circulation2010-03-23

(Circulation. 2010;121:1286-1294.)
© 2010 American Heart Association, Inc.

abstract 1 of 8

Arrhythmia/Electrophysiology
Augmentation of Left Ventricular Contractility by Cardiac Sympathetic Neural Stimulation
Christian Meyer, MD*; Obaida R. Rana, MD*; Erol Saygili, MD; Christopher Gemein, MD; Michael Becker, MD; Kay W. Nolte, MD; Joachim Weis, MD; Thomas Schimpf, MD; Christian Knackstedt, MD; Karl Mischke, MD; Rainer Hoffmann, MD; Malte Kelm, MD; Dainius Pauza, PhD; Patrick Schauerte, MD
From the Division of Cardiology (C.M., O.R.R., E.S., C.G., M.B., T.S., C.K., K.M., R.H., M.K., P.S.) and Institute for Neuropathology (K.W.N., J.W.), RWTH Aachen University, Aachen, Germany, and Institute of Neuroanatomy, Kaunas University, Kaunas, Lithuania (D.P.).
Correspondence to Patrick Schauerte, MD, RWTH–Aachen University, Division of Cardiology, Pauwelsstr 30, 52074 Aachen, Germany. E-mail pschauerte@ukaachen.de
Received April 27, 2009; accepted January 15, 2010.
Background— Electric stimulation of mediastinal sympathetic cardiac nerves increases cardiac contractility but is not selective for the left ventricle because it elicits sinus tachycardia and enhanced atrioventricular conduction. The aim of this study was to identify sympathetic neural structures inside the heart that selectively control left ventricular inotropy and can be accessed by transvenous catheter stimulation.
Methods and Results— In 20 sheep, high-frequency stimulation (200 Hz) during the myocardial refractory period with electrode catheters inside the coronary sinus evoked a systolic left ventricular pressure increase from 97±20 to 138±32 mm Hg (P<0.001) without changes in sinus rate or PR time. Likewise, the rate of systolic pressure development (1143±334 versus 1725±632 mm Hg/s; P=0.004) and rate of diastolic relaxation (531±128 versus 888±331 mm Hg/s; P=0.001) increased. The slope of the end-systolic pressure-volume relationship increased (2.3±0.8 versus 3.1±0.6 mm Hg/mL; P=0.04), as did cardiac output (3.5±0.8 versus 4.4±0.8 L/min; P<0.001). Systemic vascular resistance and right ventricular pressure remained unchanged. There was a sigmoid dose-response curve. Ultrasound analysis revealed an increase in circumferential and radial strain in all left ventricular segments that was significant for the posterior, lateral, and anterior segments. Pressure effects were maintained for at least 4 hours of continued high-frequency stimulation and abolished by β1-receptor blockade. Histology showed distinct adrenergic nerve bundles at the high-frequency stimulation site.
Conclusions— Cardiac nerve fibers that innervate the left ventricle are amenable to transvenous electric catheter stimulation. This may permit direct interference with and modulation of the sympathetic tone of the left ventricle.

abstract 2 of 8

Epidemiology and Prevention
Urinary Creatinine Excretion Rate and Mortality in Persons With Coronary Artery Disease
The Heart and Soul Study
Joachim H. Ix, MD, MAS; Ian H. de Boer, MD, MS; Christina L. Wassel, PhD; Michael H. Criqui, MD, MPH; Michael G. Shlipak, MD, MPH; Mary A. Whooley, MD
From the Division of Nephrology, Department of Medicine (J.H.I.), Division of Preventive Medicine, Department of Family and Preventive Medicine (J.H.I., C.L.W., M.H.C.), and Division of Cardiology, Department of Medicine (M.H.C.), University of California San Diego; Nephrology Section, Veterans Affairs San Diego Healthcare System, San Diego (J.H.I.); Division of Nephrology and Kidney Research Institute, Department of Medicine, University of Washington, Seattle (I.H.d.B.); and General Internal Medicine Section, San Francisco Veterans Affairs Medical Center and Departments of Medicine and of Epidemiology and Biostatistics, University of California San Francisco (M.G.S., M.A.W.).
Correspondence to Joachim H. Ix, MD, MAS, Division of Nephrology and Hypertension, Department of Medicine, University of California San Diego, and VA San Diego Healthcare System, 3350 La Jolla Village Dr, Mail Code 111-H, San Diego, CA 92161. E-mail joeix@ucsd.edu
Received August 17, 2009; accepted January 15, 2010.
Background— In persons with coronary artery disease, low body mass index is associated with greater mortality; however, it is uncertain whether low muscle mass is a risk factor for mortality in this setting.
Methods and Results— In this study, 903 individuals with coronary artery disease provided 24-hour urine collections. We measured urine creatinine and volume and calculated creatinine excretion rate, a marker of muscle mass. Cox proportional-hazards models evaluated the association of creatinine excretion rate with mortality risk. Over a median follow-up of 6.0 years, 232 participants (26%) died. Compared with the highest sex-specific creatinine excretion rate tertile, the lowest tertile (<1068 mg/d in men, <766 mg/d in women) was associated with >2-fold risk of mortality (hazard ratio, 2.30; 95% confidence interval, 1.51 to 3.51) in models adjusted for age, sex, race, cystatin C–based estimated glomerular filtration rate, body mass index, traditional cardiovascular disease risk factors, and C-reactive protein levels. The association was essentially unaltered with further adjustment for physical fitness, left ventricular mass, left ventricular ejection fraction, or fasting insulin and glucose levels.
Conclusions— Lower creatinine excretion rate is strongly associated with mortality in outpatients with coronary artery disease, independently of conventional measures of body composition, kidney function, and traditional coronary artery disease risk factors. Future studies should determine whether low creatinine excretion rate may be a modifiable risk factor for mortality among persons with coronary artery disease, potentially through resistive exercise training or nutrition interventions.

Abstract 3 of 8

Epidemiology and Prevention
Parental Occurrence of Stroke and Risk of Stroke in Their Children
The Framingham Study
Sudha Seshadri, MD; Alexa Beiser, PhD; Aleksandra Pikula, MD; Jayandra J. Himali, MSc; Margaret Kelly-Hayes, DEd, RN; Stephanie Debette, MD, PhD; Anita L. DeStefano, PhD; Jose R. Romero, MD; Carlos S. Kase, MD; Philip A. Wolf, MD
From the Department of Neurology, School of Medicine (S.S., A.B., A.P., J.J.H., M.K.-H., S.D., A.L.D.S., J.R.R., C.S.K., P.A.W.), and Department of Biostatistics, School of Public Health (A.B., J.J.H., A.L.D.S.), Boston University, Boston, Mass; and NHLBI’s Framingham Heart Study, Framingham, Mass (S.S., A.B., A.P., J.J.H., M.K.-H., S.D., A.L.D.S., J.R.R., C.S.K., P.A.W.).
Correspondence to Dr Sudha Seshadri, Associate Professor, Department of Neurology, Boston University School of Medicine, 72 E Concord St, B602, Boston, MA 02118. E-mail suseshad@bu.edu
Received January 27, 2009; accepted January 6, 2010.
Background— Data relating parental history of stroke to stroke risk in offspring remain surprisingly inconsistent, largely because of heterogeneity of study design and the absence of verified, as opposed to historical, data on parental stroke status.
Methods and Results— We determined whether prospectively verified parental occurrence of stroke increased incident stroke risk among offspring in a community-based sample by studying 3443 stroke-free Framingham offspring (53% female; mean age, 48±14 years) with verified parental stroke status (by 65 years of age) who attended the first, third, fifth, and/or seventh offspring examinations and were followed up for up to 8 years after each baseline examination. Over up to 11 029 such person-observation periods (77 534 person-years), we documented 106 parental strokes by 65 years of age and 128 offspring strokes (74 parental and 106 offspring strokes were ischemic). Using multivariable Cox models adjusted for age, sex, sibship, and baseline stroke risk factors, we observed that parental stroke, both all stroke generally and ischemic stroke specifically, was associated with an increased risk of incident stroke of the same type in the offspring (hazard ratio, 2.79; 95% confidence interval, 1.68 to 4.66; P<0.001 for all stroke; and hazard ratio, 3.15; 95% confidence interval, 1.69 to 5.88; P<0.001 for ischemic stroke). This was true for both maternal and paternal stroke.
Conclusions— Documented parental stroke by 65 years of age was associated with a 3-fold increase in risk of offspring stroke. This increased risk persisted after adjustment for conventional stroke risk factors. Thus, verified parental stroke may serve as a clinically useful risk marker of an individual’s propensity to stroke.

Abstract 4 of 8

Genetics
Heterogeneity of Genetic Modifiers Ensures Normal Cardiac Development
Julia B. Winston, MS; Jonathan M. Erlich, BS; Courtney A. Green, BS; Ashley Aluko; Kristine A. Kaiser, MD; Mai Takematsu, MD; Robert S. Barlow, MD, PhD; Ashish O. Sureka, MD; Martin J. LaPage, MD; Luc L. Janss, PhD; Patrick Y. Jay, MD, PhD
From the Departments of Pediatrics (J.B.W., J.M.E., C.A.G., A.A., K.A.K., M.T., R.S.B., A.O.S., M.J.L., P.Y.J.) and Genetics (P.Y.J.), Washington University School of Medicine, St. Louis, Mo; and Radboud University Nijmegen Medical Centre, Donders Centre for Neuroscience, Nijmegen, the Netherlands (L.L.J.).
Correspondence to Dr Patrick Y. Jay, Departments of Pediatrics and Genetics, Washington University School of Medicine, Box 8208, 660 S Euclid Ave, St. Louis, MO 63110. E-mail jay_p@kids.wustl.edu
Received June 18, 2009; accepted January 7, 2010.
Background— Mutations of the transcription factor Nkx2-5 cause pleiotropic heart defects with incomplete penetrance. This variability suggests that additional factors can affect or prevent the mutant phenotype. We assess here the role of genetic modifiers and their interactions.
Methods and Results— Heterozygous Nkx2-5 knockout mice in the inbred strain background C57Bl/6 frequently have atrial and ventricular septal defects. The incidences are substantially reduced in the Nkx2-5+/– progeny of first-generation (F1) outcrosses to the strains FVB/N or A/J. Defects recur in the second generation (F2) of the F1xF1 intercross or backcrosses to the parental strains. Analysis of >3000 Nkx2-5+/– hearts from 5 F2 crosses demonstrates the profound influence of genetic modifiers on disease presentation. On the basis of their incidences and coincidences, anatomically distinct malformations have shared and unique modifiers. All 3 strains carry susceptibility alleles at different loci for atrial and ventricular septal defects. Relative to the other 2 strains, A/J carries polymorphisms that confer greater susceptibility to atrial septal defect and atrioventricular septal defects and C57Bl/6 to muscular ventricular septal defects. Segregation analyses reveal that 2 loci influence membranous ventricular septal defect susceptibility, whereas 2 loci and at least 1 epistatic interaction affect muscular ventricular and atrial septal defects.
Conclusions— Alleles of modifier genes can either buffer perturbations on cardiac development or direct the manifestation of a defect. In a genetically heterogeneous population, the predominant effect of modifier genes is health.

Abstract 5 of 8

Health Services and Outcomes Research
Recent Declines in Hospitalizations for Acute Myocardial Infarction for Medicare Fee-for-Service Beneficiaries
Progress and Continuing Challenges
Jersey Chen, MD, MPH; Sharon-Lise T. Normand, PhD; Yun Wang, PhD; Elizabeth E. Drye, MD, SM; Geoffrey C. Schreiner, BS; Harlan M. Krumholz, MD, SM
From the Section of Cardiovascular Medicine, Department of Medicine, Yale University School of Medicine, New Haven, Conn (J.C., H.M.K.); Department of Health Care Policy, Harvard Medical School, and Department of Biostatistics, Harvard School of Public Health, Boston, Mass (S.-L.T.N.); Center for Outcomes Research and Evaluation, Yale–New Haven Hospital, New Haven, Conn (E.E.D., G.C.S., Y.W., H.M.K.); and Robert Wood Johnson Clinical Scholars Program, Department of Medicine, and the Section of Health Policy and Administration, School of Public Health, Yale University School of Medicine, New Haven, Conn (H.M.K.).
Correspondence to Jersey Chen, Yale University School of Medicine, 333 Cedar St, New Haven, CT 06520. E-mail jersey.chen@yale.edu
Received March 2, 2009; accepted December 17, 2009.
Background— Amid recent efforts to reduce cardiovascular risk, whether rates of acute myocardial infarction (AMI) in the United States have declined for elderly patients is unknown.
Methods and Results— Medicare fee-for-service patients hospitalized in the United States with a principal discharge diagnosis of AMI were identified through the use of data from the Centers for Medicare and Medicaid Services from 2002 to 2007, a time period selected to reduce changes arising from the new definition of AMI. The Medicare beneficiary denominator file was used to determine the population at risk. AMI hospitalization rates were calculated annually per 100 000 beneficiary-years with Poisson regression analysis and stratified according to age, sex, and race. The annual AMI hospitalization rate in the fee-for-service Medicare population fell from 1131 per 100 000 beneficiary-years in 2002 to 866 in 2007, a relative 23.4% decline. After adjustment for age, sex, and race, the AMI hospitalization rate declined by 5.8%/y. From 2002 to 2007, white men experienced a 24.4% decrease in AMI hospitalizations, whereas black men experienced a smaller decline (18.0%; P<0.001 for interaction). Black women had a smaller decline in AMI hospitalization rate compared with white women (18.4% versus 23.3%, respectively; P<0.001 for interaction).
Conclusions— AMI hospitalization rates fell markedly in the Medicare fee-for-service population between 2002 and 2007. However, black men and women appeared to have had a slower rate of decline compared with their white counterparts.

Abstract 6 of 8

Pediatric Cardiology
Modeled Economic Evaluation of Alternative Strategies to Reduce Sudden Cardiac Death Among Children Treated for Attention Deficit/Hyperactivity Disorder
Peter Denchev, PhD; Jonathan R. Kaltman, MD; Michael Schoenbaum, PhD; Benedetto Vitiello, MD
From the National Institute of Mental Health (P.D., M.S., B.V.) and National Heart, Lung, and Blood Institute (J.R.K.), Bethesda, Md.
Correspondence to Peter Denchev, PhD, Division of Services and Intervention Research, National Institute of Mental Health, 6001 Executive Blvd, Bethesda, MD 20892. E-mail denchevp@mail.nih.gov
Received August 11, 2009; accepted January 14, 2010.
Background— Stimulants are widely used to treat children with attention deficit/hyperactivity disorder and may increase the risk for sudden cardiac death (SCD). We examined the cost-effectiveness of pretreatment screening with ECG for reducing SCD risk in children diagnosed with attention deficit/hyperactivity disorder who are candidates for stimulant medication.
Method and Results— We constructed a state-transition Markov model with 10 annual cycles spanning 7 to 17 years of age. Taking a societal perspective, we compared the cost-effectiveness of 3 screening strategies: (1) performing a history and physical examination with cardiology referral if abnormal (current standard of care); (2) performing a history and physical examination plus ECG after negative history and physical examination, with cardiology referral if either is abnormal; and (3) performing a history and physical examination plus ECG, with cardiology referral only if ECG is abnormal. Children identified with SCD-associated cardiac abnormalities would be restricted from stimulants and from playing competitive sports. The expected incremental cost-effectiveness over strategy 1 was $39 300 and $27 200 per quality-adjusted life-year for strategies 2 and 3, respectively. Monte Carlo simulation found that the chance of incremental cost-effectiveness was 55% for strategy 2 and 71% for strategy 3 (willingness to pay $50 000 per quality-adjusted life-year). Both strategies 2 and 3 would avert 13 SCDs per 400 000 children seeking stimulant treatment for ADHD, for a cost of $1.6 million per life for strategy 2 and $1.2 million per life for strategy 3.
Conclusions— Relative to current practice, adding ECG screening to history and physical examination pretreatment screening for children with attention deficit/hyperactivity disorder has borderline cost-effectiveness for preventing SCD. Relative cost-effectiveness may be improved by basing cardiology referral on ECG alone. Benefits of ECG screening arise primarily by restricting children identified with SCD risk from competitive sports.

Abstract 7 of 8

Vascular Medicine
Complement Regulator CD59 Protects Against Angiotensin II–Induced Abdominal Aortic Aneurysms in Mice
Gongxiong Wu, MD, PhD; Ting Chen, PhD; Aliakbar Shahsafaei, BS; Weiguo Hu, MD, PhD; Roderick T. Bronson, PhD; Guo-Ping Shi, PhD; Jose A. Halperin, MD; Huseyin Aktas, PhD; Xuebin Qin, MD, PhD
From the Department of Medicine, Brigham and Women’s Hospital, Boston, Mass (G.W., T.C., A.S., W.H., G.-P.S., J.A.H., H.A., X.Q.); Harvard Medical School, Laboratory for Translational Research, Cambridge, Mass (G.W., T.C., W.H., J.A.H., H.A., X.Q.); Department of Medical Neurobiology and Neuroanatomy, Medical School of Sun Yat-sen University, Guangzhou, PR China (G.W.); and Rodent Histopathology Core, Dana Farber/Harvard Medical School, Boston, Mass (R.T.B.).
Correspondence to Dr Xuebin Qin, Harvard Medical School, One Kendall Square, Bldg 600, 3rd Floor, Cambridge, MA 02139. E-mail xuebin_qin@hms.harvard.edu
Received December 15, 2008; accepted January 15, 2010.
Background— Complement system, an innate immunity, has been well documented to play a critical role in many inflammatory diseases. However, the role of complement in the pathogenesis of abdominal aortic aneurysm, which is considered an immune and inflammatory disease, remains obscure.
Methods and Results— Here, we evaluated the pathogenic roles of complement membrane attack complex and CD59, a key regulator that inhibits the membrane attack complex, in the development of abdominal aortic aneurysm. We demonstrated that in the angiotensin II–induced abdominal aortic aneurysm model, deficiency of the membrane attack complex regulator CD59 in ApoE-null mice (mCd59ab–/–/ApoE–/–) accelerated the disease development, whereas transgenic overexpression of human CD59 (hCD59ICAM-2+/–/ApoE–/–) in this model attenuated the progression of abdominal aortic aneurysm. The severity of aneurysm among these 3 groups positively correlates with C9 deposition, and/or the activities of MMP2 and MMP9, and/or the levels of phosphorylated c-Jun, c-Fos, IKK- /β, and p65. Furthermore, we demonstrated that the membrane attack complex directly induced gene expression of matrix metalloproteinase-2 and -9 in vitro, which required activation of the activator protein-1 and nuclear factor- B signaling pathways.
Conclusion— Together, these results defined the protective role of CD59 and shed light on the important pathogenic role of the membrane attack complex in abdominal aortic aneurysm.

Abstract 8 of 8

Vascular Medicine
Adipocyte Modulation of High-Density Lipoprotein Cholesterol
YuZhen Zhang, MD, PhD*; Fiona C. McGillicuddy, PhD*; Christine C. Hinkle, MS; Sean O'Neill, PhD, MBA; Jane M. Glick, PhD; George H. Rothblat, PhD; Muredach P. Reilly, M***h
From the Cardiovascular Institute (Y.Z., F.C.M., C.C.H., S.O., M.P.R.) and Institute of Translational Medicine and Therapeutics (Y.Z., F.C.M., C.C.H., S.O., M.P.R.), Departments of Medicine and Cell and Developmental Biology (J.M.G.), University of Pennsylvania School of Medicine, Philadelphia; Division of Nutrition, Children’s Hospital of Philadelphia, Philadelphia, Pa (G.H.R.); and Nutrigenomics Research Group, UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin, Ireland (F.C.M.).
Correspondence to Muredach P. Reilly, M***h, University of Pennsylvania Medical Center, 609 BRB 2/3, 421 Curie Blvd, Philadelphia, PA 19104-6160. E-mail muredach@mail.med.upenn.edu
Received July 25, 2009; accepted January 15, 2010.
Background— Adipose harbors a large depot of free cholesterol. However, a role for adipose in cholesterol lipidation of high-density lipoprotein (HDL) in vivo is not established. We present the first evidence that adipocytes support transfer of cholesterol to HDL in vivo as well as in vitro and implicate ATP-binding cassette subfamily A member 1 (ABCA1) and scavenger receptor class B type I (SR-BI), but not ATP-binding cassette subfamily G member 1 (ABCG1), cholesterol transporters in this process.
Methods and Results— Cholesterol efflux from wild-type, ABCA1–/–, SR-BI–/–, and ABCG1–/– adipocytes to apolipoprotein A-I (apoA-I) and HDL3 were measured in vitro. 3T3L1 adipocytes, labeled with 3H-cholesterol, were injected intraperitoneally into wild-type, apoA-I transgenic, and apoA-I–/– mice, and tracer movement onto plasma HDL was monitored. Identical studies were performed with labeled wild-type, ABCA1–/–, or SR-BI–/– mouse embryonic fibroblast adipocytes. The effect of tumor necrosis factor- on transporter expression and cholesterol efflux was monitored during adipocyte differentiation. Cholesterol efflux to apoA-I and HDL3 was impaired in ABCA1–/– and SR-BI–/– adipocytes, respectively, with no effect observed in ABCG1–/– adipocytes. Intraperitoneal injection of labeled 3T3L1 adipocytes resulted in increased HDL-associated 3H-cholesterol in apoA-I transgenic mice but reduced levels in apoA-I–/– animals. Intraperitoneal injection of labeled ABCA1–/– or SR-BI–/– adipocytes reduced plasma counts relative to their respective controls. Tumor necrosis factor- reduced both ABCA1 and SR-BI expression and impaired cholesterol efflux from partially differentiated adipocytes.
Conclusions— These data suggest a novel metabolic function of adipocytes in promoting cholesterol transfer to HDL in vivo and implicate adipocyte SR-BI and ABCA1, but not ABCG1, in this process. Furthermore, adipocyte modulation of HDL may be impaired in adipose inflammatory disease states such as type 2 diabetes mellitus.