tbuckley/cabot-search huggingface dataset:
Abstract 180: Mild Systemic Hypothermia Induced by Preferential Brain Cooling Suppresses Cardiovascular Functions More Significantly Than That Induced by Systemic Cooling in a Rabbit Model
Authors: Jun Guan, Mengyuan Diao, Zhaofen Lin, Zhe Zhang, Yan Xiao
Journal: Circulation (2013)

Introduction: The optimal target temperature for preferential brain cooling is unclear. Hypothesis: Preferential brain cooling suppresses cardiovascular functions more significantly than systemic cooling with the same core body temperature (Tc) target of therapeutic mild hypothermia (TMH). Methods: After anesthesia and instrumentation, five rabbits first received preferential brain cooling by using a semiconductor neck cooling collar starting from 37°C of Tc to the target of 34°C. Then after rewarming to 37°C of Tc by warming blanket, the animals received systemic cooling with the same Tc target by ice pads and fan. Another five rabbits first received systemic cooling, and then received neck cooling with the same procedures. Mean arterial pressure (MAP), heart rate (HR), left ventricular systolic pressure (LVSP), LV dp/dt, LV -dp/dt, respiratory rate (RR), PetCO2, brain temperature (Tb) and Tc were continuously monitored and recorded at 0.2°C interval of Tc during hypothermia in all animals. For monitoring Tb and Tc, thermoprobes were placed into brain parenchyma and rectum respectively. Paired t-test were used to compare measurements at 37°C and 34°C of Tc. Results: During systemic cooling, Tb decreased in parallel with Tc. Only HR decreased significantly from 249±13 bpm at 37°C to 216±14 bpm at 34°C, P&lt;0.001. No significant changes were detected in MAP, dp/dt, -dp/dt, LVSP, RR and PetCO2. In contrast, during neck cooling, Tb decreased 3.1±1.2°C more than Tc at 34°C of Tc. At meantime, MAP decreased significantly from 98±8 mmHg at 37°C to 84±7 mmHg at 34°C, P&lt;0.001. HR, dp/dt, LVSP also decreased significantly, all p&lt;0.01. RR, PetCO2 and -dp/dt did not change significantly. Pearson correlation analysis showed MAP was more closely related to Tb than to Tc, the coefficients were 0.539 (P&lt;0.001) and 0.158 (P=0.002) respectively. Multiple linear regression analysis also showed a higher standardized coefficient of Tb than that of Tc for MAP (0.667 vs. -0.224), indicating that Tb has a greater effect on MAP than Tc. Conclusions: Preferential brain cooling suppresses cardiovascular functions more significantly than systemic cooling when achieving the same core body temperature target of TMH. Brain temperature has a greater impact on MAP than core body temperature during TMH.
Abstract 18030: Electrophysiological Effects of Efferent and Afferent Right and Left Vagal Nerve Stimulation on Regional Ventricular Myocardial Repolarization
Authors: Kentaro Yamakawa, Eileen L So, Jonathan Hoang, Nupur Makkar, Olujimi A Ajijola, Wei Zhou, Aman Mahajan, Kalyanam Shivkumar, Marmar Vaseghi
Journal: Circulation (2013)

BACKGROUND: Vagal nerve stimulation (VNS) is thought to be cardioprotective and decreases ventricular arrhythmias. Regional ventricular electrophysiological differences of left and right and afferent vs. efferent VNS are unclear. The purpose of this study was to evaluate effects of right vs. left and afferent vs. efferent VNS on ventricular repolarization. METHODS: In 8 pigs, the heart, bilateral cervical vagus nerves, and stellate ganglia were exposed. A 56 electrode sock was placed on the ventricles and used to record activation recovery interval (ARI), a marker of action potential duration. ARIs were obtained at baseline and during intact left and right VNS. Further, ARIs were analyzed with afferent (proximal end) or efferent (distal end) VNS under 3 conditions: 1) contralateral vagus intact 2) bilateral vagal transection and 3) bilateral vagal nerve transection plus stellectomy. A Millar conductance catheter was used to record hemodynamics. RESULTS: Intact and efferent left and right VNS decreased heart rate, blood pressure, and dp/dt, P&lt;0.05 for all parameters. Intact and efferent VNS increased ARI by 49±20 ms (right intact), 45±16 ms (left intact), 46±15 ms (right efferent), and 36±8 ms (left efferent), P&lt;0.05 for all conditions vs. baseline. No significant regional differences in ARI were found with efferent VNS. Transection of the contralateral vagus nerve did not alter the effects of ipsilateral efferent VNS (403±36 ms vs. 396±31 ms, P=NS). Afferent VNS had no significant influence on ventricular ARI, with contralateral vagus nerve intact (from 365±27 ms to 373±28 ms, P=NS) or transected (from 354±25 ms to 346±27 ms, P=NS). Stellectomy reduced the impact of efferent VNS (412±26 ms pre vs. 382±25 ms post stellectomy, P&lt;0.05). CONCLUSIONS: Unlike left and right sympathetic innervation, epicardial vagal innervation is uniform without significant regional differences. Effects of efferent VNS are diminished by sympathectomy. Afferent VNS had no impact on ARI.
Abstract 10092: Renal Evidence of Remote Ischemic Conditioning for Elective Coronary Revascularization: A Meta-analysis of 13 Randomized Trials
Authors: Chenghui Zhou, Lihuan Li, Yuehua Li, Derek Hausenloy, Yunseok Jeon
Journal: Circulation (2015)

Background: Several early small trials have concerned about the renal effect of periprocedural remote ischemic conditioning(RIC) in patients with coronary artery disease(CAD), however, negative results were widely obtained. Hence, we sought to summarize the renal evidence of RIC in patients undergoing coronary artery bypass grafting(CABG) or percutaneous coronary intervention(PCI). Methods: A systematic search was performed in Pubmed, Embase, Cochrane library, and scientific sessions of AHA, ACC and ESC (up to April 2015). Randomized controlled trials with data on postoperative acute kidney injury(AKI) during elective coronary revascularization were included. Odds ratio(OR) with 95% confidence interval(CI) was calculated. Random-effect models were used for the potential clinical inconsistency. Publication bias assessment and sensitivity analysis were performed to evaluate the robustness of the results. Results: Thirteen RCTs with a total of 1861 CAD patients were identified and selected. Compared with controls, RIC significantly reduced the incidence of AKI (6.61% vs 11.6%;OR= 0.54; 95% CI, 0.37 to 0.78; P=0.001; I2=8.5%; Figure 1). No evidence of significant publication bias were observed (P=0.784, Begg’s test; P=0.096, Egger’s test). Sensitivity analysis of mortality excluding each included study at one time revealed that most individual study was consisted with the direction and size of the overall effect (All P≥0.01).There was no significant difference between CABG subgroup (9.8% vs 16.6%;OR=0.54;95%CI, 0.32 to 0.92; P=0.02; I2=0.0%) and PCI subgroup(5.3% vs 9.4%;OR=0.54; 95% CI, 0.30 to 1.00;P=0.05; I2=36.5%) (P=1.00 for subgroup difference). Conclusions: Based on the available evidence, RIC provides renal protection by reducing the postprocedural AKI in elective coronary revascularization. Such effect is similar between CABG and PCI.
Abstract 11652: Sex-Specific Association of Retinal Microvascular Signs With Atrial Fibrillation: The Multi-Ethnic Study of Atherosclerosis
Authors: Gen-Min Lin, Laura Anne Colangelo, Ronald Klein, Barbara E.K. Klein, Mary Frances Cotch, Tien Y Wong, Carol Y Cheung, Susan R Heckbert, Alvaro Alonso, Younghoon Kwon, Richard A Kronmal, Donald M Lloyd-Jones, Kiang Liu
Journal: Circulation (2016)

Background: Atrial fibrillation (AF) affects men more frequently than women in elderly individuals. Several risk factors have been identified; however the relationship of microvascular characteristics with AF is unclear. Assessment of the relationship of retinal microvascular signs with AF in men and women may provide insights into such a relationship. Methods: We prospectively examined the sex-specific association of retinal microvascular signs with incident AF events in 2,394 men and 2,618 women ages 47-86 years, who were free of prior AF, underwent fundus photography at the second exam (2002-2004) of the Multi-Ethnic Study of Atherosclerosis (MESA), and were followed through 2012. Retinal microvascular signs evaluated include retinal vascular caliber measurements from computer software (defined as the central retinal arteriolar equivalents (CRAE) and venular equivalents (CRVE)), and presence of retinopathy signs. AF events were identified using hospital discharge records, Medicare claims data, and electrocardiographic findings at visit. Results: Over an 8.8-year average follow-up period, 255 and 202 AF events were identified in men and women respectively. In Cox regression analyses, we adjusted for age, race, body mass index, smoking status, diabetes status, systolic blood pressure, lipid profile, HbA1c, C-reactive protein, anti-hypertensive therapy, lipid-lowering therapy, cardiovascular disease, and heart failure. In men, wider CRVE (wider venular diameter) was associated with lower risk of incident AF (hazard ratio [HR] and 95% confidence interval per 10-μm increase in CRVE: 0.92 [0.86-0.99]), whereas in women, wider CRVE was associated with higher risk of incident AF (HR: 1.09 [1.01-1.18], p-value for interaction of sex = 0.0023). There were no associations of CRAE or of any retinopathy with AF in men or women. Conclusions: We found associations of narrower retinal venular diameters in men and wider retinal venular diameters in women at baseline with the incidence of AF but with no evidence of relationships of retinal arteriolar diameters or the presence of any retinopathy at baseline to the incidence of AF in either men or women. The reasons for the interaction are not understood and its clinical relevance remains to be determined.
Abstract 10829: Biological and Pharmacological Properties of the Protease Proprotein Convertase Subtilisin-Like Kexin Type 9 Antagonists <i>(Best of Basic Science Abstract)</i>
Authors: Nabil A Elshourbagy, Harold V Meyers, Shaker A Mousa, Sherin S Abdel-Meguid
Journal: Circulation (2015)

Protease proprotein convertase subtilisin-like kexin type 9 (PCSK9) is a new important target for the treatment of hypercholesterolemia. Currently, several pharmaceutical companies are racing to develop new drugs against PCSK9, which could be the newest weapon against heart disease since the introduction of statins in the 80’s. However, those companies have focused primarily on the development of mAbs, not small molecules, as drugs. PCSK9 is a serine protease that is synthesized as a zymogen that undergoes autocatalytic processing and secretion. Secreted PCSK9 binds to the LDL-receptor (LDLR) and chaperones it to the degradation pathway. This study focused on the identification of antagonists of the PCSK9/LDLR interaction and explored their mechanism of action using a range of functional assays, as well as determined pharmacokinetic (PK) and pharmacodynamic (PD) properties of the lead compounds. Potential inhibitors of the PCSK9/LDLR interaction were identified through a virtual screen at the PCSK9 surface where the LDLR-EGF-A binds. The top hits exhibited inhibition of PCSK9/LDLR binding in the low micromolar (μM) range, a 5-fold upregulation of the LDLR at an inhibitor concentration of 1.6 μM in recombinant cell-based assays, and an increase in the fluorescently labeled DiI-LDL uptake in the nanomolar (nM) range in situ . Pharmacological studies revealed that subcutaneous injection of 4 mg/kg of one of these compounds resulted in a 32% reduction of the total cholesterol and 20% reduction in LDL-C levels in mice fed a high fat/high cholesterol diet. Moreover, administration of 40mg/kg of atorvastatin resulted in a 27% total cholesterol reduction and 20% reduction in LDL-C level. Additional studies were performed to evaluate the effect of the combination of our PCSK9 inhibitor with atorvastatin. Administration of the PCSK9 inhibitor (4 mg/ kg) in combination with atorvastatin (40 mg/kg) resulted in more than a 40% reduction in LDL-C in mice fed a high fat/high cholesterol diet. In vivo PK and PD evaluation of our lead PCSK9 inhibitor demonstrated that it was efficacious and exhibited 13% oral bioavailability. To our knowledge, no small molecule orally bioavailable antagonist against PCSK9 has been reported, only mAbs.
Abstract 17996: Study of the Role of Scn5a in the Occurrence of Arrhythmic Events During Myocardial Infarction and Post-ischemic Remodeling
Authors: Benoit Jagu, Thierry Le Tourneau, Flavien Charpentier, Gilles Toumaniantz
Journal: Circulation (2013)

The sodium channel Nav1.5, encoded by the Scn5a gene, is responsible for the excitability and the conduction of electrical impulses through the heart. Nav1.5 mutations are involved in rhythmic or structural pathologies. During the acute phase of myocardial infarction (MI), ventricular arrhythmias were associated with an increased risk of mortality. Over time, progressive left ventricular remodeling such as dilation, hypertrophy and fibrosis, will lead to heart failure. Objectives: The association of mutations carried by genes encoding for cardiac channels with acquired forms of ventricular arrhythmias and post-ischemic myocardial remodeling, are not well characterized. This project studied the role of Nav1.5 channel alterations in the occurrence of ventricular arrhythmias, structural and contraction abnormalities during the acute phase of MI. Methods: The Nav1.5 contribution in this pathological context was evaluated after permanent occlusion of left anterior descending coronary artery performed on mouse invalidated at the heterozygous state for the Scn5a gene (Scn5a+/-; 10-12 w old). After MI validation by echocardiography, they were studied in vivo by echo and electrocardiography and in vitro using molecular investigations during 48 hours post-MI. Results: Scn5a+/--MI mice present a higher mortality due to arrhythmic events. In addition, the ECG recorded by telemetry revealed that they present an increased incidence of premature ventricular beats (5.6±2.7 &amp; 33.1±11 PVB/hour respectively for WT &amp; Scn5a+/--MI) without any difference in structural and functional remodelling. However, mRNA expression revealed that Scn5a+/--MI mice have an increased up-regulation of pro-inflammatory factors IL-6 (3.7±0.9 &amp; 17.4±9.3 Relative Quantity respectively) and IL-1β mRNA (1,8±0.3 &amp; 4.6±0.8 RQ respectively) and downregulation of Cx43 mRNA (0.61±0.08 &amp; 0.39±0.03 RQ respectively) without interstitial fibrosis induction. Conclusions: These observations, 48 hours post-MI, suggest that Scn5a+/- mice present factors for the establishment of a more severe post-ischemic heart failure. In addition, preliminary results obtained on small series of animals revealed that Scn5a+/- mice seem to have a more pronounced LV remodelling at 4 weeks post-MI.
Abstract 18077: Endothelial Behavior and Signaling on Micro and Submicro- Patterned Titanium
Authors: Prashanthi Vandrangi, Shannon Gott, Ryan Kozaka, Masaru P Rao, Victor G Rodgers
Journal: Circulation (2013)

Reestablishment of functional endothelium is crucial to long-term success in vascular stenting. However, numerous studies have shown potential for endothelial dysfunction on current drug eluting stents (DES), due to their reliance upon anti-inflammatory and immunosuppressive drugs for suppression of neointimal hyperplasia. We report results demonstrating that EC adhesion, proliferation, and morphology on Ti substrates can be enhanced significantly in vitro through surface patterning with gratings composed of periodic arrays of grooves with widths as small as 0.5 μm. We further asses the EC function on these surfaces. Patterned substrates were fabricated using our Ti deep reactive ion etching (Ti DRIE) process. After substrate sterilization, HECs were seeded and cultured for 1-3 days. Substrates were then rinsed with phosphate buffered solution (PBS) and adherent HECs were fixed and permeabilized and immuno-histo chemistry was performed and imaged using confocal fluorescent techniques, and processed. Figure 1 shows HECs aligned in the direction of sub-micron grooves and the corresponding signaling results. Activation of vWF, a vital anti-thrombotic, was significantly enhanced on all grating sub-patterns relative to unpatterned control (p value=0.05). Activation of eNOS, a potent vasodilator, generally increased with decreasing feature size. The phosphorylation of AMPK, which is reported to enhance cell polarity and division, was significantly higher on submicron-patterns of 0.75 and 0.5 μm (p value=0.5). Expression of VE Selectin, a metastatic cancer marker, was suppressed on most gratings. Finally, VCAM1, an anti-inflammatory, was negatively transcribed on sub-μm gratings (p value=0.05). These results demonstrate that nanopatterning can promote activation and suppression of atheroprotective and atheroscleotic biomolecules in vitro, thus suggesting promise for promoting native functionality in vivo.
Abstract 10447: The Relationship Between Cerebral Regional Oxygen Saturation During Extracorporeal Cardiopulmonary Resuscitation and Neurological Outcome
Authors: Tomoya Hirose, Naoki Ehara, Tadahiko Shiozaki, Akinori Wakai, Tetsuro Nishimura, Nobuto Mori, Mitsuo Ohnishi, Daikai Sadamitsu, Takeshi Shimazu
Journal: Circulation (2015)

Introduction: In recent years, measurement of cerebral regional oxygen saturation (rSO2) has attracted attention during resuscitation. The objective of this study was to clarify the relationship between serial changes in cerebral rSO2 during extracorporeal cardiopulmonary resuscitation (ECPR) and neurological outcome. Hypothesis: Cerebral rSO2 during ECPR would predict neurological outcome. Methods: We measured serial changes in cerebral rSO2 in patients with out-of-hospital cardiac arrest before and after ECPR in Osaka National Hospital. Results: From January 2013 through March 2015, serial changes in cerebral rSO2 were evaluated in 16 patients. Their outcomes as measured by the Glasgow Outcome Scale (GOS) score at discharge included Good Recovery (GR) in 4 patients, Vegetative State (VS) in 2 patients, and Death (D) in 10 patients. In the poor neurological group (VS and D: n=12, 52.8±4.0 years), the values of cerebral rSO2 increased significantly with ECPR (5 min before ECPR: 52.0±1.8%; 2 min before: 56.1±2.3%; 2 min after ECPR: 63.5±2.2%; 5 min after: 66.4±2.2%; 10 min after: 67.6±2.3% [p&lt;0.01]) (Figure). Contrastingly, in the good neurological group (GR: n=4, 53.8±6.9 years), the values of cerebral rSO2 did not increase significantly with ECPR (5 min before: 61.9±3.1%; 2 min before: 57.1±4.0%; 2 min after: 59.6±3.8%; 5 min after: 61.0±3.7%; 10 min after: 62.0±3.8% [p=0.88]) (Figure). Our study suggested that the patients who maintained a high value of cerebral rSO2 at admission and who did not have significant improvement of cerebral rSO2 after ECPR might have a good neurological prognosis. Conclusion: Cerebral rSO2 during ECPR could predict neurological outcome. Further evaluation of the validity of rSO2 monitoring during ECPR may lead to a new resuscitation strategy.
Abstract 11521: Circulating Thymosin Beta-4 is Elevated in Women With Heart Failure
Authors: Warren K Tan, Siew Pang Chan, Leroy S Pakkiri, Jenny P Chong, Zhaojin Chen, Oi Wah Liew, Tze Pin Ng, Lieng Hsi Ling, David K Sim, Gerard K Leong, Daniel P Yeo, Hean-Yee Ong, Fazlur R Jaufeerally, Raymond C Wong, Ping Chai, Adrian F Low, Pia Davidsson, Li-Ming Gan, Bhat Ratan, Kristy Purnamawati, Carolyn S Lam, Arthur M Richards, Chester L Drum
Journal: Circulation (2016)

Background: Heart failure with preserved ejection (HFpEF) predominates in females, is often difficult to diagnose, has no specific circulating biomarkers, and no proven therapeutic options. Thymosin beta-4 (TB4) is an endogenously produced peptide with cardioprotective properties. In animal models, exogenously delivered TB4 was reported to reduce apoptosis, attenuate inflammation, minimize fibrosis, activate stem cells, preserve ejection fraction, and promote angiogenesis. Measurements of circulating TB4 in humans are limited, and its levels in heart failure (HF) relative to controls is not known. Hypothesis: We hypothesized that TB4 is upregulated in HF as a compensatory mechanism, and may be a plasma marker of HF with either preserved ejection fraction (HFpEF) or reduced ejection fraction (HFrEF). Because TB4 is an X-linked gene, sex-specific regulation is suspected. Methods: To measure plasma levels of TB4, we developed a quantitative and targeted liquid chromatography mass spectroscopy (LCMS) assay. The assay was applied to age- and sex- matched HFpEF (n=219), HFrEF (n=219) and controls (n=219) from a prospective nationwide study. Results: Compared to controls, plasma TB4 was elevated in HFpEF [985(421-1723) ng/mL vs. 1401(720-2379) ng/mL, p&lt;0.001], but not in HFrEF [1106(556-1955) ng/mL, p=0.642]. Stratifying by sex, only women [1623(1040-2625) ng/mL vs. 942(386-1891) ng/mL, p&lt;0.001], but not men [1238.5(586-1967) ng/mL vs 1004(451-1538) ng/mL, p=1.0], had elevated TB4 in the setting of HFpEF. Over 2 years, there were 60 deaths among patients with HF. TB4 predicted time to all-cause mortality in women (p=0.046) but not men (p=0.454) with HF, independent of clinical risk factors and N-terminal pro-B-type natriuretic peptide (adjusted hazards ratio for LnTB4=1.64; 95% CI, 1.01-2.67). Conclusion: Circulating TB4 is a novel marker of HFpEF in women. The independent prognostic impact of plasma TB4 in women with HFpEF suggests the presence of sex-specific mechanisms in HFpEF.
Abstract 11369: Circulating Very Long-Chain Saturated Fatty Acids and Heart Failure
Authors: Rozenn N Lemaitre, Barbara McKnight, Amanda Fretts, Waqas T Qureshi, David S Siscovick, Nona Sotoodehnia, Bruce M Psaty, Dariush Mozaffarian
Journal: Circulation (2016)

Introduction: Myocardial fibrosis with apoptosis contributes to heart failure (HF), and ceramides, with their role in apoptosis, may contribute to this pathophysiological process. However, experimental studies show that ceramides carrying a VLSFA are in fact protective against apoptosis, providing strong evidence that very long-chain saturated fatty acids (VLSFA) impart different biological activity to ceramides. Hypothesis: Circulating VLSFA are associated with lower risk of HF. Methods: We addressed this hypothesis in the Cardiovascular Health Study (CHS), a prospective study of older adults (mean age 72 at entry) with repeated measures of plasma phospholipid fatty acids. Circulating fatty acids were measured at the study baseline in 1992-93, and again where possible, in the 6 th year and 13 th year of follow-up, in plasma phospholipids. We assessed the associations of three VLSFA, arachidic acid (20:0), behenic acid (22:0) and lignoceric acid (24:0), with risk of incident HF using Cox regression with time-dependent covariates and fatty acids. Results: The analyses included 4,060 CHS participants with fatty acid data at least at one time point. During 43,430 person-years, we identified 1228 incident HF. In analyses adjusted for age, sex, race, center, blood pressure, BMI, waist circumference, physical activity, smoking, history of coronary heart disease, atrial fibrillation, diabetes, and current use of antihypertensive medications, higher levels of 22:0 and 24:0 were associated with lower risk of incident HF (Table). With further adjustment for fatty acids previously found to be associated with HF, all three VLSFA were associated with lower risk of incident HF. Conclusions: Higher levels of circulating VLSFA are associated with lower risk of incident HF. These novel findings may open a new avenue of research into these little studied saturated fatty acids and their possible beneficial role in preventing HF.