Ventricular remodelling in prediabetes: the heart of the matter!

proteolytic enzymes that degrade collagens, and their tissue inhibitors (TIMPS), may lead to increased degradation, contributing to ventricular dilatation and remodelling. Moreover, the role of hyperglycaemia in ventricular remodelling is emerging, and may prove to be an important pathological target, linking activation of the type β transforming growth factor (TGFβ) signalling pathway with extracellular matrix protein deposition and myocyte hypertrophy. In this issue of Experimental Physiology, D’Souza et al. (2011) present compelling evidence that the remodelling of the ventricular myocardium, which ultimately results in decompensated heart failure, occurs during mild hyperglycaemia, prior to the onset of type II diabetes. The authors modelled the prediabetic state utilizing the non-obese Goto‐Kakizaki rat, which exhibits impaired glucose tolerance and mildly elevated fasting blood glucose levels at 8 weeks of age, compared with agematched control animals. The presence of ventricular remodelling was confirmed morphologically, by myocyte hypertrophy, increased extracellular matrix deposition andfibrosis,measuredasincreasedcollagen density. Similar findings have also been identified in myocardial infarction-induced heart failure in diabetic Goto‐Kakizaki rats (Vahtola et al. 2010). D’Souza and colleagues also note a potentially interesting difference in intercalated disk configuration between Goto‐Kakizaki rats in prediabetes and control animals, which reflects altered structural contact between myocytes, but may also have a bearing on electrical coupling and conduction within the ventricle, and may warrant further attention. This study by D’Souza et al. (2011),clearlydemonstratesthatthelevelof hyperglycaemia in prediabetes is sufficient to stimulate recapitulation of the fetal gene phenotype, indicated by increased levels of brain natriuretic peptide and cellular αskeletal actin, both of which are typically upregulated in hypertensive hypertrophy and diabetes-induced hypertrophy and are associated with elevated TGFβ1 expression. Upregulation of MMP2 and MMP9 was also observed compared with control rats, consistent with the perturbation of the extracellular matrix. The MMP/TIMP family is diverse, and its expression is suggested to be region specific. Matrix metalloproteinases 2 and 9 have been shown previously to be upregulated in different facets of cardiac dysfunction, including dilated cardiomyopathy and myocardial infarction, which is supported by overexpression studies (Spinale, 2007). However, studies of ventricular pressure and volume overload suggest a more complex MMP/TIMP profile. Further work will be required to establish a fully comprehensive profile of the MMP/TIMP expression levels that exist in prediabetes and, most importantly, how they develop during disease progression. An important area in which study by D’Souza et al. (2011) is lacking is the presence of functional data to confirm ventricular impairment, and it is imperative that future studies combine mechanistic examination of the signalling processes underlying structural remodelling with functional studies.