Eccentric Myocardial Wall Thickening and Increased Interstitial Fibrosis Underlie Cardiac Dysfunction in Long-Term Type 1 Diabetic Canines
Diabetic cardiomyopathy is an increasingly recognized disease associated with cardiac dysfunction, even in the absence of hypertension or coronary disease. The mechanism and myocardial substrate for this dysfunction, however, remain poorly understood. We hypothesize that hypertrophy and increased fibrosis in the diabetic (DB) heart promote myocardial stiffening and underlie cardiac dysfunction.
To test this hypothesis, a total of 33 partial pancreatectomy Type 1 DB canines (mean age 8.0±1.1years) and 10 control canines (CTRL, mean age 8.0±1.8years) were studied. DB canines were diabetic for 6.5±1.4 years. Of the total canines in this study, 10 DB and 6 CTRL canines were studied by echo to assess cardiac dysfunction. The remaining 23 DB and 4 CTRL canines had their hearts excised, weighed, sectioned and measured, for morphological and histological assessment according to standard techniques.
In general, DB had significantly larger mean left ventricular (LV) wall thickness and smaller chamber diameter (13.2±0.8 and 29.3±4.3mm, respectively) compared to CTRL (12.1±1.3 and 34.8±3.9mm, p<0.03), despite being age- and heart- weight matched. Interestingly, regional analysis revealed heterogeneous LV thickening in DB, localized to apical posterior regions (12.0±1.9 vs. 10±1.2mm, p<0.04) and basal anterior regions (14.4±2.1 vs. 11±1.4mm, p<0.01) compared to CTRL. No significant differences in LV thickness were observed at septal or lateral regions. Histological analysis showed no notable myocyte atrophy, myocardial disarray or replacement fibrosis. However, regional analysis revealed a significant increase in interstitial fibrosis in DB compared to CTRL (Collagen score: 2.6±0.6 vs. 1.2±0.3 AU, p<0.01), with larger levels (p<0.01) localized at the epicardium relative to other regions, in CTRL and DB. Notably, echo assessment of cardiac function demonstrated slower early diastolic transmitral velocity (E) (0.7±0.1 vs. 0.9±0.2 m/s, p<0.05) and smaller E/A ratio (1.1±0.2 vs. 1.4±0.3, p<0.05) in DB compared to CTRL, confirming the diastolic dysfunction.
These data suggest that in Type 1 DB canines, heterogeneous cardiac remodeling, eccentric myocardial thickening, and passive stiffness due to interstitial fibrosis may play a role in altering diastolic function, thereby, contributing to manifestation of the diabetic cardiomyopathy phenotype.