tbuckley/cabot-search huggingface dataset:
Abstract 9013: Myeloperoxidase is Critically Linked to the Development of Diastolic Heart Failure Following Pressure Overload
Authors: Florian Deuschl, Anna Klinke, Kai Friedrichs, Florian Weinberger, Denise Lau, Volker Rudolph, Tanja Rudolph, Birgit Geerts, Anne Geisler, Matti Adam, Tanja Zeller, Francisco Ojeda-Echevarria, Stefan Blankenberg, Thomas Eschenhagen, Stephan Baldus
Journal: Circulation (2011)

Background: Plasma levels of the leukocyte derived enzyme myeloperoxidase (MPO) are elevated in patients with heart failure (HF). We have shown previously that MPO promotes vasoconstriction, leukocyte recruitment and myocardial fibrosis - suggesting that MPO may be mechanistically linked to the pathophysiology of HF. Here we assessed whether MPO is modulating systolic and diastolic myocardial performance in a pressure overload model. Methods and Results: C57Bl/6-Wild-type (WT) and MPO-deficient (Mpo-/-) mice were subjected to mild transverse aortic constriction (TAC, Δp max: 50 ±10 mmHg). After 6 weeks, echocardiography revealed significantly reduced left ventricular (LV) ejection fraction (EF) in TAC-treated animals as compared to sham operated controls. In vivo hemodynamic assessment of left ventricular function using pressure-volume loops revealed an upward shift of enddiastolic pressure volume relation (EDPVR) in both TAC groups as compared to sham animals (p&lt; 0.001). Of note WT-TAC revealed a significantly higher upward shift than Mpo-/- TAC (3.18 ±0.74 mmHg/µl vs. 1.17 ±0.17 mmHg/µl; n=8; p=0.02). Enddiastolic pressure was higher in WT-TAC as compared to Mpo-/- TAC (6.23 ±1.88 mmHg vs. 2.82 ±0.33 mmHg; n=8; p = 0.05). In WT-TAC heart weight and lung weight normalized on tibia length was significantly increased as compared to Mpo-/- TAC mice (15.21 ±0.67 mg/mm vs. 12.65 ±0.79 mg/mm; n=10; p&lt;0.02; respectively 20.15 ±2.65 mg/mm vs. 10.78 ±1.00 mg/mm; n=10; p=0.006). mRNA of matrix metalloproteinase 9 was increased in WT-TAC mice compared to Mpo-/- TAC (2.58 ±0,84 vs. 0,95 ±0,15, n=11; p=0,06). In accordance with this experimental observations MPO plasma levels of 5,000 patients enrolled in the Gutenberg Health Study were associated with left ventricular hypertrophy (median (IQR): 310pmol/l (240/384) vs. 297pmol/l (237/369); p=0.034). Conclusions: The current data reveal that MPO is critically linked to impaired diastolic compliance during pressure overload. This suggests that leukocyte activation in general and MPO release in particular is not only a prognostic marker in heart failure but evolves as an important pathophysiological link and potential pharmacological target in this disease.
Abstract 98: New Technique of Gas Adiabatic Expansion for Brain and General Hypothermia in Rabbit
Authors: Guy H Fontaine, Frederic Lapostolle, Alban Pages, Julie Piquet, Adrien Lalot, Jean Philippe Didon, Johan Jacob Schmid, Xavier Jouven, Jean Charles Chachques
Journal: Circulation (2012)

Background: Irreversible brain damage is a major issue in the acute treatment of OHCA. Brain protection by fossa nasalis cooling on the field has been reported. We propose a new technique to produce cooling by adiabatic gas expansion. Preliminary in vitro and animal studies have demonstrated that Carbon Dioxyde was able to produce significant cooling. The purpose of this work was to quantify the amount of cooling produced by this method on a rabbit model. Method: Study population consisted of 8 New-Zealand rabbits 3.5 kg studied under ketamine anesthesia without ventilation. Three lead ECG were displayed and sampled. Temperatures in °C, were measured by thermocouples every minute: close to the injector exit located inside a 12mm Ø, 2mm thick PVC canula inserted in the mouth up to the oropharynx, in the mouth close to the canula, in the nasopharynx (equivalent to tympanic) and in the rectum. Temperature curves were displayed on line on a computer screen. Data were processed by Statistica v6.0. A p value ≤ 0.05 was considered as significant. After stabilization of temperatures, gas regulated at around 500 psi was delivered during a period of 13 ± 2.7 min and expanded at the exit of the injector. Results: The initial 90% drop of temperature was obtained near the injector in 3 ± 1.47 minutes. The table below compares the temperatures recorded at the Start of cooling and at the End of this experiment. A significant low temperature was observed near the injector (-16.9°C), the nasopharynx (37.7°C) and the oropharynx (31.2°C). A tendency not reaching statistical significance was obtained on the core temperature (39.4°C). No adverse side effect was observed during and after the experiment especially no injury to the throat by direct visual inspection. Discussion: Core temperature drop was similar to that reported in pigs after nasopharynx PFC evaporation (Yu et al Crit Care Med. 2010). The lowest temperature (-16.9°C) was recorded as expected at the exit of gas, however, oral and nasal temperatures remained within tolerable values. Stronger effect on nasal temperature can be due to better mechanical contact of the canula against the upper oropharynx wall. Non-significant core cooling was probably due to the limit imposed by distance despite normal blood circulation. Nevertheless, a clear tendency was obtained as previously observed with other techniques of fossa nasalis cooling. Conclusion: This study demonstrates for the first time that carbon dioxyde adiabatic expansion in the mouth is effective for brain and body hypothermia in a rabbit model. This new technique which is simple, not expensive and easy to use by a lay person opens new vistas for the treatment of OHCA which can be started intra-arrest before CPR.
Abstract 277: Cerebral Perfusion Targeted Resuscitation: A Novel Method of Cardiac Arrest Resuscitation
Authors: Sam Parnia, Asad Nasir, Anna Ahn, Paul Richman, Hanan Malik, Francis Dorazi
Journal: Circulation (2012)

Background: A major hurdle limiting the ability to improve outcomes from cardiac arrest has been the lack of a non-invasive real-time detection system capable of monitoring the quality of cerebral and other vital organ perfusion and oxygen delivery during cardiopulmonary resuscitation (CPR). Furthermore, although, the detection of poor oxygen delivery is important, the benefits of such a system can only be realized through a system aimed at improving the quality of oxygen delivery to the brain as well as other vital organs in real-time. Here we report on the first application of such a novel system of cerebral perfusion targeted resuscitation. Method: We evaluated the role of cerebral oximetry (Equanox, Nonin, USA) as a real-time marker of cerebral perfusion and oxygen delivery in in-hospital cardiac arrest. We then evaluated the impact of perfusion targeted resuscitation by increasing real-time oxygen delivery using an automated mechanical CPR system (A-CPR) (Life Stat, Michigan Instruments, Michigan, USA) on return of spontaneous circulation (ROSC). Results: Cerebral oximetry provided real time information regarding the quality of perfusion and oxygen delivery. At baseline there was a significant difference in regional cerebral oxygen (rSO2) (mean% ±SE) in patients who achieved ROSC (n=7) compared to those without ROSC (n=15) (38%±3 vs. 22%±2 p&lt;0.002) using conventional manual CPR (M-CPR). Furthermore at mean rSO2 below 30% nobody achieved ROSC. The use of A-CPR (n=12) led to a significant increase in rSO2 compared to M-CPR (n=22) (49%±3 vs. 27%±2 p&lt;0.0001) as well as a significant increase in ROSC (75% vs. 45% p&lt;0.05) reflecting the impact of improved oxygen delivery. Discussion: Real-time recognition and optimization of oxygen balance during resuscitation is critical. While further studies are needed to determine the optimal rSO2 required for longer term outcomes, the novel application of a system of continuous non-invasive real-time monitoring of the quality of oxygen delivery combined with measures aimed at improving this parameter may significantly alter the clinical practice of resuscitation by providing staff with timely information regarding the quality of cerebral oxygen delivery and the means to improve it which has so far been lacking.
Abstract 19668: Primary Care Physician Density and Heart Failure Hospitalization Rates: The Atherosclerosis Risk in Communities (ARIC) Study -Community Surveillance
Authors: Norrina B Allen, Lisa Wruck, Anna Kucharska-Newton, Mercedes Carnethon, Chris Baggett, Wayne Rosamond
Journal: Circulation (2012)

Background: Prior research has demonstrated an association between the density of primary care physicians and avoidable hospitalizations. We aimed to determine the association of primary care physician density on rates of acute decompensated heart failure (ADHF) admissions among residents of the four communities in the Atherosclerosis Risk in Communities (ARIC) Study. Methods: We examined hospitalization rates for ADHF from 2005-2008 among Primary Care Service Areas (PCSA) included in the ARIC community surveillance areas. Validated ADHF hospitalizations were assigned to a PCSA based on the patients’ address. We calculated age, sex and race-adjusted rates for each PCSA using indirect standardization, weighted to account for the stratified random sample. Physician density was defined as the age and sex-adjusted rate of primary care physicians per 100,000 population in 2005, from the AMA Masterfile and centered on the US average. We used GEE Poisson models to examine the association of ADHF hospitalization rates with physician density taking into account the nested structure of the data and adjusted for median family income. Results: This study included 7,233 ADHF hospitalizations from the 3 ARIC surveillance areas (Jackson, MS; Minneapolis, MN; Washington Co., MD) which included more than 1 PCSA. Adjusted physician densities ranged from 55.6 - 92.8 primary physicians per 100,000 pop. Adjusted ADHF hospitalization rates decreased with increasing primary care physician density (see figure). For every increase in the density of primary care physicians of 10 physicians per 100,000 the adjusted rate of ADHF decreased by 24% (p&lt;0.0001). Findings were consistent when family practitioners and internal medicine physician densities were examined separately. Conclusion: Primary care physician densities are associated with heart failure hospitalization with PCSAs. Increasing the availability of primary care physicians may improve heart failure outcomes in the US.
Abstract 9782: Genetic Variation at the <i>SLCO1B1</i> Gene Locus and Low Density Lipoprotein Cholesterol Lowering Response to Pravastatin in the Elderly
Authors: Hironobu Akao, Eliana Polisecki, Kouji Kajinami, Stella Trompet, J Wouter Jukema, Anton J de Craen, Rudi G Westendorp, James Shepherd, Christopher Packard, Brendan M Buckley, Ernst J Schaefer
Journal: Circulation (2011)

Background: Statins have been shown to significantly lower the risk of coronary heart disease morbidity and mortality, and these benefits have been related t lowering of low density lipoprotein (LDL) cholesterol lowering. Statin metabolism is affected by the liver X receptor alpha ( LXRA ) and the solute carrier organic anion transporter ( SLCO1B1 ). The SLCO1B1 rs4149056 variant has been linked to an increased risk of statin induced myositis due to decreased liver uptake of the statin, increased blood levels, and presumably greater statin uptake in muscle tissue. Our goal was to determine whether genetic variation at these gene loci would influence low density lipoprotein (LDL) cholesterol lowering with pravastatin, baseline heart disease, or cardiac endpoints on trial. Methods: We examined associations of single nucleotide polymorphisms (SNPs) at the LXRA (rs12221497) and SLCO1B1 (rs4149056 and rs2306283) gene loci with these variables in 5411 participants in PROSPER (Prospective Study of Pravastatin in the Elderly at Risk) (mean age 75.3 years), who had been randomized to pravastatin 40 mg/day or placebo and were followed for a mean of 3.2 years. Results: No relationships between genetic variation at the LXRA gene locus with statin induced LDL lowering response or other parameters were noted. Both the SLCO1B1 rs4149056 (valine for alanine at 174) and the rs2306283 (asparagine for aspartic acid at 130) SNPs affect the amino acid of the SLCO1B1 gene product. No effects of the rs2306283 SNP on any of the variables was noted. However the presence of the rs4149056 SNP was associated with significantly less LDL cholesterol lowering response to pravastatin (wildtype, 71.5% of the population, -37.0%, heterozygotes, 25.8% of the population, -36.0%, and homozygotes, 2.7% of the population, -31.8%, p=0.003. Conclusions: Our data indicate that the presence of the rs4149056 non-synonymous SNP at the SLCO1B1 gene locus, especially in the approximately 3% of the population that are homozygous for this variant, can significantly decrease the pravastatin induced LDL cholesterol lowering response. Therefore the presence of this variant not only predicts statin induced myositis, but also statin induced LDL lowering response.
Abstract 8321: Reduced Estimated Glomerular Filtration Rate Levels to Predict Mortality Depend on Presence of Hypertension or Diabetes
Authors: Hisako Tsuji
Journal: Circulation (2011)

BACKGROUND: The current staging system of chronic kidney disease based on estimated glomerular filtration rate (eGFR) led to a marked increase in number of subjects to target for intervention and better methods for identifying those at high risk of adverse outcomes is needed. Hypertension (HT) and diabetes (DM) are the leading causes of end-stage renal disease and effect of reduced eGFR on mortality may be different among subjects with HT or DM. We examined effect of reduced eGFR on all-cause mortality according to presence or absence of HT and DM. METHODS: We studied 16,461 subjects (mean age 54±13 years, men 26%) who had the annual health examination offered to adult citizens of Moriguchi city, Osaka, Japan in 1997. The new equation for eGFR based on inulin renal clearance for Japanese was applied. The relative risks (RR) were calculated for mortality of each group according to eGFR levels of &lt;30 mL/min/1.73m 2 (group 1), 30-44 mL/min/1.73m 2 (group 2) and 45-59 mL/min/1.73m 2 (group 3), relative to the highest eGFR group (&gt;60 mL/min/1.73m 2 ; group 4), using proportional hazards regression analyses adjusted for age, sex, smoking, drinking, hypercholesterolemia, and history of cardiovascular disease, separately in DM subjects (with DM), HT only subjects (with HT without DM) and control subjects (no HT or DM). RESULTS: Reduced eGFR &lt;60 mL/min/1.73m 2 was observed in 13.5%. During a mean follow-up of 11.0±3.0 years (median 12.2 years), there were 1,208 deaths. In DM subjects, the RRs were significantly higher in group 3 (HR=1.65, 95% CI=1.12 to 2.42), group 2 (HR=2.03, 95% CI=1.04 to 3.97), and group 1 (HR=8.86, 95% CI=4.28 to 18.31), compared to group 4. In HT only subjects, the RRs were significantly higher in group 2 (HR=1.91, 95% CI=1.32 to 2.78) and group 1 (HR=3.42, 95% CI=1.86 to 6.28). In control subjects, the RR was significantly higher only in group 1 (HR=2.98, 95% CI=1.39 to 6.39). (figure). CONCLUSIONS: Reduced eGFR level to predict mortality depended on presence of HT or DM.
Abstract 19635: Glutathione-S-Transferase P Regulates Endothelial Progenitor Cell (EPC) Function in a c-Jun N-terminal kinase(JNK)-Dependent Manner and Enhances Neovascularization in Post-Infarction Heart Failure
Authors: Guihua Zhou, Tariq Hamid, Mohamed Ameen Mohamed Ismahil, Sumanth D Prabhu
Journal: Circulation (2012)

Glutathione-S-transferase P (GSTP), via non-catalytic inhibition of JNK, modulates proliferation of bone marrow (BM) myeloid progenitors; however, its effects on EPCs are unknown. We hypothesized that GSTP supports normal EPC function via JNK suppression in BM-derived cells, and thereby promotes neovascularization in heart failure (HF). EPCs (CD34+VEGFR2+) and activated monocytes (F4/80+CD11b+) in BM and peripheral blood (PB) were determined by flow cytometry in wild type (WT) and GSTP-/- mice. Compared with WT, GSTP-/- mice exhibited significantly (p&lt;0.01) reduced EPC number in PB (0.13±0.03 vs 0.21±0.07%) and BM (1.0±0.2 vs 1.7±0.6%), and increased activated monocytes, despite augmented numbers of CD34+CD45+ BM hematopoietic stem cells (HSCs; 6.7±0.8 vs 5.8±0.44%). PB EPCs in GSTP-/- mice were restored (p&lt;0.05) with 5 days treatment in vivo with the specific JNK inhibitor, SP600125 (0.26±0.05% vs 0.15±0.04% before SP60025), whereas circulating activated monocytes were significantly reduced. Compared with WT, GSTP-/- BM-derived mononuclear cells cultured in endothelial growth medium for 10 d demonstrated reduced EPC colonies, less EPC migration in Transwell plates (VEGF gradient), and diminished vascular tube formation, indicating that GSTP deficiency decreased EPC differentiation from BM progenitors and EPC functional characteristics. All of these parameters were restored upon concomitant treatment with SP600125, and JNK phosphorylation, which was augmented in GSTP-/- BM, was significantly decreased by SP600125, suggesting JNK dependence of the GSTP-mediated effects on EPCs. Furthermore, EPCs, monocytes, and cardiac remodeling were examined WT and GSTP-/- mice with HF induced by left coronary ligation. As compared with WT, GSTP-/- HF mice exhibited (p&lt;0.05): 1) fewer circulating PB EPCs and increased activated monocytes; 2) increased BM-HSCs but reduced BM EPCs; and 3) exaggerated pathological remodeling, augmented inflammation, and reduced capillary density and neovascularization in failing hearts. We conclude that GSTP promotes EPC function, mediated by inhibition of JNK in BM-derived progenitor cells, and also suppresses inflammation, and thereby imparts cardioprotective benefits in the post-infarct failing heart.
Abstract 19453: Mechanical Unloading with a Micro LVAD after Acute Myocardial Infarction Reduces Adverse Cardiac Remodeling and Left Ventricular Systolic Asynchrony
Authors: Xufeng Wei, Tieluo LI, Pablo Sanchez, Katrina Williams, Shuying Li, Pei Zhang, Zhongjun Wu, Bartley griffith
Journal: Circulation (2012)

Introduction: Mechanical stress plays a critical role during cardiac remodeling post-MI. LVADs can provide circulatory support and profound mechanical unloading both to the preload and afterload of the left ventricle. To demonstrate that short-term cardiac unloading with a left ventricular assist device (LVAD) after an acute myocardial infarction (MI) can prevent cardiac remodeling and improve heart function. Methods: Adult ovine hearts were unloaded with an axial-flow LVAD (Impella LD) during the first 2 weeks after an acute MI and were analyzed for 10 more weeks (n=8, MI+LVAD group). Eight sheep with a MI only and 4 sham sheep were used as controls. Regional diastolic and contractile strain in the left ventricle was measured by sonomicrometry. Apoptosis, hypertrophy, and the related ultrastructures were studied regionally in the remote zone and the non-ischemic adjacent zone. Left ventricular systolic asynchrony was analyzed by sonomicrometry. Results: The regional myocardial strain (stretch) was minimized during the unloading period and even attenuated at 12 weeks compared to the MI only group. LV dilation and cardiac dysfunction were alleviated in the unloaded animal at 12 weeks (EDV: 81.9±5.4 ml vs. 105.9±9.5 ml; EF value: 39.3±4.2% vs. 46.4±1.8%, p&lt;0.05). Infarct size was smaller in the unloaded animal at 12 weeks although the initial infarct size had no statistical difference in the two groups. Regional apoptosis, hypertrophy, and ultrastructural changes in the adjacent zone were prevented by the short-term LVAD unloading and the Calcineurin/BAD apoptotic pathway and the Raf/MEK/ERK hypertrophic pathway were involved. Left ventricular systolic asynchrony was evident among the remote zone, adjacent zone, and infarcted zone in the MI group, but reduced in the unloaded group. Conclusion: Short-term LVAD unloading can reduce apoptosis, hypertrophy, prevent left ventricular systolic asynchrony, and improve heart function during the post-infarct period. This translational study supports the application LVAD at the early stage post MI to prevent cardiac remodeling rather to “reverse” remodeling at the end-stage of heart failure.
Abstract 8445: Outcomes from Symptom and Economic Evaluation of Fluid Restriction in Persons with Heart Failure
Authors: Carolyn M Reilly, Melinda Higgins, Andrew Smith, Steven D Culler, Sandra B Dunbar
Journal: Circulation (2011)

Introduction: Fluid restrictions (FR) are routinely prescribed for persons with heart failure (HF), yet little is known regarding patient adherence and outcomes from this self-care behavior. Purpose: To evaluate adherence and outcomes in persons with HF randomized to receive attention control (AC) or an education and behavioral intervention (EBI) consisting of FR education, rationale, skill building for quantifying fluid intake, strategies, and goal setting. Methods: 25 NYHA Class II-IV persons (age 44-83 years, 56% male, 20% minority, mean EF 23.0 +11.7%, on standard HF medications) were evaluated at baseline, 3 and 6 months. Measures included adherence with the prescribed FR, physical measures [BNP, congestion score, and intrathoracic impedance (IIM)], and patient reported outcomes (thirst distress, HF symptoms, and HRQL), analyzed using multi-level mixed models, RM-ANCOVA, and time series analyses. Results: Relationships between self-reported fluid status, fluid congestion, symptom distress, and HRQL were observed. While the sample size was small, moderate effect sizes were noted in all measures that trended toward significance ( p &lt;.10). Patients randomized to the EBI group demonstrated decreased total fluid consumption ( paired t (11)= 2.243, p &lt; .05, large effect size (ES) 0.56), less frequency of HF symptoms ( t(24.720) = -2.048, p = .05, moderate ES 0.38), less severity of symptoms ( t(24.335) = -1.914, p = .07, moderate ES 0.36), and less interference of HF symptoms with physical activity ( t(25.647) = -2.032, p = .05, moderate ES 0.37). Thirst distress was noted to worsen in this group ( t(27.424) = 1.993, p = .06, moderate ES 0.36) while HRQL did not change in the EBI group but improved in the AC ( t(22.880) = -1.755, p = .09). Time series indicated a negative relationship between weight &amp; IIM, positive correlation between weight &amp; daily fluid intake, and a potential negative association between fluid intake &amp; IIM. Conclusion: This pilot and feasibility study demonstrated that adherence with a prescribed FR is possible and may lead to improved typical HF symptoms, but may also increase symptoms of thirst. More research into the effects and benefits of FR including the level of FR that confers the best outcomes for the least patient distress, is warranted.