(Circulation. 1996;93:1905-1912.)
© 1996 American Heart Association, Inc.
Articles |
Aminoguanidine Prevents the Decreased Myocardial Compliance Produced by Streptozotocin-Induced Diabetes Mellitus in Rats
From the Departments of Physiology (G.R.N., A.J.W.) and Nuclear Medicine (G.C.), University of the Witwatersrand, Johannesburg, South Africa.
Background A decreased cardiac compliance is a major feature of the cardiomyopathy of diabetes mellitus. Either an increase in the resistance afterload to the LV or an increase in collagen cross-linking induced by the formation of advanced glycosylation end products (AGEs) of collagen may be responsible for the stiff myocardium. To evaluate these hypotheses, we examined the effect of captopril, an afterload-reducing agent, and aminoguanidine, a nucleophilic hydrazine that prevents the accumulation of collagen AGEs, on left ventricular end-diastolic (LVED) compliance after 4 months of streptozotocin (0.26 mmol/kg)–induced diabetes mellitus in rats.
Methods and Results Diabetes mellitus produced a decrease in LV chamber compliance as a result of an increased myocardial stiffness (slope of the linearized LVED stress–LVED strain relation [unitless]: diabetes mellitus, 47±4; control, 27±3; P<.001) and an increase in blood pressure as a result of an elevated vascular resistance. LV end-systolic elastance was unaltered by diabetes mellitus. The stiff myocardium was not associated with changes in the myocardial collagen volume fraction or total hydroxyproline concentration but was associated with an increased myocardial collagen fluorescence (fluorescence units/µg hydroxyproline) (diabetes mellitus, 11±1.1; control, 6.6±0.7; P<.01). Captopril therapy (0.22 mmol ·kg-1·d-1), despite producing a decrease in blood pressure through alterations in vascular resistance, failed to decrease myocardial stiffness in rats with diabetes mellitus. Alternatively, administration of aminoguanidine (7.35 mmol·kg-1·d-1) prevented both the enhanced myocardial collagen fluorescence (7.1±1.2) and the increased slope of the linearized LVED stress–LVED strain relation (29±2) but did not change markers of blood glucose control.
Conclusions These results demonstrate that diabetes mellitus can produce a stiff myocardium before the development of myocardial fibrosis. The stiff myocardium in the early stages of the development of the cardiomyopathy of diabetes mellitus is not a consequence of an increase in ventricular resistance afterload and in these circumstances is associated with the formation of collagen AGEs.
Key Words: aminoguanidine • diabetes mellitus • myocardium • diastole • cardiomyopathy
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