bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 2832: Which Cardiac Marker is Most Useful to Predict Final Infarct Size and Cardiac Function Following Primary Percutaneous Coronary Intervention For Acute Myocardial Infarction?
Authors: Chia Stanley , Raffel O. Christopher , Merchant Faisal , Wackers Frans J , Senatore Fred , Jang Ik-Kyung
Published: July 2021

Background:
Assessment of cardiac biomarker release has been traditionally used to estimate the size of myocardial damage after acute myocardial infarction (AMI). However, the significance of cardiac biomarkers in the setting of primary percutaneous coronary intervention (PCI) has not been systematically studied in a large patient cohort. We evaluated the usefulness of serial and single time-point measures of various cardiac biomarkers (creatine kinase (CK), CK-MB, troponin T and I) in predicting infarct size and left ventricular ejection fraction (LVEF) after primary PCI.

Methods:
EVOLVE (Evaluation of MCC-135 for Left Ventricular Salvage in AMI) was a randomized double-blind, placebo-controlled trial comparing the efficacy of intracellular calcium modulator as an adjunct to primary PCI in patients with first large AMI. Levels of cardiac biomarkers (CK, CK-MB mass, troponin T and I) were determined in 375 patients at baseline before PCI and 2, 4, 12, 24, 48 and 72 hours thereafter. Single photon emission computed tomography imaging was performed to measure infarct size and LVEF on day 5.

Results:
Area under curve and peak concentrations of all cardiac markers: CK, CK-MB mass, troponin T and troponin I were significantly correlated with myocardial infarct size and LVEF determined on day 5 (Spearman correlation, all
P<
0.001; Table

). Troponin I, however provided the best predictor and a single measure at 72 hr was a strong indicator of both infarct size and LVEF. Using receiver operator characteristics curve, troponin I cutoff value of >55 pg/mL at 72 hr has 90% sensitivity and 70% specificity for detection of large infarct size≥10% (
c
=0.88;
P<
0.001).

Conclusions:
Plasma levels of CK, CK-MB, troponin T and troponin I remain useful predictors of infarct size and cardiac function in the era of primary PCI for AMI. A single measurement of circulating troponin I at 72 hours can provide an effective and convenient indicator of infarct size and LVEF in clinical practice.

Correlation of cardiac biomarkers with Day 5 SPECT determined infarct size and LVEF
Abstract 3038: Influence Of Beta-blockade On Mitral Regurgitant Volume In Patients With Degenerative Mitral Valve Prolapse
Authors: Stewart Ralph A , Gabriel Ruvin , Raffel Owen C , Cowan Brett , Young Alistair , Whalley Gillian , Occleshaw Chris , Zeng Irene , Kerr Andrew
Published: July 2021

Introduction:
Beta-blockers may be indicated for treatment of hypertension or atrial arrhythmias in patients with degenerative mitral valve prolapse (MVP) and moderate-severe mitral regurgitation (MR). However the influence of beta-blockade on the mitral regurgitant volume is uncertain.

Methods:
The influence of metoprolol on regurgitant volume was studied in 25 asymptomatic patients with moderate-severe MR due to MVP in a randomized double-blind cross over study. Metoprolol or placebo were titrated by an independent investigator according to symptoms, blood pressure and resting heart rate (mean dose 119mg, range 23.75 to 195mg/day). Severity of MR was assessed by cardiac magnetic resonance imaging (MRI) and echo-Doppler after 10 –14 days on each treatment. Regurgitant fraction was calculated using MRI from the difference between stroke volume by LV volumetry and aortic forward flow by phase contrast analysis.

Results. Conclusion:
Although metoprolol decreased heart rate and systolic blood pressure it does not influence the mitral regurgitant volume in patients with degenerative mitral valve prolapse.
Abstract 3381: Usefulness of Carperitide as an Adjunctive Therapy for Acute Myocardial Infarction in Patients with Chronic Kidney Disease -Subgroup Analysis of J-WIND-ANP trial
Authors: Asakura Masanori , Kim Jiyoong , Asanuma Hiroshi , Myoishi Masafumi , Seguchi Osamu , Shintani Yasunori , Tomoike Hitonobu , Kitakaze Masafumi
Published: July 2021

Background Chronic kidney disease (CKD) is highly prevalent in patients with cardiovascular disease. Recent investigation suggests that nesiritide (human brain natriuretic peptide) increases the risk of worsening renal function in patients with acute heart failure, whereas carperitide (human atrial natriuretic peptide) has beneficial effects on renal function.

Methods We evaluated the usefulness of carperitide as an adjunctive therapy for acute myocardial infarction (AMI) in 158 patients with low eGRF (<60ml/min) estimated by the modified MDRD equation in J-WIND-ANP trial. Of 158 patients, 78 received carperitide (67±9 years old, male 54 patients) and 80 received placebo (67±9 years old, male 54 patients). Other risk factors such as hypertension, diabetes mellitus, and smoking were comparable between two groups. There was no difference in elapsed time between carperitide group (3.6hr 95%CI 3.0hr–5.9hr) and placebo group (3.5hr 95%CI 2.5hr-5.5hr). We analyzed the effects of carperitide on AUC of CK, ejection fraction (EF) at 6 months, and cardiac events.

Results Carperitide administration reduced AUC of CK compared with placebo (carperitide group 65,040 mg/dl vs placebo group 79,286 mg/dl, p<0.05). Carperitide increased EF at 6 months after the onset of AMI compared with placebo (carperitide group 48.1±7.6% vs placebo group 44.0±10.0%, p<0.05). We found no significant difference in total death, cardiac events and reperfusion injury between both groups.

Conclusions Carperitide reduced infarct size and improved chronic left ventricular function in AMI patients with CKD. These results suggest that carperitide is useful as an adjunctive therapy for AMI in AMI patients with CKD.
Abstract 3472: The Prediction of Ischemic Events After Percutaneous Coronary Intervention by Platelet Reactivity to Adenosine Diphosphate: First Evidence for an Oral Antiplatelet Therapeutic Target Determined by an
Ex Vivo
Test of Platelet Function.
Authors: Gurbel Paul , Bliden Kevin P , Dichiara Joseph , Antonino Mark J , Suarez Thomas A , Lookman Lawal , Tantry Udaya S
Published: July 2021

Background:
High on-treatment platelet reactivity to adenosine diphosphate (HPR-ADP) may be a risk factor for ischemic events after percutaneous coronary intervention (PCI). We determined whether a cutpoint of HPR-ADP, similar to the INR used to guide anticoagulant therapy, could predict ischemic event occurrence after PCI.

Methods
: Post-procedural platelet reactivity to ADP was measured by conventional aggregometry in 352 consecutive patients undergoing non-emergent PCI followed for up to 2 years for post-discharge ischemic events. All patients had received clopidogrel and aspirin therapy at the time of aggregation measurements.

Results:
Eighty-two patients (23%) suffered ischemic events and had higher 5 and 20 μM ADP-induced aggregation compared to patients without ischemic events (46 ± 14% and 60 ± 13% versus 30 ± 17% and 43 ± 19%, respectively, p<0.0001 for both measurements). Using a combined receiver operator curve analysis, HPR-ADP cutpoints of 46% aggregation following 5μM ADP stimulation and 59% aggregation following 20μM ADP stimulation were associated with 63% and 74% of ischemic events, respectively. Multivariate Cox regression demonstrated significance between events and post-procedural HPR-ADP cutpoints (20μM ADP, OR=8.6, p<0.0001; and 5μM ADP, OR=2.9, p=0.01).

Conclusions:
High on-treatment platelet reactivity to ADP is an independent risk factor for ischemic events within 2 years of non-emergent PCI. These data are the first to support a therapeutic target for antiplatelet therapy based on an
ex vivo
platelet function test, similar to the INR used for anticoagulant therapy. The study is a step towards a personalized medicine approach to guide the intensity of antiplatelet therapy.
Abstract 3712: A Randomized Placebo-Controlled Trial of a Conjugate Nicotine Vaccine (NicVAX®) in Smokers Who Want to Quit: 12 Month Results
Authors: Rennard Stephen I , Jorenby Douglas E , Gonzales David , Rigotti Nancy A , de Vos Arjen , Bortey Enoch B , Akhavain Roxanne , Hatsukami Dorothy K
Published: July 2021

Background:
Cigarette smoking triples the risk of dying from heart disease among middle-aged men and women. A nicotine vaccine (NicVAX®) has been developed to produce nicotine-specific antibodies as a means of reducing entry of nicotine into the brain as an aid to smoking cessation.

Objective:
To assess 12-month safety, efficacy and immunogenicity of NicVAX in smokers who want to quit.

Method:
Randomized, double-blinded, placebo-controlled multicenter clinical trial with 2 dose levels of NicVAX (200μg & 400μg) and 2 schedules. Generally healthy adults who smoked ≥ 15 cigarettes/day were recruited. Subjects were randomized 2:1, active:placebo, at 9 sites in the US. The primary endpoint was self reported continuous abstinence for weeks 19 – 26 confirmed by expired CO levels of ≤ 8 ppm. Secondary endpoints include point prevalence abstinence at 12 months.

Results:
301 subjects (52% female) with a mean age of 48, smoking on average 24 cigarettes/day were enrolled. A pre-defined analysis of antibody levels for subjects receiving NicVAX were reviewed and divided into low and high responder groups, with the top 30
th
percentile representing the high responder group. Analysis for the primary endpoint demonstrated that 15/61 (24.6%) of subjects having the highest antibody titers achieved an 8 week period of continuous abstinence between weeks 19 –26, compared to 13/100 (13.0%) for the subjects who received placebo (p=0.04). In contrast, the quit rate for those subjects that did not achieve a high antibody titer was not significantly different from placebo (14/140, 10%). There was a significant relationship between anti-nicotine antibody levels and continuous abstinence from smoking (p=0.0001). NicVAX was well-tolerated and showed no differences in adverse events or in local/systemic reactions between placebo and each active vaccine group.

Conclusion:
Proof-of-concept has been established by the strong correlation of high antibody titers with smoking abstinence. Interim data (6 months post vaccination) demonstrate that generating antibodies to nicotine may be a useful approach for aiding smoking cessation. This study will be completed in Sept 2007. Immunogenicity, sustained smoking cessation and relapse rates at 12 months after vaccination will be presented.
Abstract 3740: Prognostic Significance of Plasma Osteopontin Levels in Patients Undergoing Percutaneous Coronary Intervention
Authors: Momiyama Yukihiko , Tanaka Nobukiyo , Ohmori Reiko , Kato Ryuichi , Taniguchi Hiroaki , Arakawa Koh , Nakamura Haruo , Ohsuzu Fumitaka
Published: July 2021

Osteopontin (OPN) mRNA was shown to be highly expressed in atherosclerotic plaques. We reported plasma OPN levels to be high in patients (pts) with coronary artery disease. Moreover, OPN levels were recently shown to be high in acute coronary syndrome. Increased OPN mRNA expression was also shown in rat arteries after balloon injury. OPN transgenic mice showed markedly increased neointimal formation after arterial injury. OPN may play a role in the development of restenosis after percutaneous coronary intervention (PCI).

Methods:

We investigated the prognostic value of pre-procedural plasma OPN levels by ELISA on restenosis and clinical outcome in 130 pts undergoing PCI, of whom 89 (68%) had bare metal stent. Pts with AMI were excluded. Restenosis was defined as >50% diameter stenosis at follow-up angiography. Pts were followed up for 3 years for major adverse cardiovascular events (MACE) (death, MI, unstable angina, stroke).

Results:

At 7±3 months after PCI, re-angiography was performed in 91 (70%) pts, of whom 40 had restenosis. Between 40 pts with restenosis and 51 without it, plasma OPN (492±200 vs 482±224 ng/ml) and C-reactive protein (CRP) (median 0.78 vs 0.70 mg/l) levels did not differ. In multivariate analysis, reference diameter and smoking were independent predictors for angiographic restenosis, but OPN or CRP levels were not. During the 3-year follow-up, MACE occurred in 21 pts. Compared with 109 pts without MACE, 21 with it had higher OPN (586±230 vs 438±195 ng/ml, P<0.005) and CRP (1.30 vs 0.70 mg/l, P<0.002) levels. Pts with MACE more often had OPN level >500 ng/ml (62% vs 35%) and CRP >3.0 mg/l (33% vs 12%) than without it (P<0.05). OPN did not correlate with CRP levels. To clarify the association between MACE and OPN, pts were divided into 2 groups by OPN levels. Kaplan Meier analysis showed a lower event-free survival rate in pts with OPN level >500 ng/ml than those without it (P<0.05). In multivariate analysis, both OPN and CRP levels were independent predictors for MACE. Hazard ratios for MACE were 2.9 (95%CI=1.3–5.5) for OPN >500 ng/ml and 4.3 (1.3–14.0) for CRP >3.0 mg/l.

Conclusion:

Plasma levels of OPN as well as CRP were found to be independent predictors for cardiovascular events in pts undergoing PCI, but they were not predictors for restenosis.
Abstract 519: The Early Decrease of Plasma ADAMTS13 Antigen Levels is a Significant Predictor of Future Thrombotic Events in Patients with Acute Myocardial Infarction
Authors: Matsukawa Masakazu , Kaikita Koichi , Soejima Kenji , Fuchigami Shunichirou , Nakamura Yoshinori , Honda Tsuyoshi , Tsujita Kenichi , Nagayoshi Yasuhiro , Kojima Sunao , Shimomura Hideki , Sugiyama Seigo , Fujimoto Kazuteru , Nakagaki Tomohiro , Hisao Ogawa
Published: July 2021

Von WilIebrand factor (VWF) is an important cofactor in platelet adhesion and aggregation. Generally, it is known that multimer of VWF is closely associated with strong platelet adherence and aggregation. The early increase of VWF has been reported to be a risk factor for adverse outcome in acute coronary syndrome. Recently, a metalloprotease that cleaves VWF multimers has been identified, namely, ADAMTS13. We previously reported that ADAMTS13 antigen was localized in coronary thrombi obtained from patients with acute myocardial infarction (AMI). The aim of this study was to investigate serial changes in plasma VWF and ADAMTS13 antigen levels and the detailed analysis of the relationship between these plasma levels and prognosis after AMI. We measured serial changes of plasma VWF and ADAMTS13 antigen levels in 92 AMI patients (after admission, one, three, seven, and 14 days after AMI) and 40 control subjects. Plasma VWF antigen levels were significantly higher in AMI patients compared with controls (P < 0.001) on admission, peaked at three days, and gradually decreased afterward. Plasma VWF antigen levels at one day in the AMI patients accompanied with subsequent thrombosis (thrombosis group), including myocardial infarction, unstable angina pectoris, cerebral infarction, subacute thrombosis, and ischemic cardiac death, were significantly increased compared with non-thrombosis group. On the other hand, the plasma ADAMTS13 antigen levels were significantly decreased in AMI patients compared with controls (P < 0.0001) on admission and remained decreased for 14 days. The ADAMTS13 antigen levels in the thrombosis group decreased until three days and gradually increased afterward. Kaplan-Meier analysis and Cox hazards analysis demonstrated that patients with low ΔADAMTS13 levels (Δ = the value at day 3 - value at admission) had significantly higher probabilities of developing thrombosis during one-year follow-up period (P = 0.0104). These findings suggested that monitoring the changes of VWF and ADAMTS13 antigen levels in the early phase of AMI might be valuable for predicting and preventing thrombosis during one-year follow-up in patients with AMI.
Abstract 42: Effects Of Intracerebroventricular Application Of Granulocyte Colony-stimulating Factor On Cerebral Recovery After Cardiac Arrest In Rats
Authors: Rabsahl Tobias , Popp Erik , Vogel Peter , Teschendorf Peter , Boettiger Bernd W
Published: July 2021

Introduction:
After transient global cerebral ischemia, selective vulnerable brain areas show delayed neuronal degeneration with characteristic signs of apoptosis. Recent data demonstrated potent neuroprotective effects of the application of granulocyte colony-stimulating factor (G-CSF) after focal cerebral ischemia. In order to assess possible effects of intracerebroventricular application of G-CSF on cerebral recovery after global cerebral ischemia due to cardiac arrest (CA) neurological testing according to a tape removal test as well as histological analysis of the hippocampal CA-1 sector were performed.

Methods:
Global cerebral ischemia was initiated by ventricular fibrillation in rats during general anesthesia. After 6 min of CA cardio pulmonary resuscitation (CPR) was initiated. After restoration of spontaneous circulation (ROSC) the animals were divided into two groups (G-CSF vs. placebo; n=16 per group). G-CSF (4μl=3.84μg) or placebo was applied in single shot technique 30 min after ROSC. During CA, CPR and for the first 24 h after ROSC all animals were kept normothermic using a feedback control system with intraperitoneal implanted telemetric probes. The tape removal test was applied pre-CA, 24 h, 3 d, 7 d, 10 d and 14 d after ROSC. After 14 days histological analysis was done by counting TUNEL positive neurons in the hippocampal CA-1 sector. All experiments were performed in a randomized and blinded setting.

Results:
All animals were kept normothermic within the first 24 h after ROSC (G-CSF: 37.3 ± 0.3 °C; placebo: 37.5 ± 0.5 °C). Pre-CA all animals removed the adhesive tapes promptly. After ROSC in both treatment groups a clear neurological damage was shown that improved within the first 14 days, without reaching baseline values. No statistically significant differences between the group could be seen. With regard to TUNEL-positive neurons in the hippocampal CA-1 sector no significant differences could be observed between the groups (G-CSF: 47 ± 22; placebo: 51 ± 24).

Conclusions:
Regarding neurological recovery and neurohistopathological outcome 14 d after global cerebral ischemia, the present study was not able to show any beneficial effects of G-CSF, despite the well known effects of G-CSF in non global cerebral ischemia models.
Myocardial Substrate Determines Acute Cardiac Retention and Lung Biodistribution of Intramyocardially Injected Cardiac-Derived Stem Cells—A PET/CT Experimental Study
Authors: Bonios Michael
Published: July 2021

Abstract 1080

Michael Bonios, Johns Hopkins University, Baltimore, MD; John Terrovitis, Cedars Sinai Medical Ctr, Los Angeles, CA; Brian O’Rourke, James Fox, Jianhua Yu, James M Engles, Takahiro Higuchi, Riikka Lautamäki, Martin Pomper, Richard L Wahl, Benjamin M Tsui, Frank M Bengel, Johns Hopkins University, Baltimore, MD; Eduardo Marbαn, Cedars Sinai Medical Ctr, Los Angeles, CA; M. Roselle Abraham, Johns Hopkins University, Baltimore, MD

Michael Bonios, 2008 Finalist and Presenting Author
Relationship Between the Spectral Characteristics of Atrial Fibrillation and Atrial Tachycardias That Occur After Catheter Ablation of Atrial Fibrillation
Authors: Yoshida Kentaro
Published: July 2021

Abstract 1136

Kentaro Yoshida, Aman Chugh, Univ of Michigan, Ann Arbor, MI; Magnus Ulfarsson, Univ of Iceland, Reykjavik, Iceland; Eric Good, Krit Jongnarangsin, Frank Pelosi, Frank Bogun, Fred Morady, Hakan Oral, Univ of Michigan, Ann Arbor, MI

Kentaro Yoshida, 2008 Finalist and Presenting Author
Abstract 5920: Usefulness of Late Gadolinium Enhancement as Non-invasive Arrhythmic Risk Marker in Patients with Heart Failure and Systolic Dysfunction
Authors: Valle Alfonso , Nadal Mercedes , Estornell Jordi , Martinez Nieves , Corbi Miguel , Quesada Aurelio , Palanca Victor , Romaguera Rafael , Laynez Ana , Rodriguez Candela , Paya Rafael , Ridocci-Soriano Francisco
Published: July 2021

The identification of prognostic markers in patients with heart failure of both ischemic and non ischemic etiology is an increasing need in the era of devices therapy. Risk stratification for sudden cardiac death (SCD) remains problematic with reliance on left ventricular function which predicts total mortality rather than arrhythmic events (AE). Recently cardiac magnetic resonance was employed to predict susceptibility for malignant arrhythmias. This study sought to determine the utility of late gadolinium enhancement (LGE) to predict AE. Three hundred consecutive patients with symptomatic heart failure and systolic dysfunction of both ischemic and non ischemic cause undergoing CMR, were classified into two groups attending to the presence (n 160) or absence of LGE (n 140), and were followed prospectively during 842 days. The primary endpoint was the combined of SCD or Ventricular tachycardia (VT). 23 patients had AE (8 SCD/15 VT) during the follow-up, 19 of them presenting LGE (83%). The presence of LGE was associated to a significantly higher AE rate (11.8.% vs 2.8% p< 0.001)(figure

). Compared to patients without LGE, midwall fibrosis and an ischemic pattern of LGE predicted AE. (3% vs 5% vs 14%, p= 0.001) LGE is a new non-invasive predictor of AE in patients with heart failure and systolic dysfunction. This suggest a potential role for risk stratification and better selection of patients who needs device therapy
Abstract 3116: Subclinical Coronary Atherosclerosis Detected by Coronary CT Angiography in Asymptomatic Population with and without Mild Renal Insufficiency
Authors: Cho Iksung , Min Hee-Suk , Oh Byung-Hee , Park Young-Bae , Kim Sang-Hyun , Choi Sang Il , Chun EunJu , Suh Jung-Won , Choi Dong-Ju , Kim Chul-Ho , Chang Hyuk-Jae
Published: July 2021

BACKGROUND The prevalence of coronary artery disease (CAD) increased in patients with moderate to severe renal insufficiency. The impact of renal insufficiency on the development of CAD may increase as renal function continues to deteriorate, however, there is no data available in mild renal insufficiency. The purpose of this study was to explore the association between mild renal insufficiency and coronary atherosclerosis, using coronary CT angiography (CCTA).

METHODS We consecutively enrolled 4984 asymptomatic subjects (mean age 49 ± 10 years, 61% male), who underwent CCTA (64-slice MDCT) as part of a general health evaluation. We categorized subjects based on their estimate of renal function (estimated glomerular filtration rate (eGFR), using MDRD equation: ≥ 60 vs. 45 to 59 ml/min/1.73 m
2
). Patients with eGFR less than 45 ml/min/1.73 m
2
were excluded. Coronary artery calcium score (CACS), presence of plaque, and significant stenosis (≥ 50% lumen diameter) were compared between 2 groups. Regression analysis was performed to assess the correlation between CAD and mild renal insufficiency.

RESULTS Three hundreds forty-two subjects (7%) had mild renal insufficiency (eGFR: 45 to 59) and 4642 (93%) had normal renal function (eGFR: ≥ 60 ml/min/1.73 m
2
). Subjects with mild renal insufficiency showed higher incidence of CAD (124 (36%) vs. 1039 (22%), p<0.001) and significant stenosis (31 (9%) vs. 147 (3%), p<0.001). However, after adjusting conventional risk factors, mild renal insufficiency was no longer an independent risk factor for the presence of CAD and significant stenosis. Furthermore, after age and sex-matching, there was no significant difference in incidence of moderate to severe (≥ 100) CACS (44 (13%) vs. 39 (12%), p=0.64), CAD (122 (36%) vs. 114 (34%), p = 0.57), and significant stenosis (11 (9%) vs. 9 (6%), p = 0.19) between 2 groups.

CONCLUSIONS The higher incidence of CAD and significant stenosis in subjects with mild renal insufficiency was observed, however, which are primarily attributed to the effect of other conventional risk factors. Mild renal insufficiency may not act as an independent risk factor for coronary atherosclerosis.
Abstract 3194: Clinical Characteristics And Physical Activity Patterns Among The Least-fit And The Next-least-fit Quintile Of Individuals With Cardiovascular Disease
Authors: Mandic Sandra , Myers Jonathan , Oliveira Ricardo B , Abella Joshua P , Froelicher Victor F
Published: July 2021

A graded non-linear relationship exists between fitness and all-cause mortality with the most remarkable difference in mortality rates observed between the least-fit (first, Q1) and the next-least-fit (second, Q2) quintile of fitness. The purpose of this study was to compare clinical characteristics, exercise test responses and physical activity patterns in Q1 versus Q2 in individuals with cardiovascular disease (CVD). A total of 5101 consecutive patients referred for clinical exercise testing from 1987 to 2006 were followed for a mean (±SD) of 9.1±5.5 years. All subjects had a history of CVD and/or abnormal exercise test results. Subjects were classified into quintiles of exercise capacity measured in metabolic equivalents (METs) and the first 2 quintiles were compared (Q1: METs <4.2 (n=923); Q2: METs 4.3–5.9 (n=929)). In a subset (n=655), recreational physical activity was assessed using a questionnaire. Q1 had an almost 2-fold increase in age-adjusted relative risk of mortality compared to Q2 (cardiovascular mortality: HR (95% CI): 3.79 (1.73, 8.29) vs. 2.04 (1.9, 4.6), p<0.05; reference group: fittest subjects (Q5, METs >10.0)). Q1 were older (67±9 vs. 64±10 years, p<0.001), had more extensive use of medications and were more likely to have a history of typical angina (35% vs. 28%, p<0.004), myocardial infarction (30% vs. 24%, p=0.003), chronic heart failure (25% vs. 14%, p<0.001), claudication (15% vs. 9%, p<0.001) and stroke (9% vs. 6%, p=0.027) compared to Q2. Prevalence of dyslipidemia, current smoking rates, treatment with ACE-inhibitors, statins and diuretics, and exercise test responses were lower in Q1 versus Q2. Recent (1263±1783 kcal/week vs. 1566±2161 kcal/week, p=0.22) and lifetime (1323±1847 kcal/week vs. 1619±1830 kcal/week, p=0.23) recreational physical activity were not different between the groups. Marked differences in mortality rates between the least-fit and the next-least-fit quintiles appear to be due to a greater severity of disease and comorbidities rather than differences in physical activity patterns. These findings suggest that higher levels of fitness are required to improve survival in individuals with CVD.
Abstract 3195: Is the Extent of Exercise VO
2
Oscillations Related to the Severity and Prognisis of Heart Failure?
Authors: Taniguchi Takuya , Takaki Hiroshi , Ibuki Motoaki , Namikawa Ryo , Oishi Shogo , Kawakami Rika , Noguchi Teruo , Goto Yoichi , Sugimachi Masaru
Published: July 2021

Purpose
: Exercise VE or VO
2
oscillation (OSC) as well as exercise hyperventilation is an ominous sign in patients with heart failure. However, unlike exercise hyperventilation that is readily evaluated by VE/VCO
2
slope, OSC have only been estimated in a qualitative manner (i.e., “present” or “absent”). We hypothesized that the extent of OSC may be related to the severity and prognosis of heart failure.

Methods
: From a consecutive series of >4700 cardiopulmonary bicycle exercise tests for recent 5.5 years, we examined the presence of OSC both by visual inspection and by our previously developed method where we estimated Ratio (Low frequency power/Total power) indicative of abnormal slow VO2 OSC (0.5–1.25 cycle/min) by repeating FFT power spectrum analysis (4-min time-window, overlapping every 30 sec).

Results
: We found VO
2
OSC (defined as Ratio >34.2%) in 175 patients, who were grouped by a median split into Group-H with moderate-to-pronounced OSC (Ratio >42, n=88) and Group-L with mild OSC (Ratio <42, n=87). Compared with Group-L, Group-H had lower peak VO
2
(17.5 ± 4.4 vs 20.9 ± 4.4 ml/min/kg, p< 0.0001) and exhibited higher VE/VCO
2
slope (38.3 ± 12.4 vs 32.5±5.7, p=0.0001), BNP level (308 ± 306 vs 172 ± 144 pg/ml, p<0.001), and NYHA functional class (1.9 ± 0.7 vs 1.6 ± 0.6, p=0.006). During the median follow-up period of 1093 days, cardiac deaths and hospital admissions for heart failure more frequently occurred in Group-H than in Group-L (see Figure

).

Conclusions
: The data indicate that the more pronounced the exercise VO
2
oscillations, the more severe the status of heart failure. Moderate-to-pronounced forms of exercise VO
2
oscillations predict an even poorer prognosis.
Abstract 349: Signal Transducer and Activator of Transcription 3 (Stat3) in the Matrix of Cardiomyocyte Mitochondria
Authors: Boengler Kerstin , Konietzka Ina , van de Sand Anita , Hilfiker-Kleiner Denise , Heusch Gerd , Schulz Rainer
Published: July 2021

STAT3 (signal transducer and activator of transcription 3) transduces signals from the plasma membrane to the nucleus and is central for the cardioprotection by ischemic pre- and postconditioning. However, preliminary data suggest that STAT3 is also located in mitochondria. The aim of the present study was to confirm the presence of STAT3 in cardiomyocyte mitochondria, to elucidate its submitochondrial localization and to identify interacting proteins and the import mechanism of STAT3. STAT3 was detected by Western blot analysis in mitochondrial preparations from rat left ventricle (LV), which were negative for marker proteins of other subcellular compartments (sarcolemma, sarcoplasmic reticulum, nucleus, and cytosol). This finding was confirmed by confocal laser scan microscopy on mouse LV mitochondria (n=4). In contrast, no STAT3 was detected in mitochondria isolated from the LV of mice with a cardiomyocyte-specific deletion of STAT3 (n=3). Immunoprecipitation and confocal laser scan microscopy showed that, apart from total STAT3, also Ser727- and Tyr705-phosphorylated STAT3 was present in rat mitochondria. The analysis of subfractionated mitochondria by Western blot displayed STAT3 predominantly in the fraction negative for marker proteins of the outer membrane (voltage dependent anion channel), inner membrane (ATP synthase alpha), and the intermembrane space (cytochrome c), but positive for marker proteins of the matrix such as cyclophilin D (n=4). Immunoprecipitation of STAT3 from right ventricular and mitochondrial proteins showed a co-precipitation of connexin 43 (Cx43), which is present both at the sarcolemma and at the inner mitochondrial membrane and is also involved in cardioprotection, but not with GSK3β, MnSOD or cytochrome c. Furthermore, STAT3 co-precipitated with Tom20 (translocase of the outer membrane 20), which regulates the import of proteins into the mitochondria. Taken together,

total and phosphorylated STAT3 are present in the matrix of cardiomyocyte mitochondria,

STAT3 is possibly imported via a Tom20-dependent pathway, and

STAT3 interacts with mitochondrial Cx43, and is thus possibly involved in Cx43-mediated cardioprotection.
Abstract 1707: Murine γHerpesvirus-68 Infection Induces Pulmonary Vascular Disease in S100A4 Overexpressing Mice Associated with Elastase Activity and Altered MicroRNA Expression
Authors: Kim Yu-Mee , Spiekerkoetter Edda , Wang Lingli , Rabinovitch Marlene
Published: July 2021

Human γ herpesvirus infection is linked to idiopathic pulmonary arterial hypertension (IPAH). S100A4, a metastasis gene, is highly expressed in the plexiform lesions of IPAH patients. Previously, we reported that murine γherpesvirus-68 (M1-MHV-68) infection in S100A4 overexpressing but not in C57 wild-type (WT) mice induced mild neointimal formation in pulmonary arteries (PA) associated with heightened serine elastase activity. We hypothesized that these neointimal lesions would progress during an extended reactivation phase, in the S100A4 mice in association with ongoing elastolysis and that the susceptibility in S100A4 mice was related either to viral load, inflammation or differential induction of host miRNAs in response to infection. We now report that the % of vessels with neointimal lesions progressively increased from 25 to 40%, between 3 and 6 mo after viral infection (P < 0.05) in S100A mice but were not observed in WT. The extent of neointimal lesions correlated with progressive fragmentation of the elastic laminae, (P < 0.001). Interestingly, these features were not sufficient to induce elevated RVSP or RVH, in the absence of muscularization or loss of distal PAs. Susceptibilty of S100A4 mice was not related to an increase in viral DNA in intra-pulmonary arteries assessed by laser capture microscopy, nor could we establish a relationship with the severity of perivascular inflammation or cytokine expression (IFN-γ and TNF-α). However, we confirmed higher lung serine elastase activity in S100A4 vs. C57 mice as early as 1 wk after viral infection. Since expression of miRNAs may be responsible for host susceptibility, we compared lungs of C57 and S100A4 mice at 6 mo using microArrays followed by qRT-PCR. Induction of miR-466 in WT mice infected with virus (P < 0.01), was not observed in S100A4 mice. miR-466 can target the 3′ UTR of RUNX1, a transcription factor for serine elastase, and reduce its expression. The inability to reduce RUNX1 in S100A4 mice in response to viral infection may be related to elevated serine elastase activity. Our studies show that viral infection can lead to progressive neointimal formation and that the susceptibility of S100A4 mice associated with heightened elastase may be linked to differential expression of miR-466.

This research has received full or partial funding support from the American Heart Association, AHA Western States Affiliate (California, Nevada & Utah).
Abstract 1756: Angiotensin II Induced End Organ Damage is Attenuated in Mice Lacking the Gene for TNF: A Mitochondrial Perspective
Authors: Mariappan Nithya , Sriramula Srinivas , Francis Joseph
Published: July 2021

Recent findings from our lab and others suggest that the renin-angiotensin system and cytokine interaction contribute to the pathophysiology of cardiovascular disease. In this study, we determined the role played by tumor necrosis factor (TNF) in angiotensin II (ANGII) induced end organ damage at the mitochondrial level.

Method

: Wild type (WT) and TNF knockout (TNF (−/−)) mice were implanted with osmotic minipumps containing ANG II (1 μg/kg/min) or saline for 14 days. Blood pressure was recorded using telemetry. At the end of the study, left ventricular (LV) function was measured using echocardiography. Mice were sacrificed and the LV was removed and mitochondria isolated for oxidative stress measurement using Electron paramagnetic resonance spectroscopy. Structural integrity of mitochondria was assessed by electron microscopy (EM) and function by measuring mitochondrial redox status.

Results:

(see table

) ANGII infusion in WT mice resulted in a significant increase in blood pressure and was accompanied by a decrease in fractional shortening. These animals also had increased levels of superoxide and ROS in the LV tissues. The mitochondrial integrity of the cardiomyocytes was damaged both in the isolated mitochondria and tissue as evidenced by EM studies. Mitochondrial superoxide and total ROS were increased and this was accompanied by a decrease in complex activity and reduced ATP production. In contrast, ANGII infusion in TNF (−/−) attenuated cardiac damage, mitochondrial oxidative stress and restored ATP production.

Conclusion:

ANGII induced cardiac damage is mediated by TNF. These data also demonstrate that ANGII induced increase in TNF inhibits mitochondrial function by affecting electron transport chain activity and indirectly through an increase in oxygen free radicals thereby decreasing ATP synthesis and contributing to end organ damage in hypertension.
Abstract 1779: Autophagy is an Important Survival Response to Bnip3-Mediated Mitochondrial Injury
Authors: Rikka Shivaji , Quinsay Melissa N , Gustafsson Asa B
Published: July 2021

Myocardial ischemia and reperfusion (I/R) is associated with increased autophagy and cell death. We previously found that the mitochondrial death protein Bnip3 contributes to I/R injury and induces autophagy in cardiac cells. However, the role of Bnip3-mediated autophagy is not clear and has been reported to be a protective, as well as a detrimental process. In this study, we investigated the functional role of Bnip3-mediated autophagy by utilizing adenoviral infections of cells coupled with fluorescence deconvolution microscopy for the analysis of autophagy and Bnip3 function. Imaging of cells infected with adenoviruses expressing GFP-LC3 and Bnip3 or beta-galactosidase (beta-gal) allowed us to monitor the formation of autophagosomes in live cells. Cell death was measured by assessing LDH activity in the media. Monitoring of GFP-LC3 incorporation into autophagosomes confirmed that overexpression of Bnip3 induced upregulation of autophagy in HL-1 myocytes and neonatal myocytes. We previously found that Bnip3 mediates cell death via Bax/Bak and that mouse embryonic fibroblasts (MEFs) lacking Bax and Bak are resistant to Bnip3-mediated cell death. Bnip3 still caused significant upregulation of autophagy in Bax/Bak−/− MEFs and imaging using high resolution fluorescence microscopy showed that a majority of the cells mitochondria were sequestered in autophagosomes. These results were confirmed by electron microscopy which also revealed the presence of a number of giant mitochondria in the cytosol, suggesting stimulation of mitochondrial biogenesis. Although Bnip3 alone did not cause cell death in Bax/Bak−/− MEFs, addition of 3-methyladenine (3-MA), an inhibitor of autophagy induced significant cell death in cells infected with Bnip3 but had no effect on cells overexpressing beta-gal. Overexpression of Bnip3 caused significant cell death in wild type MEFs, which was enhanced when inhibiting autophagy with 3-MA. These results suggest that Bnip3 stimulates autophagy to remove damaged mitochondria and mitochondrial biogenesis to synthesize new functional mitochondria. Since Bnip3 is upregulated in heart failure, stimulation of autophagy and mitochondrial biogenesis might represent potential therapeutic targets to treat heart disease.

This research has received full or partial funding support from the American Heart Association, AHA National Center.
Abstract 3716: Endothelial-specific Deletion Of The Gap Junction Protein Connexin43 Reduces Atherosclerosis In Mice
Authors: Morel Sandrine , Sutter Esther , Roth Isabelle , Foglia Bernard , Deutsch Urban , Theis Martin , Kwak Brenda R
Published: July 2021

Decreasing the expression of the gap junction protein connexin43 (Cx43) in mice provides beneficial effects on both the progression and composition of the atherosclerotic lesions. During atherosclerotic lesion development, Cx43 expression is temporarily up-regulated in intimal smooth muscle cells, induced in macrophages close to the lipid core and triggered in a subset of endothelial cells covering the shoulder of atherosclerotic lesions. The purpose of this study was to examine the role of endothelial Cx43 in the development of atherosclerosis in vivo. For this purpose, we have used the Cre-loxP system to create an atherosclerosis-susceptible mouse line in which Cx43 is deleted from the endothelium only. The natural progression of atherosclerosis and the composition of the atherosclerotic lesions were studied in 18 month-old male TIE2Cre+ Cx43fl/fl ApoE−/− mice and TIE2Cre- Cx43fl/fl ApoE−/− littermate controls. Body weights were not different between both groups. Interestingly, the progression of atherosclerosis (measured as % of surface stained with Sudan IV) was significantly reduced in the thoracic-abdominal aorta of TIE2Cre+ Cx43fl/fl ApoE−/− mice (21.53±7.14%; N=4) compared with TIE2Cre- Cx43/fl/fl ApoE−/− controls (46.84±11.60%, N=6, P<0.05). In addition, advanced atheroma in TIE2Cre+ Cx43fl/fl ApoE−/− mice contained less lipids and showed decreased calcium deposition compared with lesions in TIE2Cre- Cx43fl/fl ApoE−/− controls. Thus, endothelial-specific deletion of Cx43 in mice provides beneficial effects on both the natural progression and composition of the atherosclerotic lesions. Future studies are aimed at obtaining insight into the participation of Cx43 in macrophages and smooth muscle cells in atherosclerosis.
Abstract 3863: Deletion Of Integrin Alpha7 Leads To Altered Cardiac Conduction And Sudden Death Associated With Connexin43 Downregulation
Authors: Nadif Raja , Emerson Michael , Mayer Ulrike , Neyses Ludwig , Cartwright Elizabeth
Published: July 2021

Effective propagation of the electrical impulse throughout the myocardium is highly dependent on cell-to-cell and cell-to-extracellular matrix interactions. Increasing evidence indicates that dysregulation of cellular adhesion is a critical determinant in the genesis of arrhythmia. Null mutations in the integrin α7 gene, an essential mediator of cellular adhesion in cardiac and skeletal muscles, have been linked to myopathy in humans, however, the
in vivo
role of the integrin α7 subunit in the heart is undefined. The mouse model of integrin α7 deletion dies prematurely at one year of age. We therefore analysed the cardiac phenotype in integrin α7 deficient mice (α7
−/−
) to determine whether their premature death was associated with altered cardiac conduction. One year old integrin α7
−/−
mice exhibited altered cardiac conduction characterised by spontaneous atrial fibrillation and prolonged QTc duration (α7
−/−
: 25.7±0.74ms, α7
+/+
: 19.5±0.61ms; n=6; p<0.001, QTc=QT/(RR/100)
1/2
). The abnormal cardiac conduction was associated with downregulation of connexin43. However, no significant changes were observed in the expression of ion chanels that have been linked to long QT syndrome or atrial fibrillation (kv1.1, kv1.5, kcne1, kcnq1, erg1, Cav1.2 and Cav1.3). In addition, α7
−/−
mice displayed increased susceptibility to drug-induced arrhythmias: treatment with ouabain (2mg/kg BW) in combination with isoprenaline (2.5mg/kg BW) induced atrial fibrillation and ventricular tachycardia and eventually death in 6 month-old integrin α7
−/−
mice, but not in α7
+/+
mice. Interestingly, α7
−/−
also displayed concentric ventricular hypertrophy with increased septal wall thickness and reduced left ventricular end-diastolic diameter starting from 6 months of age. These structural changes were accompanied by an increase in myocyte size and increased ERK1/2 phosphorylation. In conclusion, deletion of the integrin α7 gene in mice leads to ventricular hypertrophy and to abnormal cardiac conduction. The integrin α7 deficient mice have a marked propensity to lethal arrhythmias through alterations in gap junctions but not ion channels. The integrin α7 knockout model provides new insight into the link between the extracellular matrix and cardiac conduction.
Abstract 5369: Mesenchymal Stem Cells Overexpressing CXCR4 (CXCR4
+
-MSCs) Attenuate Remodeling of Post-Myocardial Infarction by Releasing Anti-Fibrotic Enzymes
Authors: Wang Tao , Wang Yigang , Zhang Dongsheng , Zhao Tiemin , Ashraf Atif , Xu Meifeng , Ashraf Muhammad
Published: July 2021

We hypothesize that CXCR4
+
-MSCs penetrate and proliferate in infracted heart by releasing collagen degrading enzymes. We genetically engineered male mouse MSCs using ex vivo adenoviral transduction for over-expression of CXCR4/GFP or GFP alone. MSCs (G-I) or CXCR4
+
-MSCs (G-II) or CXCR4
+
-MSCs treated with epigallocarechin gallate (EGCG, 50μg/ml), a MT1-matrix metalloproteinases (MMPs) inhibitor (G-III) or CXCR4
+
-MSCs with AMD3100 (5 μg/mL), a CXCR4-selective antagonist (G-IV). A Trans-Matrigel Chemoinvasion Assay was used to evaluate the ability of MSCs to cross the basement membrane. MMPs were analyzed by Western blot and MMP antibody staining. Sex mismatched MSCs were infused into female mice via a tail vein injection 3 days after MI. Mice in G-III were treated with EGCG (100 mg/kg, oral gavage, daily for 2 weeks) to inhibit MMPs and G-IV was treated with AMD3100 (1 mg/kg, i.p. given continually for 6 days after MI). LV fibrosis was detected by Picrosirius red staining. Echocardiography was performed at 4 weeks after MI and hearts were harvested for histological analysis.
In vitro,
cell migration was significantly higher in G-II in the presence of SDF-1α as compared with other groups, (
p
<0.01). EGCG or AMD3100 markedly prevented this response. MMP-9 and MT1-MMP were upregulated significantly only in G-II (p<0.01) exposed to hypoxia. Infiltration of GFP and Y chromosome positive cells in the peri- or infarct area was increased significantly in G-II. CXCR4
+
-MSCs penetrated more effectively into the infarcted region and survived in the ischemic environment as compared to control group. These effects were reduced with EGCG or AMD3100. The ventricular remodeling and interstitial fibrosis were also reduced in G-II but not in other groups. G-II also had less LV dilation (diastolic dimension 4.9±0.2 vs. 6.2±0.3 mm, p<0.05), EF (62±3 vs. 44±4%, p<0.05). Infarct size (31±3.8 vs 43±4.7% of LV, p<0.05) and collagen area fraction (16±2 vs. 28±4 %, p<0.05) were significantly reduced in G-2 compared to G-I. Under hypoxic conditions MMPs were upregulated in CXCR4
+
-MSCs which crossed the basement membrane by releasing enzymes leading to breakdown or reduction of scar formation thus facilitating cell homing and proliferation.
Abstract 5564: Sequencial Activation of VEGF/Flk-1/MKK2/NFkappaB Signaling in Ischemic Preconditioning Induced Neovascularization: A Study with Flk-1+/− and MKK2−/− Knockout Mice
Authors: Thirunavukkarasu Mahesh , Akita Yozu , Samuel Samson Mathews , Zhan Lijun , Huang Chi-Kuang , Gaestel Matthias , Maulik Nilanjana
Published: July 2021

Ischemic preconditioning mediated activation of VEGF-FLK-1-MKK2/NFkappaB pathway identifies these components as a critical regulator of myocardial angiogenesis in an infarcted myocardium. In the present study we used Flk-1+/− and MKK2−/− knockout mice in an attempt to address and prove this important clinical issue by identifying potential downstream candidates of VEGF signaling through Flk-1 receptor that trigger angiogenic signal during ischemic preconditioning (IP). Both wild type (WT) and Flk1+/− mice were subjected to either permanent LAD ligation (MI) or Ischemic preconditioning (IP) followed by MI. Flk-1+/− mouse hearts displayed significant increase in infarct size in Flk-1+/−PCMI (46%) group as compared to WTPCMI (33%) groups. Immunohistochemical analysis demonstrated decreased capillary and arteriolar density in both Flk-1+/−MI and Flk-1+/−PCMI groups as compared to WTMI and WTPCMI. Echocardiography demonstrated significant decrease in fractional shortening ( 21% vs 28%) and ejection fraction (42% vs 54%) following 4 weeks of myocardial infarction in Flk-1+/−PCMI group as compared with WTPCMI. As expected we found Flk-1+/− resulted in disruption of the cardioprotective effect by IP compared to WT. IP induced phosphorylation of p38MAPK, MKK2 was found to be inhibited (1.8 and 2 folds) significantly in both the Flk-1+/−MI and Flk-1+/−PCMI groups by Western blot analysis. Similarly Gelshift analysis showed down regulation of transcription factor NFkappaB (2 fold) in the Flk-1+/− mice as compared to WT. We further extended our experiments to validate our data in MKK2−/− mice. Hearts were subjected to LAD ligation. After 4-days of MI BSL-lectin infusion demonstrated significant disruption of neovascularization (capillary density) in the MKK2−/−PCMI (1520 counts/mm2) group compared to the WTPCMI ( 1850 counts/mm2). Gel-shift analysis in MKK2−/−PCMI group documented reduced NFkappaB activity (1.5 fold) compared to WTPCMI (2.4 fold). Taken together, this study validated for the first time that NFkappaB is a novel downstream mediator of VEGF/FLK-1/p38MAPK-MKK2 signaling and it induces IP mediated cardioprotection and angiogenesis via MKK2 signaling.