circulation2010-08-17

(Circulation. 2010;122:682-689.)
© 2010 American Heart Association, Inc.
Abstract 1 of 7

________________________________________Cardiovascular Surgery
Prediction Models for Prolonged Intensive Care Unit Stay After Cardiac Surgery
Systematic Review and Validation Study
Roelof G.A. Ettema, MSc; Linda M. Peelen, PhD; Marieke J. Schuurmans, PhD, RN; Arno P. Nierich, MD, PhD; Cor J. Kalkman, MD, PhD; Karel G.M. Moons, PhD
From the University of Applied Science Utrecht, Faculty of Health Care, Utrecht (R.G.A.E., M.J.S.); Julius Center for Health Sciences and Primary Care (L.M.P., K.G.M.M.) and Division of Perioperative Care and Emergency Aid (C.J.K.), Department of Rehabilitation, Nursing Science & Sports (M.J.S.), University Medical Center Utrecht, Utrecht; and Department of Anesthesiology and Intensive Care, Isala Clinics, Zwolle (A.P.N.), Netherlands.
Correspondence to Roelof G.A. Ettema, University of Applied Science Utrecht, Faculty of Health Care, Bolognalaan 101 3584 CJ Utrecht, Netherlands. E-mail Roelof.Ettema@hu.nl
Received November 27, 2009; accepted June 4, 2010.
Background— Several models have been developed to predict prolonged stay in the intensive care unit (ICU) after cardiac surgery. However, no extensive quantitative validation of these models has yet been conducted. This study sought to identify and validate existing prediction models for prolonged ICU length of stay after cardiac surgery.
Methods and Results— After a systematic review of the literature, the identified models were applied on a large registry database comprising 11 395 cardiac surgical interventions. The probabilities of prolonged ICU length of stay based on the models were compared with the actual outcome to assess the discrimination and calibration performance of the models. Literature review identified 20 models, of which 14 could be included. Of the 6 models for the general cardiac surgery population, the Parsonnet model showed the best discrimination (area under the receiver operating characteristic curve=0.75 [95% confidence interval, 0.73 to 0.76]), followed by the European system for cardiac operative risk evaluation (EuroSCORE) (0.71 [0.70 to 0.72]) and a model by Huijskes and colleagues (0.71 [0.70 to 0.73]). Most of the models showed good calibration.
Conclusions— In this validation of prediction models for prolonged ICU length of stay, 2 widely implemented models (Parsonnet, EuroSCORE), although originally designed for prediction of mortality, were superior in identifying patients with prolonged ICU length of stay.
Abstract 2 of 7
Epidemiology and Prevention
Cardiac Index Is Associated With Brain Aging
The Framingham Heart Study
Angela L. Jefferson, PhD; Jayandra J. Himali, MS; Alexa S. Beiser, PhD; Rhoda Au, PhD; Joseph M. Massaro, PhD; Sudha Seshadri, MD; Philimon Gona, PhD; Carol J. Salton, BA; Charles DeCarli, MD; Christopher J. O'Donnell, MD, MPH; Emelia J. Benjamin, MD, ScM; Philip A. Wolf, MD; Warren J. Manning, MD
From the Department of Neurology (A.L.J., J.J.H., A.S.B., R.A., S.S., P.A.W.), Alzheimer’s Disease Center (A.L.J., S.S.), Whitaker Cardiovascular Institute (A.L.J., E.J.B.), and Department of Medicine (A.L.J., E.J.B.), Boston University School of Medicine, Boston, Mass; Department of Biostatistics, Boston University School of Public Health, Boston, Mass (J.J.H., A.S.B., J.M.M., P.G.); National Heart, Lung and Blood Institute’s Framingham Heart Study, Framingham, Mass (J.J.H., A.S.B., R.A., J.M.M., S.S., P.G., C.J.O., E.J.B., P.A.W.); Departments of Medicine (Cardiovascular Division) (C.J.S., W.J.M.) and Radiology (W.J.M.), Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass; Department of Neurology, Center for Neuroscience, and Imaging of Dementia and Aging Laboratory, University of California at Davis (C.D.); and Department of Medicine (Cardiology Division), Massachusetts General Hospital, Harvard Medical School, Boston (C.J.O.).
Correspondence to Angela L. Jefferson, PhD, Alzheimer’s Disease Center, Boston University School of Medicine, 72 E Concord St, B-7800, Boston, MA 02118. E-mail angelaj@bu.edu
Received August 27, 2009; accepted June 4, 2010.
Background— Cardiac dysfunction is associated with neuroanatomic and neuropsychological changes in aging adults with prevalent cardiovascular disease, theoretically because systemic hypoperfusion disrupts cerebral perfusion, contributing to subclinical brain injury. We hypothesized that cardiac function, as measured by cardiac index, would be associated with preclinical brain magnetic resonance imaging (MRI) and neuropsychological markers of ischemia and Alzheimer disease in the community.
Methods and Results— Brain MRI, cardiac MRI, neuropsychological, and laboratory data were collected on 1504 Framingham Offspring Cohort participants free of clinical stroke, transient ischemic attack, or dementia (age, 61±9 years; 54% women). Neuropsychological and brain MRI variables were related to cardiac MRI–assessed cardiac index (cardiac output/body surface area). In multivariable-adjusted models, cardiac index was positively related to total brain volume (P=0.03) and information processing speed (P=0.02) and inversely related to lateral ventricular volume (P=0.048). When participants with clinically prevalent cardiovascular disease were excluded, the relation between cardiac index and total brain volume remained (P=0.02). Post hoc comparisons revealed that participants in the bottom cardiac index tertile (values <2.54) and middle cardiac index tertile (values between 2.54 and 2.92) had significantly lower brain volumes (P=0.04) than participants in the top cardiac index tertile (values >2.92).
Conclusions— Although observational data cannot establish causality, our findings are consistent with the hypothesis that decreasing cardiac function, even at normal cardiac index levels, is associated with accelerated brain aging.
Abstract 3 of 7
Exercise Physiology
Prevalence and Clinical Significance of Aortic Root Dilation in Highly Trained Competitive Athletes
Antonio Pelliccia, MD; Fernando M. Di Paolo, MD; Elvira De Blasiis, MD; Filippo M. Quattrini, MD; Cataldo Pisicchio, MD; Emanuele Guerra, MD; Franco Culasso, PhD; Barry J. Maron, MD
From the Institute of Sports Medicine and Science, Italian National Olympic Committee, Rome, Italy (A.P., F.M.D.P., E.D.B., F.M.Q., C.P., E.G.); Department of Experimental Medicine, University La Sapienza, Rome, Italy (F.C.); and Hypertrophic Cardiomyopathy Center, Minneapolis Heart Institute Foundation, Minneapolis, Minn (B.J.M.).
Correspondence to Antonio Pelliccia, MD, Institute of Sports Medicine and Science, Largo Piero Gabrielli, 1, 00197 Rome, Italy. E-mail ant.pelliccia@libero.it
Received August 12, 2009; accepted June 1, 2010.
Background— Few data are available that address the impact of athletic training on aortic root size. We investigated the distribution, determinants, and clinical significance of aortic root dimension in a large population of highly trained athletes.
Methods and Results— Transverse aortic dimensions were assessed in 2317 athletes (56% male), free of cardiovascular disease, aged 24.8±6.1 (range, 9 to 59) years, engaged in 28 sports disciplines (28% participated in Olympic Games). In males, aortic root was 32.2±2.7 mm (range, 23 to 44; 99th percentile=40 mm); in females, aortic root was 27.5±2.6 mm (range, 20 to 36; 99th percentile=34 mm). Aortic root was enlarged 40 mm in 17 male (1.3%) and 34 mm in 10 female (0.9%) subjects. Over an 8-year follow-up period, aortic dimension increased in these male athletes (40.9±1.3 to 42.9±3.6 mm; P<0.01) and dilated substantially (to 50, 50, and 48 mm) in 3, after 15 to 17 years of follow-up, in the absence of systemic disease. Aortic root did not increase significantly (34.9±0.9 to 35.4±2.1 mm; P=0.11) in female athletes. Multiple regression and covariance analysis showed that aortic dimension was largely explained by weight, height, left ventricular mass, and age (R2=0.63; P<0.001), with type of sports training having a significant but lower impact (P<0.003).
Conclusions— An aortic root dimension >40 mm in highly conditioned male athletes (and >34 mm in female athletes) is uncommon, is unlikely to represent the physiological consequence of exercise training, and is most likely an expression of a pathological condition, mandating close clinical surveillance.
Abstract 4 of 7
Exercise Physiology
Exercise Training Stimulates Ischemia-Induced Neovascularization via Phosphatidylinositol 3-Kinase/Akt-Dependent Hypoxia-Induced Factor-1 Reactivation in Mice of Advanced Age
Xian Wu Cheng, MD, PhD; Masafumi Kuzuya, MD, PhD; Weon Kim, MD, PhD; Haizhen Song, MD; Lina Hu, MD; Aiko Inoue, MS; Kae Nakamura, PhD; Qun Di, MD; Takeshi Sasaki, PhD; Michitaka Tsuzuki, MD, PhD; Guo-Ping Shi, DSc; Kenji Okumura, MD, PhD; Toyoaki Murohara, MD, PhD
From the Departments of Cardiovascular Research Medicine (X.W.C., H.S., K.O.), Cardiology (W.K., M.T., T.M.), and Geriatrics (M.K., L.H., A.I., K.N., Q.D., T.S.), Nagoya University Graduate School of Medicine, Nagoya, Japan; Department of Internal Medicine (X.W.C., W.K.), Kyung Hee University Hospital, Seoul, Korea; Department of Geriatrics (Q.D.), First Affiliated Hospital of Nanjing University, Nanjing, China; Department of Cardiovascular Medicine (G.-P.S.), Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass; and Department of Cardiology (X.W.C.), Yanbian University Hospital, Yanji, Jilin, China.
Correspondence to Xian Wu Cheng, MD, PhD (main communicator and reprint requests), Department of Cardiovascular Research Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan, E-mail chengxw0908@yahoo.com.cn or Toyoaki Murohara, MD, PhD, Department of Cardiology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8550, Japan, E-mail murohara@med.nagoya-u.ac.jp
Received September 17, 2009; accepted June 14, 2010.
Background— Exercise stimulates the vascular response in pathological conditions, including ischemia; however, the molecular mechanisms by which exercise improves the impaired hypoxia-induced factor (HIF)-1 –mediated response to hypoxia associated with aging are poorly understood. Here, we report that swimming training (ST) modulates the vascular response to ischemia in aged (24-month-old) mice.
Methods and Results— Aged wild-type mice (MMP-2+/+) that maintained ST (swimming 1 h/d) from day 1 after surgery were randomly assigned to 4 groups that were treated with either vehicle, LY294002, or deferoxamine for 14 days. Mice that were maintained in a sedentary condition served as controls. ST increased blood flow, capillary density, and levels of p-Akt, HIF-1 , vascular endothelial growth factor, Fit-1, and matrix metalloproteinase-2 (MMP-2) in MMP-2+/+ mice. ST also increased the numbers of circulating endothelial progenitor cells and their function associated with activation of HIF-1 . All of these effects were diminished by LY294002, an inhibitor of phosphatidylinositol 3-kinase; enhanced by deferoxamine, an HIF-1 stabilizer; and impaired by knockout of MMP-2. Finally, bone marrow transplantation confirmed that ST enhanced endothelial progenitor cell homing to ischemic sites in aged mice.
Conclusions— ST can improve neovascularization in response to hypoxia via a phosphatidylinositol 3-kinase–dependent mechanism that is mediated by the HIF-1 /vascular endothelial growth factor/MMP-2 pathway in advanced age.
Abstract 5 of 7
Heart Failure
Angiotensin-Converting Enzyme 2 Suppresses Pathological Hypertrophy, Myocardial Fibrosis, and Cardiac Dysfunction
JiuChang Zhong, MD; Ratnadeep Basu, MD; Danny Guo, BSc; Fung L. Chow, MSc; Simon Byrns, BSc; Manfred Schuster, PhD; Hans Loibner, PhD; Xiu-hua Wang, PhD; Josef M. Penninger, MD; Zamaneh Kassiri, PhD; Gavin Y. Oudit, MD, PhD
From the Division of Cardiology (J.C.Z., D.G., F.L.C., S.B., G.Y.O.), Department of Medicine (J.C.Z., R.B., D.G., F.L.C., S.B., Z.K., G.Y.O.) Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Canada; Department of Physiology (R.B., X.-h.W., Z.K.), University of Alberta, Edmonton, Canada; Apeiron Biologics (M.S., H.L.), Vienna, Austria; and Institute of Molecular Biotechnology of the Austrian Academy of Sciences (J.M.P.), Vienna, Austria.
Correspondence to Gavin Y. Oudit, MD, PhD, FRCP(C), Division of Cardiology, Department of Medicine, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, T6G 2S2, Canada. E-mail gavin.oudit@ualberta.ca
Received November 4, 2009; accepted June 14, 2010.
Background— Angiotensin-converting enzyme 2 (ACE2) is a pleiotropic monocarboxypeptidase capable of metabolizing several peptide substrates. We hypothesized that ACE2 is a negative regulator of angiotensin II (Ang II)–mediated signaling and its adverse effects on the cardiovascular system.
Methods and Results— Ang II infusion (1.5 mg • kg–1 • d–1) for 14 days resulted in worsening cardiac fibrosis and pathological hypertrophy in ACE2 knockout (Ace2–/y) mice compared with wild-type (WT) mice. Daily treatment of Ang II–infused wild-type mice with recombinant human ACE2 (rhACE2; 2 mg • kg–1 • d–1 IP) blunted the hypertrophic response and expression of hypertrophy markers and reduced Ang II–induced superoxide production. Ang II–mediated myocardial fibrosis and expression of procollagen type I 1, procollagen type III 1, transforming growth factor-β1, and fibronectin were also suppressed by rhACE2. Ang II–induced diastolic dysfunction was inhibited by rhACE2 in association with reduced plasma and myocardial Ang II and increased plasma Ang 1-7 levels. rhACE2 treatment inhibited Ang II–mediated activation of protein kinase C- and protein kinase C-β1 protein levels and phosphorylation of the extracellular signal-regulated 1/2, Janus kinase 2, and signal transducer and activator of transcription 3 signaling pathways in wild-type mice. A subpressor dose of Ang II (0.15 mg • kg–1 • d–1) resulted in a milder phenotype that was strikingly attenuated by rhACE2 (2 mg • kg–1 • d–1 IP). In adult ventricular cardiomyocytes and cardiofibroblasts, Ang II–mediated superoxide generation, collagen production, and extracellular signal-regulated 1/2 signaling were inhibited by rhACE2 in an Ang 1-7–dependent manner. Importantly, rhACE2 partially prevented the development of dilated cardiomyopathy in pressure-overloaded wild-type mice.
Conclusions— Elevated Ang II induced hypertension, myocardial hypertrophy, fibrosis, and diastolic dysfunction, which were exacerbated by ACE2 deficiency, whereas rhACE2 attenuated Ang II– and pressure-overload–induced adverse myocardial remodeling. Hence, ACE2 is an important negative regulator of Ang II–induced heart disease and suppresses adverse myocardial remodeling.
Abstract 6 of 7
Resuscitation Science
Intra-Arrest Transnasal Evaporative Cooling
A Randomized, Prehospital, Multicenter Study (PRINCE: Pre-ROSC IntraNasal Cooling Effectiveness)
Maaret Castrén, MD, PhD*; Per Nordberg, MD*; Leif Svensson, MD, PhD; Fabio Taccone, MD; Jean-Louise Vincent, MD, PhD; Didier Desruelles, MD; Frank Eichwede, MD; Pierre Mols, MD, PhD; Tilmann Schwab, MD; Michel Vergnion, MD; Christian Storm, MD; Antonio Pesenti, MD, PhD; Jan Pachl, MD, PhD; Fabien Guérisse, MD; Thomas Elste, MD; Markus Roessler, MD, DEAA; Harald Fritz, MD; Pieterjan Durnez, MD; Hans-Jörg Busch, MD; Becky Inderbitzen, MSE; Denise Barbut, MD
From the Department of Clinical Science and Education (M.C., P.N., L.S.), Karolinska Institutet, and Department of Prehospital and Emergency Medicine (M.C., L.S.) and Department of Cardiology (P.N.), Södersjukhuset, Stockholm, Sweden; Department of Intensive Care (F.T., J.-L.V.), Erasme University Hospital, Brussels, Belgium; Universitair Ziekenhuis Gasthuisberg Leuven (D.D.), Leuven, Belgium; Medizinisches Zentrum Kreis Aachen gGmbH (F.E.), Würselen, Germany; Le Centre Hospitalier Universitaire Saint-Pierre (P.M.), Brussels, Belgium; Universitätsklinikum Freiburg (T.S., H.-J.B.), Freiburg, Germany; Centre Hospitalier Regional de la Citadelle (M.V.), Liège, Belgium; Charité-Universitätsmedizin (C.S.), Campus Virchow Klinikum, Berlin, Germany; Università degli Studi Milano Bicocca-AREU Lombardia (A.P.), Milano Italy; Faculty Hospital Královské Vinohrady (J.P.), Prague, Czech Republic; Le Centre Hospitalier Universitaire de Tivoli (F.G.), La Louvière, Belgium; Otto von Guericke Universität (T.E.), Magdeburg, Germany; Georg August Universität Göttingen (M.R.), Göttingen, Germany; Krankenhaus Martha-Maria Halle-Dölau gGmbH (H.F.), Halle/Saale, Germany; Heilig Hartziekenhuis Roeselare (P.D.), Roeselare, Belgium; and BeneChill Inc (B.I., D.B.), San Diego, Calif.
Correspondence to Per Nordberg, Department of Cardiology, Södersjukhuset, Sjukhusbacken 10, 118 83 Stockholm, Sweden. E-mail per.nordberg@sodersjukhuset.se
Received December 26, 2009; accepted May 24, 2010.
Background— Transnasal evaporative cooling has sufficient heat transfer capacity for effective intra-arrest cooling and improves survival in swine. The aim of this study was to determine the safety, feasibility, and cooling efficacy of prehospital transnasal cooling in humans and to explore its effects on neurologically intact survival to hospital discharge.
Methods and Results— Witnessed cardiac arrest patients with a treatment interval 20 minutes were randomized to intra-arrest cooling with a RhinoChill device (treatment group, n=96) versus standard care (control group, n=104). The final analysis included 93 versus 101 patients, respectively. Both groups were cooled after hospital arrival. The patients had similar demographics, initial rhythms, rates of bystander cardiopulmonary resuscitation, and intervals to cardiopulmonary resuscitation and arrival of advanced life support personnel. Eighteen device-related adverse events (1 periorbital emphysema, 3 epistaxis, 1 perioral bleed, and 13 nasal discolorations) were reported. Time to target temperature of 34°C was shorter in the treatment group for both tympanic (102 versus 282 minutes, P=0.03) and core (155 versus 284 minutes, P=0.13) temperature. There were no significant differences in rates of return of spontaneous circulation between the groups (38% in treated subjects versus 43% in control subjects, P=0.48), in overall survival of those admitted alive (44% versus 31%, respectively, P=0.26), or in neurologically intact survival to discharge (Pittsburgh cerebral performance category scale 1 to 2, 34% versus 21%, P=0.21), although the study was not adequately powered to detect changes in these outcomes.
Conclusions— Prehospital intra-arrest transnasal cooling is safe and feasible and is associated with a significant improvement in the time intervals required to cool patients.
Abstract 7 of 7
Resuscitation Science
Induction of Therapeutic Hypothermia by Paramedics After Resuscitation From Out-of-Hospital Ventricular Fibrillation Cardiac Arrest
A Randomized Controlled Trial
Stephen A. Bernard, MD; Karen Smith, BSc, PhD; Peter Cameron, MD; Kevin Masci; David M. Taylor, MD; D. James Cooper, MD; Anne-Maree Kelly, MD; William Silvester, MB, BS, for the Rapid Infusion of Cold Hartmanns (RICH) Investigators*
From the Ambulance Victoria (S.A.B., K.S., K.M.), Monash University (S.A.B., P.C., D.J.C.), The Alfred Hospital (S.A.B., P.C., D.J.C.), Western Health (A.-M.K.), Royal Melbourne Hospital (D.M.T.), and Austin Hospital (W.S., D.M.T.), Melbourne, Australia.
Reprint requests to Stephen Bernard, MD, The Intensive Care Unit, The Alfred Hospital, Commercial Rd, Prahran, VIC 3118, Australia. E-mail stephen.bernard@alfred.org.au
Received September 6, 2009; accepted April 26, 2010.
Background— Therapeutic hypothermia is recommended for the treatment of neurological injury after resuscitation from out-of-hospital cardiac arrest. Laboratory studies have suggested that earlier cooling may be associated with improved neurological outcomes. We hypothesized that induction of therapeutic hypothermia by paramedics before hospital arrival would improve outcome.
Methods and Results— In a prospective, randomized controlled trial, we assigned adults who had been resuscitated from out-of-hospital cardiac arrest with an initial cardiac rhythm of ventricular fibrillation to either prehospital cooling with a rapid infusion of 2 L of ice-cold lactated Ringer’s solution or cooling after hospital admission. The primary outcome measure was functional status at hospital discharge, with a favorable outcome defined as discharge either to home or to a rehabilitation facility. A total of 234 patients were randomly assigned to either paramedic cooling (118 patients) or hospital cooling (116 patients). Patients allocated to paramedic cooling received a median of 1900 mL (first quartile 1000 mL, third quartile 2000 mL) of ice-cold fluid. This resulted in a mean decrease in core temperature of 0.8°C (P=0.01). In the paramedic-cooled group, 47.5% patients had a favorable outcome at hospital discharge compared with 52.6% in the hospital-cooled group (risk ratio 0.90, 95% confidence interval 0.70 to 1.17, P=0.43).
Conclusions— In adults who have been resuscitated from out-of-hospital cardiac arrest with an initial cardiac rhythm of ventricular fibrillation, paramedic cooling with a rapid infusion of large-volume, ice-cold intravenous fluid decreased core temperature at hospital arrival but was not shown to improve outcome at hospital discharge compared with cooling commenced in the hospital.