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World J Diabetes. Jul 10, 2015; 6(7): 943-960
Published online Jul 10, 2015. doi: 10.4239/wjd.v6.i7.943
Contractile apparatus dysfunction early in the pathophysiology of diabetic cardiomyopathy
Mark T Waddingham, Amanda J Edgley, Hirotsugu Tsuchimochi, Darren J Kelly, Mikiyasu Shirai, James T Pearson
Mark T Waddingham, Amanda J Edgley, Darren J Kelly, Department of Medicine, St Vincent’s Hospital, University of Melbourne, Melbourne, Victoria 3065, Australia
Amanda J Edgley, James T Pearson, Department of Physiology, Monash University, Clayton, Victoria 3800, Australia
Hirotsugu Tsuchimochi, Mikiyasu Shirai, Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka 565-8565, Japan
James T Pearson, Monash Biomedical Imaging Facility, Monash University, Clayton, Victoria 3168, Australia
James T Pearson, Australian Synchrotron, Clayton, Victoria 3168, Australia
Author contributions: Waddingham MT, Edgley AJ and Pearson JT wrote the paper; all authors provided intellectual input, edited and approved the final manuscript.
Supported by The research funding from the International Synchrotron Access Program (AS/IA133) of the Australian Synchrotron (to Pearson JT); A Grant-in-Aid for Scientific Research (#E056, 26670413) from the Ministry of Education, Culture, Sports, Sciences and Technology of Japan (to Shirai M).
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: James T Pearson, PhD, Monash Biomedical Imaging Facility, Monash University, 770 Blackburn Road, Clayton, Victoria 3168, Australia. james.pearson@monash.edu
Telephone: +61-3-99029783 +61-3-99029500
Received: August 27, 2014
Peer-review started: August 28, 2014
First decision: December 17, 2014
Revised: December 30, 2014
Accepted: March 5, 2015
Article in press: March 9, 2015
Published online: July 10, 2015
Processing time: 317 Days and 8.7 Hours
Abstract

Diabetes mellitus significantly increases the risk of cardiovascular disease and heart failure in patients. Independent of hypertension and coronary artery disease, diabetes is associated with a specific cardiomyopathy, known as diabetic cardiomyopathy (DCM). Four decades of research in experimental animal models and advances in clinical imaging techniques suggest that DCM is a progressive disease, beginning early after the onset of type 1 and type 2 diabetes, ahead of left ventricular remodeling and overt diastolic dysfunction. Although the molecular pathogenesis of early DCM still remains largely unclear, activation of protein kinase C appears to be central in driving the oxidative stress dependent and independent pathways in the development of contractile dysfunction. Multiple subcellular alterations to the cardiomyocyte are now being highlighted as critical events in the early changes to the rate of force development, relaxation and stability under pathophysiological stresses. These changes include perturbed calcium handling, suppressed activity of aerobic energy producing enzymes, altered transcriptional and posttranslational modification of membrane and sarcomeric cytoskeletal proteins, reduced actin-myosin cross-bridge cycling and dynamics, and changed myofilament calcium sensitivity. In this review, we will present and discuss novel aspects of the molecular pathogenesis of early DCM, with a special focus on the sarcomeric contractile apparatus.

Keywords: Diabetes; Prediabetes; Insulin resistance; Myocardium; Sarcomere; Protein kinase C; Rho kinase

Core tip: Pathological changes in cardiac muscle underlie diabetic cardiomyopathy (DCM) independent of hypertension and atherosclerosis. In advanced diabetes, fibrosis, hypertrophy and apoptosis, reduce myocardial compliance, which leads to increased diastolic filling pressures and overt left ventricular diastolic dysfunction. However, detrimental changes in sarcomeric and other cytoskeletal proteins in the cardiomyocytes of animal models of diabetes precede remodeling of the cardiac extracellular matrix, which has until now been considered the main contributor to diabetic diastolic dysfunction. An important target for preventing early DCM are the protein kinase C/rho-kinase pathways that drive oxidative stress and reduce myosin head cycling and prolong Ca2+ transients.