Heart disease represents the leading cause of death among patients with DM (Stamler et al. 1993). Epidemiological studies indicate that DM is a potent and prevalent risk factor for ischaemic heart disease and heart failure (HF) (Kannel et al. 1974; Redfield et al. 2003). In addition, the coexistence of DM with either myocardial ischaemia or HF is associated with extremely poor outcomes (Beller 2001; Bell 2003a). Although coronary atherosclerosis is frequently implicated in the development of HF in diabetic patients, recent evidence indicates that DM can cause cardiac dysfunction independently of coronary disease or hypertension (Fang et al. 2004; Bell 2003b; Poornima et al. 2006; Marwick 2006). Screening assessment of ventricular function by echocardiography and tissue Doppler revealed the presence of diastolic dysfunction in 25-75% of young, asymptomatic patients with T1DM or T2DM (Zabalgoitia et al. 2001; Boyer et al. 2004; Rajan and Gokhale 2002; Schannwell et al. 2002). T2DM patients seem to be more susceptible than T1DM subjects, possibly due to the cardio-protective action of insulin supplementation in the latter (Schaible et al. 1983). In the Strong Heart Study and Heart Outcomes Prevention Evaluation (HOPE) Trial, the degree of diastolic dysfunction and the risk of evolution to HF were proportional to the levels of microalbuminuria and presence of microvascular complications (Liu et al. 2003; Arnold et al. 2003). Because microalbuminuria is a marker of endothelial dysfunction in the kidney, it was postulated that parallel impairment of endothelial function in the myocardium may contribute to increased ventricular scarring and stiffness (Poornima et al. 2006). Mechanisms of diabetic cardiomyopathy are complex. Poor glycaemic control, increased oxidative stress, abnormalities in calcium handling and local activation of the renin-angiotensin system concurrently cause cardiomyo- cyte and microvascular endothelial cell apoptosis and death (Fiordaliso et al. 2000; Frustaci et al. 2000). Reduction of coronary flow reserve, microvascular spasm and reperfusion injury ascribed to endothelial dysfunction and microangiopathy contribute to focal cardiomyocyte loss by apoptosis and replacement fibrosis (Warley et al. 1995). Furthermore, healing mechanisms are impaired in the diabetic heart, including altered paracrine control of reparative angiogenesis (Yoon et al. 2005) and myocyte survival (Kajstura et al. 2001), as well as accelerated ageing of resident cardiac progenitor cells (Rota et al. 2006). A few studies highlight the differential expression of a subset of miRNAs in proangiogenic cells (PACs) in patients with heart disease (Zhang et al. 2011; Meng et al. 2012; Xu et al. 2012).
MiRNAs may control these cell functions at different levels with their altered expression being the cause or the result of the diabetic complication. In particular, the cardiac and skeletal muscle-specific miR-133a may play a role in the development of the disease by controlling genes related to fibrosis. MiR-133a downregula- tion in the hearts of diabetic mice has been associated with increased TGF-p1 and collagen IV (COL4A1) expression (Chen et al. 2014b). Of note, recent findings suggest miR-133a may be implicated in the control of cardiomyocyte function in diabetes via the targeting of methylation enzymes (Chavali et al. 2012). The muscle-specific miR-1 is upregulated in a rat cardiomyocyte cell line exposed to high glucose, inhibiting the anti-apoptotic action of IGF-1 (Yu et al. 2008). Another study with a similar in vitro model found again that miR-1 was upregulated and negatively regulated heat-shock protein 60 expression (Shan et al. 2010). In a diabetic mouse model, we found that cardiomyopathy was associated with a rise in miR-1 and a concurrent decline in the levels of a target Pim-1, which itself plays a key role in the cardiac response to stressors (Katare et al. 2011b). A different profile is seen in the specific case of established diabetic cardiomyopathy, where miR-1 has been found to be downregulated in affected rats (Yildirim et al. 2013). This was associated with an upregulation of the target junctin1 and a consequent increase in oxidative stress (Yildirim et al. 2013). In humans, a study of left ventricle biopsies demonstrated the differential expression between diabetics and nondiabetics of six miRNAs: miR-34b, miR-34c, miR-199b, miR-210, miR-650 and miR-223. These data were confirmed for miR-199a, miR-199b and miR-210 in vitro in cardiomyocytes and endothelial cells subjected to hypoxia and high glucose (Greco et al. 2012).
MiRNAs can exert their action in the cell of origin, but can also act in a paracrine fashion via release in the circulation where they travel bound to protein but also embedded in extracellular vesicles (see previous Sect. 3.3 for more details). In addition, via extracellular vesicle transport, miRNAs can be transferred directly to neighbouring cells and target mRNA expression in the recipient cell. This relatively newly discovered behaviour of miRNAs is currently attracting interest in the cardiovascular field. A recent report demonstrates that cardiomyocytes isolated from T2DM diabetic rats actually transfer the antiangiogenic miR-320 to endothelial cells and affect their function. This effect was counterbalanced in healthy cardiomyocytes by angiogenic miR-126 transport (Wang et al. 2014b).
A prolonged QT interval is an adverse cardiac feature of diabetes that can result in arrhythmias and is an independent predictor of mortality in DM (Rossing et al. 2001). This occurs as a result of dysfunction of multiple ion channels, predominantly the IK/HERG (human ether-a-go-go) channel (Xiao et al. 2007). MiR-133 levels are significantly upregulated in the hearts of diabetic rabbits, where it targets HERG (Xiao et al. 2007). This suggests a role for miR133 dysregulation in prolonging the QT interval, and causing the resultant arrhythmias, in diabetes (Xiao et al. 2007).