**8. Sudden cardiac death due to diabetes-induced cardiomyopathy**

**Figure 4** illustrates the various pathways and events leading to diabetes-induced cardiomyopathy, arrhythmias and SCD due to the diabetes-induced hyperglycemia. These pathways include structural changes to cardiac muscles as well as apoptosis, altered calcium handling, insulin resistance in the heart, increased lipid uptake into the heart, glucotoxicity, metabolic disturbances, fibrosis, hypertrophy and the renin-angiotensin-aldosterone system (RAAS). DM can also affect cardiac structure

**141**

**Figure 4.**

*Mechanisms of Diabetes Mellitus-Induced Sudden Cardiac Death*

and function without causing changes in either high blood pressure (HBP) or CAD resulting in a debilitating condition called diabetic cardiomyopathy (DC) [24]. This term was first described by cardiac clinicians in 1972 after the examination of patients with DM and HF but without the appearance of HBP or CAD [25]. It is now well established that DC is responsible for mortality and morbidity among diabetics [26]. DC generally refers to the dysfunction of the left ventricle due to an enlarged weak heart in diabetic patients independent of CAD or HBP. The onset of DC is triggered by the diabetes–induced hyperglycemia leading to the production of a number of insults in the myocardium including TGF-beta 1, reactive oxygen species and reactive carbonyl species which in turn induce cellular structural damage to the heart. As a consequence, the initial effect is diastolic dysfunction in which the heart is unable to relax properly due to a derangement in cellular calcium homeostasis or elevated diastolic calcium due to impairment in cellular calcium regulatory transporting proteins in the myocardium. Following this, systolic dysfunction develops in which the heart is unable to pump blood efficiently to meet the demand of the body or heart failure. The final effect over time is arrhythmias and subsequently SCD. The most common contributors to DC onset and progression are left ventricular hypertrophy, metabolic abnormalities, extracellular matrix changes, small vessel disease, cardiac autonomic neuropathy, insulin resistance, oxidative stress and

*Flow diagram showing the relationship between obesity and other risk factors-induced diabetes and sudden cardiac death (SCD) in the myocardium. Diabetes-induced hyperglycemia elicits structural, functional, and biochemical changes via different cellular pathways in the heart leading to diabetic cardiomyopathy,* 

As DC was first reported in 1972, considerable data on its pathogenesis and clinical feature have been collected. DC affects the heart by enhancing fatty acid metabolism, suppresses glucose oxidation and modifies intracellular signaling, all of which lead to alteration in multiple steps of excitation-contraction coupling process, inefficient energy production, increased susceptibility to ischemia and

DM leads to structural and functional changes in the heart. The structural changes are manifested by left ventricular muscle disarray and hypertrophy, interstitial fibrosis, increased cell death (apoptosis) and oxidative stress, all of which result in diastolic and systolic dysfunctions as well as impaired contractile reserve [30]. In DM, the mass of the left ventricle is an independent marker for

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

*arrhythmias, and sudden cardiac death (SCD).*

apoptosis, all leading to cardiac remodeling [27].

contractile dysfunction [28, 29].

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

#### **Figure 4.**

*Sudden Cardiac Death*

**7. Cardiac muscle**

dysfunction of the CCS in the diabetic heart (see **Figure 2**). Moreover, it was demonstrated by Zhang et al. [18] that diabetes-induced fibrosis of the heart was associated with the reduction of potassium channel (HCN4), Cav1.3, Cav3.1 (calcium channel), NCX1, (sodium-calcium exchanger) and connexin (Cx45) protein expression in the sinoatrial node of the heart which in turn resulted in brady-arrhythmia and possibly SCD [18]. Moreover, reduced ryanodine (RyR2) and sodium-calcium exchanger (NCX1) protein expression in the atrio-ventricular junction of the heart (AVJ) is believed to contribute in part to the prolongation of the PR interval. Similarly, reduced protein expressions of RyR2, NCX1, Cx40, Cx43, and Cx45 in the Purkinje fibers (PFs) are responsible for the prolongation of QRS complex. The downregulation of neuro-filament M sub-unit (NF-M) and β1 adrenergic receptor could also be linked to the reduced autonomic nervous control of the heart [17, 18]. All these cellular and molecular processes subsequently result in cardiac arrhythmias, QT interval prolongation and SCD of diabetic patients [19].

In order to appreciate how diabetes-induced hyperglycemia is inducing fibrosis and cardiomyopathy, it is paramount importance to understand first, the structure of the cardiac cell or cardiomyocyte. Cardiac muscle, at the microscopic level, can be described as a composite tissue. It is made of various cell types, mainly myocytes and fibroblasts which are supported by extracellular matrix (ECM), all of which are permeated by fluids [15]. The myocardial ECM is made of macro-molecules which are produced by local fibroblasts. They consist of a fibrillar collagen network, a basement membrane and proteoglycans [20]. The function of the fibrillar collagen network is to strengthen the matrix, thereby giving strong structural support of the adjoining cardiomyocytes and the means by which they shorten to exert their contractile effect efficiently during ventricular pump action and thus, contributes to myocardial diastolic stiffness [21]. The heart is composed of different types of collagens including fibrillar collagen type I with the tensile strength of steel and fibrillary collagen type III which is the most abundant phenotypes [21]. Secondly, the basement membrane which surrounds the myocyte is attached to the sarcolemma and to the fibrillar collagen network. The myocyte adherence to basement membrane is a major determinant in maintaining cell shape and positional integrity within the ventricular wall [22]. Thirdly, the proteoglycans are composed of a protein core to which polysaccharide chains called glycosaminoglycans are covalently bound. These negatively charged molecules possess significant osmotic activity helping to trap and to store growth factors within ECM. Proteoglycan molecules in the connective tissue form a highly hydrated, gel-like "ground substance" in which the fibrous proteins are embedded. [22, 23]. The function of the polysaccharide gel is to prevent any compressive forces on the matrix thereby allowing the rapid diffusion of nutrients, metabolites and hormones between the blood and the cardiac tissue cell [23].

**8. Sudden cardiac death due to diabetes-induced cardiomyopathy**

**Figure 4** illustrates the various pathways and events leading to diabetes-induced cardiomyopathy, arrhythmias and SCD due to the diabetes-induced hyperglycemia. These pathways include structural changes to cardiac muscles as well as apoptosis, altered calcium handling, insulin resistance in the heart, increased lipid uptake into the heart, glucotoxicity, metabolic disturbances, fibrosis, hypertrophy and the renin-angiotensin-aldosterone system (RAAS). DM can also affect cardiac structure

**140**

*Flow diagram showing the relationship between obesity and other risk factors-induced diabetes and sudden cardiac death (SCD) in the myocardium. Diabetes-induced hyperglycemia elicits structural, functional, and biochemical changes via different cellular pathways in the heart leading to diabetic cardiomyopathy, arrhythmias, and sudden cardiac death (SCD).*

and function without causing changes in either high blood pressure (HBP) or CAD resulting in a debilitating condition called diabetic cardiomyopathy (DC) [24]. This term was first described by cardiac clinicians in 1972 after the examination of patients with DM and HF but without the appearance of HBP or CAD [25]. It is now well established that DC is responsible for mortality and morbidity among diabetics [26]. DC generally refers to the dysfunction of the left ventricle due to an enlarged weak heart in diabetic patients independent of CAD or HBP. The onset of DC is triggered by the diabetes–induced hyperglycemia leading to the production of a number of insults in the myocardium including TGF-beta 1, reactive oxygen species and reactive carbonyl species which in turn induce cellular structural damage to the heart. As a consequence, the initial effect is diastolic dysfunction in which the heart is unable to relax properly due to a derangement in cellular calcium homeostasis or elevated diastolic calcium due to impairment in cellular calcium regulatory transporting proteins in the myocardium. Following this, systolic dysfunction develops in which the heart is unable to pump blood efficiently to meet the demand of the body or heart failure. The final effect over time is arrhythmias and subsequently SCD. The most common contributors to DC onset and progression are left ventricular hypertrophy, metabolic abnormalities, extracellular matrix changes, small vessel disease, cardiac autonomic neuropathy, insulin resistance, oxidative stress and apoptosis, all leading to cardiac remodeling [27].

As DC was first reported in 1972, considerable data on its pathogenesis and clinical feature have been collected. DC affects the heart by enhancing fatty acid metabolism, suppresses glucose oxidation and modifies intracellular signaling, all of which lead to alteration in multiple steps of excitation-contraction coupling process, inefficient energy production, increased susceptibility to ischemia and contractile dysfunction [28, 29].

DM leads to structural and functional changes in the heart. The structural changes are manifested by left ventricular muscle disarray and hypertrophy, interstitial fibrosis, increased cell death (apoptosis) and oxidative stress, all of which result in diastolic and systolic dysfunctions as well as impaired contractile reserve [30]. In DM, the mass of the left ventricle is an independent marker for

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 and generally stiffness of the heart [31].

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 subsequently to arrhythmias and SCD.
