Abstract
Background: The causal factors underpinning the onset and progression of diabetic heart disease (DHD) remain to be fully elucidated. Myocardial function is critically dependent on optimal coronary blood flow. Considering vascular disease occurs early in diabetes due to endothelial dysfunction, this study aimed to determine whether impaired coronary perfusion contributes to the origins of myocardial dysfunction in DHD, or whether coronary and cardiac dysfunction are independent pathologies associated with diabetes.Methods: Synchrotron radiation microangiography was used to image the coronary circulation of type-2 diabetic db/db and non-diabetic db/+ mice in vivo at 8, 16, and 24 weeks of age. We further assessed vascular function based on the vasodilatory responses to acetylcholine (ACh, 3 μg/kg/min), sodium nitroprusside (SNP, 5 μg/kg/min) and the Rho-kinase inhibitor, fasudil (20 mg/kg, i.v.). Cardiac function was assessed using echocardiography, and cardiac eNOS and ROCK expression were measured using immunohistochemistry.Results: Coronary and cardiac function were normal in 8-week-old diabetic mice. However, by 16 weeks of age, diabetic mice had advanced cardiac dysfunction. In comparison, normal coronary perfusion was preserved in diabetes until 24 weeks of age. Moreover, only the 24-week-old diabetic mice showed clear evidence of advanced coronary vascular dysfunction, based on (i) the absence of a vasodilatory response to ACh, and (ii) an exaggerated vasodilatory response to fasudil. Interestingly, fasudil also restored normal coronary perfusion in the 24-week-old diabetic heart by restoring blood flow to previously constricted vessels (diameter < 100 μm). Importantly, there was a ubiquitous decrease, and increase, in the cardiac expression of eNOS and ROCK, respectively.Conclusion: These results suggest that both cardiac and coronary dysfunction appear to have independent origins associated with diabetes and Rho-kinase pathway may be playing a role in the onset and progression of DHD.
Highlights
The causal factors underpinning the onset and progression of diabetic heart disease (DHD) remain to be fully elucidated
For both diabetic and non-diabetic mice, ACh did not significantly alter heart rate (HR), but it did cause a significant decrease in Mean arterial blood pressure (MABP, 20.9 and 8.9% decrease in MABP, respectively), which trended to be smaller in magnitude, albeit not significant, for the diabetic mice (Figures 5A,D)
The primary findings of this study highlight that (i) impaired coronary perfusion and endothelial dysfunction only become fully established in the db/db mouse model of diabetes at 24 weeks of age, moderate impairment of endothelium dependent dilation is evident in the microvessels at 16 weeks of age, and (ii) sustained ROCK-mediated vasoconstriction may potentially have a role in reduced coronary perfusion in type 2 diabetes at an advanced stage
Summary
The causal factors underpinning the onset and progression of diabetic heart disease (DHD) remain to be fully elucidated. Myocardial function is critically dependent on optimal coronary blood flow. Considering vascular disease occurs early in diabetes due to endothelial dysfunction, this study aimed to determine whether impaired coronary perfusion contributes to the origins of myocardial dysfunction in DHD, or whether coronary and cardiac dysfunction are independent pathologies associated with diabetes. Impaired coronary perfusion is often a pathological precursor to the onset of cardiac dysfunction in many disease states, but it is less clear if this is the case in DHD. The functional capacity of the heart is highly dependent on adequate coronary blood flow to ensure O2 delivery to the myocardium is tightly matched to O2 demand, i.e., myocardial autoregulation (Crossman, 2004). If coronary blood flow is adversely impaired, such as in coronary artery disease, the functional capacity of the heart can be irreversibly compromised
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
