Date Published: October 1, 2018
Publisher: Public Library of Science
Author(s): Tina M. Pedersen, Neoma T. Boardman, Anne D. Hafstad, Ellen Aasum, Jun Yu.
Although murine models for studying the development of cardiac dysfunction in diabetes mellitus are well established, their reported cardiac phenotypes vary. These reported divergences may, in addition to the severity of different models, also be linked to the methods used for cardiac functional assessment. In the present study, we examined the functional changes using conventional transthoracic echocardiography (in vivo) and isolated heart perfusion techniques (ex vivo), in hearts from two mouse models; one with an overt type 2 diabetes (the db/db mouse) and one with a prediabetic state, where obesity was induced by a high-fat diet (HFD). Analysis of left ventricular function in the isolated working hearts from HFD-fed mice, suggested that these hearts develop diastolic dysfunction with preserved systolic function. Accordingly, in vivo examination demonstrated maintained systolic function, but we did not find parameters of diastolic function to be altered. In db/db mice, ex vivo working hearts showed both diastolic and systolic dysfunction. Although in vivo functional assessment revealed signs of diastolic dysfunction, the hearts did not display reduced systolic function. The contrasting results between ex vivo and in vivo function could be due to systemic changes that may sustain in vivo function, or a lack of sensitivity using conventional transthoracic echocardiography. Thus, this study demonstrates that the isolated perfused working heart preparation provides unique additional information related to the development of cardiomyopathy, which might otherwise go unnoticed when only using conventional echocardiographic assessment.
The transition to a more sedentary lifestyle and overnutrition, has led to increased incidence of obesity, hyperglycaemia, insulin resistance, dyslipidaemia, and metabolic syndrome—all known risk factors of cardiovascular disease. Consequently, cardiovascular disease is the primary cause of morbidity and mortality in diabetes patients. Diabetes also predisposes to a distinct cardiomyopathy defined as ventricular dysfunction in the absence of coronary heart disease or hypertension [1–3], which leads to the development of diastolic dysfunction prior to systolic dysfunction and finally heart failure.
The present study demonstrates differences between the ex vivo and in vivo cardiac functional phenotype within the same murine models of diabetes. While isolated perfused working hearts from diabetic mice showed clear signs of dysfunction, conventional transthoracic echocardiography did not reveal this to the same extent. Although lack of in vivo cardiac dysfunction may be due to a low sensitivity of the M-Mode and Doppler assessment, it may also relate to systemic factors (such as altered neurohormonal status and/or changes in pre- and afterload) which might mask subtle functional changes in vivo. This study therefore shows how ex vivo examination can add valuable information when describing the progression of cardiomyopathy.
Although continued advances in in vivo imaging will provide access to new and more sensitive modalities for cardiac phenotyping, this study demonstrates that the isolated heart preparation remains a valuable tool for assessment of the myocardial function per se, and by that may bridge in vitro assays and in vivo approaches.