Left ventricular performance and remodeling in rabbits after myocardial infarction: Effects of a thyroid hormone analogue

Kenneth W. Mahaffey, Thomas E. Raya, Gregory D. Pennock, Eugene Morkin, Steven Goldman

Research output: Contribution to journalArticle

85 Citations (Scopus)

Abstract

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(β,β) 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. Methods and 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, β- and α-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 (τ) (P=.001 for both variables). Postinfarction treatment with DITPA decreased left ventricular end-diastolic pressure and τ (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 τ 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.

Original languageEnglish (US)
Pages (from-to)794-801
Number of pages8
JournalCirculation
Volume91
Issue number3
StatePublished - Feb 1 1995
Externally publishedYes

Fingerprint

Ventricular Remodeling
Thyroid Hormones
Myocardial Infarction
Rabbits
Acids
Myosin Heavy Chains
Protein Isoforms
Infarction
Blood Pressure
Heart Failure
Coronary Vessels
Heart Rate
Hemodynamics
Therapeutics
Contractile Proteins
Densitometry
Coronary Occlusion
Ventricular Pressure
Treatment Failure
Left Ventricular Function

Keywords

  • 3,5-diiodothyropropionic acid
  • Heart failure
  • Thyroid
  • Ventricles

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Left ventricular performance and remodeling in rabbits after myocardial infarction : Effects of a thyroid hormone analogue. / Mahaffey, Kenneth W.; Raya, Thomas E.; Pennock, Gregory D.; Morkin, Eugene; Goldman, Steven.

In: Circulation, Vol. 91, No. 3, 01.02.1995, p. 794-801.

Research output: Contribution to journalArticle

Mahaffey, Kenneth W. ; Raya, Thomas E. ; Pennock, Gregory D. ; Morkin, Eugene ; Goldman, Steven. / Left ventricular performance and remodeling in rabbits after myocardial infarction : Effects of a thyroid hormone analogue. In: Circulation. 1995 ; Vol. 91, No. 3. pp. 794-801.
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abstract = "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(β,β) 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. Methods and 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, β- and α-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 (τ) (P=.001 for both variables). Postinfarction treatment with DITPA decreased left ventricular end-diastolic pressure and τ (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 τ 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.",
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