Abstract
BackgroundDiabetic patients have an increased predisposition to thromboembolic events, in most cases originating from thrombi in the left atrial appendage (LAA). Remodeling of the LAA, which predisposes to thrombi formation, has been previously described in diabetic patients with atrial fibrillation, but whether remodeling of the LAA occurs in diabetics also in the absence of atrial fibrillation is unknown. To investigate the contribution of diabetes, as opposed to atrial fibrillation, to remodeling of the LAA, we went from humans to the animal model.MethodsWe studied by echocardiography the structure and function of the heart over multiple time points during the evolution of diabetes in the Cohen diabetic sensitive rat (CDs/y) provided diabetogenic diet over a period of 4 months; CDs/y provided regular diet and the Cohen diabetic resistant (CDr/y), which do not develop diabetes, served as controls. All animals were in sinus rhythm throughout the study period.ResultsCompared to controls, CDs/y developed during the evolution of diabetes a greater heart mass, larger left atrial diameter, wider LAA orifice, increased LAA depth, greater end-diastolic and end-systolic diameter, and lower E/A ratio—all indicative of remodeling of the LAA and left atrium (LA), as well as the development of left ventricular diastolic dysfunction. To investigate the pathophysiology involved, we studied the histology of the hearts at the end of the study. We found in diabetic CDs/y, but not in any of the other groups, abundance of glycogen granules in the atrial appendages , atria and ventricles, which may be of significance as glycogen granules have previously been associated with cell and organ dysfunction in the diabetic heart.ConclusionsWe conclude that our rodent model of diabetes, which was in sinus rhythm, reproduced structural and functional alterations previously observed in hearts of human diabetics with atrial fibrillation. Remodeling of the LAA and of the LA in our model was unrelated to atrial fibrillation and associated with accumulation of glycogen granules. We suggest that myocardial accumulation of glycogen granules is related to the development of diabetes and may play a pathophysiological role in remodeling of the LAA and LA, which predisposes to atrial fibrillation, thromboembolic events and left ventricular diastolic dysfunction in the diabetic heart.
Highlights
Diabetic patients have an increased predisposition to thromboembolic events, in most cases originating from thrombi in the left atrial appendage (LAA)
Timeline We studied the animals at four time points: At “baseline” at age 6–7 weeks; after 1 month of Diabetogenic diet (DD) or Regular diet (RD), by which time the diabetic phenotype was already fully expressed in Cohen diabetesprone (CDs/y)-DD but not in any other group; after 2.5 months; and after 4 months of DD or RD, to allow the diabetes-related phenotype to evolve in full in the experimental group
In the current study, we focused on the contribution of diabetes to alterations in the heart that predispose diabetic patients to thromboembolic events leading to cerebrovascular events
Summary
Diabetic patients have an increased predisposition to thromboembolic events, in most cases originating from thrombi in the left atrial appendage (LAA). The arterial emboli during atrial fibrillation originate in the majority of cases from the LAA. The LAA, an anatomical structure pouching out of the LA of the heart, is distinct embryonically and anatomically from the atrium [5]. It acts as a “decompression” chamber during left ventricular systole, when atrial pressure is high [6]. The anatomical location and shape of the LAA favor stasis of blood and thrombus formation [7, 8], predisposing to thromboembolic events during atrial fibrillation [9]
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