Effects of diabetes on the myocardium

Both systolic and diastolic abnormalities have been demonstrated in patients with diabetes without symptomatic evidence of cardiovascular disease. These abnormalities correlate with duration of diabetes and evidence of retinopathy / neuropathy (Annonu etal., 2001). A full review of the molecular processes occurring in the heart of patients with diabetes is outwith the scope of this chapter and has been reviewed elsewhere (Taegtmeyer etal., 2002; Young etal., 2002). There are many putative metabolic mechanisms of the effect of diabetes on the myocardium, but most have been demonstrated in animals rather than in patients with CHF:

• Hyperinsulinaemia - In rats, insulin stimulates an increase in myocardial mass (Holmang etal., 1996). Insulin may be a myocardial growth factor, increasing myocardial hypertrophy.

• Advanced Glycosylation End-products (AGEs) - In hyperglycaemia, glucose reacts non-enzymatically with proteins, producing AGEs (Jyothirmayi etal., 1998). The AGEs are thought to be involved in a number of detrimental biochemical processes in diabetes. For example, in the myocardium of dogs with diabetes, cross-linking of collagen and subsequent deposition in the myocardium leads to increased chamber stiffness (Jyothirmayi etal., 1998).

• Reactive Oxygen Species - Prolonged hyperglycaemia causes increased oxidative stress that leads to apoptosis in the myocardium of diabetic rats (Rosen etal., 1998; Bojunga etal., 2004). Increased oxidative stress has been noted in human failing myocardium (Sam etal., 2005) and diabetic myocardium (Frustaci etal., 2000).

• Sarcoplasmic/ Endoplasmic-Reticulum Ca2+-ATPase 2a (SERCA2a) - SERCA2a replenishes intracellular calcium stores and is thought to play an important role in cardiac relaxation. AGEs cause post-translational modification of SERCA2a and result in a decrease in its activity in diabetic rats (Bidasee etal., 2004). Subsequent treatment of the diabetic rats with insulin was found to decrease the modification of SERCA2a by AGEs and significantly improve cardiac function.

• Free Fatty Acids (FFAs) - Diabetic myocardium is more dependent on FFAs than normal myocardium. When insulin resistance is present, excess FFAs rather than glucose and lactate are metabolised by the myocardium. Patients with diabetes have increased plasma levels of FFAs, demonstrate increased utilisation and oxidation of FFAs in their myocardium and decreased myocardial glucose uptake (Herrero etal., 2006). In obese rats, prolonged exposure to elevated levels of FFA causes myocardial apoptosis and contractile dysfunction (Zhou etal., 2000). Increased FFA utilisation results in the uncoupling of oxidative phosphorylation, the inhibition of membrane ATPase activity and increased myocardial oxygen consumption. High levels of plasma FFAs in humans post-MI have been linked to an increase in serious arrhythmias (Gupta etal., 1969; Tansey and Opie, 1983; Oliver and Opie, 1994). During myocardial ischaemia, FFAs have been shown to suppress myocardial contractility in rats (Henderson etal., 1969). The partial inhibition of FFA oxidation in ischaemic swine myocardium leads to improved contractility (Chandler etal., 2003). The influence of FFAs on contractility and apoptosis has not been demonstrated in patients with CHF.

• Protein Kinase C - Increased activation of the signal transduction pathway for protein kinase C has been demonstrated in diabetic rat hearts (Way etal., 2001), and elevated levels of protein kinase C are found in failing human myocardium (Bowling etal., 1999). In transgenic mice, over-expression of protein kinase C has lead to myocardial hypertrophy and dysfunction (Wakasaki etal., 1997). Elevations in protein kinase C activity in response to hyperglycaemia have been demonstrated in various animal tissues and cultured endothelium (Way etal., 2001). Increased protein kinase C activity leads to an increase in extracellular matrix deposition, causing thickening of the basement membrane, altered blood flow and increased vascular permeability. In rat cardiomyocytes, protein kinase C increases levels of ACE, leading to increases in angiotensin II (Zhang etal., 2003).

• Vascular Endothelial Growth Factor (VEGF) - VEGF is expressed in response to hypoxia and may play an important role in the response to vascular injury. Following myocardial infarction, VEGF mRNA is increased in arteriolar smooth-muscle cells and infiltrating macrophages around the infarct site (Shinohara etal., 1996). In patients with diabetes, there is a reduction in the amount of VEGF and its receptor found in the myocardium in comparison to patients without diabetes (Chou etal., 2002). This is consistent with pathological reports of decreased collateralisation in diabetic myocardium following ischaemia (Abaci etal., 1999).

In addition, there may be abnormalities of gene expression in the diabetic heart:

• In the myocardium of diabetic rats, prolonged hyperglycaemia has been shown to increase gene expression of muscle carnitine palmitoyltransferase-1 (Zhang etal., 2002). This is a mitochondrial enzyme involved in the transportation of FFAs into the mitochondria, promoting myocardial use of FFAs.

• In non-ischaemic heart failure in humans, SERCA2a gene expression was decreased in those with diabetes (Razeghi etal., 2002). An induction of the foetal gene programme occurs in patients with diabetes (Bristow, 1998; Razeghi etal., 2001). Myosins are actin-based molecular motors. After birth p (slow)-myosin heavy chain (MHC) is down-regulated and a (fast)-MHC is up-regulated. In the diabetic rat heart there is induction of the fetal gene program and p-MHC is re-expressed whilst a-MHC is down-regulated (Depre etal., 2000). This results in impaired contractility of the myocardium in diabetic animals (Dillman, 1980; Malhotra and Sanghi, 1997). A similar induction of the foetal gene programme, or down-regulation of the adult genes, is seen in the human failing heart (Bristow, 1998; Razeghi etal., 2001). Diabetic patients with CHF are found to have lower levels of a-MHC gene expression than non-diabetics with CHF (Razeghi etal., 2002). It may be that these changes are adaptive to reduce myocardial energy expenditure in the failing heart. Beta-blockers decrease expression of p-MHC and increase SERCA2a gene expression in patients with CHF (Young etal., 2002; Yasumura etal., 2003).

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