bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 4001: Relationship between Exposure to the Prasugrel Active Metabolite with TIMI Major/Minor Bleeding in TRITON-TIMI 38
Authors: Salazar Daniel E , Ernest C. Steven , Wrishko Rebecca E , Weerakkody Govinda J , Small David S , Li Ying G , Rhohatagi Shashank , Dornseif Bruce E , Ni Lan , Antman Elliot M , Wiviott Stephen D , Macias William L , Riesmeyer Jeffrey S
Published: July 2021

In TRITON-TIMI 38, patients treated with prasugrel had a higher incidence of TIMI bleeding compared to treatment with clopidogrel. Increased bleeding was most evident in patients <60 kg or ≥75 years. The relationship between exposure to prasugrel active metabolite (Pras-AM) and TIMI Major/Minor (M/M) bleeding was assessed in 1159 patients enrolled in the TRITON pharmacokinetic substudy ~17% of treated population. The relationship between exposure and bleeding was also assessed in the subset of patients <60 kg or ≥75 years. A multi-linear regression model was used to quantitatively predict Pras-AM from measurement of its 2 downstream inactive metabolites. Exposure quartiles for Pras-AM were constructed for all patients, as well as for patients ≥60 kg or <75 years. TIMI bleeding by exposure quartiles was assessed. The risk of bleeding for patients <60 kg or ≥75 years was assessed using the quartiles constructed for the complementary population. Relationship between exposure and bleeding was analyzed through 3 days from the first dose of study drug to evaluate the effect of the loading dose (LD; prasugrel 60 mg) and after 3 days from the first dose of study drug to evaluate the effect of the maintenance dose (MD; prasugrel 10 mg). In the overall population, a higher estimated exposure to Pras-AM was associated with a higher incidence of bleeding after 3 days (P<0.05), but not through 3 days from the first dose of study drug. For patients ≥75 years, TIMI M/M bleeding was higher in the upper 2 quartiles of exposure (12.5%) compared to the lower 2 quartiles (2.5%). Patients ≥75 years in the lower quartile of exposure to Pras-AM had similar TIMI M/M bleeding compared to patients <75 years. For patients <60 kg, TIMI M/M bleeding was observed only in the upper quartile of exposure (14.8%). Increased estimated exposure to Pras-AM with the MD was associated with increased bleeding but exposure during LD was not associated with increased bleeding. In patients ≥75 years or <60 kg, increased TIMI M/M bleeding was confined to patients in the highest exposure quartiles to Pras-AM. Patients <75 years or 60 kg in the lower estimated exposure quartiles to Pras-AM had similar TIMI M/M bleeding compared to patients <75 years or ≥60 kg, respectively.
Abstract 4008: PSGL-1-Expressing CD4 T Cells are Enriched in Culprit Coronary Artery Lesion of Acute Coronary Syndrome
Authors: Gomita Keiko , Sato Kayoko , Kitamura Kazutaka , Hagiwara Nobuhisa
Published: July 2021

Background:
Recently, several evidences on the crucial role of adhesion molecules in the development of atherosclerosis and plaque instability have been reported. While expression of VCAM-1, ICAM-1 and L-selectin has been consistently observed in atherosclerotic plaques it is still uncertain how adhesion molecules on T cells contribute to the incidence of acute coronary syndrome (ACS). In this study, we examined whether adhesion molecules on T cells in ACS have a significant role in the plaque stability and prone to cause ACS.

Methods and Results:
Fresh CD4 T cells were isolated from the peripheral blood of 76 ACS patients (AMI=35, UAP=41) and 74 age-matched controls (NC). CD69, an activation marker of T cells, was strongly expressed on CD4 T cells from ACS than from NC by FACS (P<0.0001). CD4 T cells from ACS highly expressed p-selectin glycoprotein ligand-1 (PSGL-1) and integrin β (CD18), but not L-selectin by FACS (P < 0.03, P < 0.01, n.s., respectively). Soluble PSGL-1 (sPSGL-1) levels in plasma were lower in ACS patients than in NC (P=0.0001), which correlated negatively with the PSGL-1 expression on CD4 T cells (R=0.405, P<0.02). We further investigated the thrombus-aspirating device samples (n=14) and fresh CD4 T cells derived from both the coronary artery and peripheral blood from the each same patient with ACS. CD4 T cells from the coronary artery strongly expressed PSGL-1 (P<0.002), but not integrin β (CD18) and L-selectin by FACS. Finally, PSGL-1 was expressed on T cells, but not on CD68 positive macrophage, MPO positive neutrophil, or CD41 positive platelets in the thrombus-aspirating device samples.

Conclusions:
From these results, we demonstrated that PSGL-1-expressing CD4 T cells are enriched in the culprit coronary artery lesion of ACS, contributing to the acceleration of plaque instability and occurrence of ACS.
Abstract 4018: The Comparison of Clopidogrel Effectiveness in Patients with Hemodynamically Stable vs. Unstable Acute Myocardial Infarction
Authors: Osmancik Pavel P , Jirmar Radovan , Hulikova Katarina , Peroutka Zdenek , Bednar Frantisek , Widimsky Petr
Published: July 2021

Clopidogrel represents the standard of care in patients with ST-elevation myocardial infarction (STEMI) treated by primary PCI. However, as a prodrug, it has to be metabolized to the active form in the liver. Furthermore, this drug exists in oral form only and sufficient absorption from gastrointestinal tract is needed. We hypothezied, clopidogrel efficacy might be lower in patients with severe hemodynamic instability, where splanchnic and liver ischemia is present. Forty patients with STEMI were enrolled in the prospective, case-control designed study. Twenty (unstable) were in severe hemodynamical instability (cardiogenic shock (n=8), severe pulmonary oedema (n=4), prolonged resuscitation due to arrhythmias (n=8)). All of them were on mechanical ventilation and catelcholamine support on admission (inclusion criteria=MI, mechanical ventilation, catecholamine support). The other 20 patients (stable) served stbale (Killip I) cross-matched control. All 40 patients were treated by PCI. Blood samples were drawn before (baseline), 4h (4h+), 24h (1d+) and 2 days (2d+) after clopidogrel administration. Clopidogrel efficacy was assessed by measurement of Vasodilator-Stimulated Phosphoprotein phosphorylation (VASP-P) using flow cytometry. Unstable patients had higher lactate level (5.4+4.8 vs. 1.7+0.6, p=0.009) on admission and also higher markers of liver dysfunction (INR at 1d+: 1.1+0.1 vs. 1.5+0.4, p<0.01). However, the ejection fraction of left ventricle (44.5+9.1 vs. 36.0+15.8, p=0.1) and peak troponin levels were not different between both groups- The decrease of VASP-P was substantially lower in unstable patients compared with stable ones (ANOVA, p<0.05). In stable patients and compared with baseline, the VASP-P decreased significantly by 22% at 4h+ and by 34% at 1d+, and remaiend decreased by 34% at 2d+ (all p<0.05). In unstable patients, the VASP-P decreased nonsignificantly by 5% at 4h+, and no further decrease of VASP-P was present (−2.4% at 1d+, −6% at 2d+; all p=n.s.). Clopidogrel efficacy is lower in hemodynamically unstable MI patients. Insufficient absorption and biotransformation of clopidogrel due to splanchnic and liver ischemia might be the cause of this fact.
Abstract 4101: The Effect of Dronaderone on Hospitalizations in Patients with Atrial Fibrillation. Results from the ATHENA Study
Authors: Torp-Pedersen Christian , Page Richard L , Conolly Stuart J , Crijns Harry J , van Eickels Martin , Gaudin Christophe , Hohnloser Stefan H
Published: July 2021

The ATHENA study has demonstrated that dronaderone reduces a combined endpoint of cardiovascular hospitalizations and cardiovascular death in patients with paroxysmal or persistent atrial fibrillation or flutter (AF). Two previous studies have demonstrated dronaderone to reduce risk of AF recurrence. Here we examine the impact of dronaderone on hospitalizations. ATHENA is a double-blind, placebo controlled parallel group study. Eligible patients needed to have documented AF as well as documented sinus rhythm within 6 months year prior to randomization. Patients further needed to document increased risk by an age above 75 years or an age above 70 years and additionally either diabetes, prior stroke, hypertension, reduced left ventricular function or an enlarged left atrium. New York heart association class IV was an exclusion criterion. Randomized patients received dronaderone 400 mig bid or matching placebo. Mean follow-up was 21 months. The primary outcome was cardiovascular hospitalization or death. Cardiovascular hospitalization was a secondary outcome. There were 675 first cardiovascular hospitalizations on dronaderone and 859 on placebo, hazard ratio 0.75 (95% cl 0.67– 0.82, p<0.001). The main reasons for first hospitalization on dronaderone/placebo were: AF 296/457, ischemic heart disease 93/102, heart failure 78/92. Overall there were 438/511 cardiovascular hospitalizations not related to AF/AFL, hazard ratio 0.86 (0.75– 0.97, p=0.02). There were 516/533 non-cardiovascular hospitalizations, hazard ratio 0.98 (0.87–1.11, p=0.8). Examining total hospitalization burden (cardiovascular and non-cardiovascular) there were 9995 nights in hospital on dronaderone and 13986 on placebo, a reduction of 28% (p<0.001). For cardiovascular hospitalizations the number of nights were 5875/9073, a reduction of 35% (p<0.001). In patients with paroxysmal or persistent AF dronaderone substantially reduces the risk of cardiovascular hospitalization and substantially reduces total hospitalization burden.
Abstract 4116: Electrocardiographic Markers of Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy: A reappraisal
Authors: Jain Rahul , Dalal Darshan , Evenson Ariana , Jain Rohit , Daly Amy , Tichnell Crystal , James Cynthia , Plantholt Stephen , Calkins Hugh
Published: July 2021

Background:
The Task Force criteria for diagnosis of arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) rely on depolarization and repolarization abnormalities detected on a surface ECG. Terminal activation delay (TAD) has recently been presented as specific and sensitive marker of ARVD/C. The purpose of this study was to evaluate the sensitivity and specificity of TAD in patients with ARVD/C.

Methods
: In a cohort of 74 patients with definite ARVD/C (51% male); age 36 ± 12 years) and 48 phenotypically normal non cardiac patients (35% male); age 35 ± 14 years) we studied the ECG criteria used to diagnose ARVD/C with specific a focus on TAD. The parameters analyzed were: T wave inversion (TWI) in ≥ V2, TWI ≥ V3, epsilon wave, QRS ≥ 110ms in V1 to V3, parietal block defined as QRSd V1–V6 or V2–V6 or V3–V6 >25 ms in the presence of QRS ≥ 100ms in at least 2 right precordial leads, TAD in V1-V3 and QRSd in V1+V2+V3/V4+V5+V6 ≥ 1.2. Sigma scan software was used for the ECG analysis.

Results
: In the ARVD/C group, the prevalence of TWI ≥ V2 was 82%, TWI ≥ V3 was 66%, epsilon wave: 1%, QRSd ≥ 110ms V1-V3: 39%, parietal block: 16%, TAD: 46 %, QRSd ratio ≥ 1.2: 19%. In the non cardiac group the prevalence of TWI ≥ V2 was 6 %, TWI ≥ V3: 6%, epsilon wave: 0%, QRSd ≥ 110ms V1–V3: 4%, parietal block: 2%, TAD: 12%, and QRSd ratio ≥ 1.2: 4% (Figure).

Conclusion
: The results of this study reveal that terminal activation delay has only moderate sensitivity and specificity for the diagnosis of ARVD/C. Our results also reveal that T wave inversion in the right precordial leads is a very sensitive marker of ARVD/C.
Abstract 4131: ICD and Shock Experience In Dialysis Patients
Authors: Shah Anuj , Bhavnani Sanjeev , Guertin Danette , Coleman Craig , Clyne Christopher , Yarlagadda Ravi , Kluger Jeffrey
Published: July 2021

BACKGROUND: The occurrence of ventricular arrhythmias in end stage renal disease (ESRD) patients on hemodialysis (HD) is common. There are limited data on ICD patients with ESRD on HD.

METHODS: We analyzed a prospectively collected database of patients with ICD implants at our institute. The patients with and without ESRD were compared for the baseline demographic variables, co-morbidities and outcomes, especially the rates of VT storm, total ICD therapies and all-cause mortality.

RESULTS: There are 1438 patients with ICD implantation and follow up at our institution from April 1995 to August 2007. Of these 40 (3.3%) were on hemodialysis secondary to ESRD. The mean follow up was shorter in ESRD patients (536 ± 455 vs. 886 ± 881, p − 0.05). The ESRD group was comparable to the general ICD population for age, gender distribution, ejection fraction (mean EF 28.8 ± 15 vs. 28.9 ± 14), presence of HTN, ischemic heart disease, use of Amiodarone, beta-blockers, Digoxin and incidence of implants for primary prevention (85% vs. 74%, p - NS). The ESRD group had higher incidence of Diabetes (45% vs. 26%, p - 0.01) and lower use of Ace-inhibitors (32.5% vs. 50%, p - 0.03), biventricular pacemakers (10% vs. 24.8%). The ESRD patients had significantly worse overall mortality (52.5% vs. 23.8%, p - 0.01), one year mortality (17.5% vs. 7.4%, p - 0.029)), appropriate ICD therapies (30% vs. 17%, p - 0.03) and VT storms (17.5% vs. 5.2%, p < 0.001). On Multivariate analysis, presence of ESRD was the strongest predictor of overall mortality (see table

) but not an independent predictor of one year mortality.

Conclusion: In our single center experience, the dialysis patients had significantly worse outcomes than the general ICD patients, in terms of higher mortality, ICD therapies and cluster shocks. Presence of ESRD was an independent predictor of overall survival but does not predict one year mortality.
Abstract 4177: Quantitative Evaluation of Regional Myocardial Blood Flow Using Multi-detector Row Computed Tomography in Pre- and Post- Coronary Artery Bypass Grafting Patients; Assessment with Regional Left Ventricular Function
Authors: Imagawa Hiroshi , Shikata Fumiaki , Kido Teruhito , Kurata Akira , Higashino Hiroshi , Inoue Yuma , Ryugou Masahiro , Nagashima Mitsugi , Kawachi Kanji , Mochizuki Teruhito
Published: July 2021

Introduction: The advent of high resolution multidetector computed tomography (MDCT) created the potential to quantify myocardial blood flow (MBF) reduction. The effect in regional MBF produced by coronary artery bypass grafting has not been quantitatively evaluated. The purpose of this study was to test the hypothesis that adenosine stress/rest MDCT can detect ischemia by measuring MBF differences in pre- versus post-CABG patients.

Methods: Ninety regional areas in 10 patients (median age 71; 65–79, 7 males), scheduled for CABG at our institution, were studied. Each patient underwent adenosine stress 64-slice MDCT perfusion imaging in both pre- and postoperative period. Myocardial blood flow was calculated with Patlak plots analysis. Regional left ventricular function (LVF) was assessed by Echocardiography.

Results: Preoperative mean MBF in ischemic and non-ischemic areas was 0.76±0.49 (ml/g/min) and 2.15±0.66, respectively (p<0.05). Postoperative MBF increased to 1.40±0.77 (ml/g/min) in ischemic areas (p<0.05), though the non-ischemic area showed no differences. The degree of ischemia on MDCT was correlated to change in regional LVF. Postoperative assessment revealed the improved regional LVF that was correlated with the increase in regional MBF.

Conclusions: The regional MBF can be quantitatively assessed by adenosine stress 64-slice MDCT perfusion imaging. This technique provides quantitative information about regional MBF in pre- and post- CABG patients, which may predict the regional LVF recovery after CABG.
Abstract 4220: Low Calcium Score Does Not Exclude Significant Coronary Stenosis in Women at Intermediate Risk
Authors: Rabdiya Vimal , Primiano Charles , Lundbye Justin
Published: July 2021

Introduction
: Coronary calcium deposition is associated with atherosclerosis and its quantification provides independent and incremental information to the clinical risk assessment. In women with low to intermediate clinical risk, how well zero or low calcium score predicts the absence of obstructive coronary artery disease (CAD) has not been elucidated.

Hypothesis
: To examine the extent of CAD on 64-slice multidetector computed tomography (MDCT) coronary angiography in women with zero or low calcium score.

Methods
: We studied 495 consecutive patients referred to coronary MDCT for clinically suspected CAD. Of these we identified 184 women with low to intermediate risk of CAD who had zero or low calcium score. A low calcium score was defined as an Agatston score of 1–100. Luminal stenosis of 50% or more was considered as obstructive CAD. Prevalence and severity of CAD were assessed and analyzed on per patient basis.

Results
: Calcium scores of 0 and 1–100 were found in 101 and 83 patients respectively. Patients with zero calcium score were younger (54.92 ± 10.34 vs. 61.21 ± 10.25 years, p = 0.0001), but none of the risk factors showed a significant difference as compared to patients with score of 1 - 100. Obstructive CAD was present in 4 patients (3.9%) with 0 calcium score as compared to 21 patients (22.9%) with calcium score of 1 - 100. (p = 0.0001) Later group also had more extensive disease, i.e., 2 patients had 3-vessel disease, 2 had 2-vessel disease. (p=0.05)

Conclusions:

In women with low to intermediate risk, although zero calcium score markedly reduces possibility of significant CAD; low calcium scores are significantly less predictive of prevalence or severity of underlying CAD.

Low calcium score does not preclude the need for further assessment and MDCT coronary angiography might be a useful noninvasive imaging modality in this population.
Abstract 4231: Impact of Stress Echocardiography on Patient Outcome: An Effective Gatekeeper for Coronary Angiography
Authors: Yao Siu-Sun , Bangalore Sripal , Shah Ajay , Silva-Encisco Jorge , Chaudhry Farooq A
Published: July 2021

Stress echocardiography is an established technique for the diagnosis, risk stratification and prognosis of patients with known or suspected coronary artery disease. The impact of stress echo in patient selection for coronary angiography is unclear. We assessed 3121 patients (60 ± 13 years, 48% male) undergoing stress echo (41% treadmill, 59% dobutamine). Follow-up (mean 2.8 ± 1.1 years) for subsequent angiography (<<26>2 months), confirmed non-fatal myocardial infarction (n = 76) and cardiac death (n = 83) were identified. Stress echo was abnormal in 34% and normal in 66%. Peak wall motion score index (pWMSI) effectively risk stratified patients into low-normal stress echo (0.8%/year), intermediate (2.6%/year) and high (5.5%/year) risk groups (p < 0.0001). Early coronary angiography was performed in only 128 patients (1.7%) with normal stress echo and increased with worsening stress echo - 226 patients (22.9%) with pWMSI=1.1–1.7 and 191 patients (41.9%) with pWMSI>1.7. Multivariate logistic regression analysis identified pWMSI as the strongest predictor of future angiography (relative risk 2.04, 95% confidence interval 1.67–2.5, p<0.0001) and cardiac events (relative risk 2.45, 95% confidence interval 2.09 –2.88, p<0.0001). Stress echo is an effective gatekeeper for coronary angiography. The overall mortality rate for patients with normal stress echo was 0.8%/year. Only 1.7% of patients with normal stress echo were referred for early angiography.
Abstract 4234: Prognostic Implication of the Continuous Prognostic Spectrum of Coronary Flow Reserve in Patients with and without Angiographically Obstructive Coronary Artery Disease
Authors: Cortigiani Lauro , Rigo Fausto , Gherardi Sonia , Sicari Rosa , Gianfaldoni Maria Luisa , Galderisi Maurizio , Bovenzi Francesco , Picano Eugenio
Published: July 2021

Dual imaging of wall motion and coronary flow reserve (CFR) on left anterior descending (LAD) artery is now the state-of-the art technique for vasodilator stress echo. The additive prognostic value of CFR over regional wall motion has been established, but there is more than a binary (normal-abnormal ) response in CFR, which can be continuously titrated.

Objectives. To assess the prognostic value of Doppler echocardiographic derived CFR in patients with and without angiographically obstructive coronary artery disease (CAD). 1244 patients (785 men, age 64±11 yy) with known or suspected CAD underwent dipyridamole (up to 0.84 mg/kg over 6′) stress echo with CFR evaluation of left anterior descending artery by Doppler and coronary angiography. Patients were followed-up for a median of 17 months. Mean CFR in the entire population was 2.25±0.64. During follow-up, there were 227 events (26 deaths, 55 STEMI, and 146 NSTEMI). Patients (n=384) undergoing revascularization were censored. Using the Kaplan-Meier method, the lowest quartile of CFR (<1.80) was associated with a significantly (p<0.0001) worst event rate than other quartiles (Figure

), both considering the group with (83 vs 53%, p<0.0001) and without (53 vs 12%, p<0.0001) obstructive CAD at angiography. CFR is a strong and independent prognostic predictor in patients with known or suspected CAD, but the spectrum of prognostic stratification is expanded if the response is titrated according to a continuous scale rather than artificially dichotomized.
Abstract 4275:
TGFBR2
Mutations Reduce Expression of Contractile Proteins in Aortic Smooth Muscle Cells and Predispose Individuals to Thoracic Aortic Aneurysms and Dissections
Authors: Inamoto Sakiko , Kwartler Callie , Lafont Andrea , Liang Yao Yun , Fadulu Van Tran , Duraisamy Senthil , Willing Marcia , Estrera Anthony , Safi Hazim , Hannibal Mark , Carey John , Wiktorowicz John , Tan Filemon , Feng Xin-Hua , Pannu Hariyadarshi , Milewicz Dianna
Published: July 2021

Mutations in the TGF-β receptor type II gene (
TGFBR2
) cause thoracic aortic aneurysms and dissections (TAAD). Studies have suggested a gain of function effect for these mutations, leading to increased TGF-β signaling in the aortic media and resulting in vascular disease. We sought to characterize the phenotype of smooth muscle cells (SMCs) harboring heterozygous missense
TGFBR2
mutations and our data suggest that instead of a gain of function,
TGFBR2
mutations cause TAAD as a result of a loss of function resulting in defective SMC differentiation. Using primary aortic SMCs from patients harboring
TGFBR2
mutations (n=4), we show a global decrease in expression of SMC contractile proteins (
ACTA2
,
MYH11
,
CNN1
,
SMTN
,
TPM1
,
TPM2
, p <0.001) by quantitative PCR analysis when these cells are compared with age and gender matched control SMCs (n=4), along with no change in the expression of cytoskeletal proteins. Consistent with the decreased expression of contractile proteins in the mutant cells, there was increased expression of S100A4, a marker of de-differentiated SMCs (p<0.001). Analysis of fixed and frozen aortas from patients with
TGFBR2
mutations (n=3) confirmed decreased
in vivo
expression of SMC contractile proteins when compared to control aortas (n=3). In control SMCs, addition of TGF- β significantly increased the expression of the SMC contractile proteins but the
TGFBR2
SMCs showed no significant increase in expression of these proteins with TGF-β stimulation. We found that fibroblasts explanted from patients with
TGFBR2
mutations (n=8) consistently fail to transform into myofibroblasts as assessed by expression of SMC contractile proteins after TGF-β stimulation, when compared with age and gender matched control fibroblasts (n=8). Finally, introduction of
TGFBR2
missense mutations into a mouse mesenchymal embryonic cell line that is used as a model of SMC differentiation (10T1/2 cells) disrupts the expression of contractile proteins in these cells when assessed post-differentiation. These data suggest that
TGFBR2
mutations disrupt differentiation of SMCs and myofibroblasts. This is the first genetic defect identified to lead to defective SMC differentiation.
Abstract 4307: New Insights into Surgical Atrial Fibrillation Ablation Therapy: Initial Experience with a Novel Permanently Implantable Heart Rhythm Monitor Device
Authors: Hanke Thorsten , Karlub Antje , Charitos Efstratios , Hagemann Axel , Graf Bernhard , Stierle Ulrich , Sievers Hans-H.
Published: July 2021

Introduction: Surgical atrial fibrillation (AF) therapy is gaining widespread acceptance among cardiothoracic surgeons. However, assessment of therapy success is until now solely based on short time -“snapshot”-rhythm surveillance often at irregular time intervals. In order to evaluate the ablation’s success we intraindividually compared two different types of follow-up strategies: conventional 24h-Holter monitoring and direct long time rhythm surveillance achieved by a new implantable monitor device (IRMD).

Methods: 20 cardiac surgical patients (male 16, mean age 69±9y) with a mean AF of 30±48m (paroxysmal n=7, persistent n=9, long standing persistent n=4) were treated intraoperatively with epicardial high intensity focus ultrasound (HIFU) ablation (+CABG n=10, +AVR n=5, +AVR/CABG n=2, +valve preserving ascending aorta replacement n=2, +endoaneurymoraphy n=1, lone atrial fibrillation n=1). Postoperative heart rhythm monitoring was accomplished in all patients with a 24h-Holter-monitor at prescheduled time intervals and additionally with a new implantable monitor device (Reveal XT, Medtronic®, MN, USA). A more than 0.5% of “time in AF” as reported by the IRMD was considered as recurrence of AF. Telemetry of the IRMD was performed simultaneously after completion of 24h-Holter monitoring.

Results: During a mean FU of 8.7±1.4m a total of 29 24 h-Holter-monitors were obtained. Sinus rhythm was documented in 21, the IMRD however revealed AF recurrence in 11 of these cases. Thus, conventional 24 h ECG monitoring failed to identify AF recurrence in 59% of cases (p<0.027). Success rate after surgical ablation therapy (defined as freedom from AF recurrence of more than 0.5% of observational period) was 72% with 24h Holter monitoring, but only 35% using continuous ECG monitoring with IRMD.

Conclusion: In order to evaluate better “real life” outcomes after atrial fibrillation ablation therapy, long term continuous heart rhythm surveillance instead of -“snapshot” - heart rhythm monitoring is mandatory. This is particularly important for the decision to alter medical therapies, e.g. oral anticoagulation or antiarrhythmic treatment.
Abstract 4332: Stable Precursor Fragments of Vasoactive Peptides Predict Outcome in Patients with Chronic Heart Failure. Data from the GISSI-Heart Failure Trial
Authors: Masson Serge , Febo Oreste , Tagliamonte Ercole , Floresta Marina , Cervello Ospedale V. , Milani Valentina , Struck Joachim , Bergmann Andreas , Maggioni Aldo P , Tognoni Gianni , Sud Consorzio Mario Negri , Latini Roberto
Published: July 2021

The clinical evaluation of several hormones directly involved in the pathophysiology of HF may be hindered by their instability, in particular when dealing with real-life multicenter studies. We assessed the prognostic performance of their stable precursor fragments in patients with chronic HF. Stable fragments of the precursors of atrial natriuretic peptide (mid-regional MR-proANP), endothelin-1 (C-terminal CT-proET-1), adrenomedullin (MR-proADM) and vasopressin (CT-proAVP) were measured at baseline (immunoassays BRAHMS) in 1237 patients with chronic HF enrolled in the multicenter GISSI-HF trial (80.4% males, age 66±11 y, NYHA III-IV 26%, 88% with LVEF<0.40). Association between markers and all-cause mortality (follow-up 3.9 yrs) was tested with multivariable analyses, prognostic discrimination with ROC curves. Plasma levels of MR-proANP (206 [127–322] pM), CT-proET-1 (81 [64 –105] pM), MR-proADM (0.74 [0.58 – 0.97] nM) and CT-proAVP (13.8 [7.56 –24.2] pM) were elevated and correlated with traditional risk factors (age, NYHA class, ischemic etiology, diabetes, atrial fibrillation or COPD). All four biomarkers showed independent association with mortality (HR [95%CI] by medians): MR-proANP 2.52 [1.93–3.30], MR-proADM 1.81 [1.36 –2.40], CT-proET-1 1.79 [1.35–2.36], CT-proAVP 1.54 [1.21–1.98], all p<0.0001) and a prognostic discrimination (AUC range 0.70 – 0.74) similar to BNP (0.72), except for CT-proAVP (0.66). Novel and stable precursor fragments of vasoactive peptides are associated to known clinical risk factors and independently predict outcome in a large representative population of patients with chronic HF.
Abstract 4352: Closing the Treatment Gap in Heart Failure. Angiotensin Converting Enzyme Inhibitor Therapy in Patients with Renal Failure and Effect on Survival
Authors: Thayer Virginia B , McHugh Vicki L , Kallies Kara A , Mathiason Michelle A , Porcari John P , Akosah Kwame O
Published: July 2021

Background:
Heart failure (HF) clinical trials exclude subjects with renal failure (RF), and it is unclear if these patients can be treated as recommended by the guidelines. We sought to determine if poor outcomes is this population is due to RF or to the failure to receive recommended medications.

Methods:
Retrospective analysis of 500 subjects admitted to Gundersen Lutheran HF disease management clinic from 4/99 to 1/03. RF was defined as serum creatinine ≥2.0 mg/dL. Data were collected annually for seven years. Endpoints were defined as all cause hospitalization and all cause death.

Results:
Complete data was available on 449 subjects. Of these, 140 met criteria for RF and 309 had normal renal function. Subjects with RF were older (71±12 vs. 67±13 years, p=0.002) but had higher LVEF (26±9 vs. 23±10%, p=0.011). Subjects were followed for a median of 6.8 years. Overall, subjects with RF had worse outcomes for all cause death (p=0.001) and for all cause hospitalizations (p=0.001) compared to subjects without RF. Among subjects with RF, the success rate for treatment with ACEI/ARB was 90% (n=126). Subjects treated were classified as Group1, and those not tolerating treatment as Group 2. Death rates at one year were better among those treated (17% vs. 23 %). However, hospitalization rates at one year were similar (41% vs. 43%). KM analysis revealed significant group effect of ACEI/ARB outcomes (p=0.001).

Conclusion:
90% of subjects with RF were successfully treated and treatment was associated with better survival. This suggests that benefit of ACEI/ARB does extend to those with RF, and research is needed on mechanisms to apply the guidelines to subjects with RF.
Abstract 4362: Antibodies against KChIP2 Induce Ionic Imbalance and Cell Death in Isolated Rat Cardiomyocytes
Authors: Choudhury Sangita , Schnell Michael , Lüdemann Jan , Staudt Alexander , Kroemer Heyo K , Völker Uwe , Felix Stephan B , Landsberger Martin
Published: July 2021

Disturbances of humoral immunity have been described in patients with dilated cardiomyopathy (DCM). Antibodies against Kv channel-interacting proteins (KChIPs) may be associated with heart failure. Isolated rat cardiomyocytes were treated with antibodies against rat KChIP2 (80 pmol/ml) up to 24 hours. RNA and proteins were isolated after two hours by standard procedures and mRNA (TaqMan®) and protein (Western blot) expression was quantified. Translocations of NF-κB subunits p50, p65, c-Rel, and Rel-B were measured in nuclear protein extracts by ELISA after 60 minutes. Mitochondrial membrane potential ΔΨm and caspase-3 and -9 activities were determined by flow cytometry. Necrotic and apoptotic cells were distinguished by staining with Hoechst 33258 and propidium iodide. Total Ca
2+
and K
+
concentrations were quantified by a colorimetric assay and atomic absorption spectrometry, respectively, and normalized to the protein content of the cells. Antibodies against KChIP2 induced nuclear translocation of all NF-κB subunits analyzed. Pre-incubation with a blocking peptide or an NF-κB inhibitor, CAPE, prevented nuclear translocation. Anti-KChIP2-treatment for two hours significantly reduced KChIP2 mRNA (55±10%; n=4) and protein (73 ±5%, n =4) expression compared to cells treated with experimental buffer (100%). Treatment for 24 hours did not induce changes in mitochondrial membrane potential, ΔΨm. Caspase-3 and -9 activities were not altered as well. The anti-KChIP2-treated cell population consisted of 75±3% necrotic, 2±1% apoptotic, and 13±2% viable cells. In contrast, cells treated with experimental buffer were viable to 86±1%. After five minutes, anti-KChIP2 induced significant increases in total intracellular Ca
2+
(plus 11±2%) and K
+
(plus 18±2%) concentrations. These antibody-mediated effects were prevented in the presence of a blocking peptide. Antibodies against KChIP2 induce ionic imbalance, activate the transcription factor NF-κB, down-regulate KChIP2 expression and enhance cell death rate probably due to necrosis. Antibodies against KChIP2 may contribute to the development and progression of dilated cardiomyopathy.
Abstract 4375: Potential Effects of Immunoadsorption and Subsequent IgG Substitution on Cardiopulmonary Exercise in DCM Patients
Authors: Herda Lars R , Trimpert Christiane , Hummel Astrid , Nauke Ute , Stiftungen Pfeiffersche , Dörr Marcus , Hoffmann Wolfgang , Ewert Ralf , Felix Stephan B , Staudt Alexander
Published: July 2021

Recent data indicate that cardiac antibodies play an active role in the pathogenesis of dilated cardiomyopathy (DCM), and may contribute to cardiac dysfunction of DCM patients. Previous studies have suggested that immunoadsorption with subsequent IgG substitution (IA/IgG) improves left ventricular function in DCM. The potential influence of this immunomodulatory therapy on cardiopulmonary exercise remains to be elucidated. 60 patients with DCM (
n
= 60, NYHA II-IV, left ventricular ejection fraction ≤ 45%) underwent either IA/IgG (
n
= 30), or were followed up without IA (
n
= 30). IA/IgG was performed in one course of five consecutive days. After three months we compared echocardiographic assessment of left ventricular function and spiroergometric exercise parameters in both groups. Left ventricular ejection fraction (LVEF) improved significantly in the IA/IgG group from 33.0 ± 1.2% to 40.1 ± 1.5% (p < 0.001 vs. control, p < 0.001 vs. baseline). In the control group, spiroergometric exercise parameters did not change during follow-up. In contrast, patients receiving IA/IgG improved significantly in the following parameters: peak oxygen uptake (peak VO
2
; 17.3 ± 0.9 ml/min/kg to 21.8 ± 1.0 ml/min/kg; p < 0.01 vs. control, p < 0.01 vs. baseline), oxygen pulse (10.7 ± 0.7 ml/bpm to 13.6 ± 0.7 ml/bpm; p < 0.05 vs. control, p < 0.01 vs. baseline), and anaerobic threshold (VO
2
AT; 10.3 ± 0.5 ml/min/kg to 13.2 ± 0.5 ml/min/kg; p < 0.001 vs. control, p < 0.001 vs. baseline). The ventilatory response to exercise (V
E
/VCO
2
slope) decreased after IA/IgG therapy from 32.3 ± 1.5 to 28.7 ± 0.9 (p = 0.18 vs. controls, p = 0.02 vs. baseline), whereas there was no significant change in the control group after 3 months. IA/IgG therapy in DCM patients may induce improvement in echocardiographic and cardiopulmonary exercise parameters.
Abstract 4400: Comprehensive Open Reading Frame Mutational Analysis of the
RYR2-
Encoded Ryanodine Receptor/Calcium Channel in Patients Diagnosed Previously with Either Catecholaminergic Polymorphic Ventricular Tachycardia or Genotype Negative, Exercise-Induced Long QT Syndrome
Authors: Medeiros-Domingo Argelia , Tester David J , Ackerman Michael J
Published: July 2021

Pathogenic mutations in the
RYR2
-encoded cardiac ryanodine receptor cause type 1 catecholaminergic polymorphic ventricular tachycardia (CPVT1), a cardiac channelopathy with increased propensity for lethal ventricular dysrhythmias. Most
RYR2
mutational analyses target three canonical domains encoded by < 40% of the translated exons. The extent of mutations localizing outside of these domains remains unknown as
RYR2
has not been examined comprehensively in most patient cohorts. Mutational analysis of all 105
RYR2
exons was performed using PCR, DHPLC, and DNA sequencing on 108 unrelated patients (57% females, 96% white, age at diagnosis 18 ± 13 years, mean QTc 424 ± 26 ms) with either an explicit referral diagnosis of CPVT (N = 60) or an initial diagnosis of exercise-induced long QT syndrome (LQTS) but with QTc < 480 ms and a subsequent negative LQTS genetic test (N = 48). Two hundred healthy individuals from the Human Genetic Cell Repository were examined to assess allelic frequency for all non-synonymous variants detected. Thirty-eight (15 novel) possible CPVT1-associated mutations absent in 400 reference alleles, were detected in 44 unrelated patients (41%). Three cases (7%) had >1
RYR2
mutation. Besides the 25 exons known previously to contain causative mutations, eight new mutation-containing exons were identified: 10, 12, 13, 21, 26, 40, 42, and 48. Nearly two-thirds of the CPVT1-positive patients had mutations that localized to one of only 7 exons: 8, 14, 47, 90, 93, 100, and 101. In addition, 5 (2 novel) common non-synonymous single nucleotide polymorphisms were identified. This study represents one of the largest cohorts of patients for which
RYR2
was examined in its entirety. Possible CPVT1 mutations in
RYR2
were identified in approximately 41% of both CPVT referrals and LQTS gene-negative patients with exercise-induced syncope and QTc <480 ms. Including the eight new exons hosting mutations in this study, 33 of the 105 translated exons are now known to host possible mutations. Considering that two-thirds of CPVT1-positive cases would be discovered by selective analysis of <10 exons, a tiered targeting strategy for mutation discovery may afford a more cost-effective approach to CPVT genetic testing.
Abstract 4416: Genetic Variability of Methyl-Tetrahydrofolate-Reductase Modifies eNOS Coupling in Human Arteries and Veins: Effects on Vascular Superoxide Generation and Nitric Oxide Bioavailability
Authors: Antoniades Charalambos , Shrirodaria Cheerag , Leeson Paul , Van-Assche Tim , Ratnatunga Chanti , Pillai Ravi , Tousoulis Dimitris , Stefanadis Christodoulos , Refsum Helga , Channon Keith M
Published: July 2021

5-methyl-tetrahydrofolate (5MTHF) administration improves endothelial nitric oxide synthase (eNOS) coupling in human vessels. However, it is unclear whether endogenous variations of vascular 5MTHF levels due to the functional 5MTHF-reductase (MTHFR) polymorphism C677T, has an impact on vascular function. We examined the effect of this polymorphism on vascular 5MTHF levels, NO bioavailability and eNOS coupling in human vessels. The C677T polymorphism was determined in 218 patients undergoing coronary bypass surgery. Saphenous veins (SV) and internal mammary arteries (IMA) were obtained to determine vasomotor responses of SV to acetylcholine (ACh) ex-vivo, vascular O2- production (+/− eNOS inhibitor LNAME, by chemilumineschence) and vascular 5MTHF (by HPLC). The genotype distribution was CC:100(46%) CT:94(43%) and TT:24(11%). This polymorphism had a strong effect on vascular (Fig. a

) and plasma 5MTHF (p<0.001). Furthermore, the T allele was associated with lower vasomotor responses of SV to Ach (Fig. b

) as well as higher vascular O2- (Fig. c

) and greater LNAME inhibitable O2- (Fig d

., suggesting eNOS uncoupling) in IMA segments. The C677T polymorphism on MTHFR gene is a strong determinant of vascular 5MTHF, and has a significant effect on NO bioavailability and vascular redox state, by modifying eNOS coupling in human vessels.
Abstract 4428: Similar Response to Spironolactone in Whites and African American Patients with Resistant Hypertension
Authors: Husain Saima , Nishizaka Mari K , Pimenta Eduardo , Gaddam Krishna K , Oparil Suzanne , Calhoun David A
Published: July 2021

Primary aldosteronism (PA) is a common cause of resistant hypertension with a prevalence of approximately 20%. Spironolactone is the drug of choice for the medical management of patients with PA. Blacks have been reported to have low-renin HTN and respond better to diuretics and calcium channel blockers. Racial differences in response to spironolactone in patients with resistant hypertension have not been previously described. Consecutive subjects referred to the University of Alabama at Birmingham hypertension clinic for resistant hypertension had been evaluated with a plasma aldosterone concentration (PAC), plasma renin activity (PRA), and a 24-hr urine collection for aldosterone, sodium, and potassium during the patient’s usual diet. The BP response to spironolactone was compared retrospectively in patients. For clinical reasons, subjects had been treated with a median dose of 25 mg of spironolactone and the BP response at 6 weeks, 3 and 6 months was compared retrospectively. A total of 117 patients with resistant hypertension were included in the analysis, including 59 white and 58 black subjects. Both groups had a similar number of antihypertensive medications at baseline. PAC, PRA, U-aldo and serum potassium levels were also similar. BP reduction at 6-weeks, 3- and 6-months after treatment with spironolactone was similar in black and white subjects. At 3 months, the mean reduction in systolic BP was −19.5±19.0 and −23.2±20.0 for blacks and whites, respectively (p= 0.321). These data indicate that African American and white subjects with resistant hypertension respond equally well to spironolactone.
Abstract 4437: Genome-Wide Association Study for the Response to Antihypertensive Medication: HOMED-BP-GENE Study
Authors: Katsuya Tomohiro , Asayama Kei , Inoue Ryusuke , Sugimoto Ken , Ohkubo Takayoshi , Metoki Hirohito , Obara Taku , Ishiakwa Kazuhiko , Fujisawa Tomomi , Ohishi Mitsuru , Ogihara Toshio , Imai Yutaka , Rakugi Hiromi
Published: July 2021

AAntihypertensive therapy is a powerful approach to prevent the cardiovascular disease. However, the responsiveness of the therapy is highly individual due to the variability of genetic or environmental factors. To elucidate the genetic background underlying antihypertensive drug responsiveness, we carried out a genome-wide association study (GWAS). The subjects studied were recruited from the participants of HOMED-BP study (UMIN Registered ID C000000137, http://www.cpt.med.tohoku.ac.jp/HOMED-BP/) after obtaining the informed consent for the genetic analysis. After DNA extraction from peripheral blood, about half million single nucleotide polymorphisms (SNPs) were examined using GeneChip Genome-Wide Human SNP5.0 Array (Affymetrix). Home blood pressure (HBP) was measured every day within 1 hour after wake-up and before going to bed using HEM747-IC-N (Omron). The study protocol was approved by the ethical committee of Osaka University. SNP5.0 Array analysis was demonstrated for 300 participants. Antihypertensive therapy for 4weeks decreased their average HBP from 149.9/88.8mmHg to 137.7/82.2mmHg in early morning and 142.6/82.3mmHg to 129.1/74.7mmHg before going to bed. We excluded the SNPs data that showed low call rate, lack of Hardy-Weinberg’s equilibrium and minor allele frequency less than 0.05. Eight SNPs were significantly (p<0.001) associated with mean HBP reduction both in the early morning and at bedtime. Nine SNPs were more significantly (p<0.0001) associated with morning HBP reduction and 3 SNPs were associated with bedtime HBP reduction. In conclusion, GWAS of antihypertensive medication revealed several candidate loci responsible for a month therapy with the difference between morning and evening.
Abstract 4439: Insular Cortex Atrophy as an Independent Determinant of Disrupted Diurnal Rhythm of Ambulatory Blood Pressure in Elderly Hypertension
Authors: Nagai Michiaki , Hoshide Satoshi , Ishikawa Joji , Shimada Kazuyuki , Kario Kazuomi
Published: July 2021

Recently, insular cortex (Ic) is suggested to be a key site in limbic-autonomic integration. Association of Ic damage with diurnal blood pressure (BP) variation disruption, higher level of brain natriuretic peptide (BNP) and catecholamine were reported. We examined the relationship of Ic volume with ambulatory BP measures and these biomarkers. Amubulatory BP monitoring and brain MRI were performed in 55 elderly hypertensives. Right and left Ic volumes were measured using Intensity Contour-Mapping Algorithm. BNP, adrenaline and noradrenaline concentration were evaluated. Subjects were classified into Ic-atrophy group (n=14) and non-atrophy group (n=41) based on total Ic volume (right and left side) of 12.6 cm
3
(lowest quartile). In Ic-atrophy group, 24hr (144.5 vs 134.2 mmHg, p=0.032), sleep (143.4 vs 127.2 mmHg, p=0.002) systolic BP (SBP), nocturnal SBP dipping (1.30 vs 8.54 %, p=0.027) and BNP (60.6 vs 28.1 pg/ml, p=0.008) were significantly, and noradrenaline (373.5 vs 296.5 pg/ml, p=0.084) was marginally different from those in non-atrophy group. Right Ic volume was significantly correlated with 24hr (r=−0.271, p=0.046), sleep (r=−0.420, p=0.001) SBP, nocturnal SBP dipping (r=0.311, p=0.021) and noradrenaline (r=−0.334, p=0.013), while left Ic volume with 24hr (r=−0.279, p=0.039), sleep (r=−0.498, p=0.0001) SBP, nocturnal SBP dipping (r=0.409, p=0.002) and BNP (r=−0.363, p=0.006). In multiple linear regression analysis adjusted for age, gender and body mass index, left Ic volume was significantly negatively associated with sleep SBP (p=0.008) and BNP (p=0.001), and positively with nocturnal SBP dipping (p=0.044). In elderly hypertensives, predominant left Ic atrophy was significantly associated with sleep SBP measures and BNP. Ic damage, specifically in the left side, may partly contribute to disruption of diurnal ambulatory BP rhythm as well as cardiac function via central autonomic dysregulation.
Abstract 4460: Supported High-Risk Percutaneous Coronary Intervention Using The Impella LP2.5 Device. The Europella Registry
Authors: Sjauw Krischan D , Hassager Christian , Danna Paolo L , Konorza Thomas , Engström Annemarie E , Minden Hans-Heinrich , Machado F P , Pedrazzini Giovanni , Wagner Daniel R , Wagner Daniel R , Kerber Sebastian , Schamberger Rainer , Schofer Joachim , Mathey Detlef G , Erbel Raimund , Viecca Maurizio , Engström Thomas , Henriques José P
Published: July 2021

Background
Patients with complex or high risk coronary lesions, due to extensive and diffuse multivessel, left main or last remaining coronary artery disease are increasingly being treated with percutaneous coronary intervention (PCI). As peri-procedural hemodynamic compromise and complications may occur rapidly, many of these high-risk procedures are being performed with mechanical cardiac assistance, particularly in patients with poor left ventricular (LV) function. The Impella LP2.5, a novel percutaneous implantable LVAD able to provide flow up to 2.5 L/min, may be a superior alternative to the traditionally used IABP.

Methods
We studied safety and feasibility of LV support with the Impella LP2.5 in 144 high-risk PCI patients. All patients were enrolled in the Europella registry, a prospective multicenter registry comprising 10 high volume tertiary PCI centers in Europe.

Results
Patients were old (62% >70 years), 53% had previous myocardial infarction, 54% had a LV ejection fraction ≤30% and the prevalence of co-morbid conditions was high. Mean EuroSCORE was 8.2 (SD 3.4) and 43% of the patients were refused for CABG. PCI was considered high risk due to left main, last remaining and multivessel coronary artery disease, and low LV function respectively in 53%, 17%, 81% and 35% of the cases. The mean assist time was 1 hour and 28 minutes (SD 51min). There were no intra-procedural major adverse cardiac and cerebral events. In-hospital and 30-day mortality were 4.7% and 5.5%. Rates of myocardial infarction, stroke, bleeding requiring transfusion/surgery and vascular complications at 30 days were respectively 0%, 0.7%, 1.4% and 4.0%

Conclusions
The safety and feasibility findings of Impella LP2.5 are encouraging. Our study, supports the potential usefulness of hemodynamic support with Impella LP2.5 to prevent intra-procedural major adverse events and hemodynamic compromise in high-risk PCI.