tbuckley/cabot-search huggingface dataset:
Abstract 19278: The Impact of Chronic Kidney Disease on Clinical Outcomes in Patients Admitted with Acute Myocardial Infraction in an Australian Setting
Authors: Sradha S Kotwal, Isuru Ranasinghe, Martin P Gallagher, Alan Cass
Journal: Circulation (2012)

Background: International data suggests the presence of chronic kidney disease (CKD) increases morbidity and mortality following acute myocardial infarction (AMI) and reduces the likelihood of revascularisation. However, the impact of CKD on longer term clinical outcomes and health resource usage remains unclear. Aim: To assess the impact of CKD upon clinical outcomes for patients admitted with AMI. Methods: New South Wales (NSW) is Australia’s most populous state with an estimated population of 7.2 milllion, representing 32.3% of the total Australian populaton. The NSW admitted patient data collection (NSW APDC) is an administrative coding dataset collecting data on all admissions to NSW hospitals. Coding uses the International Classification of Disease 10 Australian Modification (ICD10 AM). All patients admitted to a NSW hospital with a principle diagnosis of AMI (ICD10 codes: I21.0-I21.3 and I21.4) between 2004 and 2008 were extracted from NSW APDC and linked to the NSW Registry of Births Deaths and Marriages. We analysed outcomes of 30 day, 1 year and medium term (median follow up) all cause mortality, length of stay (LOS) and revascularisation crude rates based on the presence or absence of a diagnostic code of CKD (N18, N19, Z49). Results: A total of 40,482 patients with AMI were analysed, including 1565 with a CKD code, to a median follow up 3.5 years. Unadjusted analyses of patients coded as having CKD showed higher 30 day mortality (15% versus 7%, p&lt;0.001), 1 year mortality (40% versus 14.5%, p&lt;0.001), 3.5 year mortality (67% versus 25%, p&lt;0.001), LOS (mean 10.4 days versus 7.5 days, p &lt; 0.001) and lower revascularisation rates (14% versus 35%, p&lt; 0.001) compared to those without a CKD code. Conclusions: Patients admitted to NSW hospitals with an AMI and coding history of CKD have lower rates of intervention, despite significantly higher mortality and length of stay. CKD coding was used infrequently and further research is required to explore the utilisation of CKD diagnostic codes and the poorer outcomes they portend.
Abstract 19316: Family History of Cardiovascular Disease in a First Degree Relative is Associated with High Risk Profile, but not Healthier Lifestyle
Authors: Gia Mudd-Martin, Misook L Chung, Susan K Frazier, Terry A Lennie, Martha J Biddle, Alison L Bailey, Baretta Casey, M. J Novak, Debra K Moser
Journal: Circulation (2012)

Background: Family history (FH) of premature cardiovascular disease (CVD) and stroke is a risk factor for personal CVD. Engagement in healthy lifestyle behaviors and preventative health screenings may lessen risk. Objective: To compare CVD risk profiles, lifestyle behaviors, and health screening practices of rural Kentucky residents with and without high-risk FH and examine the association of FH with personal CVD diagnosis. Methods: Data were obtained from 687 participants (77% female; age 49 ± 13 years) who completed a FH questionnaire. High-risk FH was defined as having one or more first degree relatives with a history of myocardial infarction (MI) or stroke before age 60 years. CVD risk profile was assessed using the Framingham 10-year risk score for CVD. MOS-Specific Adherence Scale items on activity and diet were used to assess lifestyle behaviors, with unhealthy behavior defined as the response “none of the time” on the 4-point Likert scale. Screening was determined by asking about frequency of blood pressure, glucose, and cholesterol checks by a health professional. Self-reported diagnosis of MI, heart failure, and stroke was used to assess personal CVD. Differences in CVD risk profile, lifestyle behaviors, and screening between those with and without high-risk FH were evaluated using independent samples t-test or Chi square tests. Logistic regression was used to assess the association of FH with personal CVD, controlling for gender, age, and diabetes. Results: A total of 36.8% had a high-risk FH. Those with a high-risk FH had significantly worse CVD risk profiles than those without ( p = .001). The only significant difference in lifestyle behaviors was greater adherence to a low saturated/trans fat diet among persons with high-risk FH compared to those without (80.6% vs. 73.7%, p = .04); no significant differences in screening practices were found. Participants with high-risk FH had a 2.5 times greater odds of personal CVD diagnosis (95% CI 1.4 - 2.5, p = .002). Conclusion: Despite having greater personal risk and worse CVD risk profiles than those without, individuals with a high-risk FH of MI or stroke had similar lifestyle and screening behaviors. Robust preventative interventions are needed to promote effective risk-reduction for high risk individuals.
Abstract 19618: Effect of Electroanatomically Guided versus Conventional Renal Sympathetic Denervation on Radiation Exposure and Blood Pressure in the SAVE Trial
Authors: Sandeep R Gangireddy, Petr Neuzil, Susie N Sennhauser, Vivek Y Reddy
Journal: Circulation (2012)

Introduction: SYMPLICITY -2 demonstrated that renal sympathetic denervation (RSDN) is effective in lowering blood pressure in patients with resistant hypertension. RSDN is typically performed using fluoroscopy. Our aim was to assess the clinical utility of electroanatomic mapping systems (EAM) on radiation exposure and treatment results in a prospective trial. Methods: Pre-specified analysis of outcomes in both the non-randomized Impact of Renal Sympathetic Denervation on Chronic Hypertension (SAVE) trial (n=10), and the randomized Renal Sympathetic Denervation for the Management of Chronic Hypertension (RELIEF) trial (n=10). Both trials enroll patients with refractory HTN, defined as BP≥140/90 mmHg despite treatment with at least 3 anti-HTN drugs. Patients in the SAVE cohort underwent catheter based RSDN using EAM (NavX, CARTO), and were compared with case-matched controls in the RELIEF trial who underwent RSDN using fluoroscopy. All patients underwent bilateral renal angiography prior to RSDN, resulting in radiation exposure. Blood pressure was measured at 1 month post-procedure in an office setting. Results: Radiation exposure was significantly reduced in the EAM group (39,175 ± 14,463 mGycm2 vs 61,209 ± 22,259 mGycm2, P=0.0172). Total procedure duration was comparable between the EAM group (77.0 ± 35.5 min) and conventional group (75.6 ± 33.8 min, P=0.8837). The SBP at 1 month (147 ± 11 vs 156 ± 19 mmHg, P=0.3662) and DBP at 1 month (91 ± 11 vs 88 ± 15 mmHg, P=0.6998) were similar between the EAM and conventional group. Conclusion: The use of electroanatomic mapping systems during RSDN significantly reduces radiation exposure, without increasing procedure duration.
Abstract 19659: Long Term Left Ventricular Assist Device Therapy: Renal Response to Pulsatile vs Continuous Flow
Authors: Pavol Sajgalik, Park Soon J, Brooks S Edwards, Sudrih Kuswaha, Richard Daly, Lyle D Joyce, Peter Nemec, Tomas Kara, John C Brunett, Barry Boilson, Horng Chen, John A Schirger
Journal: Circulation (2012)

Background: Left ventricle assist device (LVAD) support, a well established therapy in advanced CHF, improves renal function assessed by creatinine. While renal function in large numbers of continuous flow (CF) LVADs vs pulsatile flow (PF) LVADs has been evaluated at 3 mo., long term studies are needed with large numbers of CF vs PF devices. To date longer term analysis comparing renal function in CF vs PF devices have relied on a small number of CF devices. We evaluated renal function assessed by creatinine in a large number of CF (HM II) (n=119) devices and compared this to renal function in a group of subjects treated with PF devices (HM XVE) (n=8) at 6 mo. post implant. Our aim was to evaluate change in creatinine between 3 and 6 months in these groups. Methods and Results: Plasma creatinine was evaluated at 3 and 6 months in two groups: subjects with CF HM II (n=119) and PF LVAD (HM XVE, n=8). The data were collected from two centers in patients undergoing implant for destination or bridge to transplant therapy. Baseline creatinine was higher in the HM XVE group at baseline (BL), and decreased at 3 mo. (1.7 [1.1-2.1] vs 1.1 [0.8-1.5] mg/dL, p&lt;0.05). BL creatine in the HM II group decreased at 3 mo as well (1.2 [1-1.5] vs 1.1 [0.9-1.3] mg/dL, p,0.05). Between 3 and 6 months there was no difference in degree of creatinine change in CF vs PF, however both groups had an increase in Creatinine in this time frame: PF (1.1 [0.8-1.5] vs 1.35 [1.05-1.9] mg/dL, p&lt;0.05); CF (1.1 [0.9-1.3] vs 1.2 [0.92-1.4] mg/dL, p&lt;0.05). Conclusion: This is the first study to demonstrate with large numbers of CF LVAD that creatinine does not incrementally increase between 3 and 6 mo. in comparison to PF LVAD. Further studies are required with large numbers of continuos flow LVADs evaluating the comparative effect of long term continuous flow vs pulsatile flow. Additionally, it remains important to identify surrogates of pulsatility in subjects with continuous flow devices and evaluate prognostic impact on renal function long term.
Abstract 19351: Reduced Proteasome Heterogeneity Augments Cardiac Remodeling
Authors: David Liem, Franziska Koser, Osamu Tsukamoto, Yibin Wang, Markus Hecker, Peipei Ping, Oliver Drews
Journal: Circulation (2012)

The ubiquitin proteasome system regulates cellular function through targeted degradation of signaling and structural proteins. In the mammalian heart, there exist proteasome subpopulations with distinct functionality, conferring the capacity to adjust proteolytic function under physiological and pathological conditions. In fact, the composition of proteasome subpopulations seems to be highly dynamic during cardiac remodeling. However, whether proteasome composition in turn affects myocardial remodeling is not known. Therefore, aim of the study was to determine whether specific proteasome subpopulations impact cardiac remodeling. Analyses of cardiac proteasome assembly during seven day catecholamine treatment of mice demonstrated that the inducible proteasome subunits β1i and β5i were increasingly incorporated in proteasome complexes (up to 50%), whereas the incorporation of constitutive subunits remained unchanged. During the treatment, heart weight to body weight ratio (HW/BW) increased by approx. 50% (6.1 vs 4.1), documenting that the mice developed cardiac hypertrophy. Functional assays of proteasome activities in hypertrophic hearts showed heterogeneous regulation of substrate specificity and turn-over, further indicating a shift in the composition of proteasome subpopulations. Unchallenged mice lacking the subunit β1i and the corresponding proteasome subpopulation are visually indistinguishable from wild-type mice and have a HW/BW ratio of approx. 4.4. Remarkably, catecholamine challenge for seven days induced a more severe cardiac phenotype in those mice with increased HW/BW of approx. 70% (7.6 vs. 4.4). In conclusion, this study demonstrates for the first time that the ubiquitin proteasome system has the capacity to modulate cardiac tissue mass in response to a hypertrophic stimulus via specific proteasome subpopulations, providing a novel mechanism to regulate cardiac remodeling.
Abstract 19343: Chemical Chaperone Mediated Inhibition of Activating Transcription Factor 6 (ATF6) is a Novel Therapy in Pulmonary Arterial Hypertension (PAH)
Authors: Peter Dromparis, Roxane Paulin, Trevor H Stenson, Alois Haromy, Gopinath Sutendra, Evangelos D Michelakis
Journal: Circulation (2012)

The high mortality associated with PAH is in part, due to the poorly understood pathogenesis. Endoplasmic reticulum (ER)-stress is a potential commonality among many molecular triggers of PAH, including mutations, viruses, inflammation and hypoxia. The ER forms a functional unit with the mitochondria (the ER-mito unit), allowing for exchange of Ca2+. Recently, we showed that ER-mito unit disruption was critical in PAH pathogenesis. In pulmonary artery smooth muscle cells (PASMCs), ER-stress activated the transcription factor ATF6, increased levels of the ER protein Nogo, disrupted the ER-mito unit, and resulted in the apoptosis-resistance that is central to pulmonary vascular remodeling in PAH. Chemical chaperones including the FDA-approved 4-phenylbutyrate (PBA) attenuate ER-stress and have been studied in metabolic diseases and cancer. We hypothesized that attenuation of ER stress-induced ATF6 activation with PBA will prevent the disruption of the ER-mito unit and prevent/reverse PAH. Hypoxic mice or monocrotaline-injected rats were treated with PBA in their drinking water (~500mg/kg/day) in prevention (days 0-28) and reversal (days 14-28) protocols. Mechanistic studies were performed in lungs and PASMCs exposed to hypoxia. PBA decreases ATF6 activation (nuclear localization, luciferase, target gene (Nogo/GRP78) expression) and normalizes mitochondrial function (mitochondrial-Ca2+, membrane potential, reactive oxygen species). Both in vivo and in vitro, PBA suppresses proliferation (Ki67) and induces apoptosis (TUNEL). Treated mice had less pulmonary artery remodeling, improved hemodynamics, decreased right ventricular hypertrophy and better functional capacity compared to vehicle-treated controls (see table; data presented as mean±SEM). Treated rats responded similarly. Chemical chaperones improve PAH by inhibiting ATF6 activation, a pathway compatible with several PAH-triggers that induce ER-stress.
Abstract 8633: Right Ventricular Origin of Arrhythmias in <i>Scn5a+/-</i> Mice Modeling Brugada Syndrome is Due to Reduced Na <sup>+</sup> and Higher K <sup>+</sup> Channel Expression and Function in the Right Ventricle
Authors: Claire A Martin, Urszula Siedlecka, Kristin Kemmerich, Jason Lawrence, James Cartledge, Laila Guzadhur, Nicola Brice, Andrew A Grace, Christof Schwiening, Cesare M Terracciano, Christopher L Huang
Journal: Circulation (2011)

Brugada syndrome is associated with ventricular tachycardia originating in the right ventricle (RV); this has been attributed to either depolarization abnormalities or increased repolarization heterogeneities. We use a heterozygotic Scn5a+/- murine model to test these hypotheses. Na v 1.5 mRNA and protein expression were lower in Scn5a+/- than wild-type (WT) hearts, with a further reduction in the RV (panel A, n = 4, significant differences: * = WT vs Scn5a+/- ; # = LV vs RV). There were higher expression levels of K v 4.2, K v 4.3 and KChIP2 in RV than LV in both groups. Action potential (AP) upstroke velocity was decreased in Scn5a+/- (RV: 59.43 +/- 2.70 V/s to 30.26 +/- 4.03 V/s, p &lt; 0.0001, n = 20), and furthermore was smaller in RV than LV. AP durations were smallest in the RV of Scn5a+/- myocytes. Transient outward current density ( I to ) was greater in the RV of both WT and Scn5a+/- (panel B, n = 17), with similar voltage dependence of activation. Time constants of inactivation were larger in RV than LV, and voltage dependence of inactivation was shifted to more negative values in RV compared to LV, but to more positive values in Scn5a+/- compared to WT. Maximum Na + current density ( I Na ) was decreased in Scn5a+/- , with a further reduction in the RV (panels C, D, n = 17). Voltage dependence of activation was unchanged, but inactivation was shifted to more negative values in Scn5a+/- . Maximum persistent Na + current density ( I pNa ) was decreased in a similar pattern to I Na (RV: -0.30 +/- 0.03 pA/pF, n = 15 vs -0.17+/- 0.02 pA/pF, n = 22, p =0.0009). Our findings show preferential upregulation of the single Scn5a gene in the LV of the Scn5a+/- mice compared to RV. The reduced expression of Na + channels in RV leads to smaller I Na , resulting in slowed conduction, and smaller I pNa , which in combination with increased I to , results in shorter AP durations and greater heterogeneity of repolarization, thus suggesting arrhythmogenesis may be initiated by both mechanisms in the RV of Scn5a+/- hearts.
Abstract 19356: Pulmonary Valve Replacement Can be Delayed in Repaired Tetralogy of Fallot Patients with Preserved RVEF
Authors: Peter Ermis, Wayne Franklin, Dhaval Parekh
Journal: Circulation (2012)

BACKGROUND Surgical pulmonary valve replacement (PVR) is common in repaired Tetrology of Fallot. PVR is indicated for right ventricle (RV) remodeling. Previous studies have found that RV size normalization is rare in larger RVs that exceed RV end-diastolic volume (RVEDV) 160 mL/m2. METHODS A retrospective chart review was conducted in patients &gt; 18 years who had PVR at our institution from 2000-2011. Demographic and clinical data, pre and post-operative MRI, and ECG, were collected. RESULTS 19 patients were included. Average age was 24.9 years (range 18-44y). Average age at PVR was 20.3 years (range 12-40y). Only 2 patients had a pre-operative RVEDV &lt; 160 mL/m2, with one patient whose RVEDV normalized ( 160 mL/m2 normalized RVEDV following PVR. All 4 patients without significant post-operative pulmonary regurgitation and preserved RVEF normalized. All had pre-operative RVEDVs &gt; 160 mL/m2, with three &gt;190 mL/m2. Table 1 shows, overall RV volume and function improved significantly following PVR while QRS duration remained unchanged by paired t-test. CONCLUSION In contrast to prior studies, delaying PVR in patients with preserved RVEF may be a reasonable management strategy. Our findings suggest that in patients with preserved RVEF, PVR can be delayed until the RVEDV reaches 190mL/m2. In patients with preserved RVEF, PVR with RVEDV &lt; 160 mL/m2 may not be warranted.
Abstract 9145: Tyrosine <sub>705</sub> Phosphorylation of STAT3 is Causally Involved in Cardioprotection by Ischemic Postconditioning in Pigs
Authors: Andreas Skyschally, Judith Musiolik, Nilgün Gedik, Gerd Heusch
Journal: Circulation (2011)

In mice, the signal transducer and activator of transcription (STAT) 3 is causally involved in protection by ischemic postconditioning (PoCo) against myocardial infarction. However, signal transduction in rodents differs from that in larger mammals. We have now determined the impact of PoCo on STAT3 activation/phosphorylation in pig hearts, which more closely resemble human hearts in size, coronary anatomy, heart rate, and infarct development. Anesthetized pigs were subjected to 90 min low flow ischemia and 120 min reperfusion, initiated with either PoCo (six cycles of 20 s reperfusion/re-occlusion, n=8) or immediate full reperfusion (IFR, n=8). Eight additional pigs were treated with the JAK/STAT inhibitor AG490 (9 µg/kg/min i.c.; 10 min before ischemia until the end of reperfusion; AG-PoCo n=4, AG-IFR n=4). Myocardial biopsies were taken at baseline, 85 min ischemia and 10, 30, and 120 min reperfusion. STAT3 phosphorylation and total STAT3 protein were quantified by Western blot analysis. Area at risk (AAR) and regional myocardial blood flow (microspheres) during ischemia were not different between groups. PoCo reduced infarct size (TTC staining) from 38±2 to 26±3 % of the AAR (p&lt;0.05). AG490 abolished this infarct size reduction (AG-IFR: 36±4 vs. AG-PoCo: 36±1 % of AAR). STAT3 tyr 705 phosphorylation normalized to total STAT3 protein (Table 1) increased during ischemia/reperfusion; in pigs subjected to PoCo the STAT3 tyr 705 phosphorylation was even greater than with IFR (p&lt;0.05, ANOVA). STAT3 ser 727 phosphorylation was increased with PoCo and IFR to a similar extent. AG490 attenuated the increases in STAT3 phosphorylation in both groups to values below those with IFR and PoCo. Conclusion: In pigs, PoCo further increases STAT3 tyr 705 phosphorylation and protects the myocardium from infarction. AG490 attenuates the STAT3 tyr 705 activation at reperfusion and abolishes PoCo's protection. Thus, in pigs STAT3 is causally involved in cardioprotection by PoCo.
Abstract 19456: Does Choice of Neuromuscular Blocker Affect Outcomes in Patients Receiving Therapeutic Hypothermia Following Cardiac Arrest?
Authors: William Baker, Giovanni Geronila, Ramya Kallur, Adam Noyes, Justin B Lundbye
Journal: Circulation (2012)

Introduction: It is well recognized that the actions of neuromuscular blockers are enhanced in patients undergoing mild therapeutic hypothermia (MTH) following cardiac arrest. Little data on the association between various NMB agents and outcomes are available. Methods: We retrospectively collected data on 201 consecutive adult patients (mean age 61 ± 15 years) admitted to Hartford Hospital who survived a cardiac arrest and were admitted to our cardiac intensive care unit (CICU). Of the 201 patients, 99 (49.3%) had VF or VT and 102 (51.7%) had PEA or asystole. Use of neuromuscular blockers, including cisatracurium and vecuronium, was collected. The main outcome of interest was survival with good neurologic outcome defined using the Pittsburgh cerebral performance category (CPC) scale of 1-2. Multivariate logistic regression was used to control for potential confounders and identify independent predictors of good outcome. Results: During their CICU stay, 60 (29.9%) patients received cisatracurium and 36 (17.9%) received vecuronium. A positive correlation was seen between rate of survival with good neurologic outcome was seen in patients who received cisatracurium (p&lt;0.001) but not in those receiving vecuronium (p=0.183). Neither agent was correlated with length of stay in the CICU. Multivariate analysis showed that cisatracurium use (p=0.014) was a positive independent predictor of survival with good neurologic outcome during hospitalization in our population whereas history of diabetes (p=0.004), and either asystole (p=0.006) or PEA (p=0.002) were negative predictors. Conclusions: In our population, use of cisatracurium during MTH following cardiac arrest was positively associated with a good outcome while vecuronium did not seem to affect this outcome. A prospective direct head-to-head study is required to better characterize potential differences between neuromuscular blocking agents.
Abstract 19398: Diastolic Dysfunction and Deposition of Fibrosis in Pressure Overloaded Hearts is Dependent on Pentraxin3
Authors: Daniela Carnevale, Valentina Fardella, Giada Mascio, Giuseppe Cifelli, Stefania Fardella, Fabio Pallante, Cecilia Garlanda, Alberto Mantovani, Giuseppe Lembo
Journal: Circulation (2012)

On the basis of the underlying pathophysiology, it is possible to distinguish two major forms of heart failure (HF): HF owing to reduced left ventricular (LV) systolic function and HF owing to LV diastolic dysfunction. In both cases, chronic remodeling processes in the myocardium antedate overt HF by many years. Inflammation has a pivotal role in cardiac remodeling, and circulating markers of systemic inflammation are independently associated with risk of developing HF and with prognosis after onset. However, the pathophysiological role of many inflammatory biomarkers in HF is poorly understood. In this context, the relationship between circulating levels of pentraxin 3 (PTX3), a novel marker of inflammation, and the presence of diastolic dysfunction and/or overt HF has been emerging. PTX3 belongs to pentraxins, members of a superfamily of multimeric pattern-recognition proteins that can be short (such as CRP) or long (the prototype of this group being PTX3), with important roles at the interface of innate immune response, inflammation, and extracellular matrix remodeling. To dissect the pathophysiological role of PTX3 in the two forms of HF, we subjected mice with a genetic ablation for PTX3 to chronic pressure overload. Both echocardiographic analysis and PV loops revealed an early and sustained protection from LV diastolic dysfunction. As regard the process of cardiac remodeling to pressure overload, absence of PTX3 resulted in reduced recruitment of monocyte and deposition of fibrotic tissue. The systolic function was not affected by the absence of PTX3 and both WT and KO mice developed a comparable systolic dysfunction over time. In conclusion our data fully support the clinical association among PTX3 levels and the presence of diastolic dysfunction and candidate this molecular target as a novel therapeutic approach for HF owing to LV diastolic dysfunction.