Fish Heart Growth and Function: From Gross Morphology to Cell Signaling and Back

  • B. Tota
  • F. Garofalo


Comparative multidisciplinary efforts greatly contributed to unravel the interrelationship between heart structure and function at the molecular level. They include studies on the developing and adult fish heart, which provide necessary insights to identify functional properties residing in the cardiomyocytes from those resulting from complex interactions between the other tissues and cells of the organ and how they integrate. Although analysis from complex to simple is easier than synthesis, we will illustrate some fish paradigms hoping to furnish eventual bridges between whole-organ and cellular levels.

Beyond the uniformity of the allometric relationship, heart growth highlights specific life history related scaling factors, as epitomized by the tuna heart and its ventricular compartmentation.

Moreover, unlike mammals, the adult fish heart retained the evolutionary capacity for rapid myocardial replacement. However, patterns of cardiac growth (hypertrophy and/or hyperplasia) may differently affect compacta and spongiosa remodeling, as shown by salmonid and eel hearts.

Their slightly different growth pattern mirrors the universal trend of the heart developing as a modular organ driven by distinct transcriptional regulatory programs that control each anatomical region.

According to the zebrafish (Brachydanio rerio) model, myocardial growth appears to involve mechanisms differing from those responsible for myocardial regeneration, specifying distinct transcriptional regulatory programs and trophic interactions between the myocardial, epicardial and endocardial cells.

Using the adult eel heart again, and nitric oxide (NO) signaling as a paradigm of molecular integration, we will finally illustrate the relevant cross-talk between the endocardial endothelium and the subjacent myocardium (NO-mediated paracrine modulation), as well as the NO-mediated autocrine modulation of the beat-to-beat response of the heart.


Nitric Oxide Heart Tube Cardiac Growth Vertebrate Heart Cardiac Jelly 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



We thank D. Amelio for advices and figures.


  1. Bern HA, Madsen SS (1992) A selective survey of the endocrine system of the rainbow trout (Oncorhynchus mykiss) with emphasis on the hormonal regulation of ion balance. Aquaculture 100:237–262CrossRefGoogle Scholar
  2. Birkedal R, Shiels HA, Vendelin M (2006) Three dimensional mitochondrial arrangement in ventricular myocytes: from chaos to order. Am J Physiol Cell Physiol 291:C1148–C1158PubMedCrossRefGoogle Scholar
  3. Brodde O-E, Michel MC (1999) Adrenergic and muscarinic receptors in the human heart. Pharmacol Rev 51:651–689PubMedGoogle Scholar
  4. Brutsaert DL (2003) Cardiac endothelial-myocardial signaling: its role in cardiac growth, contractile performance, and rhythmicity. Physiol Rev 83(1):59–115PubMedGoogle Scholar
  5. Cerra MC, Imbrogno S, Amelio D, Garofalo F, Colvee E, Tota B, Icardo JM (2004) Cardiac morphodynamic remodelling in the growing eel (Anguilla anguilla L.). J Exp Biol 207:2867–2875PubMedCrossRefGoogle Scholar
  6. Chi NC, Bussen M, Brand-Arzamendi K, Ding C, Olgin JE, Shaw RM, Martin GR, Stainier DY (2010) Cardiac conduction is required to preserve cardiac chamber morphology. Proc Natl Acad Sci USA 107(33):14662–7PubMedCrossRefGoogle Scholar
  7. Chien KR, Domian IJ, Parker KK (2008) Cardiogenesis and the complex biology of regenerative cardiovascular medicine. Science 322:1494–1497PubMedCrossRefGoogle Scholar
  8. Di Maio A, Block BA (2008) Ultrastructure of the sarcoplasmic reticulum in cardiac myocytes from Pacific bluefin tuna. Cell Tissue Res 334(1):121–34PubMedCrossRefGoogle Scholar
  9. Fishman MC, Olson EN (1997) Parsing the heart: genetic modules for organ assembly. Cell 91:153–156PubMedCrossRefGoogle Scholar
  10. Fishman MC, Stainier DYR (1994) Cardiovascular development: prospects for a genetic approach. Circ Res 74:757–763PubMedCrossRefGoogle Scholar
  11. Gamperl AK, Farrell AP (2004) Cardiac plasticity in fishes: environmental influences and intraspecific differences. J Exp Biol 207:2539–2550PubMedCrossRefGoogle Scholar
  12. Garofalo F, Parisella ML, Amelio D, Tota B, Imbrogno S (2009) Phospholamban S nitrosylation modulates Starling response in fish heart. Proc Biol Sci 276(1675):4043–52PubMedCrossRefGoogle Scholar
  13. Gattuso A, Mazza R, Pellegrino D, Tota B (1999) Endocardial endothelium mediates luminal ACh-NO signaling in isolated frog heart. Am J Physiol 276(2 Pt 2):H633–H641PubMedGoogle Scholar
  14. Gattuso A, Mazza R, Imbrogno S, Sverdrup A, Tota B, Nylund A (2002) Cardiac performance in Salmo salar with Infectius Salmon Anemia (ISA): putative role of nitric oxide. Dis Aquat Org 52:11–20PubMedCrossRefGoogle Scholar
  15. Gemelli L, Martino G, Tota B (1980) Oxidation of lactate in the compact and spongy myocardium of tuna fish (Thunnus thynnus thynnus L.). Comp Biochem Physiol B 65(2):321–326Google Scholar
  16. Gerhart J, Kirschner M (1997) Cells, embryos, and evolution: toward a cellular and developmental understanding of phenotypic variation and evolutionary adaptability. Blackwell Science, OxfordGoogle Scholar
  17. Hare JM (2003) Nitric oxide and excitation–contraction coupling. J Mol Cell Cardiol 35:719–729PubMedCrossRefGoogle Scholar
  18. Hochachka PW, Somero GN (2002) Biochemical adaptation: mechanism and process in physiological evolution. Oxford University Press, New York, p 31Google Scholar
  19. Hove JR, Koster RW, Forouhar AS, Cevedo-Bolton G, Fraser SE, Gharib M (2003) Intracardiac fluid forces are an essential epigenetic factor for embryonic cardiogenesis. Nature 421:172–177PubMedCrossRefGoogle Scholar
  20. Icardo JM (2006) Conus arteriosus of the teleost heart: dismissed, but not missed. Anat Rec A 288:900–908Google Scholar
  21. Icardo JM, Colvee E (2001) The atrioventricular region of the teleost heart. A distinct heart segment. Anat Rec A 294:236–242Google Scholar
  22. Icardo JM, Imbrogno S, Gattuso A, Colvee E, Tota B (2005) The heart of Sparus auratus: a reappraisal of cardiac functional morphology in teleosts. J Exp Zool A Comp Exp Biol 303:665–675PubMedGoogle Scholar
  23. Imbrogno S, De Iuri V, Mazza R, Tota B (2001) Nitric oxide modulates cardiac performance in the heart of Anguilla anguilla. J Exp Biol 204:1719–1727PubMedGoogle Scholar
  24. Imbrogno S, Cerra MC, Tota B (2003) Angiotensin II-induced inotropism requires an endocardial endothelium-nitric oxide mechanism in the in-vitro heart of Anguilla anguilla. J Exp Biol 206:2675–2684PubMedCrossRefGoogle Scholar
  25. Imbrogno S, Angelone T, Corti A, Adamo C, Helle KB, Tota B (2004) Influence of vasostatins, the chromogranin A-derived peptides, on the working heart of the eel (Anguilla anguilla): negative inotropy and mechanism of action. Gen Comp Endocrinol 139:20–28PubMedCrossRefGoogle Scholar
  26. Imbrogno S, Angelone T, Adamo C, Pulerà E, Tota B, Cerra MC (2006) Beta3 Adrenoceptor in the eel (Anguilla anguilla) heart: negative inotropy and NO-cGMP-dependent mechanism. J Exp Biol 209:4966–4973PubMedCrossRefGoogle Scholar
  27. Iwakiri Y, Satoh A, Chatterjee S, Toomre DK, Chalouni CM, Fulton D, Groszmann RJ, Shah VH, Sessa WC (2006) Nitric oxide synthase generates nitric oxide locally to regulate compartmentalized protein S-nitrosylation and protein trafficking. Proc Natl Acad Sci USA 103:19777–19782PubMedCrossRefGoogle Scholar
  28. Johansen IB, Lunde IG, Røsjø H, Christensen G, Nilsson GE, Bakken M, Øverli Ø (2011) Cortisol response to stress is associated with myocardial remodeling in salmonid fishes. J Exp Biol 214(8):1313–1321PubMedCrossRefGoogle Scholar
  29. Kang JO, Sucov HM (2005) Convergent proliferative response and divergent morphogenic pathways induced by epicardial and endocardial signaling in fetal heart development. Mech Dev 122:57–65PubMedCrossRefGoogle Scholar
  30. Leary SC, Michaud D, Lyons CN, Hale TM, Bushfield TL, Adams M, Moyes CD (2002) Bioenergetic remodeling of heart during treatment of spontaneously hypertensive rats with enalapril. Am J Physiol 283:H540–548Google Scholar
  31. Lepilina A, Coon AN, Kikuchi K, Holdway JE, Roberts RW, Burns CG, Poss KD (2006) A dynamic epicardial injury response supports progenitor cell activity during zebrafish heart regeneration. Cell 127:607–619PubMedCrossRefGoogle Scholar
  32. Liao W, Bisgrove BW, Sawyer H, Hug B, Bell B, Peters K, Grunwald DJ, Stainier DY (1997) The zebrafish gene cloche acts upstream of a flk-1 homologue to regulate endothelial cell differentiation. Development 124:381–389PubMedGoogle Scholar
  33. Lien CL, Schebesta M, Makino S, Weber GJ, Keating MT (2006) Gene expression analysis of zebrafish heart regeneration. PLoS Biol 4(8):e260Google Scholar
  34. Lima B, Forrester MT, Hess DT, Stamler JS (2010) S-nitrosylation in cardiovascular signaling. Circ Res 106:633–646PubMedCrossRefGoogle Scholar
  35. Liu J, Bressan M, Hassel D, Huisken J, Staudt D, Kikuchi K, Poss KD, Mikawa T, Stainier DY (2010) A dual role for ErbB2 signaling in cardiac trabeculation. Development 137(22):3867–75PubMedCrossRefGoogle Scholar
  36. Lumbers ER, Boyce AC, Joulianos G, Kumarasamy V, Barner E, Segar JL, Burrell JH (2005) Effects of cortisol on cardiac myocytes and on expression of cardiac genes in fetal sheep. Am J Physiol Regul Integr Comp Physiol 288:R567–574PubMedCrossRefGoogle Scholar
  37. Massion PB, Pelat M, Belge C, Balligand J-L (2005) Regulation of the mammalian heart function by nitric oxide. Comp Biochem Physiol 142A:144–150Google Scholar
  38. Molkentin JD, Lu JR, Antos CL, Markham B, Richardson J, Robbins J, Grant SR, And Olson EN (1998) A calcineurin-dependent transcriptional pathway for cardiac hypertrophy. Cell 93:215–228PubMedCrossRefGoogle Scholar
  39. Moorman AF, Christoffels VM (2003) Cardiac chamber formation: development, genes, and evolution. Physiol Rev 83:1223–1267PubMedGoogle Scholar
  40. Morabito CJ, Dettman RW, Kattan J, Collier JM, Bristow J (2001) Positive and negative regulation of epicardial-mesenchymal transformation during avian heart development. Dev Biol 234(1):204–15PubMedCrossRefGoogle Scholar
  41. Nichols NR, Tracy KE, Funder JW (1984) Glucocorticoid effects on newly synthesized proteins in muscle and non-muscle cells cultured from neonatal rat hearts. J Steroid Biochem 21:487–496PubMedCrossRefGoogle Scholar
  42. Olson EN (2006) Gene regulatory networks in the evolution and development of the heart. Science 5795:1922–1927CrossRefGoogle Scholar
  43. Pope AJ, Sands GB, Smaill BH, LeGrice IJ (2008) Three-dimensional transmural organization of perimysial collagen in the heart. Am J Physiol Heart Circ Physiol 295:H1243–H1252PubMedCrossRefGoogle Scholar
  44. Poppe TT, Johansen R, Gunnes G, Torud B (2003) Heart morphology in wild and farmed Atlantic salmon Salmo salar and rainbow trout Oncorhynchus mykiss. Dis Aquat Organ 57(103):108Google Scholar
  45. Poss KD (2007) Getting to the heart of regeneration in zebrafish. Semin Cell Dev Biol 18(1):36–45PubMedCrossRefGoogle Scholar
  46. Poss KD, Wilson LG, Keating MT (2002) Heart regeneration in zebrafish. Science 298:2188–2190PubMedCrossRefGoogle Scholar
  47. Pottinger TG, Carrick TR (1999) Modification of the plasma 581 cortisol response to stress in rainbow trout by selective breeding. Gen Comp Endocrinol 116:122–132PubMedCrossRefGoogle Scholar
  48. Poupa O, Lindström L (1983) Comparative and scaling aspects of heart and body weights with reference to blood supply of cardiac fibers. Comp Biochem Physiol A 76(3):413–421PubMedCrossRefGoogle Scholar
  49. Poupa O, Ostadal B (1969) Experimental cardiomegalies and cardiomegalies in free-living animals. Ann NY Acad Sci 156(31):445–468PubMedCrossRefGoogle Scholar
  50. Poupa O, Gesser H, Jonsson S, Sullivan L (1974) Coronary-supplied compact shell of ventricular myocardium in salmonids: growth and enzyme pattern. Comp Biochem Physiol A 48:85–95PubMedCrossRefGoogle Scholar
  51. Poupa O, Lindstrom L, Maresca A, Tota B (1981) Cardiac growth, myoglobin, proteins and DNA in developing tuna (Thunnus thynnus thynnus). Comp Biochem Physiol 70A:217–222CrossRefGoogle Scholar
  52. Seddon M, Shah AM, Casadei B (2007) Cardiomyocytes as effectors of nitric oxide signalling. Cardiovasc Res 75:315–326PubMedCrossRefGoogle Scholar
  53. Sedmera D, Reckova M, deAlmeida A, Sedmerova M, Biermann M, Volejnik J, Sarre A, Raddatz E, McCarthy RA, Gourdie RG, Thompson RP (2003) Functional and morphological evidence for a ventricular conduction system in zebrafish and Xenopus hearts. Am J Physiol Heart Circ Physiol 284:H1152–H1160PubMedGoogle Scholar
  54. Shiels HA, Di Maio A, Thompson S, Block BA (2011) Warm fish with cold hearts: thermal plasticity of excitation-contraction coupling in bluefin tuna. Proc Biol Sci 278(1702):18–27PubMedCrossRefGoogle Scholar
  55. Stainier DY, Lee RK, Fishman MC (1993) Cardiovascular development in the zebrafish. Myocardial fate map and heart tube formation. Development 119:31–40PubMedGoogle Scholar
  56. Stainier DYR, Welnstein BM, Detrich HW, Zon LI, Fishman MC (1995) Cloche, an early acting zebrafish gene, is required by both the endothelial and hematopoietic lineages. Development 121:3141–3150PubMedGoogle Scholar
  57. Stuckmann I, Evans S, Lassar AB (2003) Erythropoietin and retinoic acid, secreted from the epicardium, are required for cardiac myocyte proliferation. Dev Biol 255:334–349PubMedCrossRefGoogle Scholar
  58. Takle H, Baeverfjord G, Helland S, Kjorsvik E, Andersen O (2006) Hyperthermia induced atrial natriuretic peptide expression and deviant heart development in Atlantic salmon Salmo salar embryos. Gen Comp Endocrinol 147:118–125PubMedCrossRefGoogle Scholar
  59. Tota B, Cimini V, Salvatore G, Zummo G (1983) Comparative study of the arterial and lacunary systems of the ventricular myocardium of elasmobranch and teleost fishes. Am J Anat 167:15–32PubMedCrossRefGoogle Scholar
  60. Urschel M, O’Brien KM (2008) High mitochondrial densities in the hearts of Antarctic icefishes are maintained by an increase in mitochondrial size rather than mitochondrial biogenesis. J Exp Biol 211:2638–2646PubMedCrossRefGoogle Scholar
  61. Vogel S (1988) Life’s devices: the physical world of animals and plants. Princeton University Press, New JerseyGoogle Scholar
  62. Vornanen M, Hassinen M, Koskinen H, Krasnov A (2005) Steady-state effects of temperature acclimation on the transcriptome of the rainbow trout heart. Am J Physiol Regul Integr Comp Physiol 289:R1177–R1184PubMedCrossRefGoogle Scholar
  63. Wendelaar Bonga SE (1997) The stress response in fish. Physiol Rev 77:591–625PubMedGoogle Scholar
  64. Wilkins BJ, Dai YS, Bueno OF, Parsons SA, Xu J, Plank DM, Jones F, Kimball TR, Molkentin JD (2004) Calcineurin/NFAT coupling participates in pathological, but not physiological, cardiac hypertrophy. Circ Res 94:110–118PubMedCrossRefGoogle Scholar
  65. Williams JC, Armesilla AL, Mohamed TM, Hagarty CL, McIntyre FH, Schomburg S, Zaki AO, Oceandy D, Cartwright EJ, Buch MH, Emerson M, Neyses L (2006) The sarcolemmal calcium pump, a-1 syntrophin, and neuronal nitric-oxide synthase are parts of a macromolecular protein complex. J Biol Chem 281:23341–23348PubMedCrossRefGoogle Scholar
  66. Wu H, Peisley A, Graef IA, Crabtree GR (2007) NFAT signaling and the invention of vertebrates. Trends Cell Biol 17:251–260PubMedCrossRefGoogle Scholar
  67. Xu KY, Huso DL, Dawson TM, Bredt DS, Becker LC (1999) Nitric oxide synthase in cardiac sarcoplasmic reticulum. Proc Natl Acad Sci USA 96:657–662PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Department of Cell BiologyUniversity of CalabriaCosenzaItaly

Personalised recommendations