**9. Metabolic disturbances and sudden cardiac death**

Metabolic disturbances such as altered lipid handling and substrate utilization, decreased mechanical efficiency, mitochondrial dysfunction, disturbances in non oxidative glucose pathways and increased oxidative stress are all hallmarks of DM [34]. Chronic hyperglycemia leads to non-enzymatic glycation of vascular and membrane proteins, producing advanced glycation end products (AGEs) and reactive oxygen species (ROS) and reactive carbonyl species (RCS) [35]. One major RCS is methylglyoxal (MGO) which is generated during glycolysis and the breakdown of lipids and glucose. In a previous study, it was reported that diabetes was associated with a large amount of collagen deposition around blood vessel and between the myofibers of heart biopsies taken from patients. Moreover, lipofuscins which are brown pigment granules that composed of lipid-containing residues were found to be deposited in left ventricular transmural biopsies. Similarly, myocardial triglyceride and cholesterol were also reported in these biopsies in large amount [36].

Insulin has a vital role to play in the regulation of cardiac metabolism and function [37]. Alterations of myocardial substrate and energy metabolism are considered as significant factors for the development of DC [38]. DM is characterized by reduced glucose and lactate metabolism and increased fatty acid (FA) metabolism [39]. In 1988, the glucose transporter GLUT family was discovered [40] and later, it was reported that glucose transport in the myocardium was impaired during diabetes because of decreased expression of GLUT1 and GLUT4 proteins and mRNA levels [41]. Likewise, glucose oxidation is reduced via the inhibitory effect of FA oxidation on pyruvate dehydrogenase complex due to high circulating FFA [42]. Insulin exerts its effect on glucose uptake in heart muscles by binding to insulin tyrosine kinase receptor (ITKR) via auto-transphosphorylation. In turn, this process initiates a signaling cascade mechanism which is accompanied by phosphorylation of phosphatidyl-inositol-3 kinase (PI3K), phosphoinositide-dependent kinase 1 (PDK1), Akt and protein kinase C (PKC). All these events allow for the translocation of GLUT1 and GLUT4 to the membrane facilitating glucose uptake into cardiac muscle cell. Contraction-evoked GLUT4 translocation represents the major mechanism that regulates glucose uptake by the myocardium heart, with only a small role by GLUT1 [43].

Both insulin resistance (IR) and hyperinsulinemia are risk factors for DC [44]. They seem to disturb insulin-induced glucose metabolism thereby significantly worsen the metabolic efficiency in cardiac and skeletal muscles. Insulin exerts its insulting effect in the diabetic heart via two processes involving the abnormalities of systemic metabolism and insulin signaling pathways, both of which are intrinsic to the cardiac tissue [45]. In the evolution of IR, the initial change that develops in

**143**

apoptosis [53].

*Mechanisms of Diabetes Mellitus-Induced Sudden Cardiac Death*

the hearts of animal models is the impairment in the ability of insulin to increase glucose transport [46]. IR is also associated with cardiac contractile dysfunction and SCD [47]. Moreover, IR is associated with metabolic alteration and the development of DC [45]. Circulating FAs and triglyceride (TG) are increased by enhanced lipolysis in adipose tissue and lipoprotein synthesis in liver as a result of hyperglycemia and IR. It is now known that the FAs are converted to a lipid- like TG or ceramide when the FAs exceed the oxidative capacity of the heart leading to lipotoxicity and cell apoptosis [48]. As a result, DM subsequently leads to an increase in the rate of FA oxidation which is accompanied by a concurrent decrease in the rate of

**10. Relationship between fibrosis and sudden cardiac death**

especially when it is combined with myocardial T1 mapping [49].

In addition, the replacement of myocytes with fibrotic tissue can reduce the number of force generating sarcomeres leading to a reduction in contractile function and subsequently arrhythmias and SCD [50]. Interstitial and perivascular fibrosis is a histological symptom of DC [25] and the extent of fibrosis correlates closely with the weight of the myocardium. The pathogenesis of fibrosis in the diabetic heart is proposed to be due to diabetic micro-angiopathy. When the diabetic heart is affected by either hypertension or CAD, there may be additive micro-angiopathy and large vessel-induced ischemia, all leading to diffuse myocardial scarring. Generalized fibrosis can result in increased wall stiffness and diastolic dysfunction [18, 51]. It is now well recognized that activation of the renin-angiotensin system (RAS) has an important biochemical role to play in the development of DC [42]. In diabetic heart, Angiotensin II (AngII) receptor density and mRNA expression are elevated [52]. It has been reported that DM can enhance the activation of RAS resulting in an increase in oxidative damage, fibrosis and cell

In contrast, the inhibition of the RAS can lead to a reduction in reactive oxygen species (ROS) level, similar to the effect observed with antioxidant treatment in streptozotocin-induced diabetic rat model [54]. One example of an ROS generating endogenous molecule is the RCS, methylglyoxal (MGO). Its accumulation to toxic levels during diabetes is due to a decrease in the activity of the enzyme (glyoxylase-1), the primary enzyme responsible for degrading MGO [55]. AngII, given exogenously to rodents, has been shown to cause cellular changes within the

myocardium leading to hypertrophy and fibrosis and even SCD [56].

Diabetes is well known to induce severe structural changes in the heart including replacement of apoptotic myocytes with fibrotic tissue and myocyte enlargement and disarray. These changes can affect electrical and mechanical activities of the heart [47]. Fibrosis can result in stiffness of the heart, remodeling, conduction abnormalities, arrhythmias and even SCD [12, 13, 17, 18]. Moreover, increased interstitial deposits of collagen filaments leading to fibrosis can act as insulating barriers, promoting not only impulse conduction slowing, but also conduction block [17, 18]. Recent experimental findings in isolated whole-heart studies indicate that fibrosis may also modulate the formation and propagation of cardiac-after potentials which can trigger electrical activity of the heart resulting in ventricular tachycardia and ventricular fibrillation (VT/VF). Since the infiltration of the myocardium with fibrosis can induce cardiovascular events as well as impairing cardiac diastolic and systolic function, it is now possible to assess the extent of myocardial fibrosis using cardiac magnetic resonance (CMR). CMR is of paramount importance as a prognostic tool in determining the different types of cardiomyopathies,

*DOI: http://dx.doi.org/10.5772/intechopen.93729*

glucose oxidation.

*Mechanisms of Diabetes Mellitus-Induced Sudden Cardiac Death DOI: http://dx.doi.org/10.5772/intechopen.93729*

*Sudden Cardiac Death*

and generally stiffness of the heart [31].

quently to arrhythmias and SCD.

**9. Metabolic disturbances and sudden cardiac death**

SDC, and it often occurs independent of blood pressure in the atria. As such, DM is an independent risk factor which is responsible for enlargement of the left ventricle

Metabolic disturbances such as altered lipid handling and substrate utilization, decreased mechanical efficiency, mitochondrial dysfunction, disturbances in non oxidative glucose pathways and increased oxidative stress are all hallmarks of DM [34]. Chronic hyperglycemia leads to non-enzymatic glycation of vascular and membrane proteins, producing advanced glycation end products (AGEs) and reactive oxygen species (ROS) and reactive carbonyl species (RCS) [35]. One major RCS is methylglyoxal (MGO) which is generated during glycolysis and the breakdown of lipids and glucose. In a previous study, it was reported that diabetes was associated with a large amount of collagen deposition around blood vessel and between the myofibers of heart biopsies taken from patients. Moreover, lipofuscins which are brown pigment granules that composed of lipid-containing residues were found to be deposited in left ventricular transmural biopsies. Similarly, myocardial triglyceride and cholesterol were also reported in these biopsies in large amount [36].

Insulin has a vital role to play in the regulation of cardiac metabolism and function [37]. Alterations of myocardial substrate and energy metabolism are considered as significant factors for the development of DC [38]. DM is characterized by reduced glucose and lactate metabolism and increased fatty acid (FA) metabolism [39]. In 1988, the glucose transporter GLUT family was discovered [40] and later, it was reported that glucose transport in the myocardium was impaired during diabetes because of decreased expression of GLUT1 and GLUT4 proteins and mRNA levels [41]. Likewise, glucose oxidation is reduced via the inhibitory effect of FA oxidation on pyruvate dehydrogenase complex due to high circulating FFA [42]. Insulin exerts its effect on glucose uptake in heart muscles by binding to insulin tyrosine kinase receptor (ITKR) via auto-transphosphorylation. In turn, this process initiates a signaling cascade mechanism which is accompanied by phosphorylation of phosphatidyl-inositol-3 kinase (PI3K), phosphoinositide-dependent kinase 1 (PDK1), Akt and protein kinase C (PKC). All these events allow for the translocation of GLUT1 and GLUT4 to the membrane facilitating glucose uptake into cardiac muscle cell. Contraction-evoked GLUT4 translocation represents the major mechanism that regulates glucose uptake by the myocardium heart, with only a small role by GLUT1 [43]. Both insulin resistance (IR) and hyperinsulinemia are risk factors for DC [44]. They seem to disturb insulin-induced glucose metabolism thereby significantly worsen the metabolic efficiency in cardiac and skeletal muscles. Insulin exerts its insulting effect in the diabetic heart via two processes involving the abnormalities of systemic metabolism and insulin signaling pathways, both of which are intrinsic to the cardiac tissue [45]. In the evolution of IR, the initial change that develops in

It is particularly noteworthy that at cellular electrical level in the diabetic heart, the cardiac action potential duration (CAP) is consistently prolonged due to elevated intracellular calcium which is essential for the myocardium contraction [32]. It is now evident that DC-induced abnormalities during cardiac muscle contractility correlate closely with alterations in intracellular free Ca2+concentration [Ca2+]i. It was previously reported that diabetic cardiac dysfunction arises as a result of changes in the expression and/or activity of transporting proteins that regulate Ca2+ during the cardiac cycle [33]. Thus, DC results in changes in biomechanical, contractile, and hypertrophic properties of the cardiac myocytes leading subse-

**142**

the hearts of animal models is the impairment in the ability of insulin to increase glucose transport [46]. IR is also associated with cardiac contractile dysfunction and SCD [47]. Moreover, IR is associated with metabolic alteration and the development of DC [45]. Circulating FAs and triglyceride (TG) are increased by enhanced lipolysis in adipose tissue and lipoprotein synthesis in liver as a result of hyperglycemia and IR. It is now known that the FAs are converted to a lipid- like TG or ceramide when the FAs exceed the oxidative capacity of the heart leading to lipotoxicity and cell apoptosis [48]. As a result, DM subsequently leads to an increase in the rate of FA oxidation which is accompanied by a concurrent decrease in the rate of glucose oxidation.

## **10. Relationship between fibrosis and sudden cardiac death**

Diabetes is well known to induce severe structural changes in the heart including replacement of apoptotic myocytes with fibrotic tissue and myocyte enlargement and disarray. These changes can affect electrical and mechanical activities of the heart [47]. Fibrosis can result in stiffness of the heart, remodeling, conduction abnormalities, arrhythmias and even SCD [12, 13, 17, 18]. Moreover, increased interstitial deposits of collagen filaments leading to fibrosis can act as insulating barriers, promoting not only impulse conduction slowing, but also conduction block [17, 18]. Recent experimental findings in isolated whole-heart studies indicate that fibrosis may also modulate the formation and propagation of cardiac-after potentials which can trigger electrical activity of the heart resulting in ventricular tachycardia and ventricular fibrillation (VT/VF). Since the infiltration of the myocardium with fibrosis can induce cardiovascular events as well as impairing cardiac diastolic and systolic function, it is now possible to assess the extent of myocardial fibrosis using cardiac magnetic resonance (CMR). CMR is of paramount importance as a prognostic tool in determining the different types of cardiomyopathies, especially when it is combined with myocardial T1 mapping [49].

In addition, the replacement of myocytes with fibrotic tissue can reduce the number of force generating sarcomeres leading to a reduction in contractile function and subsequently arrhythmias and SCD [50]. Interstitial and perivascular fibrosis is a histological symptom of DC [25] and the extent of fibrosis correlates closely with the weight of the myocardium. The pathogenesis of fibrosis in the diabetic heart is proposed to be due to diabetic micro-angiopathy. When the diabetic heart is affected by either hypertension or CAD, there may be additive micro-angiopathy and large vessel-induced ischemia, all leading to diffuse myocardial scarring. Generalized fibrosis can result in increased wall stiffness and diastolic dysfunction [18, 51]. It is now well recognized that activation of the renin-angiotensin system (RAS) has an important biochemical role to play in the development of DC [42]. In diabetic heart, Angiotensin II (AngII) receptor density and mRNA expression are elevated [52]. It has been reported that DM can enhance the activation of RAS resulting in an increase in oxidative damage, fibrosis and cell apoptosis [53].

In contrast, the inhibition of the RAS can lead to a reduction in reactive oxygen species (ROS) level, similar to the effect observed with antioxidant treatment in streptozotocin-induced diabetic rat model [54]. One example of an ROS generating endogenous molecule is the RCS, methylglyoxal (MGO). Its accumulation to toxic levels during diabetes is due to a decrease in the activity of the enzyme (glyoxylase-1), the primary enzyme responsible for degrading MGO [55]. AngII, given exogenously to rodents, has been shown to cause cellular changes within the myocardium leading to hypertrophy and fibrosis and even SCD [56].

Mitochondria are the powerhouse of cells, and they play a major role in energy production. They are also involved with a number of cellular processes including homeostasis, free radical production and cell death [57]. Mitochondria exert marked biochemical effect on FA and glucose metabolism. However, diabetes can induce mitochondrial dysfunction leading to impaired cellular metabolism. A previous study reported ultrastructural and functional changes, as well as protein composition, in cardiac muscle mitochondria following diabetes [58]. In streptozotocin-induced type 1 diabetic mice, impaired function and ultrastructure abnormalities of cardiac muscles were associated with damage to the mitochondria. The impairment of the mitochondria was accompanied by increases in 11 specific mitochondrial proteins. These include an elevation of mRNA for the mitochondrial regulatory protein and increased total mitochondrial DNA area as well as number. These findings clearly indicate that the mitochondria are the major targets of diabetes-induced damage to the heart [59]. Moreover, a recent study has shown a reduction of ATP production by the mitochondria following diabetes. Another study [60] examined the relationship between impaired insulin signaling and altered mitochondrial energetics in a mouse model of type 1 diabetes with a cardiac-specific deletion of the insulin receptor. The results reveal impaired insulin signaling in the heart and this in turn promotes oxidative stress and mitochondrial uncoupling. These processes were associated with reduced fatty acid oxidative capacity and impaired mitochondrial energetics [61]. It is now well established that mitochondria from the diabetic heart can produce more reactive oxygen species (ROS) and reactive carbonyl species (RCS) than normal mitochondria [62]. According to the molecular theory of DC, hyperglycemia (HG) is the main pathogenic factor or insult resulting in arrhythmias and SCD [60].
