**6. SCD due to diabetes-induced autonomic system neuropathy and brady-arrhythmias**

The heart is innervated by the nerves of the autonomic nervous system (ANS) [15]. The ANS consists of sympathetic and parasympathetic nerves which innervate the heart. The parasympathetic or vagus nerve originates from the inhibitory center in medulla of the brainstem. The vagal nerve innervates mainly the atria (sinoatrial node) and the atrio-ventricular node (see **Figure 2**). Upon stimulation, it releases the neurotransmitter, acetylcholine (ACh). The main function of ACh is to activate cholinergic muscarinic receptors in the heart muscles leading to reductions in

**139**

**Figure 3.**

*MGO = methylglyoxal, a reactive carbonyl species.*

*Mechanisms of Diabetes Mellitus-Induced Sudden Cardiac Death*

tandem to maintain the neural homeostasis of the heart [16].

conduction of impulse (negative dromotropic effect), rate (negative chronotropic effect), contraction (negative inotropic effect) and metabolism of the myocardium. On the other hand, the sympathetic nerve originates from the thoracic region of the spinal cord and it innervates the whole heart. It releases the neurotransmitter noradrenaline (norepinephrine) (NA) which activates beta-1–adrenergic receptors in the heart leading to increases in conduction of impulse (positive dromotropic effect), rate (positive chronotropic effect), contraction (positive inotropic effect) and enhanced metabolism of the myocardium. The two nerves of the ANS work in

**Figure 3** illustrates the relationship between diabetes-induced cardiac autonomic system neuropathy and brady-arrhythmias in SCD. In diabetes-induced cardiac autonomic neuropathy, the sympathetic nerve to the heart is damaged and its activity is reduced leading to slowing of the heart or brady-arrhythmias, heart rhythm disturbances and even SCD. Moreover, diabetes can also downregulate the beta-adrenergic receptor in the myocardium which in turn synergizes the brady-arrhythmias leading to cessation of the heart or SCD. There is new evidence that diabetes-induced cardiomyopathy is common and there is an increased risk of arrhythmias as a result of dysfunction of the cardiac conduction system (CCS) [17, 18]. This is due mainly to hyperglycemia-induced fibrosis which results in

*Flow diagram showing the cellular and molecular events in the myocardium due to diabetes-induced hyperglycemia culminating in Brady-arrhythmias and subsequently SCD. ROS = reactive oxygen species;* 

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

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

*Sudden Cardiac Death*

**Figure 2.**

*courtesy www.beyondbiology.org).*

preventing backflow. In turn, the right atrium receives retuning deoxygenated blood from the body through the superior and inferior vena cavae, while the left atrium receives oxygenated blood from the lungs through pulmonary vein. The heart itself needs a good supply of blood via the coronary arteries. These include the left anterior descending coronary artery, the left circumflex artery and the right coronary artery supplying the myocardium with oxygen-rich blood. The apex of the

*Diagram showing the electrical system of the mammalian heart with the conducting tissues including the SA node, AV node and Purkinje fiber network. SCD is usually caused by abnormal heart rhythms called arrhythmias and the most common life-threatening arrhythmia is ventricular fibrillation, which is an erratic, disorganized firing of impulses from the ventricles (see lower chambers with Purkinje network of fibers). When this occurs, the heart is unable to pump blood, and death will occur within minutes, if left untreated (image* 

heart is the pointed end and the other end is called the base of the heart [13]. The orderly events that take place during the cardiac cycle are controlled by the electrical conduction system of the heart (**Figure 2**). An impulse is initiated at the sinoatrial node (SA-node) and then passes on to the atrioventricular node (AV-node) via conducting fibers via the atria. From the AV node, the impulse is conducted throughout the ventricles via the Purkinje fibers resulting in depolarization of the heart. Damage to the conducting tissues can result in sudden arrhythmias and possible SCD. Blood is pumped by the right ventricle into the pulmonary circulation at a lower pressure than blood pumped by the left ventricle into the systemic circulation. It follows that the haemodynamic stresses in the right and left side of the heart are very different. Even within the ventricles, the electro-mechani-

cal properties of ventricular cardiac myocytes vary trans-murally [14].

**6. SCD due to diabetes-induced autonomic system neuropathy and** 

The heart is innervated by the nerves of the autonomic nervous system (ANS) [15]. The ANS consists of sympathetic and parasympathetic nerves which innervate the heart. The parasympathetic or vagus nerve originates from the inhibitory center in medulla of the brainstem. The vagal nerve innervates mainly the atria (sinoatrial node) and the atrio-ventricular node (see **Figure 2**). Upon stimulation, it releases the neurotransmitter, acetylcholine (ACh). The main function of ACh is to activate cholinergic muscarinic receptors in the heart muscles leading to reductions in

**138**

**brady-arrhythmias**

conduction of impulse (negative dromotropic effect), rate (negative chronotropic effect), contraction (negative inotropic effect) and metabolism of the myocardium. On the other hand, the sympathetic nerve originates from the thoracic region of the spinal cord and it innervates the whole heart. It releases the neurotransmitter noradrenaline (norepinephrine) (NA) which activates beta-1–adrenergic receptors in the heart leading to increases in conduction of impulse (positive dromotropic effect), rate (positive chronotropic effect), contraction (positive inotropic effect) and enhanced metabolism of the myocardium. The two nerves of the ANS work in tandem to maintain the neural homeostasis of the heart [16].

**Figure 3** illustrates the relationship between diabetes-induced cardiac autonomic system neuropathy and brady-arrhythmias in SCD. In diabetes-induced cardiac autonomic neuropathy, the sympathetic nerve to the heart is damaged and its activity is reduced leading to slowing of the heart or brady-arrhythmias, heart rhythm disturbances and even SCD. Moreover, diabetes can also downregulate the beta-adrenergic receptor in the myocardium which in turn synergizes the brady-arrhythmias leading to cessation of the heart or SCD. There is new evidence that diabetes-induced cardiomyopathy is common and there is an increased risk of arrhythmias as a result of dysfunction of the cardiac conduction system (CCS) [17, 18]. This is due mainly to hyperglycemia-induced fibrosis which results in

#### **Figure 3.**

*Flow diagram showing the cellular and molecular events in the myocardium due to diabetes-induced hyperglycemia culminating in Brady-arrhythmias and subsequently SCD. ROS = reactive oxygen species; MGO = methylglyoxal, a reactive carbonyl species.*

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].
