...many of the clinical registries in pediatric and congenital heart disease share clinical nomenclature for disease classification and procedural coding. During early childhood, a child is more ...likely to have multiple visits to the physician’s office, and children see multiple specialists throughout childhood. ...there are indeed many characteristics of pediatric care that differ from adult care. Name Employment Consultant Speaker Ownership/Partnership/Principal Research Institutional, Organizational, or Other Financial Benefit Expert Witness Jeffrey R. Boris (Chair) Children’s Hospital of Philadelphia-Clinical Professor of Pediatrics, Division of Cardiology None None None None None None Marie J. Béland Montreal Children’s Hospital None None None None None None Lisa J. Bergensen Boston Children’s Hospital-Associate in Cardiology None None None None None None Steven D. Colan Boston Children’s Hospital-Director of Clinical Research, Cardiology None None None None None None Joanna Dangel Medical University of Warsaw-Professor of Pediatric Cardiology None None None None None None Curtis J. Daniels Nationwide Children’s-Director Adolescent and Adult Congenital Heart Disease None None None None None None Christopher Davis Rady Children’s Hospital San Diego-Director, Cardiopulmonary Exercise Laboratory None None None None None None Allen D. Everett Johns Hopkins All Children’s Hospital-Director of the Pediatric Proteome Center None None None None None None Rodney Franklin Royal Brompton Hospital-Consultant Paediatric Cardiologist None None None None None None J. William Gaynor Children’s Hospital of Philadelphia-Director, Fetal Neuroprotection and Neuroplasticity Program None None None None None None Darryl T. Gray Agency for Healthcare Research and Quality-Medical Officer None None None None None None Jennifer C. Hirsch-Romano University of Michigan-Associate Director, Pediatric Cardiothoracic Intensive Care Unit None None None None None None Jeffrey P. Jacobs Johns Hopkins All Children’s Hospital-Chief, Division of Cardiovascular Surgery None None None None None None Marshall Jacobs Johns Hopkins Cardiac Surgery-Director, Pediatric Cardiac Surgery Outcomes Research None None None None None None Howard Jeffries Seattle Children’s Hospital-Medical Director, Clinical Effectiveness None None None None None None Otto Nils Krogmann Klinik Für Kinderkardiologie None None None None None None Edwin A. Lomotan Agency for Healthcare Research and Quality-Medical Officer None None None None None None Leo Lopez Nicklaus Children’s Hospital-Medical Director, Noninvasive Cardiac Imaging None None None None None None Ariane Marelli McGill University Health Centre-Associate Professor of Medicine None None None None None None Gerard R. Martin Children’s National Health System-Medical Director of Global Health None None None None None None G. Paul Matherne University of Virginia Children’s Hospital-Associate Chief Medical Officer None None None None None None Constantine Mavroudis Johns Hopkins Children’s Heart Surgery-Site Director None None None None None None Ken McCardle Mount Sinai Health System-Senior Director, Clinical Operations None None None None None None Gail D. Pearson National Heart, Lung, and Blood Institute-Director, Adult and Pediatric Cardiac Research Program None None None None None None Geoffrey Rosenthal University of Maryland-Director, Children’s Heart Program None None None None None None John S. Scott Office of the Assistant Secretary of Defense, Health Affairs-Program Director, Clinical Informatics Policy None None None None None None Gerald A. Serwer C.S. Mott Children’s Hospital-Professor, Pediatrics None None None None None None Stephen S. Seslar Seattle Children’s Hospital-Associate Professor, Pediatric Cardiology None None None None None None Robert Shaddy Chief Professor-Children’s Hospital of Philadelphia None None None None None None Timothy Slesnick Emory University School of Medicine-Assistant Professor of Pediatrics None None None None None None David F. Vener Texas Children’s Hospital-Associate Professor, Pediatrics and Anesthesiology None None None None None None Henry L. Walters III Children’s Hospital of Michigan-Chief, Cardiovascular Surgery None None None None None None Paul M. Weinberg Children’s Hospital of Philadelphia-Director, Cardiac Registry None None None None None None This table represents the relationships of committee members with industry and other entities that were determined to be relevant to this document. Meaningful Use Definition & Objectives (15) Current every day smoker Current some day smoker Former smoker Never smoker Smoker, current status unknown Unknown if ever smoked Heavy tobacco smoker Light tobacco smoker Illicit Drug Use The nonmedical use of chemicals that are prohibited by international law. listlist_itemYes/list_itemlist_itemNo/list_itemlist_itemUnknown/list_item/list World Health Organization (34) ▪CABG indicates coronary artery bypass graft; CAD, coronary artery disease; CHD, congenital heart disease; IEP, individualized education plan; NCI, National Cancer Institute; NICHD, National Institute of Child Health and Human Development; MI, myocardial infarction; and PCI, percutaneous coronary intervention.BMI indicates body mass index; BSA, body surface area; BP, blood pressure, mmHg, millimeter mercury; and RA, right arm.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
1 Department of Pediatrics, 2 Cardiovascular Research Center, and 3 Department of Biomedical Engineering, University of Virginia Health System, Charlottesville, Virginia; 4 Department of Physiology ...and Pharmacology, Karolinska Institute, Stockholm, Sweden; and 5 Griffith University, Gold Coast, Queensland, Australia
Submitted 22 February 2005
; accepted in final form 10 November 2005
Activation of A 1 adenosine receptors (A 1 ARs) may be a crucial step in protection against myocardial ischemia-reperfusion (I/R) injury; however, the use of pharmacological A 1 AR antagonists to inhibit myocardial protection has yielded inconclusive results. In the current study, we have used mice with genetically modified A 1 AR expression to define the role of A 1 AR in intrinsic protection and ischemic preconditioning (IPC) against I/R injury. Normal wild-type (WT) mice, knockout mice with deleted (A 1 KO / ) or single-copy (A 1 KO +/ ) A 1 AR, and transgenic mice (A 1 TG) with increased cardiac A 1 AR expression underwent 45 min of left anterior descending coronary artery occlusion, followed by 60 min of reperfusion. Subsets of each group were preconditioned with short durations of ischemia (3 cycles of 5 min of occlusion and 5 min of reperfusion) before index ischemia. Infarct size (IF) in WT, A 1 KO +/ , and A 1 KO / mice was (in % of risk region) 58 ± 3, 60 ± 4, and 61 ± 2, respectively, and was less in A 1 TG mice (39 ± 4, P < 0.05). A strong correlation was observed between A 1 AR expression level and response to IPC. IF was significantly reduced by IPC in WT mice (35 ± 3, P < 0.05 vs. WT), A 1 KO +/ + IPC (48 ± 4, P < 0.05 vs. A 1 KO +/ ), and A 1 TG + IPC mice (24 ± 2, P < 0.05 vs. A 1 TG). However, IPC did not decrease IF in A 1 KO / + IPC mice (63 ± 2). In addition, A 1 KO / hearts subjected to global I/R injury demonstrated diminished recovery of developed pressure and diastolic function compared with WT controls. These findings demonstrate that A 1 ARs are critical for protection from myocardial I/R injury and that cardioprotection with IPC is relative to the level of A 1 AR gene expression.
myocardial ischemia-reperfusion injury; functional genomics; genetically altered mice
Address for reprint requests and other correspondence: A. R. Lankford, Dept. of Pediatrics, Univ. of Virginia Health System Box 800386, MR4 Bldg., Charlottesville, VA 22908 (e-mail: arl2b{at}virginia.edu )
Atrial septal defects are a common congenital heart defect and may complicate the course of a premature infant by imposing volume overload to the lungs. Surgical closure requires cardiopulmonary ...bypass and, frequently, a midline sternotomy. Recently, percutaneous transcatheter devices were approved for atrial septal defect closure but have been limited to use in larger children. Here we present the first known report of a transcatheter device closure of an atrial septal defect in a premature infant, which resulted in rapid improvement of the patient's respiratory status.
Activation of myocardial A1 adenosine receptors (A1AR) protects the heart from ischemic injury. In this study transgenic mice were created using the cardiac-specific α -myosin heavy chain promoter ...and rat A1AR cDNA. Heart membranes from two transgene positive lines displayed ≈ 1,000-fold overexpression of A1AR (6,574 ± 965 and 10,691 ± 1,002 fmol per mg of protein vs. 8 ± 5 fmol per mg of protein in control hearts). Compared with control hearts, transgenic Langendorff-perfused hearts had a significantly lower intrinsic heart rate (248 beats per min vs. 318 beats per min, P < 0.05), lower developed tension (1.2 g vs. 1.6 g, P < 0.05), and similar coronary resistance. The difference in developed tension was eliminated by pacing. Injury of control hearts during global ischemia, indexed by time-to-ischemic contracture, was accelerated by blocking adenosine receptors with 50 μ M 8-(p-sulfophenyl) theophylline but was unaffected by addition of 20 nM N6-cyclopentyladenosine, an A1AR agonist. Thus A1ARs in ischemic myocardium are presumably saturated by endogenous adenosine. Overexpressing myocardial A1ARs increased time-to-ischemic contracture and improved functional recovery during reperfusion. The data indicate that A1AR activation by endogenous adenosine affords protection during ischemia, but that the response is limited by A1AR number in murine myocardium. Overexpression of A1AR affords additional protection. These data support the concept that genetic manipulation of A1AR expression may improve myocardial tolerance to ischemia.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Cardiovascular Research Center, Departments of 1 Biomedical
Engineering, 2 Pediatrics, and 3 Radiology, University of
Virginia Health System, Charlottesville, Virginia 22908
Previous studies have
...shown that high-level (300-fold normal) cardiac overexpression of
A 1 -adenosine receptors (A 1 -ARs) in transgenic
(TG) mice protects isolated hearts against
ischemia-reperfusion injury. However, this high level of
overexpression is associated with bradycardia and increased incidence
of arrhythmia during ischemia in intact mice, which interfered
with studies to determine whether this line of TG mice might also be
protected against myocardial infarction (MI) in vivo. For these
studies, we therefore selected a line of TG mice that overexpresses the
A 1 -AR at more moderate levels (30-fold normal), which
affords cardioprotection in the isolated heart while minimizing
bradycardia and arrhythmia during ischemia in intact mice.
Wild-type (WT; n = 10) and moderate-level A 1 -AR TG ( n = 10) mice underwent 45 min of
left anterior descending coronary artery occlusion, followed by 24-h
reperfusion. Infarct size and region at risk were determined by
triphenyltetrazolium chloride and phthalo blue staining, respectively.
Infarct size (% region at risk) in WT mice was 52 ± 3%, whereas
overexpression of A 1 -ARs in the TG mice markedly reduced
infarct size to 31 ± 3% ( P < 0.05).
Furthermore, contractile function (left ventricular ejection fraction)
as determined by cardiac magnetic resonance imaging 24 h after MI
was better preserved in TG vs. WT mice. Cardiac overexpression of
A 1 -ARs reduces infarct size by 40% and preserves
cardiac function in intact mice after MI.
ischemia-reperfusion; cardioprotection; transgenic mice; magnetic resonance imaging
*
Z. Yang and R. J. Cerniway contributed equally to
this work.
1 Department of Cardiology and Angiology and
2 Institute for Pharmacology and Toxicology, University
Hospital Münster, D-48129 Münster;
3 Institute for Pathology, University of Essen, D-45122
Essen, ...Germany; and 4 Department of Pediatrics and
Cardiovascular Research Center, University of Virginia, Charlottesville,
Virginia 22908-1356
Submitted 2 December 2002
; accepted in final form 2 February 2003
To investigate whether altered function of adenosine receptors could
contribute to sinus node or atrioventricular (AV) nodal dysfunction in
conscious mammals, we studied transgenic (TG) mice with cardiac-specific
overexpression of the A 1 adenosine receptor (A 1 AR). A
Holter ECG was recorded in seven freely moving littermate pairs of mice during
normal activity, exercise (5 min of swimming), and 1 h after exercise. TG mice
had lower maximal heart rates (HR) than wild-type (WT) mice (normal activity:
437 ± 18 vs. 522 ± 24 beats/min, P < 0.05; exercise:
650 ± 13 vs. 765 ± 28 beats/min, P < 0.05; 1 h after
exercise: 588 ± 18 vs. 720 ± 12 beats/min, P < 0.05;
all values are means ± SE). Mean HR was lower during exercise (589
± 16 vs. 698 ± 34 beats/min, P < 0.05) and after
exercise (495 ± 16 vs. 592 ± 27 beats/min, P <
0.05). Minimal HR was not different between genotypes. HR variability (SD of
RR intervals) was reduced by 30% ( P < 0.05) in TG compared with WT
mice. Pertussis toxin ( n = 4 pairs, 150 µg/kg ip) reversed
bradycardia after 48 h. TG mice showed first-degree AV nodal block (PQ
interval: 42 ± 2 vs. 37 ± 2 ms, P < 0.05), which was
diminished but not abolished by pertussis toxin. Isolated Langendorff-perfused
TG hearts developed spontaneous atrial arrhythmias (3 of 6 TG mice vs. 0 of 9
WT mice, P < 0.05). In conclusion, A 1 AR regulate sinus
nodal and AV nodal function in the mammalian heart in vivo. Enhanced
expression of A 1 AR causes sinus nodal and AV nodal dysfunction and
supraventricular arrhythmias.
heart rate regulation; autonomous nervous system; heart rate variability; sinus node dysfunction; atrioventricular block; atrial fibrillation
Address for reprint requests and other correspondence: P. Kirchhof,
Medizinische Klinik C, Kardiologie und Angiologie, Universitätsklinikum
Münster, Albert-Schweitzer-Strasse 33, D-48129 Münster, Germany
(E-mail:
kirchhp{at}uni-muenster.de ).
This study evaluated the ability of A
1 and A
3 adenosine receptor (AR) agonism, and A
1, A
2A, A
2B and A
3AR antagonism (revealing “intrinsic” responses), to modify post-ischemic coronary ...dysfunction in mouse heart. Vascular function was assessed before and after 20 min global ischemia and 30–45 min reperfusion in Langendorff perfused C57/Bl6 mouse hearts. Ischemic insult impaired coronary sensitivity to the endothelial-dependent dilators ADP (pEC
50
=
6.8
±
0.1 vs. 7.6
±
0.1, non-ischemic) and acetylcholine (pEC
50
=
6.1
±
0.1 vs. 7.3
±
0.1 in non-ischemic), and for the mixed endothelial-dependent/independent dilator 2-chloroadenosine (pEC
50
=
7.5
±
0.1 vs. 8.4
±
0.1, non-ischemic). Endothelium-independent dilation in response to nitroprusside was unaltered (pEC
50
=
7.0
±
0.1 vs. 7.1
±
0.1 in non-ischemic). Pre-treatment with a selective A1AR agonist (50 nM CHA) failed to modify coronary dysfunction, whereas A1AR antagonism (200 nM DPCPX) worsened the effects of I/R (2-chloroadenosine pEC
50
=
6.9
±
0.1). Conversely, A
3AR agonism (100 nM Cl-IB-MECA) did reduce effects of I/R (pEC
50s
=
8.0
±
0.1 and 7.3
±
0.1 for 2-chloroadenosine and ADP, respectively), whereas antagonism (100 nM MRS1220) was without effect. While A
2AAR agonism could not be assessed (due to pronounced vasodilatation), A
2AAR antagonism (100 nM SCH58261) was found to exert no effect, and antagonism of A
2BARs (50 nM MRS1754) was also ineffective. The protective actions of A
3AR agonism were also manifest as improved reactive hyperemic responses. Interestingly, post-ischemic coronary dysfunction was also limited by: Na
+–H
+ exchange (NHE) inhibition with 10 or 50 μM BIIB-513 (2-chloroadenosine pEC
50s
=
7.8
±
0.1, either dose), an effect not additive with A
3AR agonism; Ca
2+ antagonism with 0.3 μM verapamil (2-chloroadenosine pEC
50
=
7.9
±
0.1); and Ca
2+ desensitization with 5 mM BDM (2-chloroadenosine pEC
50
=
7.8
±
0.1). In contrast, endothelin antagonism (200 nM PD142893) and anti-oxidant therapy (300 μM MPG
+
150 U/ml SOD
+
600 U/ml catalase) were ineffective. Our data collectively confirm that ischemia selectively impairs endothelial function and reactive hyperemia independently of blood cells. Vascular injury is intrinsically limited by endogenous (but not exogenous) activation of A
1ARs, whereas exogenous A
3AR activation further limits dysfunction (improving post-ischemic vasoregulation). Finally, findings suggest this form of post-ischemic coronary injury is unrelated to endothelin or oxidant stress, but may involve modulation of Ca
2+ overload and/or related ionic perturbations.
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A Report of the American College of Cardiology Appropriate Use Criteria Task Force, American Academy of Pediatrics, American Heart Association, American Society of Echocardiography, Heart Rhythm ...Society, Society for Cardiovascular Angiography and Interventions, Society of Cardiovascular Computed Tomography, Society for Cardiovascular Magnetic Resonance, and Society of Pediatric Echocardiography Rating Panel Robert M. Campbell, MD, FACC, FAHA, FAAP, FHRS, Chairlow * Pamela S. Douglas, MD, MACC, FAHA, FASE, Moderatorlow * Louis I. Bezold, MD, FACC, FAAP, FASEdagger William B. Blanchard, MD, FACC, FAHA, FAAPlow * Jeffrey R. Boris, MD, FACClow * Bryan Cannon, MDdouble dagger Gregory J. Ensing, MD, FACC, FASE§ Craig E. Fleishman, MD, FACC, FASE|| Mark A. Fogel, MD, FACC, FAHA, FAAP¶ B. Kelly Han, MD, FACC# Shabnam Jain, MD, MPH, FAAPlow * Mark B. Lewin, MD|| Richard Lockwood, MDlow *low * G. Paul Matherne, MD, MBA, FACC, FAHAdaggerdagger David Nykanen, MD, FACCdouble daggerdouble dagger Catherine L. Webb, MD, FACC, FAHA, FASEdaggerdagger Robert Wiskind, MD, FAAPlow *American College of Cardiology representative.American Academy of Pediatrics representative.Heart Rhythm Society representative.American Society of Echocardiography representative.Society of Pediatric Echocardiography representative.Society for Cardiovascular Magnetic Resonance representative.Society of Cardiovascular Computed Tomography representative.Health Plan representative.American Heart Association representative.Society for Cardiovascular Angiography and Interventions representative.
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