Therapeutic drugs during healing after myocardial infarction modify infarct collagens and ventricular distensibility at elevated pressures.
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.
Jugdutt
Bodh I
BI
2C2 Walter MacKenzie Health Sciences Centre, Division of Cardiology, Department of Medicine and Cardiovascular Research Group, University of Alberta, Edmonton, AB, Canada, T6G 2R7. bjugdutt@ualberta.ca
Idikio
Halliday
H
Uwiera
Richard R E
RR
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D003094:Collagen / Q000737:chemistry*; D004285:Dogs; D064420:Drug-Related Side Effects and Adverse Reactions; D006909:Hydroxyproline / Q000032:analysis; D008954:Models, Biological; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000473:pathology; D011312:Pressure; D013718:Tensile Strength; D016277:Ventricular Function, Left / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects* / Q000502:physiology*; D014945:Wound Healing / Q000187:drug effects*
D003094:Collagen; D006909:Hydroxyproline