Molecular and Cellular Biochemistry

, Volume 304, Issue 1–2, pp 79–91 | Cite as

Therapeutic drugs during healing after myocardial infarction modify infarct collagens and ventricular distensibility at elevated pressures

  • Bodh I. Jugdutt
  • Halliday Idikio
  • Richard R. E. Uwiera


We investigated whether therapeutic drugs given during healing following acute myocardial infarction (AMI) modify infarct collagens and left ventricular (LV) distensibility. We treated dogs with drugs from major classes (i.e., indomethacin, ibuprofen, captopril, enalapril, verapamil, amlodipine, propranolol, isosorbide dinitrate [ISDN] and digoxin) between day 2 and 6 weeks and measured hemodynamics, LV remodeling and function during healing over 6 weeks after transmural anterior AMI, and regional collagens, LV distensibility under increasing pressure, rupture threshold (RT), and topography at 6 weeks. Relative to sham, AMI controls showed infarct zone (IZ) expansion and thinning, 9.3-fold increase in IZ collagen, LV dilation and dysfunction, and no change in distensibility and RT. Relative to controls, indomethacin as well as enalapril, captopril and amlodipine decreased IZ collagen. Infarct expansion was attenuated by ibuprofen, captopril, amlodipine and ISDN but augmented by indomethacin. Infarct thinning was prevented by captopril, amlodipine and ISDN but enhanced by indomethacin. Importantly, indomethacin and enalapril enhanced LV distensibility and lowered RT. Distensibility correlated positively with IZ type III collagen and negatively with type I/III collagen ratio and pyridinoline cross-links whereas RT correlated positively with IZ type I collagen. Systolic volume and ejection fraction deteriorated with indomethacin but were improved or preserved with other therapies. The results demonstrate that different therapeutic drugs may produce different effects on IZ collagens during healing post-AMI: drugs that attenuate or adversely alter IZ collagens also enhance LV distensibility, augment adverse remodeling and lower RT, suggesting that testing for these effects post-AMI is warranted.


Healing post myocardial infarction Collagen remodeling Ventricular distensibility Rupture threshold NSAIDs ACE inhibitors Beta-adrenergic blocker Calcium-channel blockers Nitrate Digoxin 



Grants to B. Jugdutt from the Canadian Institutes of Health Research and Canadian Heart and Stroke Foundation, Ottawa, ON supported this work. It was presented in part at the Heart Failure Society of America Annual Meeting, September 2006, Seattle, WA. We thank technicians for assistance with data collection and Catherine Jugdutt with manuscript preparation.


  1. 1.
    Jugdutt BI, Amy RW (1986) Healing after myocardial infarction in the dog: changes in infarct hydroxyproline and topography. J Am Coll Cardiol 7:91–102PubMedCrossRefGoogle Scholar
  2. 2.
    Jugdutt BI, Joljart MJ, Khan MI (1996) Rate of collagen deposition during healing after myocardial infarction in the rat and dog models: mechanistic insights into ventricular remodeling. Circulation 94:94–101PubMedGoogle Scholar
  3. 3.
    Jugdutt BI (1996) Prevention of ventricular remodeling after myocardial infarction and in congestive heart failure. Heart Failure Rev 1:115–129CrossRefGoogle Scholar
  4. 4.
    Jugdutt BI (1985) Delayed effects of early infarct-limiting therapies on healing. Circulation 72:907–914PubMedGoogle Scholar
  5. 5.
    Jugdutt BI, Basualdo CA (1989) Myocardial infarct expansion during indomethacin and ibuprofen therapy for symptomatic post-infarction pericarditis: effect of other pharmacologic agents during early remodelling. Can J Cardiol 5:211–221PubMedGoogle Scholar
  6. 6.
    Brown EJ Jr, Kloner RA, Schoen FJ et al (1983) Scar thinning due to ibuprofen administration after experimental myocardial infarction. Am J Cardiol 51:877–883PubMedCrossRefGoogle Scholar
  7. 7.
    Hammerman H, Kloner RA, Schoen FJ et al (1983) Indomethacin-induced scar thinning after experimental myocardial infarction. Circulation 67:1290–1295PubMedGoogle Scholar
  8. 8.
    Jugdutt BI (1988) Effect of nitroglycerin and ibuprofen on left ventricular topography and rupture threshold during healing after myocardial infarction in the dog. Can J Physiol Pharmacol 66:385–395PubMedGoogle Scholar
  9. 9.
    Jugdutt BI (1995) Effect of captopril and enalapril on left ventricular geometry, function and collagen during healing after anterior and inferior myocardial infarction in a dog model. J Am Coll Cardiol 25:1718–1725PubMedCrossRefGoogle Scholar
  10. 10.
    Jugdutt BI, Lucas A, Khan MI (1997) Effect of ACE inhibition on infarct collagen deposition and remodeling during healing after transmural canine myocardial infarction. Can J Cardiol 13:657–668PubMedGoogle Scholar
  11. 11.
    Jugdutt BI, Khan MI, Jugdutt SJ et al (1995) Combined captopril and isosorbide dinitrate during healing after myocardial infarction. Effect on remodeling, function, mass and collagen. J Am Coll Cardiol 25:1089–1096PubMedCrossRefGoogle Scholar
  12. 12.
    Nguyen QT, Cernacek P, Calderoni A et al (1998) Endothelin A receptor blockade causes adverse left ventricular remodeling but improves pulmonary artery pressure after infarction in the rat. Circulation 98:2323–2330PubMedGoogle Scholar
  13. 13.
    Jugdutt BI (1993) Prevention of ventricular remodelling post myocardial infarction: timing and duration of therapy. Can J Cardiol 9:103–114PubMedGoogle Scholar
  14. 14.
    Lerman RH, Apstein CS, Kagan HM et al (1983) Myocardial healing and repair after experimental infarction in the rabbit. Circ Res 53:378–388PubMedGoogle Scholar
  15. 15.
    Jugdutt BI (1987) Left ventricular rupture threshold during the healing phase after myocardial infarction in the dog. Can J Physiol Pharmacol 65:307–316PubMedGoogle Scholar
  16. 16.
    Jugdutt BI, Musat-Marcu S (2000) Opposite effects of amlodipine and enalapril on infarct collagen during healing after reperfused myocardial infarction. Can J Cardiol 16:617–625PubMedGoogle Scholar
  17. 17.
    MacDougall JD, McKelvie RS, Moroz DE et al (1992) Factors affecting blood pressure during heavy weight lifting and static contractions. J Appl Physiol 73:1590–1597PubMedGoogle Scholar
  18. 18.
    Franklin BA, Bonzheim K, Gordon S et al (1996) Snow shoveling: a trigger for acute myocardial infarction and sudden coronary death. Am J Cardiol 77:855–858PubMedCrossRefGoogle Scholar
  19. 19.
    Jugdutt BI, Khan MI, Jugdutt SJ et al (1996) Effect of prolonged inotropic stimulation on ventricular remodeling during healing after myocardial infarction in the dog: mechanistic insights. J Am Coll Cardiol 27:1787–1795PubMedCrossRefGoogle Scholar
  20. 20.
    Jugdutt BI, Tang SB, Khan MI et al (1992) Functional impact on remodeling during healing after non-Q-wave versus Q-wave anterior myocardial infarction in the dog. J Am Coll Cardiol 20:722–731PubMedCrossRefGoogle Scholar
  21. 21.
    Mirsky I (1979) Elastic properties of the myocardium: a quantitative approach with physiological and clinical applications. In: Berne RM (ed) Handbook of physiology. The cardiovascular system. Williams and Wilkins Co., BaltimoreGoogle Scholar
  22. 22.
    Bergman I, Loxley R (1963) Two improved and simplified methods for the spectrophotometric determination of hydroxyproline. Anal Chem 35:1961–1965CrossRefGoogle Scholar
  23. 23.
    Miller EJ, Rhodes RK (1982) Preparation and characterization of the different types of collagen. Methods Enzymol 82 Pt A:33–64PubMedCrossRefGoogle Scholar
  24. 24.
    Stegemann H, Stalder K (1967) Determination of hydroxyproline. Clin Chim Acta 18:267–273PubMedCrossRefGoogle Scholar
  25. 25.
    Jugdutt BI (2003) Ventricular remodeling postinfarction and the extracellular collagen matrix. When is enough enough? Circulation 108:1395–1403PubMedCrossRefGoogle Scholar
  26. 26.
    Jugdutt BI (2003) Remodeling of the myocardium and potential targets in the collagen degradation and synthesis pathways. Curr Drug Targets Cardiovasc Haematol Disord 3:1–30PubMedCrossRefGoogle Scholar
  27. 27.
    Ferrario CM, Trask AJ, Jessup JA (2005) Advances in biochemical and functional roles of angiotensin-converting enzyme 2 and angiotensin-(1–7) in regulation of cardiovascular function. Am J Physiol Heart Circ Physiol 289:H2281–H2290PubMedCrossRefGoogle Scholar
  28. 28.
    Peng H, Carretero OA, Vuljaj N et al (2005) Angiotensin-converting enzyme inhibitors: a new mechanism of action. Circulation 112:2436–2445PubMedCrossRefGoogle Scholar
  29. 29.
    Whittaker P, Boughner DR, Kloner RA (1991) Role of collagen in acute myocardial infarct expansion. Circulation 84:2123–2124PubMedGoogle Scholar
  30. 30.
    Factor SM, Flomenbaum M, Zhao MJ et al (1988) The effects of acutely increased ventricular cavity pressure on intrinsic myocardial connective tissue. J Am Coll Cardiol 12:1582–1589PubMedCrossRefGoogle Scholar
  31. 31.
    Weisman HF, Bush DE, Mannisi JA et al (1988) Cellular mechanisms of myocardial infarct expansion. Circulation 78:186–201PubMedGoogle Scholar
  32. 32.
    Olivetti G, Capasso JM, Sonnenblick EH et al (1990) Side-to-side slippage of myocytes participates in ventricular wall remodeling acutely after myocardial infarction in rats. Circ Res 67:23–34PubMedGoogle Scholar
  33. 33.
    Hochman JS, Bulkley BH (1982) Pathogenesis of left ventricular aneurysms: an experimental study in the rat model. Am J Cardiol 50:83–88PubMedCrossRefGoogle Scholar
  34. 34.
    Eaton LW, Bulkley BH (1981) Expansion of acute myocardial infarction: its relationship to infarct morphology in a canine model. Circ Res 49:80–88PubMedGoogle Scholar
  35. 35.
    Schuster EH, Bulkley BH (1979) Expansion of transmural myocardial infarction: a pathophysiologic factor in cardiac rupture. Circulation 60:1532–1538PubMedGoogle Scholar
  36. 36.
    Bates RJ, Beutler L, Resnekov L et al (1977) Cardiac rupture. Challenge in diagnosis and management. Am J Cardiol 40:429–437PubMedCrossRefGoogle Scholar
  37. 37.
    Factor SM, Robinson TF, Dominitz R et al (1987) Alterations of the myocardial skeletal framework in acute myocardial infarction with and without ventricular rupture. Am J Cardiovasc Pathol 1:91–97PubMedGoogle Scholar
  38. 38.
    Burkhoff D, Mirsky I, Suga H (2005) Assessment of systolic and diastolic ventricular properties via pressure-volume analysis: a guide for clinical, translational, and basic researchers. Am J Physiol Heart Circ Physiol 289:H501–H512PubMedCrossRefGoogle Scholar
  39. 39.
    Connelly CM, McLaughlin RJ, Vogel WM et al (1991) Reversible and irreversible elongation of ischemic, infarcted, and healed myocardium in response to increases in preload and afterload. Circulation 84:387–399PubMedGoogle Scholar
  40. 40.
    Jugdutt BI, Michorowski BL, Kappagoda CT (1988) Exercise training after anterior Q wave myocardial infarction: importance of regional left ventricular function and topography. J Am Coll Cardiol 12:362–372PubMedCrossRefGoogle Scholar
  41. 41.
    Jugdutt BI (2007) Cyclooxynenase inhibition and adverse remodeling during healing after myocardial infarction. Circulation 115:288–291PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Bodh I. Jugdutt
    • 1
  • Halliday Idikio
    • 2
  • Richard R. E. Uwiera
    • 3
  1. 1.2C2 Walter MacKenzie Health Sciences Centre, Division of Cardiology, Department of Medicine and Cardiovascular Research GroupUniversity of AlbertaEdmontonCanada
  2. 2.Department of Pathology and Laboratory MedicineUniversity of AlbertaEdmontonCanada
  3. 3.Health Sciences Laboratory Animal Services, Faculty of MedicineUniversity of AlbertaEdmontonCanada

Personalised recommendations