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Unique Aspects of Heart Failure in the Neonate

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Heart Failure in Congenital Heart Disease:

Abstract

Neonatal heart failure is characterized by many unique anatomic and physiologic features. Structural and functional differences between the mature and immature myocardium, as well as different etiologies of neonatal heart failure, pose challenges for the clinician when evaluating and treating the clinical syndrome of heart failure. Anatomically, the newborn myocardium is disorganized in its structure and has a lower density of contractile proteins. These features, as well as decreased cellular transport, may play a role in the relatively impaired contractile and relaxation functions of the immature heart. Despite these differences, the Frank-Starling relationship in the neonatal heart is intact and functional as cardiac output can be augmented with increased ventricular filling, as well as higher heart rates and inotropy. The treatment of the clinical syndrome of heart failure depends, in part, on the underlying cause of heart failure. In the presence of depressed myocardial contractility, unloading the myocardium with diuretics and afterload reducing agents often leads to symptomatic relief and improved cardiac output. Understanding the developmental changes in myocardial structure and function will add to the clinician’s ability to provide optimal care of the newborn in the setting of a failing myocardium. The purpose of this chapter is to review the key differences between the neonatal heart failure and heart failure in the older child and adult.

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References

  1. Rudolph AM, Drorbaugh JE, Auld PA et al (1961) Studies on the circulation in the neonatal period. The circulation in the respiratory distress syndrome. Pediatrics 27:551-566.

    CAS  Google Scholar 

  2. Clyman RI, Mauray F, Wong L et al (1978) The developmental response of the ductus arteriosus to oxygen. Biol Neonate 34:177-181.

    Article  PubMed  CAS  Google Scholar 

  3. Oberhansli-Weis I, Heymann MA, Rudolph AM, Melmon KL (1972) The pattern and mechanism of response to oxygen by the ductus arteriosus and umbilical artery. Ped Res 6:693-700.

    Article  Google Scholar 

  4. Clyman RI, Waleh N, Black SM et al (1998) Regulations of ductus arteriosus patency by nitric oxide in fetal lambs: the role of gestation, oxygen tension, and vasa vasorum. Ped Res 43:633-644.

    Article  CAS  Google Scholar 

  5. Friedman WF, Printz MP, Kirkpatrick SE, Hoskins EJ (1983) The vasoactivity of the fetal lamb ductus arteriosus studied in utero. Ped Res 17:331-337.

    Article  CAS  Google Scholar 

  6. Meyer WW, Lind J (1966) The ductus venosus and the mechanism of its closure. Arch Dis Child 41:597-605.

    Article  PubMed  CAS  Google Scholar 

  7. Adeagbo AS, Coceani F, Olley PM (1982) The response of the lamb ductus venosus to prostaglandins and inhibitors of prostaglandin and thromboxane. Circ Res 51:580-586.

    PubMed  CAS  Google Scholar 

  8. Heyman MA, Rudolph AM. Effects of congenital heart disease on fetal and neonatal circulations. Prog Cardiovasc Dis. 1972;15:115–143.

    Article  Google Scholar 

  9. Cook CD, Drinker PA, Jacobson HN et al (1963) Control of pulmonary blood flow in the foetal and newly born lamab. J Physiol 169:10-29.

    PubMed  CAS  Google Scholar 

  10. Teitel DF, Iwamoto HS, Rudolph AM (1990) Changes in the pulmonary circulation during birth-related events. Ped Res 27:372-378.

    Article  CAS  Google Scholar 

  11. Anversa P, Olivetti G, Loud AV (1980) Morphometric study of early postnatal development in the left and right ventricular myocardium of the rat. Circ Res 46:495-502.

    PubMed  CAS  Google Scholar 

  12. Korecky B, Rakusan K (1978) Normal and hypertrophic growth of the rat heart: changes in cell dimension and number. Am J Physiol 234:H123.

    PubMed  CAS  Google Scholar 

  13. Englemann GL, Dionne CA, Jaye MC (1993) Acidic fibroblast growth factor and heart development. Role in myocyte proliferation and capillary angiogenesis. Circ Res 72:7-19.

    Google Scholar 

  14. Zak R (1974) Development and proliferative capacity of cardiac muscle cells. Circ Res 35(Supp II):17-26.

    Google Scholar 

  15. Weiner HL and Swain JL (1989) Acidic fibroblast growth factor mRNA is expressed by cardiac myocytes in culture and the protein is localized to the extracellular matrix. Proc Natl Acad USA 86:2683-2687.

    Article  CAS  Google Scholar 

  16. Simpson P (1985) Stimulation of hypertrophy of cultured neonatal rat heart cells through an alpha 1-adrenergic receptor and induction of beating through an alpha 1- and beta 1-adrenergic receptor interaction. Evidence for independent regulation of growth and beating. Circ Res 56:884-894.

    CAS  Google Scholar 

  17. Nassar R, Reedy MC, Anderson PAW (1987) Developmental changes in the ultrastructure and sarcomere shortening of the isolated rabbit ventricular myocyte. Circ Res 61:465-483.

    PubMed  CAS  Google Scholar 

  18. Sheridan DJ, Cullen MJ, Tynan MJ (1979) Qualitative and quantitative observations on ultrastructural changes during postnatal development in the cat myocardium. J Mol Cell Cardiol 11:1173-1181.

    Article  PubMed  CAS  Google Scholar 

  19. Hoerter J, Mazet F, Vassort G (1981) Perinatal growth of the rabbit cardiac cell. Possible implications for the mechanism of relaxation. J Mol Cell Cardiol 13:725-740.

    CAS  Google Scholar 

  20. Olivetti G, Anversa P, Loud AV (1980) Morphometric study of early postnatal development in the left and right ventricular myocardium of the rat. Tissue composition, capillary growth, and sarcoplasmic alterations. Circ Res 46:503-512.

    PubMed  CAS  Google Scholar 

  21. Fisher DJ, Heymann MA, Rudolph AM (1980) Myocardial oxygen and carbohydrate consumption in fetal lambs in utero and in adult sheep. Am J Phys 238:H399-H405.

    CAS  Google Scholar 

  22. Warshaw JB, Terry ML (1970) Cellular energy metabolism during fetal development. II. Fatty acid oxidation by the developing heart. J Cell Biol 44:354-360.

    CAS  Google Scholar 

  23. Wittels B, Bressler R (1965) Lipid metabolism in the newborn heart. J Clin Invest 44:1639-1646.

    Article  PubMed  CAS  Google Scholar 

  24. Swynghedauw B (1986) Developmental and functional adaptation of contractile proteins in cardiac and skeletal muscles. Physiol Rev 66:710-771.

    PubMed  CAS  Google Scholar 

  25. Hatem SN, Sweeten T, Vetter V, Morad M (1995) Evidence for presence of Ca2+ stores in neonatal human atrial myocytes. Am J Physiol 268:H1195-H1201.

    PubMed  CAS  Google Scholar 

  26. Roca TP, Pigott JD, Clarkson CW, Crumb WJ (1996) L-type calcium current in pediatric and adult human atrial myocytes: evidence for developmental changes in channel inactivation. Pediatr Res 40:462-468.

    Article  PubMed  CAS  Google Scholar 

  27. Mahony L, Jones LR (1986) Developmental changes in cardiac sarcoplasmic reticulum in sheep. J Biol Chem 261:15257-65.

    Google Scholar 

  28. Anderson RH, Baker EJ, Macartney FJ et al (2002) Myocardium and development in paediatric cardiology. Harcourt Publishers, London, 2nd edition.

    Google Scholar 

  29. Kitten GT, Markwald RR, Bolender DL (1987) Distribution of basement membrane antigens in cryopreserved early embryonic hearts. Anatomical Record 217:379-390.

    Article  PubMed  CAS  Google Scholar 

  30. Little CD, Piquet DM, Davis LA et al (1989) Distribution of laminin, collagen type IV, collagen type I, and fibronectin in chicken cardiac jelly basement membrane. Anatomical Record 224:417-425.

    Article  PubMed  CAS  Google Scholar 

  31. Price RL, Nakagawa M, Terracio L, Borg TK (1992) Ultrastructural localization of laminin onin vivo embryonic neonatal and adult rate cardiac myocytes and in early rat embryos raised in whole embryo culture. J Histochem and Cytochem 40:1373-1381.

    CAS  Google Scholar 

  32. Legato MJ (1979) Cellular mechanisms of normal growth in the mammalian heart. Qualitative and quantitative features of ventricular architecture in the dog from birth to five months of age. Circ Res 44:250-262.

    CAS  Google Scholar 

  33. Davies P, Dewar J, Tynan M (1975) Post-natal developmental changes in the length-tension relationship of cat papillary muscles. J Physiol 253:95-102.

    PubMed  CAS  Google Scholar 

  34. Friedman WF, Lesch M, Sonnenblick EH (1973) Neonatal heart disease. New York: Grune and Stratton, 1973, p. 21-49.

    Google Scholar 

  35. Hoerter J (1976) Changes in the sensitivity to hypoxia and glucose deprivation in the isolated perfused rabbit heart during perinatal development. Pfluegers Arch 363:1-6.

    Article  CAS  Google Scholar 

  36. Hopkins SF, Jr., McCutcheon EP, Wekstein DR (1973) Postnatal changes in rat ventricular function. Circ Res 32:685-691.

    PubMed  Google Scholar 

  37. Park MK, Sheridan PH, Morgan WW, Beck N (1980) Comparative inotropic response of newborn and adult rabbit papillary muscles to isoproterenol and calcium. Dev Pharmacol Ther 1:70-82.

    PubMed  CAS  Google Scholar 

  38. Friedman WF (1972) The intrinsic physiologic properties of the developing heart. Prog Cardiovasc Dis 15:87-111.

    Article  PubMed  CAS  Google Scholar 

  39. Anderson PA, Manring A, Glick KL, Crenshaw CC (1982) Biophysics of the developing heart. A comparison of the left ventricular dynamics of the fetal and neonatal lamb heart. Am J Obstet Gynecol 143:195-203.

    CAS  Google Scholar 

  40. Teitel DF, Sidi DD, Chin T et al (1985) Developmental changes in myocardial contractile reserve in the lamb. Pediatr Res 19:948-955.

    Article  PubMed  CAS  Google Scholar 

  41. Eliot RJ, Lam R, Leake RD et al (1980) Plasma catecholamine concentrations in infants at birth and during the first 48 hours of life. J Pediatr 96:311-315.

    Article  PubMed  CAS  Google Scholar 

  42. Gilbert RD (1982) Effects of afterload and baroreceptors on cardiac function in fetal sheep. J Dev Physiol 4:299-309.

    PubMed  CAS  Google Scholar 

  43. Mahony L (1996) Calcium homeostasis and control of contractility in the developing heart. Semin Perinatol 20:510-519.

    Article  Google Scholar 

  44. Spotnitz WD, Spotnitz HM, Truccone NJ (et al) (1979) Relation of ultrastructure and function. Sarcomere dimensions, pressure-volume curves, and geometry of the intact left ventricle of the immature canine heart. Circ Res 44:679-691.

    PubMed  CAS  Google Scholar 

  45. Romero T, Covell J, Friedman WF (1972) A comparison of pressure-volume relations of the fetal, newborn, and adult heart. Am J Phys 222:1285-1290.

    CAS  Google Scholar 

  46. Nakazawa M, Miyagawa S, Ohno T et al (1988) Developmental hemodynamic changes in rat embryos at 11 to 15 days of gestation: normal data of blood pressure and the effect of caffeine compared to data from chick embryo. Pedtr Res 23:200-205.

    CAS  Google Scholar 

  47. Reed KL, Sahn DJ, Scagnelli S et al (1986) Doppler echocardiographic studies of diastolic function in the human fetal heart: changes during gestation. J Am Coll Cardiol 8:391-395.

    Article  PubMed  CAS  Google Scholar 

  48. Wladimiroff JW, Huisman TW, Stewart PA et al (1992) Normal fetal Doppler inferior vena cava, transtricuspid and umbilical artery flow velocity waveforms between 11 and 16 weeks’ gestation. Am J Obstet Gynecol 166:921-924.

    PubMed  CAS  Google Scholar 

  49. Hu N, Connuck DM, Keller BB, Clark EB (1991) Diastolic filling characteristics in the stage 12 to 27 chick embryo ventricle. Pediatr Res 29:334-7

    Google Scholar 

  50. Kirkpatrick SE, Pitlick PT, Naliboff J, Friedman WF (1976) Frank-Starling relationship as an important determinant of fetal cardiac output. Am J Physiol 231:495-500.

    PubMed  CAS  Google Scholar 

  51. Romero TE, Friedman WF (1979) Limited left ventricular response to volume overload in the neonatal period: a comparative study with the adult animal. Pediatr Res13:910-5

    Google Scholar 

  52. Anderson PA, Killam AP, Mainwaring RD, Oakeley AE (1987) In utero right ventricular output in the fetal lamb: the efect of heart rate. J Physiol 387:297-316.

    PubMed  CAS  Google Scholar 

  53. Anderson PA, Glick KL, Killam AP, Mainwaring RD (1986) The effect of heart rate on in utero left ventricular output in the fetal sheep. J Physiol 372:557-573.

    PubMed  CAS  Google Scholar 

  54. Geis WP, Tatooles CJ, Priola DV, Friedman WF (1975) Factors influencing neurohormonal control of the heart in the newborn dog. Am J Physiol 228:1685-1689.

    PubMed  CAS  Google Scholar 

  55. Friedman WF, Pool PE, Jacobowitz D et al (1968) Sympathetic innervation of the developing rabbit heart: Biochemical and histochemical comparisons of fetal, neonatal, and adult myocardium. Circ Res 23:25-32.

    PubMed  CAS  Google Scholar 

  56. Lebowitz EA, Novich JS, Rudolph AM (1972) Development of myocardial sympathetic innervations in the fetal lamb. Pediatr Res 6:887-893.

    Article  PubMed  CAS  Google Scholar 

  57. Erath HG Jr, Boerth RC, Graham TP Jr (1982) Functional significance of reduced cardiac sympathetic innervation in the newborn dog. Am J Physiol 243:H20-6.

    Google Scholar 

  58. Booker PD (2002). Pharmacological support for childrenn with myocardial dysfunction. Paediatric Anesthesia 12:5-25.

    Article  CAS  Google Scholar 

  59. Allen E, Pettigrew A, Frank D et al (1997) Alterations in dopamine clearance and catechol-O-methyltransferase activity by dopamine infusions in children. Crit Care Med 25:181-189.

    Article  PubMed  CAS  Google Scholar 

  60. Nottemran DA, Greenwald BM, Moran F et al (1990) Dopamine clearance in critically ill infants and children: effect of age and organ system dysfuntion. Clin Pharmacol Ther 48:138-147.

    Article  Google Scholar 

  61. Lawless S, Burckart G, Diven W et al (1989) Amrinone in neonates and infants after cardiac surgery. Crit Care Med 17:751-754.

    Article  PubMed  CAS  Google Scholar 

  62. Ramamoorthy C, Anderson GD, Williams GD et al (1998) Pharmacokinetics and side effects of milrinone in infants and children after open heart surgery. Anesth Analg 86:283-289.

    Article  PubMed  CAS  Google Scholar 

  63. Wettrell G (1977) Distribution and elimination of digoxin in infants. Eur J Clin Pharmacol 11:329-335.

    Article  PubMed  CAS  Google Scholar 

  64. Schwartz PH, Eldadah MK, Newth CJ (1991) The pharmacokinetics of dobutamine in pediatric intensive care. Drug Metab Dispos 19:614-619.

    PubMed  CAS  Google Scholar 

  65. Kuznetsov V, Pak E, Robinson RB et al (1995) β2-adrenergic receptor actions in neonatal and adult rat ventricular myocytes. Cir Res 76:40-52.

    CAS  Google Scholar 

  66. Bartel S, Karczewski P, Krause EG (1996) G proteins, adenylyl cyclase and related phosphoproteins in the developing rat heart. Mol Cell Biochem 163/164:31-38.

    Article  PubMed  Google Scholar 

  67. Giannuzzi CE, Seidler FJ, Slotkin TA (1995) Beta-adrenoceptor control of cardiac adenylyl cyclase during development: agonist pre-treatment in the neonate uniquely causes heterologous sensitization, not desensitization. Brain Res 694:271-278.

    Article  PubMed  CAS  Google Scholar 

  68. Zeiders JL, Seidler FJ, Iaccarino G et al (1999) Ontogeny of cardiac beta-adrenoceptor desensitization mechanisms: agonist treatment enhances receptor/G-protein transduction rather than eliciting ncoupling J Mol Cell Cardiol 31:413-423.

    CAS  Google Scholar 

  69. Zeiders JL, Seidler FJ, Slotkin TA (1999) Agonist-induced sensitization of β-adrenoceptor signaling in neonatal rat heart:expression and catalytic activity of adenylyl cyclase. J Pharmacol Exp Ther 291:503-510.

    PubMed  CAS  Google Scholar 

  70. Auman JT, Seidler FJ, Slotkin TA (2002) β-adrenoceptor control of G protein function in the neonate: Determinant of desensitization or sensitization. Am J Physiol Regul Integr Comp Physiol 283:1236-1244.

    Google Scholar 

  71. Ross RD, Daniels SR, Schwartz DC et al (1987) Plasma norepinephrine levels in infants and children with congestive heart failure. Am J Cardiol 59:911-4.

    Article  PubMed  CAS  Google Scholar 

  72. Wu JR, Chang HR, Huang TY et al (1996) Reduction in lymphocyte beta-adrenegic receptor density in infants and children with heart failure secondary to congenital heart disease. Am J Cardiol 77:170-4.

    Article  PubMed  CAS  Google Scholar 

  73. Price JF, Towbin JA, Denfield SW et al (2004) Arginine vasopressin levels are elevated and correlate with functional status in infants and children with congestive heart failure. Circulation 109:2550-3.

    Article  PubMed  CAS  Google Scholar 

  74. Kikuchi K, Nishioka K, Ueda T et al (1987) Relationship between plasma atrial natriuretic polypeptide concentration and hemodynamic measurements in children with congenital heart disease. J Pediatr 111:335-42.

    Article  PubMed  CAS  Google Scholar 

  75. Kunii Y, Kamada M, Ohtsuki S et al (2003) Plasma brain natriuretic peptide and the evaluation of volume overload in infants and children with congenital heart disease. Acta Med Okayama 57:191-197.

    PubMed  CAS  Google Scholar 

  76. Jobes DR, Nicholson SC, Steven JM, Miller M, Jacobs ML, Norwood WI Jr (1992). Carbon dioxide prevents pulmonary overcirculation in hypoplastic left heart syndrome. Ann Thorac Surg 54:150-151.

    Article  PubMed  CAS  Google Scholar 

  77. Tabbutt S, Ramamoorthy C, Montenegro LM, Durning SM, Kurth CD, Steven JM, Godinez RI, Spray TL, Wernovsky G, Nicholson SC (2001). Impact of inspired gas mixtures on preoperative infants with hypoplastic left heart syndrome during controlled ventilation. Circulation 104;I159-I164.

    Article  PubMed  CAS  Google Scholar 

  78. Acosta B, DiBenedetto R, Rahimi A et al.(2000) Hemodynamic effects of noninvasive bilevel positive airway pressure on patients with chronic congestive heart failure with systolic dysfunction. Chest 118:1004-1009.

    Article  PubMed  CAS  Google Scholar 

  79. McCrindle BW, Blackstone EH, Williams WG et al (2001) Are outcomes of surgical versus transcatheter balloon valvotomy equivalent in neonatal critical aortic stenosis? Circulation 104(12 Supp 1):I152-8.

    Google Scholar 

  80. Morse PM, Rockenmacher S, Pyeritz RE, Sanders SP, Bieber FR, Lin A, MacLeod P, Hall B, Graham, Jr, JM (1990) Diagnosis and management of infantile Marfan syndrome. Pediatrics 86:888-895.

    PubMed  CAS  Google Scholar 

  81. Case RB, Morrow AG, Stainsby W, Nestor JO (1958). Anomalous origin of the left ­coronary artery: The physiologic defect and suggested surgical treatment. Circulation 17:1062-1068.

    PubMed  CAS  Google Scholar 

  82. Wesselhoeft H, Fawcett JS, Johnson AL (1968). Anomalous origin of the left coronary artery from the pulmonary trunk: Its clinical spectrum, pathology, and pathophysiology, based on a review of 140 cases with seven further cases. Circulation 38:403-425.

    PubMed  CAS  Google Scholar 

  83. Arciniegas E, Farooki ZQ, Hakimi M, Green EW (1980) Management of anomalous left coronary artery from the pulmonary artery. Circulation 62:I180-I189.

    PubMed  CAS  Google Scholar 

  84. Kakou GM, Sidi D, Kachaner J, Villain E, Cohen L, Piechaud JF, Le Bidois J, Pedroni E, Vouhe P, Neveux JY (1988) Anomalous left coronary artery arising from the pulmonary artery in infancy: is early operation better? Br Heart J 60:522-526.

    Article  Google Scholar 

  85. Carvalho JS, Redington AN, Oldershaw PJ, Shinebourne EA, Lincoln CR, Gibson DG (1991). Analysis of left ventricular wall movement before and after reimplantation of anomalous left coronary artery in infancy. Br Heart J 65:218-222.

    Article  PubMed  CAS  Google Scholar 

  86. Adams KF, Fonarow GC, Emerman CL et al (2005) In-hospital mortality in patients with acute decompensated heart failure requiring intravenous vasoactive medications: an analysis from the Acute Decompensated Heart Failure National Registry (ADHERE). J Am Coll Cardiol 46:57-64.

    Article  PubMed  Google Scholar 

  87. Cuffe MS, Califf RM, Adams KF et al (2002). Short-term intravenous milrinone for acute exacerbation of chronic heart failure: a randomized controlled trial. JAMA 287: 1541-1547.

    Article  PubMed  CAS  Google Scholar 

  88. Felker MG, Benza RL, Chandler AB et al (2003) Heart failure etiology and response to milrinone in decompensated heart failure: results from the OPTIME-CHF study. J Am Coll Cardiol 41:997-1003.

    Article  PubMed  CAS  Google Scholar 

  89. Chang AC, Atz AM, Wernovsky G et al (1995) Milrinone: Systemic and pulmonary emodynamic effects in neonates after cardiac surgery. Crit Care Med 23:1907-1914.

    Article  PubMed  CAS  Google Scholar 

  90. Teshima H, Tobita K, Yamamura H et al (2002) Cardiovascular effects of a phosphodiesterase III inhibitor, amrinone, in infants: Non-invasive echocardiographic evaluation. Pediatr Int 44:259-263.

    Article  PubMed  CAS  Google Scholar 

  91. Hoffman TM, Wernovsky G, Atz AM et al (2003) Efficacy and safety of milrinone in preventing low cardiac output syndrome in infants and children after corrective surgery for congenital heart disease. Circulation 107:996-1002.

    Article  PubMed  CAS  Google Scholar 

  92. Leier CV, Webel J, Bush CA (1977) The cardiovascular effects of the continuous infusion of dobutamine in patients with severe cardiac failure. Circulation 56:468-472.

    PubMed  CAS  Google Scholar 

  93. O’Connor CM, Gattis WA, Uretsky BF et al (1999) Continuous intravenous dobutamine is associated with an increased risk of death in patients with advanced heart failure: insights from the Flolan International Randomized Survival Trial (FIRST). Am Heart J 138:78-86.

    Article  PubMed  Google Scholar 

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Price, J.F. (2010). Unique Aspects of Heart Failure in the Neonate. In: Shaddy, R. (eds) Heart Failure in Congenital Heart Disease:. Springer, London. https://doi.org/10.1007/978-1-84996-480-7_2

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