Left ventricular performance and remodeling in rabbits after myocardial infarction. Effects of a thyroid hormone analogue.
BACKGROUND
Because the rat postinfarction model differs from human heart failure with respect to the composition of myosin heavy chain (MHC) isoforms and other contractile proteins, alternative animal models are needed for the development of new treatments for human heart failure. The purpose of this study was threefold: (1) to test the feasibility of using the V3(beta,beta) rabbit postinfarction model for the study of heart failure by characterizing the effects of chronic coronary artery occlusion on the left ventricle; (2) to determine whether the thyroid hormone analogue 3,5-diiodothyropropionic acid (DITPA) produces improvements in left ventricular function; and (3) to determine the effects of myocardial infarction and treatment with DITPA on MHC protein isoforms.


RESULTS
Male New Zealand White rabbits underwent proximal circumflex coronary artery ligation. After infarction, rabbits were treated with DITPA (3.75 mg/kg body wt) or placebo for 21 days and then underwent conscious and open-chest hemodynamic studies. In separate groups of rabbits, beta- and alpha-MHC isoforms were separated, and relative proportions were measured using gradient sodium dodecyl sulfate-polyacrylamide gel electrophoresis and laser densitometry. Infarction resulted in increased left ventricular end-diastolic pressure and prolonged left ventricular relaxation (tau) (P = .001 for both variables). Postinfarction treatment with DITPA decreased left ventricular end-diastolic pressure and tau (P = .002 and P = .001, respectively) and increased maximum positive and negative dP/dt (P = .002 and P = .016, respectively). Infarcted rabbits treated with DITPA had no significant changes in heart rate or left ventricular systolic pressure compared with untreated rabbits with infarction. There were no significant differences in heart rate, positive dP/dt, peak systolic pressure, or tau between sham-operated rabbits and sham-operated rabbits treated with DITPA. Although infarction resulted in increased left ventricular diameter, there were no effects of DITPA on left ventricular remodeling. Neither myocardial infarction nor treatment with DITPA altered the ratio of MHC isoforms.


CONCLUSIONS
Rabbits that survive occlusion of the circumflex artery will develop myocardial dysfunction and left ventricular remodeling. Therapy with DITPA, a thyroid hormone analogue, produces improvement in ventricular performance and reduces end-diastolic pressure. The hemodynamic effects of DITPA were not associated with alterations of MHC isoforms. Whether DITPA represents the prototype of a previously undescribed class of agents for the treatment of heart failure will need to be determined by clinical trials.
Mahaffey
K W
KW
Department of Internal Medicine, Veterans Administration Medical Center, Tucson, AZ 85723.
Raya
T E
TE
Pennock
G D
GD
Morkin
E
E
Goldman
S
S
D000818:Animals; D004104:Diiodothyronines / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy / Q000503:physiopathology*; D009218:Myosins / Q000032:analysis; D011422:Propionates / Q000494:pharmacology* / Q000627:therapeutic use; D011817:Rabbits; D016277:Ventricular Function, Left / Q000187:drug effects*
D004104:Diiodothyronines; D011422:Propionates; C082182:3,5-diiodothyropropionic acid; D009218:Myosins