tbuckley/cabot-search huggingface dataset:
Abstract 9636: Autophagy Plays a Critical Role in Maintenance of Cardiac Function in Diabetes
Authors: Hiromitsu Kanamori, Genzou Takemura, Kazuko Goto, Akiko Tsujimoto, Atsushi Mikami, Atsushi Ogino, Takatomo Watanabe, Kentaro Morishita, Mitsuru Seishima, Shinya Minatoguchi
Journal: Circulation (2013)

Although diabetic cardiomyopathy, which develops in the absence of major coronary artery disease, is one of the leading causes of heart failure, the pathogenesis is still unclear. Little is known on the relationship between diabetic cardiomyopathy and autophagy which is intracellular self digesting mechanism and reported in various pathologic conditions. Here, we investigated the perturbation of autophagy in diabetic hearts. We used GFP (green fluorescent protein)-LC3 (microtubule-associated protein 1 light chain 3) transgenic mice to monitor the autophagic vacuole in which type I diabetes was induced by an intraperitoneal injection of streptozotocin (250 mg/kg). Thirty-four diabetes mice were treated with saline or an autophagy inhibitor chloroquine (10mg/kg/day) (n=17 each) for 2 weeks while so were nondiabetes control group (n=17 each). Cardiac function was evaluated by echocardiography and cardiac catheterization. In diabetes mice, although systolic cardiac function and left ventricular diameter were similar to nondiabetes mice, diastolic cardiac function was aggravated compared with nondiabetes mice. And autophagic findings were significantly augmented in diabetes heart where expression levels of LC3-II, LC3-II/I ratio, p62, and cathepsin D were increased and abundant autophagic vacuoles and lysosome were observed under electron microscopy. The AMP-activated protein kinase (AMPK) was upregulated and myocardial ATP content was decreased in diabetes heart. Treatment with chloroquine provided no significant influence on the cardiac function and geometry in nondiabetes mice. In diabetes mice, however, chloroquine treatment caused significant left ventricular dilatation and aggravation of cardiac function (both systolic and diastolic), in which autohagic findings were significantly suppressed. In addition, chloroquine treatment brought about further reduction of ATP content and further activation of AMPK in the diabetes heart. In conclusion, our findings suggest a critical role of autophagy that compensates for lack of energy to maintain cardiac function in diabetes heart.
Abstract 9933: Impact of Antiplatelet Therapy in Patients With Impaired Glucose Tolerance
Authors: Masafumi Ueno, Kosuke Fujita, Hiroyuki Yamamoto, Tomoyuki Ikeda, Tatsuya Suga, Kenji Yamaji, Shinichiro Ikuta, Kazuhiro Kobuke, Yoshitaka Iwanaga, Shunichi Miyazaki
Journal: Circulation (2013)

Background: Patients with diabetes mellitus (DM) have reduced clopidogrel-induced antiplatelet effects and increased rates of high platelet reactivity (HPR) compared with non-DM patients. Although approximately 40% of patients with coronary artery disease (CAD) have a pre-diabetic status characterized by impaired glucose tolerance (IGT). However, the impact of IGT on pharmacodynamic (PD) response to antiplatelet therapy is unknown. Objectives: To investigate the impact of IGT on PD response to antiplatelet therapy in patients with IGT. Methods: A 75g oral glucose tolerance test was performed in 52 stable CAD patients treated with maintenance aspirin and clopidogrel therapy. Blood samples were collected at 3 time-points (baseline, 1 and 2 hours after glucose load). IGT was defined as fasting plasma glucose of 110-126 mg/dl and 2 hour plasma glucose of 140-200 mg/dl. Platelet aggregation was assessed by light transmittance aggregometry using 5 and 20 μmol/L ADP stimuli. HPR rates was defined when both maximal aggregation was ≥ 59% with 20 μmol/L ADP and ≥ 46% with 5 μmol/L ADP. Results: There were 22 subjects (42%) who had IGT. At baseline, patients with IGT showed increased platelet reactivity at 5 μmol/L ADP (45.3±13.7 vs 38.6±13.4; p=0.09) and 20 μmol/L ADP stimuli (57.6±12.6 vs 47.5±14.3; p=0.01), and higher HPR rates (54.5% vs 16.0%; p=0.01) compared with non-IGT patients. Similar results were obtained at 1 hour [5 μmol/L ADP (43.1±13.7 vs 36.4±13.9; p=0.1), 20 μmol/L ADP (55.2±12.2 vs 45.4±14.3: p=0.01), HPR rates (36.4% vs 12.5%; p=0.08)], and 2 hours [5 μmol/L ADP (40.7±14.9 vs 35.8±13.9; p=0.2), 20 μmol/L ADP (52.5±12.4 vs 44.4±13.8: p=0.04), HPR rates (40.9% vs 8.3%; p=0.01)]. Conclusions: Patients with IGT on dual antiplatelet therapy with aspirin and clopidogrel have enhanced platelet reactivity and increased rates of high platelet reactivity compared with non-IGT patients, suggesting platelet dysfunction which is independent of hyperglycemia may exist in pre-diabetic patients.
Abstract 9563: High-frequency QRS Analysis is More Specific and Accurate Than Conventional ST-segment Analysis in Diagnosing Coronary Ischaemia
Authors: Ngai Y Chan, Hoi F Chow, Ho C Yuen, Pui S Chu, Suet T Lau, Ping T Tsui, Chi C Choy, Chun L Lau, Ying K Lo, Ngai S Mok
Journal: Circulation (2013)

Purpose: High-frequency QRS analysis (HFQRS) is a new tool for detecting stress-induced coronary ischaemia. This study aims to compare HFQRS with conventional ST-segment analysis (STA) in the diagnostic performance in patients with chest pain and no history of coronary artery disease, which has not been investigated before. Methods: One hundred and seventy-five patients (120 men; mean age 58.2±7.5) with chest pain referred for diagnostic workup of coronary ischaemia were recruited. They underwent symptom-limited exercise treadmill test with both HFQRS and STA, followed by myocardial perfusion imaging (MPI) to confirm presence or absence of ischaemia. Results: Coronary ischaemia was present in 20 (11.4%) patients by MPI. HFQRS was more specific (85.8 vs 68.4%; p=0.002) and similarly sensitive (45 vs 60%; p=0.371) compared with STA. HFQRS had a higher positive predictive value (29 vs 19.7%; p=0.01) and similar negative predictive value (92.4 vs 93%; p=0.61) compared with STA. The diagnostic accuracy for coronary ischaemia by HFQRS was significantly higher than STA (81.1 vs 67.4%; p=0.001). Conclusions: HFQRS is more specific and accurate than STA in diagnosing coronary ischaemia in patients with chest pain and no prior history of coronary artery disease.
Abstract 9623: Stimulatory Effects of Cardiotrophin-1 on Atherosclerosis
Authors: Takuya Watanabe, Hanae Konii, Sayaka Kikuchi, Hazuki Okiyama, Rena Watanabe, Akinori Hasegawa, Keigo Yamamoto, Kengo Sato, Fumiko Itoh, Tsutomu Hirano
Journal: Circulation (2013)

Cardiotrophin-1 (CT-1), a cytokine belonging to the interleukin-6 superfamily, was recently shown to be expressed in the intima of early atherosclerotic lesions in the human carotid artery. CT-1 stimulates pro-atherogenic molecule expression in human vascular endothelial cells (EC) and monocyte migration. However, it has not been reported whether CT-1 accelerates atherosclerosis. This study was performed to examine the stimulatory effects of CT-1 on human macrophage foam cell formation, human EC proliferation, and the migration and proliferation of human vascular smooth muscle cells (VSMCs) in vitro, and on the development of atherosclerotic lesions in apolipoprotein E-deficient (ApoE-/-) mice in vivo. CT-1 was expressed at high levels in ECs and macrophages in both humans and ApoE-/- mice. CT-1 significantly enhanced oxidized low-density lipoprotein-induced foam cell formation associated with increased levels of CD36 and acyl-CoA:cholesterol acyltransferase-1 (ACAT1) expression in human monocyte-derived macrophages. CT-1 also significantly stimulated the migration and proliferation of human aortic VSMCs, but not EC proliferation. Four-week-infusion of CT-1 into ApoE-/- mice significantly accelerated the development of aortic atherosclerotic lesions with increased monocyte/macrophage infiltration and VSMC content in the aortic wall. Activation of inflammasome, such as apoptosis-associated speck-like protein containing a caspase recruitment domain, nuclear factor-κB, and cyclooxygenase-2, was observed in exudate peritoneal macrophages from ApoE-/- mice infused with CT-1. Infusion of anti-CT-1 neutralizing antibody alone into ApoE-/- mice significantly suppressed monocyte/macrophage infiltration in atherosclerotic lesions. These results indicate that CT-1 accelerates the development of atherosclerotic lesions by stimulating the inflammasome and foam cell formation associated with CD36 and ACAT1 up-regulation in macrophages and VSMC migration and proliferation, contributing to the occurrence of atherosclerotic vascular diseases. Blockade of cardiotrophin-1 is expected to emerge as a new line of therapy against atherosclerosis and its related diseases.
Abstract 9772: Caloric Restriction Enhances Cardiomyocyte Autophagy via AMPK and ULK1 Pathways and Mitigates Postinfarction Cardiac Remodeling and Dysfunction
Authors: Takatomo Watanabe, Genzou Takemura, Hiromitsu Kanamori, Akiko Tsujimoto, Kazuko Goto, Atsushi Ogino, Kentaro Morishita, Hisayoshi Fujiwara, Takako Fujiwara, Atsushi Mikami, Shinya Minatoguchi
Journal: Circulation (2013)

We previously reported that cardiomyocyte autophagy is an innate mechanism that protects against progression of postinfarction cardiac remodeling. In the present study, we hypothesized that caloric restriction (CR), a potent inducer of autophagy, enhances cardiomyocyte authophagy and mitigates post-infarction cardiac remodeling and dysfunction.Myocardial infarction (MI) was induced in mice by ligating the left coronary artery. After one week of MI, mice were randomly divided into the following four groups. The control group was fed ad libitum (100%; n=6). Others were fed restricted diet respectively 80%, 60%, and 40% of the control mice’s total calorie (n=6 each). Three weeks later, we evaluated the left ventricular (LV) function. The dilatation and hypofunction of the LV were apparent in the control group: LV diastolic dimension (LVDd) = 4.9±0.1 mm; LV ejection fraction (LVEF) = 27±3.3%; and +dP/dt = 4677±277 mmHg/s. However, both dilatation and hypofunction were significantly mitigated in groups undergoing CR: in 80%, 60%, and 40%CR, respectively, LVDd = 4.0±0.1 mm, 3.4±0.2 mm and 4.0±0.1 mm; LVEF = 36±2.8%, 51±4.3% and 43±1.5%; and +dP/dt = 6849±221 mmHg/s, 7758±638 mmHg/s and 6923±553mmHg/s, among which the 60% CR group showed the strongest therapeutic effect on postinfarction cardiac remodeling (control vs. 60% CR: p&lt;0.001). Cardiomyocyte autophagy was markedly activated in CR groups as evidenced by the overexpressed microtubule-associated protein 1 light chain 3-II (LC3-II) and specific ultrastructural findings including autophagosome formation. Myocardial ATP contents were found significantly increased in the 60% CR group compared with other groups. The activities of AMP-activated protein kinase (AMPK), ULK1 (a homolog of yeast Atg1) and silent information regulator-1 (Sirt1) were enhanced in hearts of the CR groups. Chloroquine, an inhibitor of autophagy, brought about deleterious outcomes, accompanying inactivation of AMPK-ULK1 but not influencing Sirt1 activity.In conclusion, caloric restriction enhances cardiomyocyte autophagy via AMPK-ULK1 pathway to enhance energy status and ameliorates left ventricular remodeling in the postinfarction heart; the optimal caloric restriction is suggested to be 60%.
Abstract 278: Sodium Nitroprusside Combined With Epinephrine for Prolonged Ventricular Fibrillation Cardiac Arrest
Authors: Karl B Kern, Mathias Zuercher, Ronald W Hilwig, Arthur B Sanders, Charles W Otto, Gordon A Ewy
Journal: Circulation (2013)

Background: A new approach to resuscitation using the potent vasodilator sodium nitroprusside (SNP) combined with mechanical efforts to maintain both coronary and cerebral perfusion pressures (active compression/decompression CPR combined with an impedance threshold device and abdominal binding) has reported improved survival with good neurological function. We hypothesized that a potent vasoconstricting agent like epinephrine (E) might replace the multiple mechanical components of this approach without compromising outcomes. Methods: We studied a total of 24 swine (25±5 kg) utilizing a 10-min period of untreated ventricular fibrillation. This was followed by 2-min of chest compressions and then an attempted defibrillation. The 2-min compression and subsequent defibrillation effort was repeated. Next another 2-min of chest compressions, during which both medications were administered, followed by attempted defibrillation. This first drug administration period occurred at 14 min 20 seconds after the onset of cardiac arrest. A total of five such 2-min of chest compressions followed by drug administration were performed if needed for ROSC. Animals were randomized to receive either SNP/E or placebo. Doses included 0.5 mg of SNP every 2 min for a maximum dose of 2.5 mg over 15 min and 1.3 mg of E every 2 min for a maximum dose of 6.75 mg. The primary endpoint was normal neurological function (CPC =1) at 24 hours. Statistical analysis utilized Fisher’s Exact testing. Results: Three subjects were successfully resuscitated prior to receiving any medications and were eliminated from this comparison. A total of 7/9 SNP/E animals were resuscitated in contrast to 6/13 animal receiving placebo (p=0.2). At 24 hours a CPC score of 1 was seen in 1/7 SNP/E animals compared to 5/6 placebo animals (p=0.03). Conclusion: Sodium nitroprusside combined with epinephrine failed to improve 24-hour neurological function in this protocol designed to mimic the late administration of medications during ACLS resuscitation. Epinephrine was unable to successfully replace the previously reported mechanical components of sodium nitroprusside-enhanced CPR (SNPeCPR). The propensity for epinephrine to increase ROSC, but not longer-term endpoints, remains a concern.
Abstract 9464: International Incidence of Complications After Catheter Ablation of Persistent Atrial Fibrillation (AF): Insights From the Multicenter, Prospective, Randomized STAR AF II Trial
Authors: Atul Verma, Jiang Chen-yang, Tim Betts, Jian Chen, Isabel Deisenhofer, Roberto Mantovan, Laurent Macle, Carlos Morillo, Prashanthan Sanders
Journal: Circulation (2013)

Background: Complication rates after AF ablation are mostly reported in single center experiences or surveys. Little international, multicenter, prospective data on the contemporary incidence of complications is available. We report the incidence of complications from the large STAR AF II randomized trial. Methods: The STAR AF II trial is an international, randomized trial comparing 3 different strategies for ablation of persistent AF: pulmonary vein isolation (PVI) alone, PVI + linear ablation, and PVI + ablation of complex fractionated electrograms. 48 centers were involved across Canada, Australia, Korea, China, &amp; 8 countries in Europe. Post-ablation, patients were all followed for 18 months. All adverse events were reported by protocol and were classified as “serious” if it was fatal, life-threatening, disabling, or required/prolonged hospitalization. Adverse events were also reviewed by an independent data safety monitoring board and classified as either being related or unrelated to the ablation procedure. Adverse events related to the ablation procedure were included in this analysis. Results: Patients (n=589) were enrolled in the STAR AF II trial (age 60±10 years, 79% male, EF 56±10%, LA diameter 44±9 mm). The most common post-procedural complications were access site hematoma (n=16, 2.7%), fluid overload/pulmonary edema (n=16, 2.7%), and transient pericarditis (n=15, 2.5%). Access site arterio-venous fistulas or pseudoaneurysms occurred in 7 patients (1.2%). Complications related to sedation occurred in 5 patients (0.8%). Cardiac tamponade (n=3, 0.5%), stroke or transient ischemic attack (n=3, 0.5%), and symptomatic PV stenosis (n=1, 0.2%) were uncommon. None of the neurological events resulted in permanent deficit. There was one atrio-esophageal fistula complicated by stroke which was successfully stented, but the patient died of aspiration pneumonia three months later. Conclusions: The most common complications were access site hematoma, fluid overload, and transient pericarditis. The rates of serious adverse events such as tamponade, stroke and symptomatic PV stenosis were quite low. There was one atrio-esophageal fistula that caused late death despite successful repair.
Abstract 9638: Abnormal Glucose Metabolism Predicts Morbidity and Mortality in Adult Patients With Complex Congenital Heart Disease
Authors: Hideo Ohuchi, Kenji Yasuda, Shin Ono, Toru Iwasa, Jun Negishi, Kanae Noritake, Aya Miyazaki, Osamu Yamada
Journal: Circulation (2013)

Background: Adult patients with complex congenital heart disease (ACHD) have a high prevalence of abnormal glucose metabolism (AGM). However, the impact of AGM on their prognosis remains unclear. Purpose: This study was to clarify the prognostic value of AGM assessed by 75g oral glucose tolerance test (OGTT) in ACHD. Method and Results: We performed a 75g OGTT to detect AGM in 414 consecutive ACHD (27 ± 8 years), including 36 unrepaired patients (Cy), 135 Fontan patients, 243 post-biventricular patients, and 27 healthy controls (27 ± 5 years), and compared the results with the hemodynamics, neurohumoral activities, peak oxygen uptake, unscheduled hospitalization (USH), and all cause mortality. When compared with the control group, fasting blood glucose level (FBS) was lower, especially the group Cy, and postprandial hyperglycemia measured by area under the curve of glucose (BS-AUC) was higher in all ACHD groups (p &lt; 0.0001 for all). The lower body mass index (BMI) and hypoxia independently determined the FBS, while older age, greater BMI, high plasma renin activity and central venous pressure independently determined the high BS-AUC (p &lt; 0.05-0.01). Greater BS-AUC (per 1 g/dl, HR:1.07, 95%CI:1.01-1.13, p = 0.02) and lower FBS (per 1 mg/dl, HR:0.89, 95%CI:0.83-0.96, p = 0.002) predicted USH and mortality, respectively. Conclusions: Body composition and heart failure severity are closely associated with AGM in ACHD and the AGM predicts the morbidity and mortality, implying an importance of glucose metabolic management for the better long-term outcome in ACHD.
Abstract 9307: Acute Coronary Syndrome-Like ST-T Changes on Admission Electrocardiogram Predicts In-hospital Death in Patients With Type A Acute Aortic Dissection
Authors: Masami Kosuge, Keiji Uchida, Kiyotaka Imoto, Toshiaki Ebina, Kiyoshi Hibi, Munetaka Masuda, Satoshi Umemura, Kazuo Kimura
Journal: Circulation (2013)

Background: In patients with Stanford type A acute aortic dissection (AAD), acute coronary syndrome (ACS)-like ST-T changes such as ST segment elevation (STE) or depression (STD) or negative T wave (Neg T) have been shown to be often observed at presentation. However, the frequency and prognostic impact of such ECG findings remain unclear. Methods: We studied the relation admission ECG findings to clinical features at presentation and in-hospital mortality in 258 patients with type A AAD who were admitted within 6 h from symptom onset. Emergency surgery was underwent in 233 patients (90%). Results: Patients were divided into the 3 groups according to ECG findings on admission: ACS-like ST-T changes (n=131) [STE (n=11) and STD/Neg T (n=120)]; normal ECG (n=77), and ECG confounders (n=50) [right bundle branch block (n=20) and left ventricular hypertrophy (n=30)]. Age, sex, time to admission, the rate of emergency surgery were similar in the 3 groups. Patients with ACS-like ST-T changes had more frequently had positive troponin (17% vs 3%, 13%), severe hypertension as defined by systolic blood pressure ≥180 mmHg (18% vs 5%, 6%), pericardial effusion (46% vs 9%, 34%), cardiac tamponade (27% vs 3%, 18%), moderate/severe aortic regurgitation (27% vs 7%, 18%), shock (33% vs 3%, 12%) on admission, and in-hospital mortality (14% vs 3%, 6%) as compared with patients who had normal ECG and those who had ECG confounders (p&lt;0.05 for all). In 233 patients undergoing emergency surgery, those with ACS-like ST-T changes had higher prevalences of coronary ostial involvement (14% vs 1%, 2%), concomitant coronary artery bypass surgery (9% vs 1%, 0%) as compared with those with normal ECG and those with ECG confounders (all p&lt;0.05, respectively). On multivariate analysis, ACS-like ST-T changes (odds ratio 3.28, 95%CI 1.02 to 10.1, p=0.038) and no surgically treatment (odds ratio 4.37, 95%CI 1.29 to 14.9, p=0.018) were the independent and significant predictors of in-hospital death. Conclusions: Nearly 50% of patients with type A AAD within 6 h from symptom onset showed ACS-like ST-T changes on admission ECG, especially STD/Neg T. ACS-like ST-T changes were associated with more complicated features and independently predicted in-hospital death.
Abstract 9409: DSR-85955, a Novel Mineralocorticoid Receptor Antagonist With Carbonic Anhydrase Inhibitory Activity, Exhibits Low Hyperkalemia Risk in Rats
Authors: Hiroshi Kato, Masaya Mori, Shintome Masakazu, Tetsuro Nariai, Seiji Katayama, Seiji Hori, Futoshi Hasegawa, Kuniko Suzuki, Katsuya Fujita
Journal: Circulation (2013)

Background: Mineralocorticoid receptor (MR) antagonists, such as spironolactone and eplerenone, are useful for the treatment of hypertension and heart failure. However, these antagonists should be used carefully not to cause hyperkalemia as they can interfere with sodium/potassium exchange and reduce urinary potassium excretion. We hypothesized that increase in urinary potassium excretion can reduce elevated plasma potassium level, and accordingly identified DSR-85955 as a safe and orally effective MR antagonist with low hyperkalemia risk. We present the unique in vitro / in vivo profile of DSR-85955. Methods and Results: Using reporter gene assay, we first determined DSR-85955 selectivity for MR and compared it to that for androgen, progesterone, and glucocorticoid steroid receptors. DSR-85955 exhibited high selectivity for MR with an IC50 value of 0.39±0.1 uM (11±2.3 uM for the androgen / progesterone receptor, and 36±4.7 uM for the glucocorticoid receptor). To clarify DSR-85955 low risk for hyperkalemia, we focused on the hypokalemic side effect of other classes of diuretics. We found that DSR-85955, but not spironolactone or eplerenone, inhibits carbonic anhydrase involved in carbon dioxide transport. Next, we compared the effects of DSR-85955, spironolactone, and eplerenone on sodium excretion in deoxycorticosterone acetate-treated rats and plasma potassium levels in potassium-loaded rats. DSR-85955 (30 - 300 mg/kg) reversed sodium excretion without increasing plasma potassium level. Spironolactone and eplerenone, on the other hand, reversed sodium excretion at doses that increased plasma potassium level. In another experiment, 2-week-treatment with DSR-85955 (10 - 100 mg/kg) reduced systolic blood pressure in both uninephrectomized rats treated with aldosterone/salt (UN-Ald/Salt) and spontaneous hypertensive rats. DSR-85955 also decreased urinary albumin excretion in UN-Ald/Salt rats and heart weight in spontaneous hypertensive rats. The anti-hypertensive and organ protective effects of DSR-85955 were 2 to 3 times stronger than those of eplerenone. Conclusion: We have identified DSR-85955, a selective MR antagonist with CA inhibitory activity, as a hopeful antihypertensive candidate with low hyperkalemia risk.