**11. Obesity and sudden cardiac death**

DC is also accompanied by other comorbidities such as obesity and hypertension and these two complications often precede the development of fibrosis, apoptosis, hypertrophy, remodeling of the myocardium, diastolic and systolic dysfunctions, CAD, arrhythmias and SCD [63]. SCD in the young obese population normally happens in individuals without a known cardiac history [64]. More recently, chronic obese patients have been reported to be more susceptible to increased risk of SCD. As such, this is becoming a major concern and challenge for clinicians and health services globally, especially since the prevalence of obesity has been increasing steadily in both developed and developing countries around the world. Both obesity and DM share the main risk factors including inactivity, smoking and diets rich in sugar and fats. Most obese patients are hypertensive, pre-diabetic, as well as having fully blown diabetes, experiencing obstructive sleep apnea due to their excessive weight and metabolic syndrome. All of these pathological parameters are well-known risk factors for CVDs, including SCD. It is now evident that structural, functional and metabolic factors modulate and influence the risk of SCD in the obese population [65]. Obesity exerts numerous haemodynamic changes on the CVS such as increased cardiac output and diastolic filling pressures, both of which result in LV hypertrophy and dilatation. In addition, obesity can induce adverse electrical changes in the myocardium including prolongation of the QRS and increase in QT intervals on the ECG, as well as an increase in QT dispersion. Moreover, the late potentials on signal averaged ECG are also more common in obese compared with lean individuals. These obese-induced adverse structural and electrical insults on the heart seem to create a substrate that is susceptible to SCD [66].

**145**

*Mechanisms of Diabetes Mellitus-Induced Sudden Cardiac Death*

Obesity-induced pathogenesis of the myocardium is associated with the production of lipids, oxidized LDL particles and free FAs which activate the inflammatory process in the body and thus, trigger the development of cardiac dysfunction. Inflammation is responsible for the steps toward the development of atherosclerosis, from early endothelial cell dysfunction to the late atherosclerotic plaque formation causing complications. All these pathological processes are related to obesity, IR and diabetes. During diseased processes in the heart, fatty tissue releases adipocytokines which in turn induce IR, endothelial cell dysfunction, hypercoagulability and systemic inflammation, thereby facilitating the atherosclerotic process. Likewise, the inflammatory adipocytokine such as TNF-α also rises to higher levels in visceral obesity. As a result, the heart releases an increased level of C-reactive protein (CRP) which is associated with an enhanced risk of ischaemia, myocardial infarction and peripheral vascular disease, all of which can facilitate arrhythmias and SCD [67].

**12. Impaired calcium and potassium homeostasis and sudden cardiac** 

Calcium (Ca2+) is a major trigger, a modulator, a second messenger and a regulator of cardiac contractility [24, 68, 69]. It is well known that most of the Ca2+ that activates contraction is released from sarcoplasmic reticulum (SR) through ryanodine receptors (RyRs). RyRs are themselves activated by Ca2+ which enters the myocyte via voltage-dependent L- type Ca2+ channels and this mechanism is known as Ca2+-induced Ca2+ release (CICR) [68]. The cytosolic Ca2+ in turn interacts with cardiac contractile proteins. By binding to troponin C, the Ca2+ triggers the sliding of thin and thick filaments, which results in cardiac contraction. Ca2+ then returns to diastolic levels mainly by the uptake of Ca2+ into the SR via the SR Ca2+ pump (SERCA2a) and extrusion of Ca2+ from the cell via the sarcolemmal Na+

exchanger and the sarcolemma Ca2+-ATPase pump [24]. DM leads to mitochondrial dysfunction which contributes to the development of DC by altering ATP generation and Ca2+ mobilization [69]. A previous study has shown that diabetes-induced HG plays an integral role in altering the expression and function of RyRs, Na<sup>+</sup>

exchanger and SERCA. Failure of these three major calcium transporting proteins to function efficiently in cardiac muscles is the pivotal factor which is responsible the impairment of myocardial systolic and diastolic functions [30]. In such situations, Ca2+ homeostasis is altered during DC thereby affecting the ability of SR to take up

of the cell leading to elevated diastolic [Ca2+]i. Second, in diabetes, channel proteins within RyRs undergo carbonylation leading to asynchronous release of calcium into

Like cellular calcium, potassium homeostasis is of crucial importance for normal cellular function and it is regulated by ion-exchange pumps, co–transporters and channels. Normal plasma potassium values range between 3.8 to5.1 mmol/l [70]. The deviations to both extremes (hypo- and hyperkalaemia) are associated with increased risk of arrhythmias and SCD especially in diabetes-induced chronic kidney failure. Moreover, diabetic patients are at high risks when the failing kidneys are unable to remove potassium from the plasma and as such it builds up in the body leading to hyperkalaemia. Potassium levels below 3.0 mmol/l cause significant Q-T interval prolongation with subsequent risk of torsade des pointes, ventricular fibrillation and SCD. Potassium levels above 6.0 mmol/l cause peaked T waves, wider QRS komplexes and may result in bradycardia, asystole and SCD [70]. Tight regulation of serum potassium levels is necessary for many physiologic processes,




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

**death**

Ca2+ and the Na+

the cytoplasm from the SR [57]; (see **Figure 4**).

including normal cardiac conduction and function [71].

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

*Sudden Cardiac Death*

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 patho-

genic factor or insult resulting in arrhythmias and SCD [60].

DC is also accompanied by other comorbidities such as obesity and hypertension and these two complications often precede the development of fibrosis, apoptosis, hypertrophy, remodeling of the myocardium, diastolic and systolic dysfunctions, CAD, arrhythmias and SCD [63]. SCD in the young obese population normally happens in individuals without a known cardiac history [64]. More recently, chronic obese patients have been reported to be more susceptible to increased risk of SCD. As such, this is becoming a major concern and challenge for clinicians and health services globally, especially since the prevalence of obesity has been increasing steadily in both developed and developing countries around the world. Both obesity and DM share the main risk factors including inactivity, smoking and diets rich in sugar and fats. Most obese patients are hypertensive, pre-diabetic, as well as having fully blown diabetes, experiencing obstructive sleep apnea due to their excessive weight and metabolic syndrome. All of these pathological parameters are well-known risk factors for CVDs, including SCD. It is now evident that structural, functional and metabolic factors modulate and influence the risk of SCD in the obese population [65]. Obesity exerts numerous haemodynamic changes on the CVS such as increased cardiac output and diastolic filling pressures, both of which result in LV hypertrophy and dilatation. In addition, obesity can induce adverse electrical changes in the myocardium including prolongation of the QRS and increase in QT intervals on the ECG, as well as an increase in QT dispersion. Moreover, the late potentials on signal averaged ECG are also more common in obese compared with lean individuals. These obese-induced adverse structural and electrical insults on the heart seem to create a substrate that

**11. Obesity and sudden cardiac death**

**144**

is susceptible to SCD [66].

Obesity-induced pathogenesis of the myocardium is associated with the production of lipids, oxidized LDL particles and free FAs which activate the inflammatory process in the body and thus, trigger the development of cardiac dysfunction. Inflammation is responsible for the steps toward the development of atherosclerosis, from early endothelial cell dysfunction to the late atherosclerotic plaque formation causing complications. All these pathological processes are related to obesity, IR and diabetes. During diseased processes in the heart, fatty tissue releases adipocytokines which in turn induce IR, endothelial cell dysfunction, hypercoagulability and systemic inflammation, thereby facilitating the atherosclerotic process. Likewise, the inflammatory adipocytokine such as TNF-α also rises to higher levels in visceral obesity. As a result, the heart releases an increased level of C-reactive protein (CRP) which is associated with an enhanced risk of ischaemia, myocardial infarction and peripheral vascular disease, all of which can facilitate arrhythmias and SCD [67].
