both had adjusted P values of 0.031). The serum level of miR- 31-5p was higher in the group of responders (log2 fold change of 6.78) while the serum level of miR-30a-3p was higher in the group of non-responders (log2 fold change of 4.98).

Conclusions:
In patients with DCM undergoing CD34+ cell therapy specific serum miRNAs appear to discriminate clinical responders from non-responders. Therefore, they could be used as a tool when selecting appropriate patients for stem cell therapy.
Abstract 18978: CHA2DS2-VASc Score Predicts the Occurrence of Perioperative Stroke in CABG Patients Without Post-operative Atrial Fibrillation
Authors: Verdejo Hugo , Barra Paula , Zalaquett Ricardo , Huete Isidro , Corbalan Ramon
Published: March 2022

Introduction:
The CHA2DS2-VASc score is a clinical guideline for assessing ischemic stroke risk in patients with atrial fibrillation (AF). However, new evidence suggest that the CHA2DS2-VASc predicts vascular dysfunction and cardiovascular events in high-risk CV patients without clinical AF.

Hypothesis:
The CHA2DS2-VASc score predicts the occurrence of perioperative stroke in patients in sinus rhythm submitted to CABG in absence of post-operative AF

Methods:
We analyzed 112 consecutive patients in sinus rhythm and without history of AF who were submitted to elective CABG. Clinical and laboratory characteristics were recorded at baseline and 72 h after surgery. All subjects were monitored for 72 hours to exclude postoperative AF. A standardized MRI with stroke protocol was performed in the preoperative period in all subjects and within 5 days after surgery to detect evidence of perioperative stroke.

Results:
Patient mean age was 65 ± 15 years, 81.2% male. During follow-up, 26.8% of the patients showed new defects in MRI compatible with ischemic stroke, but only two exhibited overt neurological impairment. Baseline and postoperative inflammatory and coagulation markers, CPB and aortic clamp time as well as standard echocardiographic characteristics were similar in patients with and without perioperative stroke. CHA2DS2-VASc score was higher in patients who developed perioperative stroke (3.13 ± 1.4 vs 2.30 ± 1.2, p=0.01). Figure 1 shows the distribution of stroke cases according to CHA2DS2-VASc score. In a multivariate analysis, CHA2DS2-VASc2 was the only independent predictor of perioperative stroke in this population (HR 1.55, 95% CI 1.104-2.176, p=0.01).

Conclusions:
The CHA2DS2-VASc score predicts the occurrence of perioperative stroke in CABG patients without clinical AF. Patients with a score of 3 or more exhibit an increased risk for perioperative stroke even after adjusting for age, smoking and significant comorbidities.

FONDECYT 1100801
Abstract 19009: The Association Between Clinical and Echocardiographic Imaging Findings and T2* in End Stage Liver Disease
Authors: Brooks Gabriel , Brown Kathryn , Mehta Neil , Ordovas Karen , Rubin Nevah , Foster Elyse , Qasim Atif
Published: March 2022

Background:
Cirrhosis can lead to cardiac iron deposition (cardiac siderosis), a risk factor for heart failure (CHF) and ventricular arrhythmia. Cardiac magnetic resonance (CMR) T2* analysis is utilized to detect cardiac siderosis prior to liver transplantation (LT). Clinical and TTE correlates with T2* values in patients with end-stage liver disease are not well characterized.

Methods and Results:
We present a case series of 130 patients with cirrhosis undergoing LT evaluation with T2* and TTE analysis at our institution between 2008-2014. We compared clinical, TTE and functional CMR measures to T2* measures across three categories: <10 (excluded from LT due to high-risk for heart failure or arrhythmia), 10-20 -(cardiac siderosis of indeterminate clinical significance) and ≥20 (normal) using fisher exact test for categorical variables and ANOVA for continuous variables.

Clinical characteristics associated with lower values of T2* were: lower body mass index (p=0.01), lower systolic blood pressure (p<0.01). MELD score was higher in those with T2* values between 10-20 (p <0.01). Echocardiographic findings associated with lower T2* values included lower left ventricular (LV), ejection fraction (p<0.01), higher LV end systolic volume index (p <0.01), and higher global longitudinal strain (GLS) in the 4-Chamber, 3-chamber and the overall average GLS (all p < 0.01), though there were fewer participants that had 3-chamber GLS measurements.

Conclusions:
In this exploratory analysis of LT candidates, lower T2* values correlated with more advanced liver disease including lower BMI, lower systolic blood pressure and MELD score. Intriguingly, higher global longitudinal strain demonstrated a strong correlation with lower T2* in 4 and 3 chambers as well as overall average GLS and may be a valuable tool in the LT evaluation of suspected cardiac iron overload.
Abstract 19056: Discovery of Potent and Selective Neprilysin Inhibitors Exhibiting Sustained Pharmacodynamic Activity and Non-renal Elimination in Rats
Authors: Bourdet David L , McNamara Alex , Hill Craig , DeMent Kevin , Fleury Melissa , Yu Cecile , Hegde Laxminarayan G , Martin William , Hegde Sharath , Klein Uwe , Hughes Adam D
Published: March 2022

Introduction:
Neprilysin (NEP) inhibitors in combination with angiotensin-II receptor antagonists (ARNIs) have demonstrated benefits in patients with hypertension and chronic heart failure (CHF). A significant population of patients with cardiorenal diseases (e.g., CHF, chronic kidney disease and diabetic nephropathy) exhibit moderate to severe levels of renal impairment. Sacubitril (NEP inhibitor component of LCZ696) is extensively cleared by the kidney and systemic exposures are increased in patients with renal dysfunction thus potentially limiting its therapeutic utility. We aimed to identify potent and selective NEP inhibitors that exhibit non-renal excretion in order to discover agents that may provide optimal therapy in patients with renal dysfunction.

Methods:
In vitro enzyme activity assays at human NEP were used to assess inhibitory potencies and half-lives of the enzyme-inhibitor complexes. In vivo potentiation of ANP-induced plasma cGMP was evaluated after PO dosing in Sprague Dawley rats. Blood pressure was monitored in conscious Dahl Salt-Sensitive (Dahl/SS) hypertensive rats surgically implanted with telemetry transmitters. Urinary and biliary excretion was evaluated in bile-duct cannulated rats.

Results:
Selective NEP inhibitors (THRX-213068, THRX-134025, and THRX-124283) were identified with increased potency relative to LBQ657 (active moiety of sacubitril) at NEP (pKi 9.4, 9.3, 9.3 versus 8.2) and displayed longer enzyme residence time (T1/2 = 25, 145, and 190 versus 3 min). All three NEP inhibitors potentiated cGMP to a greater extent than LBQ657 in rat plasma after PO dosing (10 mg/kg). Sustained lowering of mean arterial pressure also was observed in Dahl/SS rats after PO dosing (24 hr average change -17 to -45 mm Hg). Negligible renal excretion was observed for all NEP inhibitors in rats after IV or PO dosing [< 5% of dose relative to 40% (IV) for LBQ657].

Conclusions:
Novel, potent, and selective NEP inhibitors were identified that exhibit sustained potentiation of cGMP and BP-lowering in rodent models. Negligible levels of renal excretion were observed in rats suggesting the possibility of providing consistent dosing in patients with cardiorenal diseases across various levels of renal dysfunction.
Abstract 19088: Atrial Late Potentials and Atrial Substrate Remodeling in Patients With Atrial Fibrillation
Authors: Bando Sachiko , Soeki Takeshi , Matsuura Tomomi , Tobiume Takeshi , Ise Takayuki , Kusunose Kenya , Yamaguchi Koji , Yagi Shusuke , Yamada Hirotsugu , Wakatsuki Tetsuzo , Sata Masataka
Published: March 2022

Backgrounds:
Patients with atrial fibrillation (AF) often have a low-amplitude potential in the terminal part of filtered P-wave (atrial late potential: aLP). However, it remains unknown what aLP reflects in AF patients. On the other hand, electrical remodeling of the atria can be precisely evaluated by the quantitative voltage map analysis using 3D mapping system. In this study, we hypothesized that we could substitute "non-invasive" aLP for "invasive" 3D mapping system to evaluate the atrial electrical remodeling and investigated the relationship between aLP and atrial substrate remodeling in AF patients.

Methods:
The P-wave single-averaged electrocardiogram (P-SAECG) was recored in 60 patients with paroxysmal AF who underwent PV isolation. Filtered P-wave duration (fPWD) and root-mean-squared voltage of the terminal 20ms of ≤2.0 μV (RMS20) were assessed by P-SAECG. The left atrial (LA) global contact mapping during sinus rhythm was performed and LA voltage zone index (LAVZI) was defined as an area with voltage < 0.5mV divided by total LA surface area.

Results:
LAVZI showed a strong positive correlation with fPWD and a strong negative correlation with RMS20 (r=-0.82, p<0.01; r=0.68, p<0.01, respectively). LV volume by echocardiography was also positively correlated with fPWD and negatively correlated with RMS20 (r=0.57, p<0.05; r=-0.69, p<0.01, respectively). In addition, LA appendage flow was negatively correlated with fPWD (r=-0.49, p<0.05). fPWD was significantly longer and RMS20 was lower in patients with AF for more than 1 year than those for less than 1 year. However, there were no significant correlations between aLP parameters and other echocardiographic findings such as left ventricular ejection fraction or plasma BNP concentration.

Conclusions:
aLP reflects precisely atrial substrate remodeling in AF patients. aLP might serve as non-invasive tool for monitoring the atrial substrate remodeling in patients with AF.
Abstract 19157: Shocks During Cardioversions are Not Uncommonly Delivered Asynchronous Including in the Vulnerable Phase of the T-wave: A Post-hoc Analysis of a Randomized Controlled Study
Authors: Schmidt Anders S , Lauridsen Kasper G , Rickers Hans , Bach Leif F , Løfgren Bo
Published: March 2022

Background:
Shock synchronized to the QRS-complex is essential to avoid cardioversion induced ventricular fibrillation. Several defibrillators are used in clinical practice, but little is known about their ability to synchronize shocks in real life use. In a randomized study, comparing two defibrillators, a major adverse event occurred and was related to synchronization failure of one device.

Aim:
To investigate if shocks are delivered asynchronous during synchronized cardioversion.

Methods:
A post-hoc analysis of a randomized study enrolling patients admitted for elective cardioversion was performed. Patients were randomized to receive cardioversion by LIFEPAK 20 (Physio-Control Inc., Redmond, WA, USA) or Schiller Defigard 5000 (Schiller AG, Baar, Switzerland). All shocks were delivered with the defibrillators in synchronization modus. Post-hoc, we investigated the ability to synchronize, i.e. the delay between the R-wave and shock delivery, by reviewing electrocardiographic shock recordings. According to the Association for the Advancement of Medical Instrumentation and the American National Standards Institute, a synchronized shock should be delivered within 60 milliseconds after the R-wave.

Results:
A total of 134 patients were randomized; 65 patients received cardioversion by LIFEPAK 20 (mean age: 67 years, 14% atrial flutter), and 70 patients Schiller Defigard 5000 (mean age: 66 years, 14% atrial flutter). Overall, 138 shocks were delivered by LIFEPAK 20, all of them delayed more than 60 milliseconds (range: 80-200 milliseconds). All LIFEPAK 20 shocks were however delivered between the R-wave and the T-wave upstroke. In total, 193 shocks were delivered by Schiller Defigard 5000. Of these, 169 (88%) shocks were delivered within 60 milliseconds (range: 0-450 milliseconds), 180 (93%) between the R-wave and the T-wave upstroke, and 13 (7%) in the vulnerable part of the T-wave. Two of these shocks resulted in malignant ventricular tachycardia.

Conclusion:
Synchronized shocks in cardioversions are not uncommonly delivered asynchronous, including in the vulnerable phase of the T-wave. Of these shocks, two resulted in cardioversion induced malignant ventricular tachycardia.