bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 12238: Myocardial Injury Induces Renal Fibrosis and Dysfunction in Association With the Activation of Renal Apoptotic and TGF-Beta Molecular Pathways
Authors: Sangaralingham S. J , Martin Fernando L , Huntley Brenda K , Ichiki Tomoko , Chen Horng H , Burnett John C
Published: July 2021

Introduction:
Human and experimental studies have suggested that a decline in renal function after myocardial infarction (MI), possibly due to the activation of adverse molecular pathways, contributes to heart failure (HF) progression and poor outcomes. The apoptosis and the transforming growth factor-beta (TGF-beta) pathways have been implicated in post-MI injury, however it is unclear if these 2 key pathways are activated post-MI in the kidney and may contribute to renal fibrosis and dysfunction.

Hypothesis:
We hypothesized that MI activates widespread renal apoptotic and TGF-beta related genes and is associated with renal fibrosis and dysfunction.

Methods:
Wistar rats were randomized into two groups: Sham-operated (S; n=10) and MI (produced by left coronary artery ligation; n=10). Cardiorenal structure and function were assessed at 3 weeks and included mean arterial pressure (MAP), EF, GFR, renal blood flow (RBF), sodium (Na) excretion and renal fibrosis by picrosirius red staining. Microarray analysis (Affymetrix GeneChip Rat Genome) was performed on kidney cortex (KC) and medulla (KM) and focused on apoptotic and TGF-beta related genes. Data presented as mean±SE,*p<0.05.

Results:
Experimental MI was characterized by a significant decrease in EF (S: 79±1, MI: 49±4 %*) and LV hypertrophy (S: 2.06±0.03, MI: 2.57±0.07 mg/g*), while MAP did not differ between groups. GFR and Na excretion were similar between the groups, however there was a significant decline in post-MI RBF (S: 14±1, MI: 8±1 ml/min*). Notably, after MI the KC (S: 1.3±0.3, MI: 3.4±0.8 %*) and KM (S: 1.0±0.3, MI: 11±2.8 %*) exhibited an increase in fibrosis. Microarray analysis revealed that 138 apoptotic and 15 TGF-beta pathway genes in the KC and 122 apoptotic and 10 TGF-beta pathway genes in the KM were significantly altered (1.5 fold, p<0.05) in the MI group.

Conclusions:
These findings demonstrate that MI results in adverse renal fibrotic remodeling together with extensive modulation of apoptotic and TGF-beta pathways of which may contribute to post-MI renal dysfunction. This study suggests that therapies should target detrimental molecular pathways in the kidney as well the heart to prevent the progression of post-MI cardiorenal failure.
Abstract 12260: Sex Differences in Cardiac Troponin I and the Risk of Death or Major Cardiovascular Events in Primary Prevention
Authors: Everett Brendan M , Glynn Robert J , Zeller Tanja , Blankenberg Stefan , Ridker Paul
Published: July 2021

Introduction:
Circulating cardiac troponin I concentrations are higher in men than in women, but the biological causes and clinical implications of this observation are poorly understood.

Methods and Results:
We measured cardiac troponin I with a novel high-sensitivity assay (hsTnI) in 4696 women and 8260 men enrolled in the JUPITER trial who had LDL-C < 130 mg/dL and hsCRP ≥ 2.0 mg/L and no diabetes or clinical evidence of vascular disease. Median (IQR) hsTnI was higher in men [3.6 ng/L (2.7-5.3)] than in women [3.1 ng/L (2.3-4.5); P<0.0001]. A higher proportion of men (3.7%) than women (2.9%) were above the proposed upper reference limit of 24 ng/L (P=0.008). In linear regression models, sex remained a significant predictor of natural log normalized hsTnI after adjusting for a wide array of confounders, including age, race, height, weight, lipids, fasting glucose, blood pressure, and renal function. Across quintiles of hsTnI measured at baseline, the unadjusted incidence rate of the composite outcome of myocardial infarction, stroke, hospitalization for unstable angina, revascularization, or death increased across hsTnI categories but appeared similar in women and men (Figure 1). In adjusted Cox models stratified by sex, the increase in the relative risk of the composite endpoint across quintiles of hsTnT appeared similar in men and women (Figure 2; P-interaction=0.45).

Conclusions:
In a contemporary primary prevention population, women have lower baseline cardiac troponin I concentrations but similar increases in the rates of vascular events and death across troponin I categories.
Abstract 12273: Benefits and Safety of Prolonged Dual Antiplatelet Therapy in Patients With Ischemic Cardiovascular Disease: A Meta-analysis of 18 Randomized Trials Including 94,306 Patients
Authors: Savarese Gianluigi , Lund Lars H , Perrone-Filardi Pasquale
Published: July 2021

Introduction:
The optimal duration of dual antiplatelet therapy (DAPT) in patients with ischemic cardiovascular (CV) disease is still debated. A previous meta-analysis demonstrated no benefit of prolonged DAPT on mortality. However, assessment of the risk and benefit of prolonging DAPT beyond current recommendations cannot overlook its effects on stroke, myocardial infarction (MI) and bleeding.

Hypothesis:
The purpose of this meta-analysis was to assess the effects of prolonged versus no or short-term DAPT on MI, stroke, bleeding and mortality.

Methods:
Trial inclusion criteria were: randomization to prolonged duration versus no or short DAPT; reporting of at least one outcome among overall and CV death, MI, stroke, major non-fatal bleeding, fatal and intracranial bleeding.

Results:
(Table) 18 randomized studies including 94,306 patients [mean age 64+2 years, 28% females, median follow-up 15 months (IQR:12-33)], were included. Prolonged DAPT, compared to no or short DAPT, significantly reduced MI by 21.3% and stroke by 18.8% but had no effect on overall or CV mortality. Prolonged DAPT significantly increased by 68.6% major non-fatal bleeding, but not intracranial or fatal bleeding. In patients with stable and unstable CV disease (with and without acute coronary syndrome, respectively) the effects of prolonged DAPT, compared to no or short DAPT, were equivalent to those observed in the main analysis. DAPT prolonged beyond 1 year, as compared with shorter or no DAPT, significantly reduced MI but not stroke, all-cause or CV death. It significantly increased the risk of major non-fatal bleeding, with no difference in intracranial and fatal bleeding.

Conclusions:
Prolonged DAPT significantly reduces ischemic CV events but not mortality. Even if a significant increase of major non-fatal bleeding was detected, no increased risks of intracranial and fatal bleeding were observed.
Abstract 12284: Hospital Patient Satisfaction Scores and 30-day Readmission and Mortality Rates of Heart Failure Patients
Authors: Hussein Mohamed G , Qayyum Rehan
Published: July 2021

Introduction:
Heart failure (HF) is associated with significant mortality and hospital readmissions. High quality health care is associated with improved outcomes in HF patients. A widely used metric to assess the quality of health care provided by hospitals is patient satisfaction. However, the relationship between a hospital’s patient satisfaction scores and that hospital’s mortality rate and readmissions for HF patients is unclear.

Methods:
We used most recent publicly available data from the Hospital Compare website to examine the relationship between patient satisfaction and 30-day unplanned readmissions and mortality for HF patients. Readmission and mortality rates are reported after adjusting for clinical risk factors. We used multivariable linear regression to explore the relationship between patient satisfaction and HF readmissions and mortality adjusting for hospital and local characteristics (hospital ownership, provision of emergency services, teaching hospital status, survey response rate, percentage insured and poverty).

Results:
Of the 3595 hospitals, 965(27%) were teaching hospitals. Mean (SD) survey response rate was 31.6%(7.3), satisfaction 69.8%(8.7), readmission rate 22.7(1.6) and mortality rate 12.0(1.5). In unadjusted regression, lower 30-day readmission rate but higher mortality rate were associated with high patient satisfaction (-1.4%/unit increase in readmission rate, p<0.001 and 0.2%/unit increase in mortality rate, p=0.03). After adjusting for potential confounders, the readmission rate remained a strong negative predictor of patient satisfaction (-0.75%, P<0.001), however, there was no significant association with mortality (-0.09%, P=0.26).

Conclusions:
We found that 30-day readmission rate, but not mortality rate, in HF patients is a strong negative predictor of patient satisfaction with hospitals. Strategies aimed at reducing HF readmissions may increase patient satisfaction with hospitals.
Abstract 12311: Platelet Force Measurements are Predictive of Triage Category and Blood Transfusion After Trauma
Authors: White Nathan J , Ting Lucas , Lim Esther B , Karchin Ari , Wang Xu , Smith Annie O , Chien Diana , Rue Tessa C , Sniadecki Nathan
Published: July 2021

Introduction:
Platelets rapidly adhere, aggregate and contract forcefully at wound sites to initiate hemostasis. This process, known as primary hemostasis, is a critical component of clot formation after trauma. However, the clinical value of monitoring primary hemostasis after trauma remains unknown. This pilot study aimed to identify the potential clinical value of monitoring primary hemostasis after trauma by measuring platelet forces.

Methods:
Blood was sampled from Emergency Department trauma patients at a U.S. Level I trauma center. Primary hemostasis was measured as contractile force generated by platelet micro-aggregates formed within a microfluidic device. Citrated blood was flowed through a microfluidic channel at high shear rate for 15 seconds, causing platelet aggregates to rapidly form, activate, and contract at collagen-coated micro-force sensors. The maximum platelet force generated over five minutes was recorded in nanonewtons (nN). ANOVA was used to compare platelet force for each trauma triage category: Healthy non-trauma control vs. Modified vs. Full trauma team activation. Logistic regression was used to identify the association of platelet force with the need for any blood product transfusion within 24 hours of hospitalization.

Results:
N=28 trauma patients and N=7 healthy control subjects were included in this pilot analysis of an ongoing cross-sectional observational study. Of the trauma subjects 7/28 (25%) met Full trauma team activation criteria, and 7/28 (25%) required a blood-product transfusion. Mean (SD) platelet force was 227(63) nN for healthy controls, 157(48) nN for Modified, and 126(35) nN for Full trauma team activations (ANOVA, p=0.004). Platelet forces were 164 (45) nN for non-transfused vs. 112(20) nN for transfused subjects (t-test, p=0.008). The platelet force unit Odds Ratio for blood product transfusion was 0.965 (95%CI= 0.936, 0.996), indicating that the odds of receiving a transfusion was decreased significantly by 3.5% for every one nN increase of platelet force.

Conclusions:
Directly measuring primary hemostasis using platelet forces may enhance trauma triage and predict the need for blood product transfusion after trauma.
Abstract 12346: Reduced Diuretic Response With Fluid Retention is a Poor Prognostic Factor in Patients With Acute Decompensated Heart Failure
Authors: Aoki Soichiro , Okumura Takahiro , Sakakibara Masaki , Sawamura Akinori , Morimoto Ryota , Bando Yasuko , Murohara Toyoaki
Published: July 2021

Introduction:
Diuretic response (DR) has been proposed as a prognostic factor in heart failure patients. The presence of leg edema or jugular venous distention reflects fluid retention (FR) and patients are treated with diuretics under the guide of FR. However, the prognostic value of DR and FR has not been clarified. The aim of this study was to investigate the relation of DR and FR to the mortality in patients with acute decompensated heart failure.

Methods:
We enrolled 188 consecutive acute heart failure inpatients survived to discharge (mean age of 78 years, 101 females). DR was calculated by the formula; in-hospital Δbody weight kg / 80mg oral furosemide (or equivalent loop diuretic dose). FR on admission was simply evaluated by the presence of leg edema or jugular venous distention. All patients were divided into 4 groups based on the median of DR and FR; Group-A (DR≤-0.49 with FR, n=65), Group-B (DR≤-0.49 without FR, n=29), Group-C (DR>-0.49 with FR, n=47) and Group-D (DR>-0.49 without FR, n=47). We followed all patients up to one year after discharge. Cardiac events were defined as cardiac deaths and re-hospitalization for worsening heart failure.

Results:
The mean of LVEF was 44% and plasma BNP level was 960 pg/mL. The median length of stay was 18 days, the dose of furosemide was 570 mg, and the Δbody weight was -3.6 kg. The blood urea nitrogen level (p=0.001), creatinine level (p=0.004) and the prior exposure to loop diuretics (p<0.001) was significantly higher in the Group-C and D. The probability of cardiac events in the Group-C was significantly higher than that in any other groups (Figure). Adjusted multivariate analysis identified the Group-C as an independent predictor of cardiac events (HR: 2.32; 95% CI: 1.43-3.78; p=0.001).

Conclusion:
Reduced DR with FR is a poor prognostic factor in patients with acute decompensated heart failure.
Abstract 12385: Past Alcohol Consumption and Incident Atrial Fibrillation
Authors: Dixit Shalini , Alonso Alvaro , Soliman Elsayed Z , Chen Lin Y , Marcus Gregory M
Published: July 2021

Introduction:
Although current alcohol consumption appears to be a risk factor for incident atrial fibrillation (AF), limitations related to self-reported alcohol use and confounding in observational studies limit the certainty of conclusions regarding causality. Whether cessation of alcohol consumption can protect against incident AF remains unknown.

Methods:
We examined all participants in the Atherosclerosis Risk in Communities (ARIC) study, a population-based cohort of 15,792 men and women aged 45-65, without prevalent AF. Past alcohol consumption was assessed via self-report during the baseline dietary intake assessment. Cases of incident AF were ascertained via study ECGs, hospital discharge ICD-9 codes, and death certificates.

Results:
Among 15,262 participants with complete survey data, 2,898 (19.0%) were former drinkers. During an average follow-up of 17.4 years, there were 380 cases of incident AF in former consumers. Both before and after adjustment for potential confounders, a longer duration of alcohol abstinence was associated with a lower risk of developing AF; previously consuming alcohol for a longer duration and consuming a greater quantity of alcohol were each associated with a higher risk of developing AF (Table).

Conclusions:
Among former drinkers, the number of years of drinking and the amount of alcohol consumed may each confer an increased risk of AF. Given that a longer duration of abstinence was associated with a decreased risk of AF, modification of alcohol use could potentially play a role in AF prevention.
Abstract 12419: Preclinical Safety and Efficacy of a Novel Thrombolytic Agent Administered by Rapid Bolus Injection: Clot Specific Streptokinase (CSSK/SMRX-11)
Authors: Shebuski Ronald J , Joshi Kishore , Pande Abhay , Sharma Ravinder , Prashar Yatindra , Kapeghian John , Sahni Girish
Published: July 2021

Introduction:
Clot specific Streptokinase (CSSK), also known as SMRX-11, is a novel recombinant protein, produced and purified from a yeast system (Pichia pastoris). Novel fibrin binding domains attached to each end of streptokinase mask the ability of the streptokinase component of SMRX-11 to interact with blood plasminogen. As a result, SMRX-11 remains inactive in the blood circulation and does not convert blood plasminogen into plasmin until the fibrin binding domains are cleaved by clot-bound plasmin. This is in contrast to native Streptokinase (SK), which indiscriminately converts plasminogen into plasmin. The molecular weight of the glycosylated SMRX-11 protein is approximately 80kD, with a specific activity of 80,000 Units/mg of protein. Results. In vitro experiments comparing SMRX-11 to other fibrinolytics (SK and tPA), demonstrated that SMRX-11 lyses experimentally-preformed human blood clots without reducing residual plasma fibrinogen levels. Initial in vitro studies compared the activity of SMRX-11 to lyse human whole blood clots to native Streptokinase (SK) and tissue Plasminogen Activator (tPA). SMRX-11 had comparable clot lysis activity to SK, with tPA eliciting a slightly greater percent clot lysis. Additional in vitro studies determined the relative fibrinogenolytic effects of SMRX-11 versus tPA. SMRX-11 demonstrated superior fibrinogen sparing compared to tPA with minimal consumption of alpha-2 antiplasmin relative to native SK. In vivo, SMRX-11 (0.7-1.4 mg/kg as an iv bolus), lysed experimentally-induced femoral arterial thrombi in cynomolgus monkeys with relatively minor fluctuation in plasma fibrinogen, forearm bleeding time or hemodynamics. In GLP safety studies, treatment with SMRX-11 at doses of 1, 3 and 10 mg/kg/day for 5 consecutive days was generally well-tolerated in male and female cynomolgus monkeys. Thus, the low dose of 1 mg/kg was considered the No-Observed Adverse Effect Level (NOAEL) for daily repeat-dose administration of SMRX-11 administered via bolus i.v. injection in cynomolgus monkeys. Conclusion. SMRX-11 represents a novel pharmacophore with the appropriate preclinical safety and efficacy profile to warrant clinical investigation for acute treatment of myocardial infarction and stroke.
Abstract 12420: Ivabradine Effectiveness in Everyday Clinical Practice: Results From a Population With Stable Coronary Artery Disease and Coronary Stenosis (>50%) Not Submitted for Revascularization
Authors: Zarifis Ioannis , Katsivas Apostolos
Published: July 2021

Introduction:
Angina pectoris is the most common manifestation of flow limited coronary stenosis, reflecting myocardial ischemia and limiting significantly ordinary activities of patients.

Purpose:
To evaluate Ivabradine’s anti-anginal effectiveness and effect on quality of life (QoL), when co-administered with a β-blocker, during a 4 month therapy of patients with coronary artery disease (CAD) and coronary stenosis (>50%) not submitted for revascularization.

Methods:
This is a post hoc analysis (563 patients with documented coronary stenosis >50%) of a Pan-Hellenic, prospective, non-interventional study including 2403 patients with CAD and stable angina. Follow-up visits were performed at baseline, at 1 and 4 months after inclusion, while patients’ QoL was assessed by EQ-5D questionnaire.

Results:
9 patients (1.6%) out of 563 enrolled CAD patients with >50% coronary stenosis, prematurely discontinued treatment. Mean heart rate decrease on study completion compared to baseline was -17.5 bpm (p<0.001), while mean number of angina attacks and nitroglycerin consumption decrease was -1.8 and -1.4 times/week respectively (p<0.001). The percentage of patients with angina CCS I (Canadian Cardiovascular Society classification), increased from 37% (baseline), to 87% (study completion) (p<0.001). For all dimensions of EQ-5D, the improvement was significant leading to an overall amelioration of daily functioning at study completion (p<0.001) At the 1st month of treatment, 52% of patients received 7.5 mg bid of Ivabradine, which was maintained throughout the study, while compliance to treatment was high; almost 97% of the population was taking their treatment “every day” or “quite often” throughout the study.

Conclusions:
Ivabradine administration presents a significant anti-anginal effect, while improving also QoL and restoring a level of satisfactory usual activity in patients with coronary stenosis >50% not submitted for revascularization.
Abstract 12430: Vicious Circle Between Progressive Right Ventricular Dilatation and Pulmonary Regurgitation in Patients After Tetralogy of Fallot Repair? Right Heart Enlargement Promotes Flow Reversal in the Left Pulmonary Artery
Authors: Kato Atsuko , Drolet Christian , Yoo Shi-Joon , Redington Andrew , Grosse-Wortmann Lars
Published: July 2021

Introduction:
The left pulmonary artery (LPA) contributes more than the right (RPA) to total pulmonary regurgitation (PR) in patients after tetralogy of Fallot (TOF) repair, but the mechanism of this difference is not well known. We hypothesized that unilaterally increased pulmonary vascular resistance (PVR), resulting from lung compression by the enlarged and levorotated heart leads to greater PR in the LPA. This study aimed to analyze the interplay between heart and lung size, mediastinal geometry, and differential PR.

Methods:
This is a single-center retrospective analysis of 50 magnetic resonance studies in patients after TOF repair. Patients with more than mild discrete branch pulmonary artery stenosis were excluded. Blood flow was measured by phase-contrast velocity encoding within the branch pulmonary arteries. On the axial image with the largest total cardiac surface area, cardiac angle (α) between the thoracic anterior-posterior line and the interventricular septum, right and left lung areas as well as right and left hemithorax areas were measured (Figure).

Results:
There was no difference in LPA and RPA diameters. The LPA showed significantly less total forward flow (p=0.04), smaller net forward flow (p=<0.001), and greater RF (p=0.001) than the RPA. Left lung area was smaller than the right (p<0.001). RVEDVi correlated with LPA RF (R=0.48, p<0.001), but not with RPA RF. Larger RVEDVi correlated with a larger α angle (R=0.46, p<0.001), i.e. a more leftward cardiac axis and with smaller left lung area (R=-0.58, p<0.001). LPA RF, but not RPA RF, correlated inversely with left lung area indexed to the left hemithorax area (R=-0.34, p=0.02).

Conclusions:
An enlarged and levorotated heart - as a result of PR - is associated with smaller left lung size, and augments diastolic flow reversal in the LPA, presumably via increased left PVR. By imposing a further volume load on the RV, LPA regurgitation may thus close a positive feed-back loop of PR and RV dilatation.
Abstract 12435: Mitochondrial Calcium Flux Modulates Pacemaker Activity in Embryonic Stem Cell-Derived Cardiomyocytes
Authors: Xie An , Zhou Anyu , Liu Hong , Shi Guangbin , Boheler Kenneth R , Dudley Samuel C
Published: July 2021

Introduction:
Ca2+ release from the sarcoplasmic reticulum (SR) is known to contribute to spontaneous activity via the cytoplasmic Na+-Ca2+ exchanger (NCX). Mitochondria are known to participate in Ca2+ cycling. We studied the role of mitochondrial Ca2+ flux in spontaneously activity of embryonic stem cells (ESC)-derived CMs.

Methods:
CMs were derived from wild type (Wt) and ryanodine receptor type 2 knockout (RYR2-/-) mouse ESCs and differentiated for 19-21 days. Action potentials (APs) were recorded by perforated whole cell current-clamp. Cytoplasmic Ca2+ transients were determined by fluorescent imaging. Mitochondrial Ca2+ transients were monitored simultaneously with APs.

Results:
While If blocker, 10μM ivabradine, had no significant effect on the automaticity, SR Ca2+ handling inhibitors, 10 μM ryanodine and 2 μM 2-APB, reduced the spontaneous beating rate to 56% and 73% respectively in Wt CMs. Inhibition of mitochondrial Ca2+ flux by 10 μM Ru360 showed a similar inhibitory effect on the pacemaker activity.To isolate the contribution of mitochondrial Ca2+, we used RYR2-/- CMs. In RYR2-/- CMs, beating rate was dependent on SR Ca2+ uptake and release from IP3 and the Na+/Ca2+ exchange current but was independent of sarcolemmal Ca2+ influx through L-type Ca2+ channels. In these cells, MCU inhibition by pharmacological or molecular biological means reduced beating rate. Depolarizing mitochondria prevented spontaneous beating. The mitochondrial NCX blocker, 1 or 3μM CGP-37157, terminated AP firings.

Conclusions:
Mitochondrial Ca2+ cycling plays a role in spontaneous beating activity in embryonic stem (ES) cell-derived cardiomyocytes. Mitochondrial dysfunction may contribute to altered pacemaker activity in cardiomyopathy.
Abstract 12443: In-Beam PET Verification of Catheter-free Arrhythmia Ablation by Scanned Carbon-12 Ion Beam Irradiation
Authors: Lehmann H. Immo , Fiedler Fine , Helmbrecht Stephan , Graeff Christian , Constantinescu Anna , Lugenbiel Patrick , Prall Matthias , Kaderka Robert , Takami Mitsuru , Richter Daniel , Eichhorn Anna , Thomas Dierk , Katus Hugo , Johnson Susan , Parker Kay , Debus Juergen , Asirvatham Samuel , bert Christoph , Durante Marco , Packer Douglas L
Published: July 2021

Introduction:
Highly precise irradiation using carbon-12 (12C) ions is a new means for catheter-free ablation. Besides energy deposition leading to the dose distribution, nuclear interactions lead to by-product β+-activity that can be measured using positron-emission-tomography (PET).

Hypothesis:
In-beam PET scanning during focused myocardial irradiation using 12C can adequately depict 12C dose deposition.

Methods:
Pigs were irradiated with 25, 40, and 55 Gy for AV node (AVN), LA-PV junction, and local LV freewall ablations. PET measurement was performed by means of a double head camera system installed at irradiation site. Coincidences were captured in end-expiration during beam extraction pauses of the accelerator.

Results:
Evaluation of PET images was qualitatively performed using the coronal plane of the activity distribution superimposed on the contrast-CT in the center of the target contour. Strong β+-activities were measured in AVN and LV ablations. In AVN ablations, activity was localized to the target location, without target activity spreading to the level of the aortic root or coronary sinus (Figure A). Local LV irradiations revealed strong activity in the target location, slightly extending into left lung and chest wall (Figure B). In 55 Gy animals, the cardiac entry channel showed increased activity, decreasing in 40 Gy and more so in 25 Gy animals.

Conclusion:
This is the first study applying in-beam PET to track 12C dose-deposition into the target location for catheter-free ablation in intact animals. Correlation of β+-activity to electrophysiological outcome, lesion induction, and potential side-effects may be critically important in dosing therapy and predicting outcomes.
Abstract 12450: Long-Term Efficacy and Safety of Lomitapide for the Treatment of Homozygous Familial Hypercholesterolemia: Results of the Phase 3 Extension Trial
Authors: Blom Dirk , Averna Maurizio , Meagher Emma , du Toit Theron Hendrik , Sirtori Cesare , Hegele Robert , Shah Prediman , Gaudet Daniel , Stefanutti Claudia , Vigna Giovanni , Foulds Pam , Bloedon LeAnne , Rader Daniel , Cuchel Marina
Published: July 2021

Background:
Homozygous familial hypercholesterolemia (HoFH) is a rare genetic condition characterized by highly elevated low-density lipoprotein cholesterol (LDL-C) levels and high cardiovascular disease risk. Lomitapide, an oral microsomal triglyceride transfer protein inhibitor, was approved for the treatment of adult HoFH based on a small phase 3 study. We report efficacy and safety results from the phase 3 long-term extension study.

Methods:
Eligible HoFH patients completing the 78-wk phase 3 pivotal trial were enrolled into a single-arm extension study where lomitapide was administered daily at the maximum tolerated dose (5-60mg/d) until lomitapide was commercially available in the patient’s country. Concurrent lipid-lowering therapies, including apheresis, were permitted.

Results:
Nineteen of 23 patients who completed the pivotal study entered the extension trial (9/19 apheresis) with 16 patients completing all end of study assessments. Mean treatment duration was 4.8 yrs (range 2.1-5.7 yrs, median 5.1 yrs). Lomitapide efficacy was maintained throughout the study (Table). Reported adverse events were similar to those in the pivotal phase 3 study (chiefly gastrointestinal). Five patients (26%) experienced transient alanine aminotransferase (ALT) elevations ≥5x upper limit of normal (ULN) that were successfully managed by dose adjustment in all but one patient who was discontinued due to persistent excessive alcohol use. One 58 year-old patient with known CAD had sudden cardiac death. Median hepatic fat increased by 10% above baseline after 3 yrs and stabilized through the treatment period (Table). No other clinically relevant findings were identified to date.

Conclusions:
The long-term efficacy of lomitapide was maintained up to 5.7 yrs in patients completing the phase 3 trial with no new safety signals observed. The clinical significance of the increase in hepatic fat remains unknown.
Abstract 12464: Exosomes Loaded With Microrna-126 Prevents Sepsis-induced Cardiac Dysfunction in Endothelial Cell Hspa12b Deficient Mice
Authors: Zhang Xia , Wang Xiaohui , Ha Tuanzhu , Liu Li , Ma He , Kalbfleisch John , Kao Race , Williams David , Li Chuanfu
Published: July 2021

We have previously shown that increased expression of endothelial heat shock protein A12B (HSPA12B) attenuates LPS-induced cardiac dysfunction. MicroRNA-126 (miR-126) specifically targets adhesion molecules in endothelial cells. This study examined the role of miR-126 in HSPA12B-induced cardioprotection in sepsis. Endothelial HSPA12B-/- (n=6) and wild type (WT, n=6) mice were subjected to cecal ligation and puncture (CLP)-induced sepsis. Sham surgery served as sham control (n=6). Cardiac function was examined by echocardiography before and 6 h after CLP. CLP sepsis significantly decreased ejection fraction (EF%) by 34.8% and fractional shortening (%FS) by 43.1% in WT mice. EF% and FS% values in HSPA12B-/- septic mice showed further decreases of 19.9% and 22.5% compared with WT septic mice. The levels of ICAM1 and VCAM1 and the infiltration of immune cells (macrophages and neutrophils) into the myocardium of HSPA12B-/- septic mice were markedly greater than WT septic mice. The vascular permeability in HSPA12B-/- septic mice was much more severe than in WT septic mice. Importantly, the levels of circulating miR-126 in HSPA12B-/- septic mice were much lower than in WT septic mice. To examine whether decreased miR-126 is responsible for cardiac dysfunction in HSPA12B-/- septic mice, we loaded exosomes with miR-126 by transfection of bone marrow stromal cells with miR-126 mimics followed by isolation of exosomes 24 hours after transfection. Scrambled miR served as the miR control (miR-control). Exosomes loaded with miR-126 or miR-control were delivered into the myocardium through the right carotid artery immediately after induction of CLP (n=5-6/group). Cardiac function was significantly improved by delivery of miR-126 into the myocardium as evidenced by increased the values of EF% (51%) and FS% (59%), when compared with HSPA12B-/- septic mice. MiR-126 delivery significantly suppressed the expression of adhesion molecules, reduced immune cell infiltration in the myocardium, and improved vascular permeability in HSPA12B-/- septic mice. Delivery of miR-control did not alter cardiac dysfunction in HSPA12B-/- septic mice. We conclude that miR-126 plays a critical protective role in endothelial HSAP12B in preservation of cardiac function in sepsis.
Abstract 12498: Antiplatelet Effects of Ticagrelor versus Clopidogrel in Native American Patients With Stable Coronary Artery Disease
Authors: DeRaad Roger , Jennings Lisa K , Hord Edward , Walder James S
Published: July 2021

Introduction:
Ticagrelor is a potent, reversibly binding, P2Y12 platelet inhibitor that, compared with clopidogrel, decreased the rate of myocardial infarction and vascular mortality in acute coronary syndrome. Although Native Americans have the highest death rate attributable to premature heart disease among all races, they are generally under-represented in clinical trials.

Hypothesis:
Native Americans with stable CAD on low dose aspirin administered with ticagrelor, compared with clopidogrel, will exhibit a faster onset and higher platelet inhibition, and maintain this difference on day 7 of the treatment.

Methods:
Single center, randomized, open-label, crossover study of Native Americans with stable CAD randomly allocated to either ticagrelor (180 mg loading dose [LD] and 90 mg twice daily maintenance dose [MD] for 7-9 days) or clopidogrel (600 mg LD and 75mg once daily MD for 7- 9 days), and then received the alternative P2Y
12
inhibitor after a washout period. All patients received aspirin 81 mg daily. Platelet reactivity was measured with the VerifyNow P2Y
12
assay, which reports results in P2Y
12
reaction units (PRU).

Results:
A total of 28 patients were evaluated. At 30 minutes after the LD, on-treatment reactivity after ticagrelor (mean ± standard error of mean) was 205 ± 53 compared with 275 ± 71 PRU after clopidogrel (
P
<0.001) (Figure 1). At 2 hours after the LD, on-treatment reactivity was 36 ± 52 and 225 ± 71 PRU for ticagrelor and clopidogrel, respectively (
P
<0.001). At 8 hours after last MD, on-treatment reactivity was 40 ± 36 with ticagrelor compared with 197 ± 78 PRU with clopidogrel (
P
<0.001). At 24 hours after last MD residual reactivity was 140
+
55 for ticagrelor and 192
+
58.3 PRU for clopidogrel (
P
<0.001). No significant adverse events were noted with either study drug.

Conclusions:
In Native Americans with stable CAD on low dose ASA, ticagrelor provided a significantly faster onset, greater extent of platelet inhibition and faster offset than clopidogrel.
Abstract 12519: Age Impacts the Interpretation of Myocardial Blood Flow Values in Cardiac PET/CT
Authors: Raasch Hannah E , McCubrey Raymond O , Ethington Jon-David , Mason Steve , Le Viet T , Dhar Ritesh , Meredith Kent G , Anderson Jeffrey L
Published: July 2021

Introduction:
Quantitative myocardial blood flow (MBF) obtained via Rb82 PET/CT using regadenoson provides the ability to assess ischemia through analysis of stress MBF and coronary flow reserve (CFR), the augmentation of flow expressed as a stress/rest ratio. It is unknown to what extent, if any, age-related changes in arteries (i.e. arterial stiffening, atherosclerosis) impact MBF and, thus, the interpretation of ischemia.

Hypothesis:
MBF values change as a function of age and impact PET interpretation.

Methods:
Patients who underwent PET/CT from May 2013 to April 2015 with normal perfusion images and no history of PCI or CABG were included (n=3329, 1720 women, 1498 men). Rest MBF, stress MBF, and CFR) (mL/min/g) were recorded in all vessels separated by gender and by age <60 or ≥60. Analysis was conducted on individual vessels and global estimates were calculated averaging all vessels. Estimated average median differences between age <60 and ≥60 were adjusted for traditional cardiovascular risk factors (BMI, smoking, diabetes, hypertension, hyperlipidemia, family history).

Results:
Effects of Age on Global MBF Adjusted for Traditional Risk Factors

Conclusions:
In patients ≥60 years of age with normal perfusion imaging, rest MBF increases, stress MBF decreases, and the resultant CFR is decreased, all statistically significant. This may reflect a higher fixed level of vasodilation in older vessels at rest and a more limited ability to vasodilate with stress independent of other CV risk factors. Given the increasing use of PET/CT for ischemia assessment, it is important to recognize expected MBF changes with age to decrease false positive studies and unwarranted invasive testing.
Abstract 12543: Smartphone Delivered Cardiac Rehab for Heart Failure Management: A Feasibility Study
Authors: Vathsangam Harshvardhan , Qiao Shuo , Berkley Julie , Adesanya Adelanwa , Sukhatme Gaurav , Grazette Luanda , Fong Michael
Published: July 2021

Background:
Congestive heart failure (CHF) is the leading cause of hospitalization. Exercise training and self-care counseling through cardiac rehab (CR) benefits CHF patients by increasing exercise tolerance, improving clinical symptoms and reducing risk of future clinical events. However, CR programs are severely underutilized due to high insurance co-pays and issues with access. Remote CR programs delivered through patients’ smartphones show promise in addressing this gap. We studied the feasibility of utilizing a mobile application to implement a home-based cardiac rehab program for CHF patients.

Methods:
Ten consecutive ambulatory patients with a prior history of CHF and an Android smartphone downloaded and received training for the cardiac rehab smartphone application. The application engaged the patient to complete daily tasks at home. Data were wirelessly collected for 14 days. Metrics evaluated included passively collected activity (minutes), compliance to weight & blood pressure tracking and viewing of educational tasks. Patient on-boarding time was also tracked.

Results:
A broad range of patients were included in the study (Table 1); 20% were inotrope dependent. On-boarding took an average of 15 minutes. Table 1 summarizes results. Participants met minimum recommended daily activity (30 minutes) an average of 8±5 days in the 14 day period. Four participants entered vital sign values only in the office, possibility indicating lack of equipment at home.

Conclusion:
A smartphone-based remote cardiac rehab is feasible and useful in a fairly ill population. Minimum daily activity can be achieved and education content can be effectively delivered. However, results indicate the need to engage participants more to complete educational tasks. Participants need to be provided scales and blood pressure cuffs to track vital signs at home. Further study is warranted to assess the effect of this application on functional capacity and symptoms.
Abstract 12566: Novel Genes Associated With Platelet Function Discovered Through Whole Genome Sequencing
Authors: Yanek Lisa R , Taub Margaret A , Iyer Kruthika R , Ruczinski Ingo , Vaidya Dhananjay , Kral Brian G , Faraday Nauder , Becker Diane M , Becker Lewis C , Mathias Rasika A
Published: July 2021

Platelet aggregation on ruptured or eroded atherosclerotic plaques can initiate arterial thromboses. GWAS have identified common loci associated with platelet aggregation, but cumulatively they account for only a small portion of the variability in platelet aggregation. We used whole genome sequencing (WGS) in 286 healthy subjects from families with early onset coronary artery disease (GeneSTAR Study) to identify additional genes harboring rare/novel functional variants that determine platelet aggregation at baseline and post-aspirin therapy (ASA, 81mg/day for 14 days). Deep (>30X) WGS was performed on the Illumina Hiseq platform with an average of ~3.7M variants per individual and analyses presented here were limited to coding functional (i.e., missense, stop-gained and stop-lost) variants that were either rare (MAF < 5%) or novel (not observed in public catalogs of variation).

Using a 2-Step process, we: (1) tested for perfect co-segregation between these variants in each gene and a variety of dichotomized platelet aggregation phenotypes in n=34 subjects from 5 African American (AA) families and n=38 subjects from 7 European American (EA) families; (2) any gene with evidence across multiple families was then replicated in a set of independent samples (n=95 AA, n=119 EA) using Skat-O. To dichotomize phenotypes, ‘hyper-aggregators’ were defined as subjects in the upper 10th percentile while ‘normals’ were those between the 25th-75th percentile for each trait.

We identified three novel genes harboring coding functional variants not previously reported to be associated with platelet aggregation in both races: (1) HMG20B, associated with baseline aggregation to ADP; (2) PGA5, associated with baseline aggregation to collagen; and (3) PLAC4, associated with post-ASA aggregation to collagen. HMG20B is involved in megakaryocyte development and platelet production and interacts with KIF4, a microtubule based motor protein, while the role of PGA5 and PLAC4 is less clear. Follow-up studies may identify new platelet biological pathways that can be targeted for clinical purposes.
Abstract 12572: Stroke Volume and Cardiovascular Event Risk in Heart Failure With Preserved Ejection Fraction
Authors: Ito Shinya , Kitai Takeshi , Yamane Takafumi , Kim Kitae , Ota Mitsuhiko , Sasaki Yasuhiro , Ehara Natsuhiko , Kobori Atsushi , Kinoshita Makoto , Kaji Shuichiro , Furukawa Yutaka
Published: July 2021

Introduction:
Heart failure with preserved ejection fraction (HFpEF) is a significant and increasing public health problem, which has similar outcomes to HF with reduced EF (HFrEF). However, the prognostic factors of HFpEF have not been clarified. Recently, it has been reported that stroke volume (SV) is often reduced in HFpEF patients regardless of preserved EF. This study aimed to determine the importance of SV assessment on clinical outcomes in patients with HFpEF.

Methods:
We retrospectively reviewed 699 consecutive patients with acutely decompensated heart failure who were admitted in our institution between 2009 and 2011. Among them, both baseline and follow-up data including echocardiography were available in 425 patients. The patients were divided into 3 groups; EF≥50% (HFpEF), 41-49% (borderline), and EF<40%(HFrEF), and clinical outcomes were compared among the groups. SV was estimated noninvasively from LV volume obtained by transthoracic echocardiography.

Results:
The mean follow-up period was 2.4±1.8 years. There were 176 patients (41%) with HFpEF, 70 (16%) with borderline and 182 (43%) with HFrEF. There were no significant differences among the 3 groups with respect to actuarial survival (67% vs 58% vs 68%, P=0.33), and event-free survival, defined as a composite of death from any cause, HF readmission, myocardial infarction and stroke (44% vs 33% vs 40%, P=0.20) at 3 years. In HFpEF patients, there were 48 patients (28%) with low SV (<35ml) who had significantly worse outcomes than those with preserved SV (≥35ml) regarding all-cause mortality and cardiovascular events (Figure).

Conclusions:
Low SV regardless of preserved EF could be a possible marker for high risk patients with HFpEF.
Abstract 12605: Derivation and External Validation of a Cardiac Resynchronization Therapy Response Score
Authors: Marijon Eloi , Providência Rui , Narayanan Kumar , Barra Sergio , Sporton Simon , Defaye Pascal , Sadoul Nicolas , Piot Olivier , Algalarrondo Vincent , Klug Didier , Gras Daniel , Fauchier Laurent , Bordachar Pierre , Babuty Dominique , Deharo Jean-Claude , Chow Anthony , Leclercq Christophe , Lambiase Pier , Boveda Serge ,   on Behalf of the DAI-PP Investigators
Published: July 2021

Introduction:
In the last decade cardiac resynchronization therapy (CRT) has emerged as one of the most important advances in the treatment of patients with advanced heart failure. Unfortunately, almost tone third of patients do not have any benefit from this therapy. We aimed to derive and validate a CRT response score to improve the selection of patients for this intervention.

Methods:
The derivation cohort was composed of patients implanted with a CRT plus defibrillator in a multi-centric French registry. Clinical independent predictors of a favourable response to CRT (either clinical or echocardiographic) were assessed. A risk score was created based on the relative odds ratio of each of the variables. Three categories for predicting CRT response were defined: low (0 to 1), medium (2 to 3) and high (4 to 5) probability of response to CRT therapy. Endpoints assessed as true surrogates of lack of response to CRT-therapy were: all-cause mortality and all-cause mortality or heart transplant.

Results:
Among the 1,011 patients implanted with a de novo CRT-D, 75.8% were responders. Independent and significant predictors of CRT response in the first 6 months on multivariate logistic regression were: female gender (OR=2.08), New York Heart Association class ≤III (OR=2.71), left ventricle ejection fraction ≥ 25% (OR=1.75), QRS duration ≥ 150ms (OR=1.70) and estimated glomerular filtration rate > 60ml/min (OR=2.01). All predictors were assigned 1 point. Likelihood of survival during 7,216 patient years in the derivation cohort was 52.9% in the low response, 75.2% in the intermediate and 90.7% in the high response group (log rank P <0.001). External validation found similar results.

Conclusion:
We derived a clinical risk score, which appears to identify three different categories of patients with different likelihood of response to CRT therapy. This score may be of interest for prognostic assessment and treatment decisions, namely early referral for heart transplant.
Abstract 12681: Determinants of Prolonged Hospital Stay for Patients Undergoing Revascularization: The ASCERT Study
Authors: Zhang Zugui , Edwards Fred , Kolm Paul , Maria Grau-Sepulveda Maria Grau-Sepulveda , O'Brien Sean , Shahian David , Ponirakis Angelo , Klein Lloyd W , Grover Frederick L , Garratt Kirk N , Mckay Charles , Weintraub William S
Published: July 2021

Background:
Prolonged hospital stay (PHS) has been a costly health care issue. Using data from the Society of Thoracic Surgeons (STS) Database and the American College of Cardiology Foundation (ACCF) National Cardiovascular Data Registry (NCDR) in ASCERT, we examined the determinants of PHS in a 30-day period after the index hospitalization for patients undergoing coronary-artery bypass grafting (CABG) versus percutaneous coronary intervention (PCI).

Methods:
The STS Database and ACCF NCDR were linked to the Centers for Medicare and Medicaid Services claims data from years 2004 to 2008 for patients who were age ≥65 years with stable 2 and 3-vessel disease undergoing revascularization. The length of stay >7 days in CABG and >2 days in PCI patients was defined as PHS, respectively; the determinants of PHS in a 30-day period after the index hospitalization for CABG and PCI patients were examined.

Results:
By 30 days, 40,694 (47.18%) of 86,244 in CABG group and 32,789 (31.67%) of 103,549 in PCI group had PHS. Of those, 7,000(17.2%) and 13,721(33.72%) were diagnosed with congestive heart failure (CHF) and unstable angina in CABG, respectively; among PCI patients, 6491 (19.8%) and 18,397 (56.11%) were diagnosed with CHF and unstable angina, respectively. We found that advanced age, gender, race, body mass index, smoking status, stroke, angina status, left ventricular ejection fraction, number of diseased vessels (2 vs 3 or more), CHF, chronic lung disease, CVD, peripheral vascular disease, diabetes, GFR, renal failure, and procedure status were significantly associated with PHS for both groups; previous MI and family CAD history were associated with PHS in CABG group (c-index=0.70) but not in PCI group; AMI, previous PCI, and discharge medication were associated with PHS in PCI group (c-index=0.75) but not in CABG group. Adjusted by other risk factors, PHS was less likely after PCI (odds ratio: 0.46, 95% CI: 0.44 to 0.49, c-index=0.76).

Conclusions:
Determinants of PHS were significantly related to specified pre-, intra- and postoperative risk factors for CABG and PCI patients in 30 days after index-hospitalization. This analysis that linked large clinical and administrative databases can be applied to inform shared decision making between providers and patients.