Decreased elasticity of the cardiovascular system is one of the
hallmarks of the normal aging process of mammals. A potential
explanation for this decreased elasticity is that glucose can react
nonenzymatically with long-lived proteins, such as collagen and lens
crystallin, and link them together, producing advanced glycation
endproducts (AGEs). Previous studies have shown that aminoguanidine, an
AGE inhibitor, can prevent glucose cross-linking of proteins and the
loss of elasticity associated with aging and diabetes. Recently, an AGE
cross-link breaker (ALT-711) has been described, which we have
evaluated in aged dogs. After 1 month of administration of ALT-711, a
significant reduction (≈40%) in age-related left ventricular
stiffness was observed [(57.1 ± 6.8
mmHg⋅m
2
/ml pretreatment and 33.1 ± 4.6
mmHg⋅m
2
/ml posttreatment (1 mmHg = 133 Pa)].
This decrease was accompanied by improvement in cardiac function.
Myocardial disease in diabetes mellitus is usually attributed to coronary atherosclerosis. To examine the influence of uncomplicated diabetes on the left ventricle, a mild noninsulin-requiring diabetes was produced in male mongrel dogs after three intravenous doses of alloxan were administered at monthly intervals. There was a persistent decline in glucose tolerance and a reduced insulin content in the pancreas of each alloxan-diabetic dog at the termination of the experiment. The dogs were anesthetized for hemodynamic and metabolic studies after approximately 11 months. Left ventricular end-diastolic volume and cardiac output were measured by the indicator-dilution method. An increase in afterload with moderate aortic pressure elevations elicited a significant rise in end-diastolic volume and stroke volume in normal control dogs. In diabetes, despite a similar end-diastolic pressure response, the end-diastolic volume and the stroke volume responses were significantly less than those in control dogs. During acute volume expansion of the ventricle with saline, the end-diastolic pressure increment in diabetic dogs was twice that in control dogs. These responses were attributed to an increased stiffness of the left ventricle that was apparently due to accumulation of glycoprotein (measured by periodic acid-Schiff staining) in the interstitium. Since similar abnormalities were observed in dogs with diabetes occurring spontaneously and were absent when the pancreatic effects of alloxan were inhibited in a separate group of dogs, the pathogenetic role of alloxan via a direct action on myocardium was excluded. Analysis of lipids in the left ventricle revealed elevated triglyceride and cholesterol concentrations despite normal plasma levels. During infusion of
14
C-1-oleic acid, cardiac oxidation appeared to be normal, but fatty acid incorporation, which was predominantly into phospholipid in the control dogs, was diverted to triglyceride in the diabetic dogs. Since an aberration of de novo synthesis was not found during studies with
14
C-acetate, triglyceride accumulation was attributed to altered intracellular metabolism, perhaps related to glycerol phosphate acyl transferase activity. The basis for cholesterol accumulation was less clear, since neither
14
C-acetate nor
14
C-oleate incorporation into sterol was enhanced. Myocardial ischemia was excluded on the basis of patency of coronary arteries and normal coronary blood flow, myocardial cation content, and mitochondrial morphology. Thus, it was concluded that chronic diabetes mellitus can alter myocardial composition and function independent of vascular effects.
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