bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 4290: Risk Factors and Prognostic Implications of Mitral Regurgitation in Severe Aortic Stenosis
Authors: Varadarajan Padmini , Pai Ramdas G
Published: July 2021

Introduction:
Mitral regurgitation (MR) is present in nearly half of the patients with severe aortic stenosis (AS). Risk factors for its development and its prognostic implications are not clear.

Methods:
Search of our echocardiographic database between 1993 to 2003 yielded 740 patients with severe AS defined as aortic valve area (AVA) ≤ 0.8cm2. Thorough chart reviews were conducted to collect clinical and pharmacological data. Mortality data was obtained from National death index.

Results:
Patient characteristics: age 74±13 years; females 60%, EF 54±20%, aortic valve area 0.67±0.17 cm2. MR grade ≥2+ were present in 339 (46%) patients: 2+ in 166 (22%), 3+ in 115 (16%) and 4+ in 58 (8%). There was a progressive decrease in survival with each grade of MR in the whole cohort as well as the surgically and medically treated subsets (p<0.0001, figure

). Presence of 3 and 4+ MR was associated with a larger LV (p<0.0001), lower EF (p<0.0001), greater age (p=0.0001), a smaller aortic valve area (p=0.001) and female gender (p=0.003). It remained an independent predictor of lower survival after adjusting for group differences using the Cox regression model. There was a lower AVR rate in those with 3 or 4+ MR compared to the rest (32 vs. 41%, p=0.03) despite a distinct independent survival advantage with AVR (RR 0.40, p<0.0001).

Conclusion:

Significant MR is present in nearly half of the patients with severe AS.

The risk factors for its development include age, greater AS severity and LV dysfunction.

It is an independent predictor of reduced survival.
Abstract 4301: Chimeric Mice Lacking Microsomal Prostaglandin E
2
Synthase-1 (mPGES) In Bone Marrow Develop Adverse Left Ventricular Remodelling After Myocardial Infarction
Authors: Rubin Barry , Konecny Philip , Keating Armand , Fazel Shafie , Wang Xing-Hua , Angoulvant Denis , Stefanski Eva , Li Ren-Ke , Lindsay Thomas , Jakobsson Per-Johan , Degousee Norbert
Published: July 2021

Introduction. mPGES functions downstream from COX-2 in the inducible PGE
2
biosynthetic pathway, and can be expressed by cardiac myocytes and inflammatory cells. mPGES gene targeted mice (mPGES
−/−
) develop LV dilation and impaired contractile function after MI. The purpose of this study was to determine if mPGES in bone marrow (BM) derived inflammatory cells regulates LV remodelling after MI.

Methods. Six week old female mPGES
+/+
mice were irradiated with 9.5 Gy and transplanted with BM from male mPGES
+/+
or mPGES
−/−
mice (BM
+/+
or BM
−/−
chimeras, respectively). After 10 weeks, the left coronary artery was ligated. Echocardiography was used to assess LV dimensions and function
in vivo
. After fixation
in situ
, LV dimensions and infarct volume was assessed by planimetry. The efficiency of BM transplantation, determined by the ratio of syr to gapdh DNA, measured by real time PCR, was 98%. Results. There was no difference in LV dimensions or function between BM
+/+
and BM
−/−
mice before MI (not shown). Between 7 and 28 days post MI, ejection fraction did not change in BM
+/+
mice, but decreased significantly in BM
−/−
mice (Table

). BM
−/−
mice also had a higher LV diameter (2.7 ± 0.1 vs. 3.1 ± 0.1 mm, p = 0.0001) and LV volume (14 ± 0.8 vs. 18 ± 1.0 mm
3
, p = 0.025) than BM
+/+
mice 28 days after MI. In contrast, there was no difference in the percentage of infarcted LV, heart rate or cardiac output between BM
+/+
and BM
−/−
mice after MI. Survival of BM
+/+
vs. BM
−/−
28 days after MI was similar (75% vs. 72%, log rank, p = 0.86).

Conclusion. mPGES1 in bone marrow cells that localize to the heart after MI is necessary to maintain post infarction LV contractile function, and to prevent adverse LV remodelling. Use of mPGES inhibitors as substitutes for COX-2 inhibitors may be detrimental in patients with coronary artery disease.
Abstract 4309: Ventricular Elastic Support Therapy (VEST) Reduces Transmural Pressure and Myocardial Strain
Authors: Fedak Paul W , Meek Cheryl , Sas Rozsa , Belenkie Israel , Tyberg John V
Published: July 2021

Background: Transmural pressure (TMP) determines myocardial strain and chamber dimensions. Epicardial ventricular support may improve mechanical function and promote reverse remodeling by reducing TMP. HeartNet (Paracor Medical Inc) is an elastic intra-pericardial ventricular support device currently evaluated in the PEERLESS-HF clinical trial. To explore the mechanism of action of VEST, we directly measured the in vivo effects of HeartNet on regional hemodynamics and myocardial strain.

Methods: We instrumented open-chest anesthetized dogs (n=6) with flat silastic-balloon epicardial pressure transducers, intravascular pressure catheters, aortic flow probes, and sonomicronometry crystals. The pericardium was re-approximated. We obtained pericardial, epicardial, LV, and aortic pressures. We measured epicardial segment length (end-diastolic myocardial strain) and LV dimensions throughout the cardiac cycle. Loading conditions were altered by volume infusion, caval occlusion, and LAD ligation to induce regional ischemia / dysfunction. Parameters were obtained in every animal with and without the HeartNet in situ (applied at 45% baseline stretch) and compared.

Results: HeartNet epicardial support was 2.8±0.2 mmHg (mean at end-diastole) and was maintained throughout the cardiac cycle and over a wide range of physiologic filling conditions (LVEDP 0 –15 mmHg) indicating that the device is compliant, elastic, and self-adjusting. TMP and end-diastolic strain were significantly reduced (P<0.01) supporting a mechanism of action for the device. After LAD ligation, HeartNet also reduced TMP (−38±8%, P<0.0001) and end-diastolic strain over the anterior wall. Negative regional stroke work was also lowered (−56±2%, P<0.001) suggesting improved overall ventricular mechanical efficiency. Aortic pressure and LV stroke volume (20±2 vs 22 ±3 mL, P=0.20) was maintained.

Conclusions: These are the first in vivo data to demonstrate that ventricular elastic support therapy improves regional myocardial mechanics throughout the cardiac cycle by reducing transmural pressure and end-diastolic strain. Elastic support therapy may provide significant benefits on acute hemodynamics and chronic remodeling in the failing heart.
Abstract 4344: Biventricular Pacemaker Therapy Corrects Dyssynchrony in Non-Obstructive Hypertrophic Cardiomyopathy
Authors: Ahmed Ibrar , Abozguia Khalid , Nallur-Shivu Ganesh , Phan Thanh T , Maher Abdul , Stegemann Berthold , Katra Rodolphe , Patel Kiran , Leyva Francisco , Sanderson John , Pellerin Denis , Elliott Perry , Frenneaux Michael
Published: July 2021

Background. Previous studies have reported dyssynchrony using Tissue Doppler in patients with hypertrophic cardiomyopathy (HCM). In this study we assessed dyssynchrony using speckle tracking echocardiography (STE) in patients with non-obstructive hypertrophic cardiomyopathy vs a healthy control group and in a subgroup of highly symptomatic patients evaluated the acute effects of biventricular pacing on STE and Tissue Doppler (TDI) derived measures of dyssynchrony.

Methods. We studied 48 healthy controls (age 48 ±18yrs, 22 males, LVEF 63 ±5%, QRS 86 ±7ms) and 57 patients with HCM (age 54 ±11yrs, 38 males, LVEF 61 ±7%, QRS 110 ±36ms). A subgroup of 15 symptomatic patients with HCM (Peak VO2<60% predicted) underwent biventricular pacing (age 53 ±12yrs, 12 males, LVEF 61 ±7%, QRS 110 ±32ms). Echocardiography was performed with the pacemaker off (VVi30) and on (DDDR, AV delay 90ms, LV-RV delay 0 – 4ms). Using STE, the standard deviation (SD) in time to peak longitudinal strain (Tϵ-SD), the time to peak longitudinal systolic velocity (Ts) for each of 18 left ventricular segments and the SD of this timing (Ts-SD) was derived. Using TDI dyssynchrony was assessed from the SD of Ts for the basal six segments and the maximum difference in Ts between any two basal segments (Ts-peak[basal]).

Results. Using STE, Tϵ-SD (54.99 ±33.61ms vs 24.55 ±21.18ms p<0.001), Ts-SD (71.06 ±32.32ms vs 46.17 ±21.50ms p<0.001) and Ts (155.74 ±23.14ms vs 123.71 ±11.25ms p<0.001) were greater in HCM than in controls. Using STE we demonstrated that biventricular pacing significantly reduced Tϵ-SD and Ts-SD to values similar to those observed in controls (Ts-SD p=0.13). Using TDI we demonstrated that biventricular pacing significantly reduced Ts, Ts-SD, and Ts-peak[basal]. See Table

. (All values expressed as mean ±SD)

Conclusion. Cardiac resynchronisation therapy significantly reduced dyssynchrony in symptomatic patients with non-obstructive HCM as demonstrated using STE and TDI.

Table
Abstract 4374: G-CSF Treatment Improves Cardiac Function In postmyocarditic Cardiomyopathy By Enhanced Circulation And Homing Of CD34+ Progenitor Cell Populations
Authors: Brunner Stefan , Theiss Hans D , Leiss Monika , Fischer Rebekka , Vallaster Markus , Huber Bruno C , Keithahn Alexandra , Sauter Martina , Klingel Karin , Franz Wolfgang-Michael
Published: July 2021

Objective
: Recently, it was shown that the physiologic repair mechanism of mobilization and homing of bone marrow-derived stem cells (BMCs) is impaired in dilated cardiomyopathy. In our study we aimed to analyze circulation and homing of CD34
+
progenitor cell populations in a murine model of dilated cardiomyopathy due to coxsackie virus B3 (CVB3) induced myocarditis and the influence of G-CSF treatment on BMC homing and cardiac function.

Methods and Results
: First, SWR/J (H-2q)-mice were infected by intraperitoneal injection of 10
5
pfu CVB3. Healthy, age-matched SWR/J (H-2q)-mice served as controls. 12 weeks after infection, DCM was verified by MRI/Millar-tip-catheter and histology. In DCM mice, CD34
+
BMC populations (CD34
+
CD31
+
, CD34
+
Sca-1
+
, CD34
+
c-kit
+
and CD34
+
CXCR-4
+
) measured by flow cytometry were significantly increased in peripheral blood, decreased in bone marrow and remained unchanged in the hearts in comparison to controls. Different from ischemic heart diseases, myocardial homing factors (SDF-1, SCF, HIF-1a, VCAM and HGF) assessed by real-time PCR were not upregulated in the CVB3-DCM group. Finally, 18 DCM-CVB3 mice were analyzed by MRI 8 weeks after CVB3 infection and randomized into G-CSF-or saline-treatment (100 μg/20μl s.c. daily for 2× 5 days). 12 weeks after infection, cardiac function was assessed using MRI: Change of ejection fraction was significantly better in the G-CSF-group compared to the controls (4.1±1.8 vs. −2.5±2.2%; p=0.03). The improvement of cardiac function was associated with enhanced homing of BMC subpopulations.

Conclusions
: We have shown that postmyocarditic cardiomyopathy is associated with a reduced migration of BMCs to the cardiomyopathic hearts due to a lack of increase of homing factors. This defect can partly be overcome by G-CSF-administration resulting in an increased number of stem cells in the myocardium and leading to a moderately improved cardiac function. Therefore our data provides new insights in the pathogenesis of dilated cariomyopathy and presents a promising non-invasive approach to ameliorate heart failure.
Abstract 4394: Chronic Administration of Urocortin 2 Prevents the Development of Heart Failure in an Animal Model of Hypertensive Heart Disease
Authors: Meili-Butz Silvia , Studer Marco , John Dietlinde , Morandi Christian , Pfisterer Matthias , Buser Peter , Vale Wylie W , Peterson Kirk L , Brink Marijke , Dieterle Thomas
Published: July 2021

Background: Recently, novel corticotropin-releasing factor (CRF)-related peptides named Urocortin (Ucn) 1, 2, and 3 were described. Available data suggest that the Ucns are part of a peripheral CRF system modulating cardiovascular function and mediating cardiovascular responses to stress. Chronic Ucn2 administration induced sustained blood pressure lowering and prevented the development of left ventricular hypertrophy (LVH) in an animal model of hypertensive heart disease. However, no data are available whether chronic administration of Ucn2 may prevent the progression from LVH to heart failure.

Methods: Experiments were performed in Dahl salt-sensitive rats. Animals were fed a high salt diet containing 4% NaCl to induce arterial hypertension, LVH, and heart failure. From the phase of LVH on (after 7 weeks of high salt diet), animals were injected with either Ucn2 at a dose of 2.5 μg/kg body weight or vehicle b.i.d. Animals underwent repetitive tail cuff blood pressure measurements and echocardiographic analysis of LV dimension and function at baseline (prior to first injection of Ucn2) and after 5 weeks of b.i.d. treatment with Ucn2.

Results: Results are given in the following table

as mean (± SD). No differences in heart weight/body weight ratios between Ucn2- and vehicle treated animals were found after 5 weeks of treatment.

Conclusion: Chronic CRF receptor stimulation by Ucn2 in the severely hypertensive Dahl salt-sensitive rat, an animal model of hypertensive heart disease, prevents the progression from LVH to LV dilatation and the deterioration of LV function. Thus, chronic administration of Ucn2 might represent a novel approach to the prevention of heart failure.
Abstract 4403: Significant Single Nucleotide Polymorphism Associated with Atrial Fibrillation Located on Chromosome 4q25 in a Whole Genome Association Study and Association with Left Atrial Gene Expression
Authors: Chung Mina K , Van Wagoner David R , Smith Jonathan D , Wirka Robert C , Topol Eric J , Desai Milind Y , Prcela Lisa , Hazen Stanley L , Barnard John
Published: July 2021

Introduction: Heritability studies of atrial fibrillation (AF) suggest a complex genetic basis for common AF. Recently a locus on chromosome 4q25 was associated with AF in a genome-wide association study (GWAS), but the mechanism by which this locus is associated with AF is unknown.

Methods: To identify genetic variations associated with AF, we performed an analysis of AF as a secondary phenotype from a case-control GWAS of myocardial infarction. 210,178 autosomal SNPs of high quality were genotyped in 138 AF cases and 546 controls. Stratified score tests of the trend/additive model and general genotypic model were performed for each SNP. Genomic control and multidimensional scaling were used to control and assess population stratification. The SNP meeting genome-wide significance was genotyped in 46 left atrial appendage tissue samples for which we obtained expression levels for 22,184 transcripts. Cis expression traits within 1 megabase of the top SNP were tested for association with the SNP genotypes.

Results: One SNP (rs4611994) met our per-SNP genome-wide significance thresholds (both a conservative Bonferroni threshold or a more liberal FDR-based threshold) for association with AF, which was in perfect linkage disequilibrium with the locus on chromosome 4q25 found in the deCODE genetics AF study (r
2
with SNP rs2200733=1.0). This SNP yielded an AF odds ratio of 2.28 under the additive model, with a p-value using genomic control/general genotype model of 5.0E-08, and a minor allele frequency 0.13 in controls and 0.25 in AF cases, and a genome-wide p-value of 0.046 by permutation analysis. In the 46 left atrial tissue samples, cis analysis demonstrated significant association between rs4611994 genotype and expression of LRIT3 (Leucine-rich repeat, immunoglobulin-like domain and transmembrane domain-containing protein 3) with q-value 2.22E-03 and the C isoform of PITX2 with q-value 7.50E-03.

Conclusions: Our GWAS for common AF has replicated the AF-associated locus on chromosome 4q25. The genotype at this locus was correlated with cis regulation of the LRIT3 and PITX2C transcripts, suggesting these genes as candidates for mechanistic studies.
Abstract 4408: Using a Large Electronic Medical Record to Validate 4q25 Variants Conferring Risk for Atrial Fibrillation
Authors: Denny Joshua C , Ritchie Marylyn D , Crawford Dana C , Havens Andrea , Weiner Justin , Watanabe Hiroshi , Darbar Dawood , Kannankeril Prince , Pulley Jill , Basford Melissa , Haines Jonathan L , Masys Dan R , Roden Dan M
Published: July 2021

Background
: Genome-wide association studies, largely in research populations, have identified susceptibility single-nucleotide polymorphisms (SNPs) for a broad range of human diseases, including variants at 4q25 associated with atrial fibrillation (AF). However, no studies have evaluated the applicability of these data to practice-based settings.

Methods
: This study was conducted in the Vanderbilt DNA Databank, a repository that accrues 500 –900 new samples/week from routine outpatient blood draws, and included 37,335 samples as of June 2, 2008. The Databank is linked to a de-identified derivative of the electronic medial record (EMR), which includes data for the last 15 years on 1.4 million subjects. We used natural language processing techniques and billing code queries to extract AF cases and controls without AF from the first 10,000 subjects entering the Databank. Cases had AF recorded in the cardiologist report of an electrocardiogram (ECG). Controls had at least one ECG and no AF, other abnormal atrial rhythms, or atrioventricular nodal ablation in any portion of the EMR, including text documents, billing codes, and ECGs. We excluded subjects with heart transplants and non-Caucasian ethnicity. Subjects were genotyped at rs2200733 and rs10033464, both located at 4q25, previously associated with AF with odds ratios (ORs) of 1.75 and 1.42, respectively.

Results
: We identified 168 cases with AF and 1695 controls. The electronic algorithms had an accuracy of 98% for identifying cases and 100% for controls over a random sample of 100 subjects each. The minor allele frequencies (MAF) for rs2200733 were 0.1419 for cases and 0.1032 for controls; the MAF for rs10033464 were 0.1019 for cases and 0.908 for controls. rs2200733 was significantly associated with AF (OR [95% confidence interval], 1.44 [1.01–2.03], p=0.04). The effect of rs10033464 on AF was not significant (OR, 1.14 [0.78 –1.67], p=0.52); however, power calculations indicate that 993 cases with AF were needed to replicate this effect.

Conclusion
: This practice-based study replicated an association identified in research datasets between a 4q25 SNP and AF. These findings support the utility of Electronic Medical Records coupled to DNA collections as resources for genomic research.
Abstract 4415: The Utility of Genotyping in the First Evaluation of a Novel Vitamin K Antagonist: ATI-5923
Authors: Ezekowitz Michael D , Milner Peter , Ellis Dave , Usman M. Haris U , Canafax Daniel M , Druzgala Pascal
Published: July 2021

(S)-Warfarin, the most active enantiomer of warfarin, is metabolized by CYP2C9. Genetic variations of the CYP2C9 gene result in slower metabolism and are major contributors to inter-patient dose variability with resultant INR instability, especially in patients on multiple medications. This leads to higher hemorrhagic and thrombotic complications. ATI-5923 (ARYx therapeutics Inc.) is a novel VKOR inhibitor that undergoes metabolism by human carboxyles-terase and not by CYP2C9. We hypothesize that time in therapeutic range (TTR) based on Rosendaal method is better for ATI-5923 than for historic warfarin and that maintenance dose is independent of CYP2C9 polymorphism, but dependent on VKOR haplotype. This was a multi-center, open-label, 3 month study of 66 patients with AF treated with ATI-5923. All except two patients were on prior warfarin. Periodic INR testing occurred twice weekly for the first 3 weeks and then weekly during the maintenance phase. Genetic testing for the CYP2C9 and VKORC1 polymorphism was performed on all patients. Drug dosing was performed using a standardized nomogram. Pre-study INRs and warfarin dose data were collected for up to one year prior to study entry. 77 % of patients were in therapeutic range (INR 2–3) after 7 days and 80% had stable INR (3 consecutive INR values within range without dose adjustment) by 3 months. For the maintenance phase the mean TTR was 71.5 and 59.3% for ATI-5923 and warfarin respectively (12.2% improvement; p=0.0009). Patients with the VKOR AA haplotype required lower maintenance doses than VKOR GA or GG haplotype (8.6 vs 15.8 and 18.7mg; p < 0.0001). CYP2C9 genotype had no influence on maintenance dose. CYP2C9 variants (n=20), showed a trend toward better control compared to warfarin; 16% improvement vs. 11% for wild type CYP2C9 (n =42). ATI-5923 has better INR control than prior warfarin therapy. VKOR AA patients require a significantly lower maintenance dose. CYP2C9 variants show a trend to added improvement compared to the CYP2C9 wild type, suggesting that, unlike warfarin, ATI-5923 is not influenced by CYP2C9 genetic variations.
Abstract 4420: Results of A Double Blind Placebo Controlled Study to Evaluate the Efficacy and Safety of PS433540 in Human Subjects with Hypertension
Authors: Neutel Joel M , Germino Wilford F , Punzi Henry , McBride Mark , Bryson Catherine C , Belder Rene
Published: July 2021

Epidemiologic studies continue to demonstrate extremely disappointing blood pressure (BP) control rates. For this reason, the search for more effective antihypertensive agents continues.
PS433540
is the first compound in a novel class of agents called Dual Acting Receptor Antagonists (DARA) which selectively block angiotensin (AT
1
) and endothelin (ET
A
) receptors. In this prospective, randomized, double blind, placebo controlled study, 234 men and women with a mean age of 56.0 years entered a 3– 4 week single blind placebo run-in period. Qualifying stage I or stage II hypertensive patients were randomized in a 1:1:1 ratio to either
PS433540
200mg, 500mg or matching placebo for a period of 4 weeks. Ambulatory BP monitoring (ABPM) was performed at the start of the study and was repeated at the end of the treatment period.
PS433540
lowered both 24HR Systolic BP (SBP) and Diastolic DBP (DBP) as well as mean office SBP and DBP to a greater extent than placebo, p<0.001. (see Table

)
PS433540
was well tolerated with 2 reported serious adverse events in the placebo group and placebo lead-in period. Three patients (all from the placebo group) were discontinued from the study for adverse events. There were no significant laboratory abnormalities. This study demonstrates that
PS433540
is an effective and well tolerated new class of antihypertensive agent that may prove to be a very important addition to our armamentarium for the management of hypertension.
Abstract 4425: Baseline Aldosterone/Renin Ratios Predict Responses to Thiazide in Essential Hypertension, Particularly for Already-Treated Patients
Authors: Chin-Chou Huang , Hsin-Bang Leu , Tao-Cheng Wu , Shing-Jong Lin , Jaw-Wen Chen
Published: July 2021

Background:
Response to diuretics are variable among hypertensive patients. Our study sought to identify patients who respond well to thiazide diuretics.

Methods:
Non-diabetic patients with either treated or untreated hypertension were evaluated if their office systolic blood pressure was ≥ 140 mmHg or if their diastolic blood pressure was ≥ 90 mmHg. After 2 weeks of a controlled diet and life style modification, patients who still had an elevated blood pressure (BP) were prospectively given hydrochlorothiazide, 50 mg per day for 2 weeks, in addition to their current treatment if there was any. Variables monitored both before and after treatment included serum aldosterone and renin, office BP.

Results:
Sixty-six patients received 2 weeks of thiazide treatment. Of the 66, the 27 (41%) who had a significant reduction (≥ 10% reduction from baseline) in office mean arterial pressure (MAP) were defined as responders. The other 39 patients, those who had a reduction in office MAP of < 10% were defined as non-responders. Responders had a higher aldosterone/renin ratio (ARR) (77.90 ± 94.08 vs. 34.67 ± 45.56,
p
= 0.009) and a lower renin activity (7.44 ± 12.34 vs. 13.88 ± 14.00 pg/mL,
p
= 0.004). MAP reductions were directly correlated to ARR and inversely correlated to renin activity. ARR ≥ 18.58 independently predicted BP responses to thiazide in patients already taking other antihypertensive medications.

Conclusions:
The ARR is an independent predictor of responders to hydrochlorothiazide in non-diabetic hypertensive patients, particularly in those already taking other antihypertensive medications.
Abstract 4448: Clopidogrel Effect Depends on Body Weight and Abolishes Platelet Leukocyte Interaction in Patients with Coronary Artery Disease Treated by Stenting
Authors: Diehl Philipp , Olivier Christoph , Halscheid Christoph , Helbing Thomas , Bode Christoph , Moser Martin
Published: July 2021

Background:
Poor response to aspirin and clopidogrel has been associated with an increased risk for thrombotic events after PCI. The optimal dose of clopidogrel is unknown as platelet aggregability (PA) is not routinely measured in clopidogrel treated patients.

Methods and Results
: In order to assess potential mechanisms of clopidogrel responsiveness we have performed bedside platelet impedance aggregometry in patients with stable coronary artery disease (group CAD; n=62) and patients who underwent elective PCI (group PCI; n=90) compared to control individuals in whom coronary artery disease was excluded by coronary angiography (group control; n=28). Control patients did not receive antiplatelet therapy, CAD patients were treated with aspirin 100mg/d, and PCI patients with aspirin 100mg/d and clopidogrel 75mg/d. Impedance aggregometry was performed using arachidonic acid [AA] (final conc [fc]: 0.5mM) or ADP (fc: 6.5μM) and the area under the curve (AUC) was quantified to detect the effect of aspirin or clopidogrel, respectively. Indeed, PA was specifically reduced by either drug (AA: [control vs. CAD vs. PCI] 877±300 vs. 183±134 vs. 111±90; ADP: [control vs. PCI] 725±275 vs. 288±174 AUC). We detected a negative correlation between body weight and clopidogrel response (r=0.28; p=0.008), suggesting that clopidogrel may have been underdosed in obese patients. Furthermore, we found a positive correlation between leukocyte counts and PA (r=0.4, p=0.028) confirming that platelets and leucocytes interact functionally. Administration of clopidogrel abolished this interaction as detected by comparison of control individuals with PCI patients but also in intra-individual follow-up tests before and after introduction of clopidogrel.

Conclusion:
Impedance aggregometry is useful to assess PA routinely. Dosage of clopidogrel may need to be adjusted in obese patients. PA depends on leukocyte counts confirming that platelet activity is modulated by leukocytes; this interaction is effectively inhibited by clopidogrel.
Abstract 4450: Does the Evidence Support Guideline Recommendations for Clopidogrel Pretreatment?
Authors: Eshaghian Shervin , Chou Stanley , Das Jayanta , Diamond George A , Shah Prediman K , Kaul Sanjay
Published: July 2021

Although few concrete data exist about the optimal timing and dose of clopidogrel pretreatment, the ACC/AHA & ESC guidelines endorse pretreatment with 300 – 600 mg of clopidogrel at least 2– 6 hours before PCI as Class IA (ACS) and Class IC (elective PCI) recommendation. To evaluate the current evidence base in support for clopidogrel pretreat-ment. Five trials examining the impact of clopidogrel pretreatment in stable and unstable CAD were evaluated: PCI-CURE, PCI-CLARITY, CREDO, PRAGUE-8, ARMYDA-5. Because of substantial clinical heterogeneity in trial design and population, concomitant therapies (glycoprotein 2b/3a inhibitors, thrombolysis, etc), loading dose, pretreatment duration and analysis plan between PCI-CURE, PCI-CLARITY and the rest, a formal meta-analysis was confined only to CREDO, PRAGUE-8, ARMYDA-5. The key data are summarized in the Table

. Clopidogrel pretreatment was associated with significant reduction in ischemic outcomes without a significant increase in major bleeding in two out of the 5 trials (PCI-CURE and PCI-CLARITY). Both these trials utilized nonrandomized subgroup comparisons with pretreatment duration longer than that typically encountered in clinical practice (<48h). A meta-analysis of the 3 trials demonstrated a nonsignificant 23% odds reduction in efficacy (P=0.1) and a nonsignificant 29% odds increase in major bleeding (P=0.24). No significant heterogeneity was observed for pooled efficacy (P=0.79) or bleeding (P=0.77) outcomes. Pretreatment hypothesis is currently not validated in rigorous prospective assessments, thereby calling into question the Class I recommendation (benefit >>>risk) endorsed by the guidelines. Clearly, further clinical data regarding dose, time course of pretreatment and associated benefit are warranted to provide unequivocal support. Until then, it is prudent to rule out surgical CAD before pretreatment to avoid bleeding risk.

Trials Assessing Clopidogrel Pretreatment
Abstract 4461: Rho-kinase Pathway Plays an Important Role in the Pathogenesis of Coronary Hyperconstricting Responses Induced by Drug-Eluting Stent
Authors: Shiroto Takashi , Yasuda Satoshi , Tsuburaya Ryuji , Ito Yoshitaka , Ishibashi-Ueda Hatsue , Ito Kenta , Takahashi Jun , Shimokawa Hiroaki
Published: July 2021

It has recently been reported that coronary vasoconstricting responses are enhanced at the edge of coronary segment implanted with drug-eluting stent (DES) as compared with bare-metal stent (BMS) in humans. We have previously demonstrated in animal models and humans that activation of Rho-kinase plays a key role in the molecular mechanism of coronary vasospasm. In this study, we thus examined whether Rho-kinase pathway also is involved in the DES-induced coronary hyperconstriction in vitro and in vivo. In cultured human coronary vascular smooth muscle cells, paclitaxel (10 –1000 nM, comparable tissue concentrations in humans, 24 hours) concentration-dependently up-regulated Rho-kinase expression (n=9) and increased Rho-kinase activity (10 nM, n=6). In a porcine model in vivo, DES (Taxus
™
) and BMS (Express
™
) were randomly implanted in the left anterior descending and circumflex coronary arteries (n=5). Four weeks after the implantation, coronary vasoconstricting responses to serotonin (5-HT, 50 and 100 μg/kg, IC) were significantly enhanced at the DES site compared with the BMS site (DES −52±4 vs. BMS −31±5%, P<0.01), and the enhanced responses were prevented by hydroxyfasudil (HF, 90 and 300 μg/kg, IC), a selective Rho-kinase inhibitor (

Figure A

). The same in vivo findings also were noted in another comparison between DES (Cypher
™
) and BMS (Velocity
™
) (DES −62±3% vs. BMS −41±3%, n=6, P<0.01) (

Figure B

). Histological analysis showed microthrombus formation only at the DES site. These results suggest that Rho-kinase pathway also plays an important pathogenetic role in the DES-induced coronary hyperconstricting responses.
Abstract 4537: Relationship Between Procedure Indications and Outcomes of Carotid Artery Stenting: Preliminary Results from the CARE Registry
Authors: Rosenfield K A , White C J , Jones P G , Spertus J A , Cates C U , Ho K K , Jaff M R , Koroshetz W J , Caldwell S P , Brindis R G , Anderson H V
Published: July 2021

Background:
In 2007 a consortium of specialty societies developed and published a clinical expert consensus document (CECD) on carotid artery stenting (CAS). This CECD listed suggested indications for CAS based on the presence of symptoms, stenosis severity, and the presence of features that increase the surgical risk of carotid endarterectomy. The National Cardiovascular Data Registry, in conjunction with multiple specialty societies, established the CARE (Carotid Artery Revascularization and Endarterectomy) Registry to provide a comprehensive national database characterizing both forms of carotid revascularization.

Methods:
CARE employs written definitions, a data dictionary, standardized data collection tools, and quality control checks. We constructed an algorithm that categorized each procedure as conforming to a Recommended Indication (RECC) if it met the indications criteria in the CECD, or as not recommended (NOTRECC) if it didn’t. Patient characteristics and outcomes of these 2 groups were compared.

Results:
There were 3118 CAS procedures submitted from 107 participating centers for the period 01/2007 through 03/2008. Of these, 2397 (77%) were RECC, while 721 (23%) were NOTRECC. Clinical profiles in the NOTRECC group were more favorable, but overall outcomes were similar. (See Table

)

Conclusions:
CAS procedures categorized as NOTRECC by CECD criteria accounted for approximately one-fourth of submissions to the CARE Registry. Clinical profiles were different. Outcomes were similar.
Abstract 4555: Impact of Mechanical Distortion on Homograft Valve Competence One Year after Insertion into Pulmonary Position: a Magnetic Resonance Imaging Study
Authors: Nordmeyer Johannes , Gaudin Regis , de Nantes CHU , Lurz Philipp , Frigiola Alessandra , Jones Alexander , Tsang Victor , van Doorn Carin , Elliott Martin J , Muthurangu Vivek , Bonhoeffer Philipp , Taylor Andrew M
Published: July 2021

Background:
Homograft valves (HV) are commonly used to restore pulmonary valve competence in congenital heart surgery. Recently, percutaneous pulmonary valve implantation (PPVI) was introduced as an alternative to repeat surgical pulmonary valve replacement (PVR). We sought to evaluate homograft competence at one year follow-up and compare it to PPVI.

Methods:
60 HV patients (mean age 21±10 years) and 66 PPVI patients (mean age 23±11 years) were assessed with echocardiography and cardiac magnetic resonance imaging (CMR) during protocolized follow-up. 2/66 (3%) PPVI patients were excluded due to an episode of endocarditis. The primary endpoint was significant pulmonary regurgitation (PR) at one year, defined as a pulmonary regurgitation fraction >20% on CMR. For the HV group, homograft-related variables (i.e. data from homograft bank) and surgery-related variables were reviewed. Furthermore, indicators of homograft geometry were studied on CMR, which involved the assessment of dimensions, inlet-to-outlet angles and pulmonary flow pattern. To study the impact of these variables on the primary endpoint, a multivariate linear regression analysis was performed.

Results:
10/60 (17%) HV patients and none of the PPVI group had significant PR (
P
<0.001). Two geometrical factors were strongly associated with a higher risk of significant PR in the HV group: greater homograft inlet-to-outlet angle in a sagittal plane and eccentric pulmonary forward flow (
P
<0.001), both suggesting mechanical distortion. Homograft- and surgery-related variables did not significantly influence the primary endpoint. 7/10 (70%) patients with significant PR at one year already showed ≥mild PR on post-operative echocardiography, emphasizing a likely role of mechanical distortion in early homograft incompetence. During follow-up, 2/10 patients underwent redo PVR (1 homograft, 1 Hancock conduit), 1/10 patient underwent PPVI and 7/10 patients are under medical follow-up.

Conclusions:
Significant PR is frequent in patients one year after homograft insertion. This valve incompetence is most likely due to distortion of the homograft, suggesting that a strong circular support - as seen in PPVI - may be needed to effectively restore valvar competence in patients requiring PVR.
Abstract 4564: Use of Adult Dyssynchrony Thresholds in Pediatric Patients Leads to a High False Positive Rate
Authors: Thomas Vincent , Fornwalt Brandon , Lamphier Carey , Fyfe Derek
Published: July 2021

Introduction
While cardiac resynchronization therapy (CRT) has been successful in adults, translation into pediatrics is complicated. Tissue Doppler echocardiographic assessment of dyssynchrony may help identify children who will benefit from CRT. However, threshold values to diagnose dyssynchrony in pediatric patients have not been defined. We
hypothesized
that adult tissue Doppler dyssynchrony thresholds would not accurately apply to pediatric patients. We aimed to define new threshold values as necessary.

Methods
Sixty controls with normal QRS on ECG and 2D echocardiography were enrolled with 20 subjects in each of three age groups: 0 –2, 2–10 and 10 –17 years. Four dyssynchrony parameters were quantified: septal to lateral delay (SLD), peak velocity difference (PVD), SD of the 12 segment model (TsSD), and cross-correlation delay (XCD). Published adult thresholds for each dyssynchrony parameter (60, 65, 34 and 31 msec for SLD, PVD, TsSD and XCD, respectively) were used to calculate false positive rates (i.e. the percentage of normal controls incorrectly diagnosed as dyssynchronous).

Results
SLD, PVD and TsSD had high false positive rates while XCD did not (Fig A

). The false positive rate for XCD approached 0% with increasing age (Fig B

). The upper limit of normal for XCD defined by mean + 2*SD was 46, 56 and 34 msec for the 0 –2, 2–10 and 10 –17 age groups, respectively.

Conclusions
Adult tissue Doppler dyssynchrony thresholds for 3 of the most commonly used parameters incorrectly diagnose 57– 85% of normal children as dyssynchronous. Cross-correlation delay shows promise in diagnosing dyssynchrony in children, and new thresholds for younger patients have been developed.
Abstract 4566: Growth and Function of Hypoplastic Right Ventricles and Tricuspid Valves in Infants with Pulmonary Atresia and Intact Ventricular Septum
Authors: Foker John E , Berry James M , Setty Shaun , Rivard Andrew , Groot Adriana C Gittenberger-de , Pyles Lee A
Published: July 2021

Objectives
The pulmonary atresia intact septum (PAIVS) spectrum includes very hypoplastic right ventricles (RVs) and tricuspid valves (TVs) as well as RV-coronary artery connections (RV-CACs). These abnormalities are often thought irreversible and only 30 – 40% reach a 2-ventricle repair (2VR). Our hypothesis, however, has been PAIVS is a developmental defect and catch-up growth is possible. We provide up to 10 year data on RV and TV growth and function after 2VR.

Methods
Follow-up echo data were sought on the 24 survivors of the 28 patients (pts) treated from 1989 –1999. Two pts with Ebstein’s anomaly and one without coronary-aorta connections were excluded. Biplane echos were required for accurately estimating RV volume, TV size, and function. Measurements were indexed (I) to determine the z-values (standard deviation of the mean from predicted).

Results
All patients had an RV outflow patch and ASD reduction. Growth required complete relief of RV obstruction and a mildly restrictive (3–5 mmHg) ASD to encourage TV flow. A central shunt was placed in 38%. RV-CACs (2.7 ± 1.6/pt) were uneventfully ligated off bypass in 9/28 (32%). For the 24 survivors, 19 adequate paired biplane studies were obtained and 12 approached 10 year follow-up. No central shunts remained. The other survivors were satisfactory on local follow-up visits. The TVs, despite increased flow, grew more slowly than RVs. But even very small TVs in 10 pts went from z-values of −4.6 ± 0.4 to −0.04 ± −1.5 within 5–10 years. Normal size was achieved in 9/10 and 1 went from z = −5.2 to −3.1. Valvotomies were done in 3. RV function was high normal (EF = 74.5 ± 0.1%) because of pulmonary regurgitation in 8 pts with adequate studies.

Conclusions
1) Catch-up growth appears reliable in PAIVS pts even for TV z-values ≤ −4.0. 2) The consequences of PAIVS can be reversed by growth when RV obstruction is relieved and TV flow increased. 3) RV function was good and resembled well repaired TOF. 4) These results encourage pursuing 2VRs in PAIVS pts.

Paired follow-up z-values and indexed sizes for the RVs and TVs
Abstract 4609: Evidence of Need for a More Comprehensive Approach to Dietary Self-Management for Patients with Heart Failure and Diabetes
Authors: Payne-Emerson Heather , Song Eun Kyeung , Heo Seongkum , Moser Debra K , Chung Misook L , Dunbar Sandra B , Pressler Susan J , Lennie Terry A
Published: July 2021

Background: Type 2 diabetes (DM) is a common comorbidity in patients with heart failure (HF). Nutritional management is a key strategy in achieving blood glucose control and decreasing the risk of microvascular complications. The ability of patients with HF to nutritionally self-manage multiple comorbidities is unknown.

Purpose: To compare nutritional intake of a group of patients with HF and DM with a group without DM.

Methods: A total of 174 patients (66 with DM, age 60± 12 yrs, 35% female, 57% NYHA class III/IV) recruited from HF clinics completed detailed 4-day food diaries that were reviewed by a registered dietitian. Nutrition Data System software was used to determine carbohydrate (total and subtype), protein, fat, cholesterol, and sodium intake. Fasting blood glucose was obtained on a subset of 123 patients. Between-group comparisons were made using independent sample t-tests.

Results: Patients with DM consumed a lower percentage of calories from carbohydrate (44% vs. 49%, p=.003) and a greater percentage of calories from protein (19% vs. 16%, p<.001) and fat (38% vs. 35%, p=.049) compared to patients without DM. With respect to carbohydrate subtypes, patients with DM consumed 30% less sucrose (29g vs. 42g, p<.001) and 39% less fructose (14g vs. 23g, p<.001) than patients without DM, but a similar amount of starch (93g vs. 95g). There were no differences in sodium (3472mg vs. 3209mg), cholesterol (321mg vs. 285mg) or saturated fat (12% vs. 11% of kcal) intake between groups with and without DM. A total of 60% of patients with DM had fasting blood glucose levels >120mg/dl and 40% had a fasting levels > 140mg/dl.

Conclusions: Patients with HF and DM primarily limited dietary sugar intake, with only moderate success. Nutritional management of HF has focused on the single nutrient sodium with limited success; these data suggest that teaching for DM may be similarly focused on the single nutrient sugar. This indicates that new, more comprehensive, approaches are needed to help patients meet the challenge of nutritionally managing multiple comorbidities.

This research has received full or partial funding support from the American Heart Association, AHA Great Rivers Affiliate (Delaware, Kentucky, Ohio, Pennsylvania & West Virginia).
Abstract 4631: The Cytochrome P450 Inhibitor Fluconazole Increases Plasma Concentrations of R-, and S-Warfarin but not ATI-5923, a Novel VKOR Inhibitor
Authors: Irwin Ian , Canafax Daniel M , Ellis Dave , Milner Peter , Druzgala Pascal
Published: July 2021

Warfarin (WARF) is a Vitamin K epoxide reductase (VKOR) inhibitor and oral anticoagulant widely used for prevention and/or treatment of stroke associated with atrial fibrillation. In spite of proven efficacy, WARF therapy is limited by numerous drug-drug interactions (DDIs). Of these, many involve inhibition of it’s cytochrome P450 (CYP) mediated metabolism, leading to increased drug exposure and risk of bleeding. ATI-5923 was created with the goal of producing a VKOR inhibitor that was non-oxidatively hydrolyzed by esterases to an inactive metabolite (ATI-5900) and thereby reduced likelihood of DDIs and maintain the benefits of WARF. We hypothesized that, unlike warfarin the pharmacokinetics (PK) of ATI-5923 is not subject to DDI with the CYP 2C9/3A4 inhibitor fluconazole (FCZ). Two groups (n=10/group) of healthy volunteers were randomized to receive a single equipotent oral doses of either WARF (17.5 mg) or ATI-5923 (50 mg). ATI-5923, ATI-5900, R-WARF and S-WARF concentrations were measured in serial plasma samples collected over a 7 day period and the PK parameters (AUC, C
max
, T
max
and T1/2) were determined. On day 7, subjects were given FCZ (400 mg/day) for 14 days and on day 21, subjects received a second dose of either WARF or ATI-5923 and FCZ was continued for 7 days and the PK study was repeated. Exposure (AUC)for WARF were dramatically increased by FCZ treatment, with the effects being more pronounced on the more active S-isomer: The AUC
inf
for S-WARF was increased more than 3 fold while this parameter was increased 2 fold for R-warf. Increased exposure appeared to result from reduced clearance: The T
1/2
increased from 48 to 104.3 hrs (R-warf) and from 31 to 87.9 hrs (S-warf). No significant effects of FCZ treatment on ATI-5923 or ATI-5900 exposures or clearance were observed. The dramatic effect of the CYP2C9/3A4 inhibitor FCZ on WARF exposure is consistent with the known CYP-mediated clearance of this drug. In the clinical setting, a corresponding increase in WARF exposures would be expected to increase anticoagulant effects and raise the risk of bleeding. In contrast, ATI-5923 which undergoes non-CYP mediated metabolism, is unaffected by FCZ treatment.
Abstract 4633: Pretreatment with Mineralcorticoid Receptor Antagonists Plus Beta Blockers and Angiotensin Converting Enzyme Inhibitors Increases the Proportion of Patients in Sinus Rhythm after Electrical Cardioversion for Persistent Atrial Fibrillation and Heart Failure
Authors: Marchetti Gabriello , Roncuzzi Renzo , Urbinati Stefano , Vivoli Daniela , Barbieri Alberto , Zaniboni Alessandra
Published: July 2021

Aim of this study was to assess the effect on sinus rhythm maintenance after electrical cardioversion of pre-treatment with mineralcorticoid receptor antagonist (MRA) added to beta blockers (BB) and angiotensin-converting enzyme inhibitors (ACEI) in patients with heart failure and persistent atrial fibrillation. We studied 168 consecutive patients with left ventricular dysfunction and persistent atrial fibrillation (AF) who underwent electrical cardioversion (ECV) in our Day Hospital.Group 1 (83 pts) was pretreated with MRA plus BB and ACEI and group 2 (85 pts) with only BB and ACEI. Mean age was 74.4 years in group 1 and 73.9 years in group 2; male gender was 70% in group 1 and 72% in group 2 ; estimated onset of arrhythmia was 5 + −2 months in two groups; ischemic heart disease was present in 55% of group 1 and 61% in group 2 .Hypertension was present in 70% of group 1 and 61% in group 2. Echocardio-graphic parameters of left atrial diameter were not statistically different in two groups:44 mm versus 47 mm ; ejection fraction was 46% (group 1) and 44% (group 2).All patients received warfarin during the 1 year follow up. Aldosterone antagonists ( plus BB and ACEI ) was continued in group 1 after ECV. Group 2 received treatment with BB and ACEI. 4 pts in group 1 and 6 pts in group 2 showed early re-initiation of AF after cardioversion and a second ECV was successfully repeated. At 1 year follow up 67% of pts of group 1 remained in sinus rhythm compared with 42% of pts not treated with aldosterone antagonists. The results in our investigation regarding the proportion of pts in sinus rhythm after ECV favour this treatment strategy for patients with persistent AF and heart failure. A possible mechanism of this result is that aldosterone too stimulates collagen production leading to atrial fibrosis. Remodeling process in heart failure can be better antagonized by combined treatment of Beta blockers, Angiotensin Converting-Enzyme inhibitors and Mineralcorticoid receptors Antagonists.