bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 14024: Results of a Phase I / II Multicenter Investigation of Udenafil in Adolescents After Fontan Palliation
Authors: Goldberg David J , Zak Victor , Goldstein Bryan H , Chen Shan , Hamstra Michelle S , Radojewski Elizabeth A , Maunsell Eileen , Mital Seema , Menon Shaji C , Schumacher Kurt R , Payne R. M , Stylianou Mario , Kaltman Jonathan R , Paridon Stephen M ,   Pediatric Heart Network Investigators
Published: April 2024

Introduction:
Many pediatric clinical trials fail due to use of sub-therapeutic dosing. This phase I / II clinical trial was designed to evaluate the short-term safety, pharmacokinetics (PK), and preliminary efficacy of udenafil, a phosphodiesterase type 5 inhibitor, in adolescents following Fontan palliation to inform dose selection for a phase III clinical trial.

Methods:
This was a dose escalation trial with 5 dosing cohorts of 6 subjects each at 37.5 mg, 87.5 mg, and 125 mg daily, as well as 37.5 mg and 87.5 mg twice daily (bid) for 5 days. Efficacy testing (echocardiography, exercise stress test, endothelial function assessment) was performed at baseline and on day 5. A control cohort of 6 subjects underwent exercise testing without drug administration. Serum samples for PK analysis were collected on days 6-8. Adverse events (AE) were recorded throughout the 8-day study period and for 3 months thereafter. Comparison between baseline and day 5 testing was performed using ANOVA and visual trend lines. PK analysis was performed using a non-linear mixed effects model.

Results:
The trial enrolled 36 subjects at a mean age of 15.8 years (58.3% male). Subject characteristics were similar between cohorts. No drug-related serious AEs were reported during the study period, while 24 subjects had non-serious AEs possibly or probably related to study drug. Headache was the most common, occurring in 20 of the 30 subjects. Other possibly or probably medication related side effects occurring in more than one subject included: facial flushing (10 subjects), nasal congestion (7), spontaneous penile erection (6), nausea (3), and abdominal discomfort (2). The 87.5 mg bid cohort achieved the highest steady state serum concentration (172 ng/mL, range 117-202), the highest maximal concentration (506 +/- 188 ng/mL), and the greatest area under the curve for 24 hours (6701 +/- 1591 ng*hr/mL). Efficacy test results did not change significantly in any cohort.

Conclusion:
Udenafil was safe and well tolerated at all dosing levels while the 87.5 mg bid cohort achieved the highest serum drug level. With a 5-day treatment period and small sample size no significant clinical changes were observed. These data suggest that the 87.5 mg bid regimen may be most appropriate for a Phase III clinical trial.
Abstract 14075: Left Ventricular Longitudinal Strain Predicts the Prognosis of ICU Septic Patients
Authors: Liu Yen-Wen , Chang Wei-Ting , Lee Wen-Huang , Lee Wei-Ting , Chen Po-sheng , Tsai Wei-Chuan
Published: April 2024

Introduction:
In the presence of sepsis-related cardiac dysfunction, conventional echocardiography may not detect subtle cardiac dysfunction. Two-dimensional left ventricular (LV) global peak systolic longitudinal strain (GLS) can detect early cardiac dysfunction. We sought to determine the prognostic value of GLS for patients with septic shock who were admitted to intensive care units (ICUs).

Methods:
We prospectively included 111 patients who were admitted to the ICU with septic shock. A full medical history was recorded for each patient, and LV systolic function, including GLS, was measured. Our endpoints were ICU and in-hospital mortality.

Results:
The ICU and hospital mortalities were 31.5% and 35.1%, respectively. There was no significant difference in LV ejection fraction of the non-survivors and the survivors; however, upon ICU admission, the non-survivors exhibited GLSs that were less negative than those of the survivors (non-survivors vs. survivors: -11.8±4.5% vs. -15.0±3.6%, p <0.001), which indicated worse LV systolic function. The patients with GLS ≥-13% exhibited higher ICU and in-hospital mortality rates (hazard ratio: 4.34, p <0.001 and hazard ratio: 4.21, p <0.001, respectively). Cox regression analyses revealed that higher Acute Physiology and Chronic Health Evaluation (APACHE) II scores and less negative GLS were independent predictors of ICU and in-hospital mortalities. GLS was found to add prognostic information to the APACHE II score.

Conclusions:
These findings suggest that combining GLS and the APACHE II score has additive value in the prediction of ICU and in-hospital mortalities and that GLS may be helpful in the early identification of high-risk septic shock patients in the ICU.
Abstract 14188: Bicuspid Aortic Valve Disease Relatives Show No Evidence of an Inherited Aortopathy
Authors: Bissell Malenka M , Biasiolli Luca , Oswal Abhishek , Watkins Hugh C , Neubauer Stefan , Myerson Saul
Published: April 2024

Introduction:
Bicuspid aortic valve (BAV) disease is known to be heritable and often shows a concomitant aortopathy. Whether this aortopathy is more prevalent in BAV family members (irrespective of inheritance of the BAV) is unclear, and little is known about aortic function.

Hypothesis:
Bicuspid aortic valve disease relatives show signs of inherited aortopathy despite having a tricuspid aortic valve.

Methods:
We prospectively enrolled 118 family members with a normal functioning tricuspid aortic valve and 55 age and sex-matched healthy volunteers. The average age was 38.7 years (range 6-90) with a mean pulse pressure 57±1.14 mmHg. Advanced aortic assessment included aortic diameters, pulse wave velocity, arterial stiffness, maximum rate of systolic dysfunction (MRSD) and distensibility by CMR, total peripheral resistance by Vicorder
©
as well as circulating matrix metalloproteinases (MMP) 2 and 9 from a peripheral blood sample. A subset of 10 family members also underwent comprehensive 4D flow CMR assessment.

Results:
Compared to sex, age and blood-pressure matched healthy volunteers all family members had normal aortic diameters at the sinuses, ascending and descending aorta. There were no differences between family members and healthy volunteers in any of the aortic function measures: pulse wave velocity (arch 5.9±0.79 vs 5.0±0.36 m/s; p=0.31), aortic strain (ascending aorta 0.16±0.03 vs 0.19±0.03; p=0.41), maximum rate of systolic dysfunction (ascending aorta 0.23 vs 0.22%/ms; p=0.61),distensibility (ascending aorta 4.0±0.65 vs 4.4±0.62 1/mmHg; p=0.65), total peripheral resistance (1.03±0.05 vs 1.06±0.04 pru; p=0.56), MMP2 and MMP9. In the subset of family members undergoing advanced 4D flow CMR assessment, there was no difference in flow angle (8.75±1.33 vs 7.75±0.78°; p=0.53), flow displacement (2.73±0.61 vs 2.44±0.24 mm; p= 0.67) and wall shear stress compared to healthy volunteers (0.69±0.07 vs 0.59±0.02 N/m
2
; p=0.22).

Conclusion:
Family members with (normal) trileaflet aortic valves of patients with a bicuspid aortic valve have normal aortic size and function. This is a further indicator that in haemodynamic factors may be a larger contributor to the aortopathy in BAV disease than underlying genetic factors.
Abstract 14278: The Impact of American-Style Football Participation on Left Ventricular Systolic Function
Authors: Lin Jeffrey , Deluca James , Wang Francis , Berkstresser Brant , Wasfy Meagan , Hutter Adolph , Weiner Rory , Baggish Aaron
Published: April 2024

Introduction:
Participation in American-Style Football (ASF) has been associated with the development of hypertension and left ventricular hypertrophy (LVH). To date, data defining the impact of ASF participation on myocardial function are lacking. We hypothesized that the LVH developed among ASF participants is accompanied by relative impairment in systolic function as measured by LV global longitudinal strain (GLS), a well-established marker of subclinical LV dysfunction.

Methods:
Collegiate ASF athletes were studied before (preseason) and after (postseason) a single competitive season with transthoracic echocardiography. LV systolic function was assessed using complementary parameters including GLS (speckle tracking) and ejection fraction (EF, 2D biplane). Analyses were stratified as a function of lineman (LM, n=30) versus non-lineman (NLM, n=57) field position.

Results:
Among 87 athletes analyzed, ASF participation was associated with significant increases in systolic blood pressure (SBP, 119±10 vs. 124±13 mmHg; p<0.05), BSA-indexed LV mass (LVMI, 95±15 vs. 104±13 g/m2; p<0.05), and prevalent LVH (8% vs. 25%, p<0.05). The majority of LM with LVH (9/11, 82%) had concentric geometry while hypertrophied NLM (8/10, 80%) had eccentric geometry. In this context, LM demonstrated a significant decrease in GLS which was associated with changes in LV mass and SBP while NLM demonstrated an increase in GLS unrelated to either mass or SBP (Figure). Left ventricular EF was similar at both time points and did not differ by field position.

Conclusions:
The geometry and functional correlates of LVH among ASF participants vary by field position. Athletes at the LM position appear to be at risk for developing concentric LVH with relative impairment of GLS, while NLM athletes tend to harbor eccentric LVH without decrement in GLS. The underlying mechanisms, reversibility, and long-term prognostic significance of these findings represent important areas of future study.
Abstract 14612: Does the Open Smooth Antrum of the Left Atrial Appendage Serve as a Nidus for Thrombus Formation in Patients With Atrial Fibrillation and Surgical Appendage Clip i
n situ
?
Authors: Mohanty Sanghamitra , Trivedi Chintan , Gianni Carola , Gunes Mahmut F , Gokoglan Yalcin , Bai Rong , Burkhardt John David , Sanchez Javier , Hranitzky Patrick , Gallinghouse G. J , Al-Ahmad Amin , Horton Rodney , Hongo Richard , Hao Steven , Beheiry Salwa , Di Biase Luigi , Natale Andrea
Published: April 2024

Introduction:
Atrial fibrillation (AF) is a significant risk factor for embolic stroke originating from the left atrial appendage (LAA). LAA occlusion is recommended in patients that are not amenable to anticoagulation therapy because of elevated CHADS
2
or CHA
2
DS
2
-VASC score. We assessed the risk of stroke off anticoagulants in AF patients following LAA occlusion with appendage clip device.

Methods:
One hundred eighty-five AF patients (age 66±13, males 69%, CHADS
2
2.6± 0.8, CHA
2
DS
2
-VASC 3.5± 1.2) that received surgical left atrial appendage occlusion device (clip) were included in this analysis. Transesophageal echocardiogram (TEE) was performed at the end of the procedure to evaluate successful closure of the antrum of the LAA and was repeated at 1 and 6-month post-procedure. Patients remained on oral anticoagulants for 1-month post-procedure after which it was discontinued. All patients were monitored for thrombo-embolic complications for at least 1 year by TEE, clinic visits at 3-month intervals and phone calls by our research staffs.

Result:
The follow-up TEE revealed the LAA clip to be stable without any secondary displacement. No LAA thrombus was detected. Interestingly, in 177 (95.6%) patients, TEE revealed the proximal part of the smooth antrum of the LAA neck below the clip, to be still open. At the end of the 24±3 months of follow-up, no stroke or transient ischemic attack (TIA) or other neurological events were observed in the study population (0 of 155, 0%).

Conclusions:
In patients with AF in whom oral anticoagulation is deemed unsuitable because of high CHADS
2
or CHA
2
DS
2
-VASC score, left atrial appendage closure with surgical clip device seems to be safe and effective in preventing stroke. It is relatively common to find incomplete obliteration of the LAA with the surgical clip with the proximal portion of the smooth antrum still remaining open as the clip is typically seen to be placed higher up in the LAA neck. However, presence of the open smooth-antrum did not increase the risk of stroke even after discontinuation of anticoagulants.
Abstract 14665: The Impact of Glomerular Filtration Rates on the In-Hospital Outcomes of Patients Undergoing Transcatheter Aortic Valve Replacement: Insights of the Healthcare Cost and Utilization Project’s National Inpatient Sample
Authors: Lima Fabio V , Yen Tzyy Y , Gruberg Luis
Published: April 2024

Background:
Transcatheter aortic valve replacement (TAVR) is currently a Class I indication for the treatment of high surgical risk patients with severe symptomatic aortic stenosis.

Hypothesis:
There is limited data on the impact of chronic kidney disease (CKD) in patients undergoing TAVR.

Methods:
The Healthcare Cost and Utilization Project’s National Inpatient Sample was screened for hospital admissions of patients undergoing TAVR in 2003-2012. Patients were divided into 3 groups according to glomerular filtration rate (GFR): GFR >60 mL/min/1.73m
2
, GFR 15 to 59 mL/min/1.73m
2
, and GFR <15 mL/min/1.73m
2
. The primary outcome was major adverse cardiac and cerebrovascular events (MACCE), the composite of in-hospital death, acute myocardial infarction (AMI) and acute cerebrovascular accident (CVA).

Results:
Data on 311 patients that underwent TAVR was available for analysis. Patients with a GFR >60 mL/min/1.73m
2
were younger but there were no significant differences regarding other comorbidities. In hospital outcomes were similar in all three groups (Fig 1). In a multivariable analysis, increased age was a predictor of MACCE in patients with a GFR <15 mL/min/1.73m
2
(OR 1.09, 95% CI 1.01-1.17) and patients with GFR >60 mL/min/1.73m
2
(OR 1.08, 95% CI 1.01-1.16). However, GFR <15 mL/min/1.73m
2
was not an independent predictor of MACCE.

Conclusions:
In a contemporary database of patients undergoing TAVR, in-hospital outcomes were good, with low mortality and stroke rates. There seemed to be a numerically higher rate of in-hospital MACCE in patients with GFR <15 mL/min or stage 5 CKD; however, a GFR <15 mL/min was not an independent predictor of MACCE but age was a predictor of worse outcome.
Abstract 14668: Prospective, Randomized Comparison of 500 mg and 250 mg Acetylsalicylic Acid I.v. and 300 mg p.o. in Patients With Acute Coronary Syndrome (ACUTE Trial)
Authors: Zeymer Uwe , Vom Dahl Juergen , Erbel Raimund , Muenzel Thomas , Trenk Dietmar , Zahn Ralf , Gebert Irmgard , Roitenberg Alexander , Hohlfeld Thomas
Published: April 2024

Background:
Current national and international guidelines recommend the use of oral and/or intravenous (IV) acetylsalicylic acid as an alternative mode of application in patients with acute coronary syndrome (ACS) who are unable to swallow. However, acetylsalicylic acid IV has not been investigated in clinical trials and is not available everywhere.

Aim:
The primary objective of the present open-label, randomized, verum-controlled, parallel-group, phase III study was to demonstrate superiority of 250 or 500 mg acetylsalicylic acid IV treatment over oral treatment with 300 mg acetylsalicylic acid tablet to inhibit thromboxane A2 release at 5 minutes after a single dose of study drug in subjects with ACS with and without ST elevation.

Methods:
Acetylsalicylic acid naive patients with ACS were randomized into three groups to receive a single dose of acetylsalicylic acid either 300 mg orally, 250 or 500 mg intravenously. ThromboxaneA2 release (measured as the stable serum metabolite thromboxane B2), platelet aggregation and prostacyclin levels were measured 5 and 20 minutes after study drug administration. Patients were followed for 30 days for clinical events.

Results:
A total of 270 patients were randomized. The results of the primary and secondary endpoints are given in the table.

Conclusion:
The administration of 250 or 500 mg acetylsalicylic acid intravenously compared to 300 mg orally is associated with a faster and more effective inhibition with respect to thromboxane generation and inhibition of platelet aggregation, without any increase in bleeding complications. Therefore, i.v. administration of acetylsalicylic acid should be preferred in the acute management of patients with ACS.
Abstract 14862: miR-223 Regulates DNA Damage Signaling in Pulmonary Arterial Hypertension
Authors: Meloche Jolyane , Le Guen Marie , Potus Francois , Ranchoux Benoit , Antigny Fabrice , Tremblay Eve , Breuils-Bonnet Sandra , Perros Frederic , Provencher Steeve , Bonnet Sebastien
Published: April 2024

Background:
Pulmonary arterial hypertension (PAH) is a devastating disease affecting lung vasculature. The pulmonary arteries become occluded due to increased proliferation and suppressed apoptosis of the pulmonary artery smooth muscle cells (PASMCs) within the vascular wall. We recently showed that the DNA damage activated PARP-1 was overexpressed in PAH and responsible for the proliferation/apoptosis imbalance in PAH-PASMCs. Nevertheless, the mechanism that regulates its overexpression in PAH remains elusive.
In silico
analyses and studies in cancer demonstrated that microRNA miR-223 targets PARP-1. We thus hypothesized that miR-223 downregulation triggers PARP-1 overexpression, as well as the proliferation/apoptosis imbalance observed in PAH.

Methods and Results:
Using qRT-PCR, we demonstrated that miR-223 is significantly decreased in human lungs, distal pulmonary arteries (PAs) and isolated PASMCs of PAH patients compared to control donors (n=5-10, p<0.01). PAH-PASMCs isolated from distal PAs exhibited a 2.5-fold decrease in miR-223 expression (n=5, p<0.05). Furthermore, using a gain and loss of function approach, we showed that increased HIF-1α (using siRNA and adenoviruses) triggers miR-223 downregulation, subsequent overexpression of PARP-1 (n=5, p<0.05) and alterations in DNA damage repair (γ-H2AX, n=4, p<0.05). Using a bidirectionnal approach, we showed that decreased miR-223 triggers the proliferation/apoptosis imbalance observed in PAH-PASMC (Ki67 and AnnexinV, n=5, p<0.05). Finally, we demonstrated that restoring the expression of miR-223, by nebulization of miR-223 mimics in lungs of rats with monocrotaline-induced PAH reversed established PAH as assessed by right heart catheterization (mean PA pressure, cardiac output) and provided beneficial effects on vascular remodeling (H&E), pulmonary resistance, right ventricle hypertrophy and survival (n=8-10 per group, p<0.05).

Conclusion:
We provide evidences that miR-223 downregulation in PAH plays an important role in numerous pathways implicated in the disease and restoring its expression is able to reverse PAH.
Abstract 14902: The Introduction of Novel Oral Anticoagulants Has Improved Overall Oral Anticoagulation Rates in Atrial Fibrillation: Insights From the NCDR PINNACLE Registry
Authors: Marzec Lucas N , Gosch Kensey L , Chan Paul S , Ting Henry H , Shah Nilay D , Maddox Thomas M
Published: April 2024

Introduction:
For patients with atrial fibrillation (AF), novel oral anticoagulants (NOACs) provide effective alternatives to warfarin. However, a better understanding is needed of how the introduction of NOAC therapy has improved use of any oral anticoagulation (OAC) for patients with AF.

Methods:
Within the NCDR PINNACLE registry, we identified 447,770 patients comprising 1,428,660 outpatient encounters with non-valvular AF and CHADS-VASc >1 between April 1, 2008 and September 30, 2014. We examined use of any OAC, any NOAC, and of dabigatran, rivaroxaban, and apixaban individually over time. Multivariable logistic regression was performed to identify factors associated with any OAC and NOAC use at the end of the study period, including CHADS-VASc score, age, weight, CAD, PAD, dyslipidemia, stroke/TIA, heart failure, gender, hypertension, and diabetes.

Results:
Use of any OAC increased from 52.1 to 61.2% during the study period among patients without a documented contraindication (p for trend <0.01) (Figure). Although warfarin use decreased from 52.1% to 36.8% (p for trend <0.01), use of NOACs increased from 0% to 24.4% (p for trend <0.01). Rivaroxaban was the most frequently prescribed NOAC at the end of the study period (12.1%), followed by dabigatran (6.6%), and apixaban (5.7%). Patient factors associated with use of OAC and NOACs are presented in the Table.

Conclusions:
In a large U.S. outpatient registry, introduction of NOACs into clinical practice has improved the use of any OAC for AF patients at high risk for stroke. However, more than 1 in 3 high risk patients without a documented contraindication were not treated with any OAC.
Abstract 14923: Is the Ross Procedure a Riskier Operation? - Perioperative Outcome Comparison With Mechanical Aortic Valve Replacement in a Propensity-Matched Cohort
Authors: Noly Pierre-Emmanuel , Bouhout Ismail , Stevens Louis-Mathieu , Cartier Raymond , Poirier Nancy , Bouchard Denis , Demers Philippe , Carrier Michel , Pellerin Michel , Perrault Louis , El-Hamamsy Ismail
Published: April 2024

Introduction:
Despite reports of improved long-term survival after the Ross procedure, concerns remain regarding increased surgical complexity and potential morbidity compared to standard aortic valve replacement (AVR).

Hypothesis:
The aim of this study was to compare perioperative outcomes in young adults following a Ross procedure versus mechanical AVR in the current era.

Patients and methods:
From 2007 to 2015, 337 elective isolated mechanical AVRs and 137 Ross procedures were performed in young adults (<65 years) at our center. The Ross cohort includes the learning curve. Patients with concomitant ascending aorta replacement were included (78 (57%) in the Ross group and 58 (17%) in the AVR group). Using a 1:1 propensity score match analysis, 164 patients were included in the study (n=82 in each group). Mean age was 48±11 years and Euroscore II was 1.1±0.6%. Perioperative outcomes were defined using STS guidelines.

Results:
There were no mortalities in the two groups. Mean cardiopulmonary bypass and crossclamp times were longer in the Ross cohort (210+/-28 and 185+/-24 min vs 82+/-29 and 62+/-21 min respectively;
p<
0.001). There were no differences in the incidence of myocardial injury (0% overall), neurological complications (0.6% overall) or intubation times (p=NS). Three (3.7%) reinterventions for bleeding were reported in the Ross cohort and 4 (4.9%) in the mechanical AVR cohort (p>0.99). A significant increase in serum creatinine (>2-fold increase) was more commonly observed after the Ross procedure (11% versus 0%;
p=0.
003), but there was no significant difference in the rate of temporary dialysis (p=0.25). Six of 9 patients (67%) with increased creatine levels occurred in the first tertile of the Ross cohort. Thirty patients (37%) required ≥1 blood product transfusion in the Ross group compared to 26 patients (32%) in the mechanical AVR group (p=0.5). Median hospital length of stay was similar in both groups (6 days in each; p=0.99).

Conclusion:
There are no differences in mortality or major perioperative outcomes in adults undergoing a Ross procedure or mechanical AVR. Acute renal injury in the Ross cohort was closely linked to the learning curve. Further follow-up is required to evaluate long-term outcomes in these cohorts.
Abstract 14997: Subclinical Device-Detected Atrial Fibrillation is Associated With a Higher Risk of Adverse Cardiovascular Outcomes to the Same Extent as Clinical Atrial Fibrillation
Authors: Verner James R , Austin Erin , Chang Ian C , Agamawi Yusuf , Adkisson Wayne O , Roukoz Henri , Sakaguchi Scott , Benditt David , Chen Lin Y
Published: April 2024

Introduction:
Atrial fibrillation (AF) is a known risk factor for adverse cardiovascular (CV) outcomes in patients with implantable cardioverter-defibrillators (ICDs). As the use of ICDs becomes more common, subclinical device-detected atrial fibrillation (SAF) is increasingly being identified. Studies have shown an association between SAF and increased risk of thromboembolic events. However, no study has compared the risk of adverse CV outcomes of SAF vs. clinical AF (CAF).

Hypothesis:
In patients with ICDs, SAF is associated with adverse CV outcomes to the same extent as CAF.

Methods:
We identified patients who had ICD implantation at the University of Minnesota Medical Center between Jan 1, 2003 and Dec 31, 2009. Baseline data on demographics, CV risk factors, diagnoses, and medications were collected. Follow-up was through Dec 31, 2012. Our primary outcome was a composite CV outcome (see table). CAF episodes were identified from clinical documents confirmed by ECGs. SAF episodes of any duration were identified from ICD interrogation reports. We fit a multivariable Cox proportional hazards model and used backwards stepwise selection to identify the most parsimonious model to predict the outcome (0.05 threshold).

Results:
We included 371 patients; 37 had incident or recurrent CAF; 88 had SAF. Median follow up was 490 days. The full model included age, sex, coronary artery disease, diabetes, ejection fraction, hypertension, and use of beta-blockers, anticoagulants, and ACE inhibitors. The table shows the most parsimonious model for prediction of the composite outcome.

Conclusions:
SAF and CAF were significantly associated with a greater than 11-fold and 9-fold increased risk of adverse CV outcomes, respectively. This study indicates that SAF is associated with increased risk of CV outcomes to the same extent as CAF. More research is needed to determine whether treatment of SAF (e.g., anticoagulation) will lead to improved outcomes in patients with ICDs.
Abstract 15461: Histone Modification in the Right Ventricle is an Useful Predictor of Right Ventricular Failure Following LVAD Implantation in Non-ischemic Dilated Cardiomyopathy
Authors: Kashiyama Noriyuki , Miyagawa Shigeru , Toda Koichi , Nakamura Teruya , Yoshikawa Yasushi , Fukushima Satsuki , Saito Shunsuke , Yoshioka Daisuke , Ito Emiko , Harada Akima , Takeda Maki , Ueno Takayoshi , Kuratani Toru , Sawa Yoshiki
Published: April 2024

Introduction:
Although right ventricular failure (RVF) is associated with poor outcome following left ventricular assist device (LVAD) implantation, predictive factors of RVF have not been fully established. Epigenetic modification in cardiomyocytes has been recently shown to be related to progression of heart failure (HF).

Hypothesis:
We herein hypothesized that reduced histone modification including methylation/acethylation of cardiomyocytes in the RV would be associated with RVF after LVAD implantation.

Methods:
This study enrolled 22 patients who were diagnosed as having non-ischemic dilated cardiomyopathy (NIDCM) and underwent LVAD implantation for bridge-to-transplantation between 2012 and 2015. The RV biopsied prior to LVAD implantation were immunohistologically labeled for histone H3 lysine 9 tri-methylation (H3K9me3) and acethylation (H3K9ac) and scored ranging from 0 to 12 according to intensity and percentage of positively labelled cardiac cell nuclei.

Results:
Eight patients (40%) presented with RVF following LVAD implantation, which was defined as need of inotropic support for 30 days or more, nitric oxygen inhalation for 2 days or more, and/or exchange to bi-VAD support. Survival of the patients with and without RVF was 66% and 90%, respectively, at 2 years post-LVAD implantation (log rank=0.2). LV ejection fraction (p=0.7), right atrial pressure (RAP, p=0.4) or Michigan RVF score (p=0.5) was not different in the patients with and without RVF, whereas RV stroke work index (SWI) was modestly lower (6.4±2.5 vs 8.5±2.7 g·m/m2/beat, p=0.09) and percentage of fibrosis in the RV was significantly higher (61±16 vs 46±12%, p=0.02) in the patients with RVF. The score of H3K9me3 and H3K9ac were significantly lower in the patients with RVF (2.6±1.2 vs 5.1±2.8, p=0.028 and 5.8±2.3 vs 9.9±2.4, p<0.001, respectively). Furthermore, The score of H3K9ac was significantly correlated with RV systolic pressure and RV peak negative dp/dt (p=0.03 and p=0.02), and most powerful predictor of RVF by ROC analysis (AUC= 0.90).

Conclusions:
The epigenetical examination targeting H3K9 methylation and acetylation in NIDCM may promise exact predictor in RVF following LVAD implantation by the combination of histological or functional analysis.
Abstract 15490: Immunogenic Verification of MHC-homo iPS Cell-derived Cardiomyocytes Transplantation to an MHC-matched Non-human Primate Ischemic Cardiomyopathy Model: Pre-clinical Study for Allogenic Therapy Using iPS Cells
Authors: Kashiyama Noriyuki , Miyagawa Shigeru , Fukushima Satsuki , Saito Atsuhiro , Masuda Shigeo , Kawamura Takuji , Kawamura Ai , Yoshida Shohei , Ueno Takayoshi , Toda Koichi , Kuratani Toru , Sawa Yoshiki
Published: April 2024

Introduction:
Derivatives of allogeneic induced pluripotent stem cell (iPSC) are promising in clinical application of iPSC-based cardiac regeneration therapy. Although major histocompatibility complex (MHC)-matched allogeneic implantation (MMAI) is theoretically useful in minimizing immune rejection against the graft, graft survival or therapeutic efficacy of MMAI is poorly understood.

Hypothesis:
We herein hypothesized that MMAI of iPSC-derived cardiomyocytes (CM)-sheet may be therapeutically effective in a non-human primate ischemic cardiomyopathy model.

Methods:
iPSCs constitutively expressing GFP were established from Macaca fascicularis with homozygous MHC haplotypes, named “HT1”. Cardiomyogenic differentiation was induced in vitro. Heterozygous HT1 Macaca fascicularis ischemic model was made by ligation of left anterior descending artery (LAD) for 2 weeks, followed by transplantation of the derivatives containing 1.0х107 cells to the cardiac surface as MMAI with tacrolimus, mycophenolate mofetil and prednisolone given.

Results:
LAD ligation for 2 weeks successfully resulted in decrease of left ventricular ejection fraction (LVEF, 50.4±0.5% to 24.9±1.6%), increase of LV end-systolic volume (ESV, 3.2±0.4 mL to 8.2±0.4 mL) and LV global wall stress (GWS, 106±8 kdyne/cm2 to 203±22 kdyne/cm2). At 4 weeks after transplantation, GFP intensity of the graft was 3.6-fold greater in the MMAI group than the sham, although GFP intensity was not different between the two at 2 months, as assessed by stereomicroscope. LVEF, LVESV and GWS were recovered in the MMAI group at 1 month after the transplantation and then preserved until 5 months (LVEF; 32.4% and 33.8%, LVESV; 7.1 and 7.8 mL, GWS; 156.4 and 165.9 kdyne/cm2, respectively), whereas the sham group showed progressive functional deterioration at 1 and 5 months (LVEF; 20.9% and 21.5%, LVESV; 9.2 and 11.6 mL, GWS; 218.6 and 265.3 kdyne/cm2, respectively).

Conclusions:
Ischemic cardiomyopathy model was established in a non-human primate, for which MHC-homo-iPSCs-CM sheets were successfully transplanted as MMAI, inducing functional recovery with persistent presence of the graft. It was suggested that MHC-homo-iPSCs may be useful to realize iPSC-based cardiac regenerative therapy.
Abstract 15497: Hematopoietic PI3-Kinase delta-Deficiency Causes Altered Macrophage and Regulatory T-cell Function and Aggravates Atherosclerosis in LDLR-/- Mice
Authors: Zierden Mario , Millarg Christopher , Vantler Marius , Berghausen Eva M , Baldus Stephan , Rosenkranz Stephan
Published: April 2024

Atherosclerosis and its consequences such as myocardial infarction and ischemic stroke remains the leading cause of death in western countries. During atherogenesis, arterial blood vessels become infiltrated by macrophages and T cells possessing inflammatory and regulatory functions. Leukocytes express the catalytic phosphoinositide 3-kinase isoform p110d (PI3Kd), exerting a key role in the regulation of immune responses including activation, differentiation and effector function. Therefore, PI3Kd represents a promising target for the modulation of inflammatory processes during atherogenesis.

To investigate the role of leukocytic PI3Kd during atherogenesis, lethally irradiated LDLR-/- mice were transplanted with bone marrow from PI3Kd-/- or PI3Kd+/+ mice and were fed an atherogenic diet for 6 weeks. Hypercholesterolemic PI3Kd-/- recipient LDLR-/- mice displayed a profound reduction of peripheral B and T cells as well as strongly impaired CD4+ T-cell activation, T-helper 1 response and regulatory T-cell numbers in paraaortic lymph nodes and spleen compared with PI3Kd+/+ transplanted controls. Surprisingly, the profoundly impaired PI3Kd-deficient immune system caused a substantial aggravation of atherosclerosis in LDLR-/- mice. Atherosclerotic lesion area at the aortic root and whole aorta of PI3Kd-/- recipient LDLR-/- mice was significantly increased by 72% and 218% compared with PI3Kd+/+ recipients, respectively (n = 10-20; P < 0.001). Importantly, atherosclerotic lesions of PI3Kd-/- transplanted LDLR-/- mice were characterized by a lower fraction of CD4+ T cells and a higher proportion of macrophages compared with controls despite unaltered circulating monocyte subsets. Moreover, PI3Kd-deficient regulatory T cells and macrophages exhibited a strongly impaired suppressive capacity and an increased inflammatory polarization, respectively.

In summary, we demonstrate that hematopoietic PI3Kd plays a crucial role in regulating innate and adaptive immune responses within the arterial wall by exerting protective functions during atherogenesis. Current studies aim to dissect PI3Kd-dependent mechanisms that modulate inflammatory and regulatory processes in multiple stages of atherosclerosis.
Abstract 15540: Retinal Vein Occlusion and the Risk of Heart Failure Development: A 12-Year Nationwide Population-Based Study
Authors: Oh Jaewon , Rim Tyler Hyungtaek , Kim Sung Soo , Kang Seok-Min , Park Sungha , Lee Sang-Hak , Choi Donghoon
Published: April 2024

Background:
Retinopathy implied by microvascular dysfunction was known to be related to the risk of heart failure (HF) development. However, there have been no studies for evaluating the risk of HF following retinal vein occlusion (RVO), another surrogate ophthalmologic parameter for microvascular dysfunction.

Methods:
National registry data were collected from the Korean National Health Insurance Research Database, comprising 1,025,340 (2.2%) random subjects who were selected from 46,605,433 Korean residents in 2002. The definition of HF development based on diagnostic code. The RVO group was composed of patients with an initial diagnosis of either central or branch RVO between January 2003 and December 2007 (n=1,523). The comparison group was composed of randomly selected patients (five per RVO patient; n=7,620) who were matched to the RVO group according to age, gender, residential area, household income, and year of RVO diagnosis. Each sampled patient was tracked until 2013. Cox proportional hazard regressions were used to calculate the overall survival rate for HF development after adjusting for potential confounders, including hypertension, diabetes mellitus, and chronic kidney disease.

Results:
HF occurred in 11.6% of the RVO group and in 7.9% of the comparison group, respectively (p<0.001). RVO was significantly associated with an increased risk of HF development after adjusting for confounders (hazard ratio (HR) 1.36, 95% Confidence Interval (CI) 1.16-1.89, p<0.001). Other comorbidities including hypertension (HR=2.08), and chronic renal failure (HR=1.88) were also increased the risk of HF development. From the subgroup analysis by age or gender, RVO was still significantly associated with an increased risk of HF development (HR=1.39 for age < 65 years; HR=1.33 for age ≥65 years; HR=1.45 for men; and HR=1.36 for women).

Conclusion:
RVO was associated with HF development after adjusting for potential confounders. These findings were limited to Korean population and should be validated by additional observational studies.
Abstract 15552: Insulin-Like Growth Factor-1 is Lower in Acute Stroke but is Not Related to Recovery
Authors: Mattlage Anna E , Rippee Michael , Sandt Janice , Billinger Sandra A
Published: April 2024

Purpose:
Insulin-like growth factor 1 (IGF1) sampled within ten days of stroke has resulted in inconsistent findings. When compared to control participants, one study found elevated levels of IGF1 while another reported lower values. Despite these reported differences, there is evidence to suggest that IGF1 may have a neuroprotective effect and may be related to admitting stroke severity and functional independence at one month post-stroke. The possibility exists that a large sampling window and no consideration for insulin-like growth factor binding protein 3 (IGFBP3), may account for the differing results. The purpose of this study was to: 1) determine the difference in IGF1, IGFBP3, and IGF1 ratio in individuals with acute stroke and controls; and 2) determine the relationship of IGF1, IGFBP3, and IGF1 ratio to admission stroke severity and functional independence at one month post stroke.

Methods:
Blood was collected from 12 individuals with a diagnosis of acute stroke (4 males; 63.9
+
8.4 years) between 7:30 and 9:00 am, after an overnight fast, and within 72 hours of hospital admission. Blood was obtained from 12 age and gender matched healthy controls (4 males; 64.8
+
9.8 years) after an overnight fast during similar hours. Plasma was obtained from blood samples, aliquoted, and frozen within 1 hour of collection. IGF1 and IGFBP3 were quantified using standard procedure ELISAs (Alpco, Salem, NH). Admission NIH Stroke Scale and the modified Rankin Scale (mRS) at one month post stroke was obtained from the electronic medical record.

Results:
IGF1 (stroke: 113 ng/mL; control: 123 ng/mL, p = .59) and IGFBP3 (stroke: 2350 ng/mL; control: 2593 ng/mL, p = .33) were lower in the acute stroke patients, but not significantly. IGF1 ratio was not different (stroke: .06; control: 05; p = .55) in acute stroke compared to controls. There were no significant relationships between any IGF marker and stroke severity (p > 0.50), nor mRS (p > 0.50).

Conclusion:
We report that IGF1 and IGFBP3 is lower in acute stroke patients. A single time point of IGF1 and IGFBP3 during acute stroke may not demonstrate a neuroprotective relationship to stroke recovery. Future work should examine percent change in the IGF family to determine whether this may be a more valuable biomarker of stroke recovery.
Abstract 15585: Using Genetics To Explore Whether The Cholesterol-lowering Drug Ezetimibe May Cause An Increased Risk Of Cancer
Authors: Lauridsen Bo K , Stender Stefan , Frikke-Schmidt Ruth , Nordestgaard Børge G , Tybjærg-Hansen Anne
Published: April 2024

Introduction:
Ezetimibe reduces plasma levels of low-density lipoprotein(LDL) cholesterol by inhibiting Niemann-Pick C1-Like protein 1(NPC1L1). However, results from a randomized trial have raised concern that ezetimibe might increase the risk of cancer.

Hypothesis:
We tested the hypothesis that genetic variation in
NPC1L1
, mimicking treatment with ezetimibe, was associated with an increased risk of cancer.

Methods:
We included 67,257 individuals from the Danish general population. Of these, 8,333 developed cancer and 2,057 died of cancer during follow-up from 1968 to 2011. To mimic the effect of ezetimibe, we calculated a weighted genotype score (from <2.0 to ≥5.0) using four
NPC1L1
variants. The score was based on the LDL cholesterol-lowering (=inhibitory) effect of each variant, and has previously shown to associate with a stepwise reduction in risk of ischemic vascular disease (=positive control). Variants were also grouped by a simple allele score. Finally, we tested the association between genotype score and allele score with risk of any cancer, death from any cancer, risk of death after a cancer diagnosis, and risk of 28 cancer subtypes.

Results:
The cumulative incidence by age of any cancer or cancer death was not associated with genotype score(P-trend across genotype scores: 0.42 and 0.98, respectively). Hazard ratios(HRs) for genotype scores ≥5.0 versus <2.0 were 1.04(95% confidence interval: 0.92-1.19) for any cancer, 1.11(0.85-1.45) for cancer death, and 0.91(0-73-1.14) for death after a cancer diagnosis (P-trend across genotype scores: 0.42, 0.81, 0.98, respectively). In contrast, the corresponding HR for ischemic vascular disease was 0.82(0.71-0.95) (P-trend=0.002). Finally, genotype score did not associate with risk of cancer subtypes (all adjusted P-values≥0.28). Results were similar using allele scores.

Conclusions:
Lifelong, genetic inhibition of NPC1L1, mimicking treatment with ezetimibe, does not associate with risk of cancer, cancer death, death after a cancer diagnosis, or risk of specific cancer subtypes. These results suggest that long-term treatment with ezetimibe does not increase the risk of cancer.
Abstract 15634: Neurologic Impact of Carotid Stenosis in Cardiac Surgery, a Retrospective Study
Authors: Ruka Emmeline , Lesur Olivier , Buruian Mara , Voisine Émile , Dagenais François , Chauvette Vincent , Voisine Pierre
Published: April 2024

Context:
The impact of carotid disease on the risk of stroke is not well established in patients undergoing surgery on cardiopulmonary bypass (CPB). The aim of this study is to evaluate the relationship between post-operative cerebrovascular events and the characteristics of concomitant carotid stenosis (CS) (degree, laterality and associated symptomatology) in patients undergoing cardiac surgery on CPB.

Methodology:
Single center retrospective cohort study with prospectively collected data including all patients undergoing cardiac surgery on CPB between January 2002 and February 2014. Data collected included patients’ pre-operative demographic characteristics, operative and post-operative variables, and were taken from a computerized database and patients’ charts. Univariate analysis and multivariate analysis with stepwise approach were performed.

Results:
Results were obtained for 19,918 patients who met the inclusion criteria. Of these, 474 (2.4%) had at least a unilateral CS ≥50%. By univariate analysis, patients with CS ≥50% had a higher risk of post-operative stroke and/or TIA than those with CS <50% (8.3% vs 2.4%, p<0.0001). In the group of patients with CS ≥50%, neither the laterality of the stenosis (p=0.75) nor the presence of CS-related symptoms (p=0.07) were significantly associated with post-operative stroke and/or TIA. By multivariate analysis, the presence of a ≥50% CS was identified as an independent risk factor for post-operative stroke and/or TIA [OR 2.84; CI95% (1.94-4.16)]. The relationship between the degree of CS (50-99%) and the neurological risk showed a trend toward significance: CS 80-99% vs CS 50-79% [OR 1.77; CI95% (0.81-3.85)], p=0.15. The risk of stroke and/or TIA was highest in the 80-99% CS group [OR 3.80; CI95% (2.14-6.73)].

Conclusion:
The presence of a ≥ 50% CS is an independent risk factor for post-operative stroke and/or TIA. Regardless of the presence of preoperative CS-related symptoms, the clinically relevant risk of stroke and/or TIA was highest for CS of 80-99%. These results suggest that a decision to perform prophylactic carotid revascularization prior to cardiac surgery should not only be based on the presence of CS-related symptoms, but also on the severity of carotid stenosis.
Abstract 15660: Clopidogrel Reloading for Acute Myocardial Infarction Patients Already on Clopidogrel Therapy: Insights From ACTION Registry - Get With the Guidelines
Authors: Doll Jacob A , Li Shuang , Chiswell Karen , Kosiborod Mikhail , Scirica Benjamin M , Roe Matthew T , Tracy Wang Y
Published: April 2024

Introduction:
Guidelines recommend an early loading dose of a P2Y
12
receptor inhibitor for STEMI and NSTEMI patients, yet whether a loading dose is needed for patients already on clopidogrel therapy is unclear.

Methods:
We examined STEMI and NSTEMI patients on clopidogrel therapy on admission and without contraindications to cardiac catheterization in the ACTION Registry GWTG from 2009 to 2014. We used inverse probability weighted propensity adjustment to compare in-hospital mortality and major bleeding risks between patients reloaded in the first 24 hours with 300-600mg of clopidogrel vs. those continued on a maintenance (<300 mg) dose without reloading.

Results:
Of 56,327 patients already on clopidogrel, 19,513 (35%) received a loading dose of clopidogrel within the first 24 hours of admission. Patients who were reloaded were younger (median 65 vs. 68 years), less likely to be female (33% vs. 38%) and to have cardiovascular risk factors such as diabetes, prior MI, and prior coronary revascularization. STEMI patients already on clopidogrel therapy were more likely to receive a loading dose than NSTEMI patients (76% vs. 26%, p<0.001). Among STEMI patients, clopidogrel reloading was associated with lower unadjusted and adjusted risks of in-hospital mortality compared with those continued on clopidogrel without reloading, however no significant mortality difference was observed among NSTEMI patients (Table). Risk of major bleeding was not significantly different between patients with and without clopidogrel reloading regardless of MI type.

Conclusion:
Despite limited supporting evidence, clopidogrel reloading occurs frequently among patients who present with MI already on clopidogrel therapy, particularly among STEMI patients. We did not observe increased bleeding risk with clopidogrel reloading. The finding of lower mortality associated with clopidogrel reloading among STEMI patients warrants further investigation.
Abstract 15690: Fibroblasts From Failing Human Heart Exhibit Increased Sensitivity to Dronedarone-Induced Oxidative Stress and Cell Death
Authors: Emelyanova Larisa , Liu Mingyuan , Yang Guangyuan , Stoeckl Elizabeth , Holmuhamedov Ekhson , Rizvi Farhan , Ross Gracious , Downey Francis X. , Tajik A. Jamil , Jahangir Arshad
Published: April 2024

Introduction:
Dronedarone (DR), a structural analog of amiodarone designed to reduce its extracardiac toxicity, recently was shown in clinical trials to increase heart failure (HF) and cardiovascular death in patients with severe myocardial dysfunction, but the mechanisms for these adverse cardiac effects are not known.

Hypothesis:
We hypothesized that DR increases oxidative stress and cell death in failing hearts with compromised energetic reserves compared to nonfailing hearts.

Methods:
Ventricular fibroblasts (VFB) from patients without HF (trauma victims) and with HF (left ventricular assist device implants) were cultured under similar conditions to passage 3 and treated with DR (0-10 μM) for 24h. Reactive oxygen species (ROS) production was assessed in cells loaded with general oxidative stress indicator CM-H2DCFDA (2μM), mitochondrial superoxide indicator MitoSOX Red (5 μM), and Hoechst 33342 (1μg/ml) for nuclear staining using confocal microscopy. Cell viability was assessed by counting the number of viable cells and lactate dehydrogenase assay.

Results:
VFB from HF patients exhibited a higher baseline level of total ROS (CM-H2DCFDA green fluorescence) when compared with non-HF patients (Fig. A). DR dose-dependently increased ROS production in VFB from HF patients (Fig. B) exhibiting a higher sensitivity to oxidative stress and cell death (Fig. C).

Conclusions:
The sensitivity of DR-induced oxidative stress and cytotoxicity is significantly increased in VFB from patients with HF and provides an explanation for adverse effects of DR reported in HF patients in clinical trials.