**3. Etiopathogenesis and pathophysiology of sudden cardiac death**

The commonest mechanism of SCD is a ventricular arrhythmia, most often ventricular tachycardia leading to vemntricular fibrillation. This accounts for 75-80% of all SCDs; the remainder are the result of bradyarrhythmias. [1] Bradyarrhythmias including high grade AV block and sinus node dysfunction may potentially be a mechanism of sudden death in cardiomyopathies. However, assessing the exact electrophysiological mechanism of sudden death may be complex since ventricular fibrillation may arise as an aftermath of a bradyar‐ rhythmia. Futhermore patients having suffered a VF arrest may be found to be in asystole (the end stage of all arrhythmic sudden death) when first coming to medical attention, so both mechanisms may be involved either as an initiator or as perpetuator in the event of sudden death. In the Implanted Cardioverter Defibrillator (ICD) era with aborted sudden deaths due to ICD shocks, bradyarrhythmic mechanisms of sudden death may be masked effectively by back up bradycardia pacing by the ICDs.

Ventricular arrhythmias associated with cardiomyopathies result from primary electrical defects inherent to the cardiomyopathy and activation of the neuro-humoral system in the body as a compensatory hemodynamic mechanism. The efficacy of neuro-humoral blockers like beta-blocker and renin-angiotensin-aldosterone axis blockers in effectively reducing the risk of sudden cardiac death in cardiomyopathy, and relation of the risk of sudden cardiac death to degree of hemodynamic jeopardy with cardiomyopathy suggest the latter mechanism. In the following sections we will discuss the current knowledge of mechanisms of sudden death in various forms of cardiomyopathies.

#### **3.1. Ischemic cardiomyopathy**

infiltration. These conditions though not strictly classifiable as cardiomyopathies, but are important and common causes of SCD in the setting of myocardial dysfunction. They include ischemic heart disease, hypertension, valvular heart disease, and myocardial involvement

**Figure 1.** Absolute numbers of events and event rates of SCD in the general population and in specific subpopulations over 1 y. General population refers to unselected population age greater than or equal to 35 y, and high-risk sub‐ groups to those with multiple risk factors for a first coronary event. Clinical trials that include specific subpopulations of patients are shown in the right side of the figure. AVID \_ Antiarrhythmics Versus Implantable Defibrillators; CASH \_ Cardiac Arrest Study Hamburg; CIDS \_ Canadian Implantable Defibrillator Study; EF \_ ejection fraction; HF \_ heart fail‐ ure; MADIT \_ Multicenter Automatic Defibrillator Implantation Trial; MI \_ myocardial infarction; MUSTT \_ Multicenter UnSustained Tachycardia Trial; SCD-HeFT \_ Sudden Cardiac Death in Heart Failure Trial. (Adapted with permission

The commonest mechanism of SCD is a ventricular arrhythmia, most often ventricular tachycardia leading to vemntricular fibrillation. This accounts for 75-80% of all SCDs; the remainder are the result of bradyarrhythmias. [1] Bradyarrhythmias including high grade AV block and sinus node dysfunction may potentially be a mechanism of sudden death in cardiomyopathies. However, assessing the exact electrophysiological mechanism of sudden death may be complex since ventricular fibrillation may arise as an aftermath of a bradyar‐ rhythmia. Futhermore patients having suffered a VF arrest may be found to be in asystole (the end stage of all arrhythmic sudden death) when first coming to medical attention, so both mechanisms may be involved either as an initiator or as perpetuator in the event of sudden death. In the Implanted Cardioverter Defibrillator (ICD) era with aborted sudden deaths due to ICD shocks, bradyarrhythmic mechanisms of sudden death may be masked effectively by

Ventricular arrhythmias associated with cardiomyopathies result from primary electrical defects inherent to the cardiomyopathy and activation of the neuro-humoral system in the

**3. Etiopathogenesis and pathophysiology of sudden cardiac death**

with conditions like sarcoidosis, amyloidosis.

from reference 165)

168 Cardiomyopathies

back up bradycardia pacing by the ICDs.

Ischemic cardiomyopathy is by far the most common cardiomyopathy leading to SCD Commonest cause of SCD in these patients is ventricular tachyarrhythmia. Beyond the early post-MI period, when recurrent MI and associated complications (mechanical and arrhythmic) are more likely, almost three-fourth of patient deaths among those with prior MI (more than three months old) and LV dysfunction are sudden and presumably arrhythmic, most likely due to ventricular arrhythmias. [2] Susceptibility to ventricular arrhythmia in these patients has multiple mechanisms. Scar resulting from myocardial infarction provides substrate for reentrant ventricular tachycardia. Re-entry circuits involve areas of residual viable relatively slowly conducting myocardial tissue inside the scars. These tracks of slowly conducting myocardial tissue inside a scar, called isthmus, connecting two healthy or relatively healthy areas form a full circuit for re-entrant arrhythmia. Patients with larger myocardial scar are more likely to have reentrant circuit. [3] Moreover, larger scars also lead to more ventricular remodeling and LV dysfunction, leading to activation of compensatory neuro-humoral factors in the setting of left ventricular dysfunction and heart failure. These factors lead to changes in repolarization and conduction properties of myocardial cells and abnormalities in intracellular calcium homeostasis which are potentially arrhythmogenic by promoting triggered activity and facilitating reentry. [4] Moreover, patients with ischemic cardiomyopathy have areas of ischemic myocardium which predispose to the arrhythmia by changes in the myocyte automaticity, excitability and refractoriness leading to dispersion of repolarization. The border zones of the myocardial scars are important substrates for arrhythmia as they are composed of fibrotic tissue as well as viable myocardium which are often ischemic. Heterogeneity of infarct tissue as assessed by magnetic resonance imaging has been shown to predispose to arrhythmia. Additionally, myocardial infarction leads to disturbances in the autonomic innervation of the myocardium in the area surrounding the post-infarct scar which makes the surrounding myocardium more susceptible to arrhythmia due to prolongation of refractory periods in the denervated myocardium. [5] Apart from these, a patient with ischemic heart disease is predisposed to SCD due to acute coronary syndrome.

#### **3.2. Hypertrophic cardiomyopathy**

Studies of HCM patients with ICDs have suggested that ventricular arrhythmias are the major causes of SCD in this group of patients, [6], [7] although availability of back up pacing for bradyarrhythmia precludes the ability of an ICD study to exclude the possibility of a bradyar‐ rhythmic etiology. [6] Bradyarrhythmias are, however, reported rarely in HCM so this seems an unlikely possibility. Multiple pathologic, molecular and physiologic mechanisms could contribute to the causation of ventricular arrhythmias in patients with HCM. HCM is charac‐ terized pathologically by hypertrophied myocardium along with increased fibrosis and myocardial disarray (figure 2). [8-10] Apart from these histopathological features that predis‐ pose to ventricular arrhythmias, there are also abnormalities of calcium handling at molecular level. Cardiomyocytes in patients with systolic and diastolic heart failure have impaired ability of calcium cycling due to altered expression and phosphorylation of sarcoplasmic calcium ATPase 2(SERCA 2) and ryanodine receptor 2, key proteins involved in intracellular calcium handling. [11], [12] Perturbed calcium fluxes have also been seen in HCM. [13], [14] Inefficient energy utilization in some of the HCM associated mutations of troponin lead to insufficient energy for the cardiomyocytes to maintain cellular calcium hemostasis, leading to increased risk of arrhythmia especially during exercise. [15], [16] Microvascular dysfuction with myocardial ischemia along with increased energy needs is another important factor contribu‐ ting to the arrhythmogenicity in HCM. [17], [18] Left ventricular outflow tract obstruction (LVOTO) and altered systolic blood pressure response to exercise may mechanistically predispose to SCD by electromechanical dissociation and demand ischemia. Hence arrhyth‐ mogenic substrates in HCM potentially include altered cellular handling of calcium, with myocardial ischemia, patchy myocardial fibrosis and hypertrophy maintaining the arrhyth‐ mias. Moreover, presence of systolic or diastolic heart failure itself may contribute to the risk by neuro-humoral activation. Apart from these intrinsic predispositions to arrhythmogenesis in the natural course of disease, there has been recent concern of iatrogenic arrhythmias in patients undergoing alcohol septal ablation, which leaves a large ventricular septal scar predisposing to scar-related re-entrant ventricular arrhythmias. [19]-[21]

**3.3. Arrhythmogenic cardiomyopathy**

arrhythmia. [23]

The hallmark of arrhythmogenic cardiomyopathy (previously called arrhythmogenic right ventricular cardiomyopathy) is a defect in cell-cell adhesion caused by genetic defects most commonly affecting the desmosomal proteins. Such defects lead to myocyte loss with fibrofatty replacement of the myocardial tissue (figure 3), most commonly involving the right ventricle, with left ventricular and biventricular involvement less commonly. This provides a substrate for ventricular tachycardia from re-entry around the fibrous scar. [22] Reports of ventricular arrhythmia in subjects harboring the genes of arrhythmogenic cardiomyopathy even in the absence of detectable histopathological and MRI changes in the myocardium suggest an additional electrical substrate distinct from simple reentry involving perhaps intracellular signaling process or heterogeneity in conduction. Gap junction remodeling with paucity of gap junctions in the myocardial cells of affected patients may also provide a substrate for

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**Figure 3.** Fibroadipose infiltration of the right ventricle, seen in the inset macroscopically top right, arrowed. Histology shows the adipose and fibrous tissue replacement of the myocyte architecture (hematoxylin & eosin). **Adapted with**

**Figure 2.** Photomicrographs showing hematoxyline and eosin-stained section with florid myocyte disarray and fibrosis in familial HCM. Disarray is characterized by hypertrophic myocytes with enlarged and pleomorphic nuclei aligned at odd angles to one another (panel A). Photomicrograph showing Masson's trichrome stain with marked increase in interstitial fibrosis, a hallmark of HCM (panel B). **Adapted with permission from chapter 'Cardiomyopathy' by Sian Hughes from the book 'Cardiac Pathololgy: A Guide to Current Practice' eds' S. Kim Suvarna ISBN: 978-1-4471-2406-1 (Print) 978-1-4471-2407-8 (Online) (Springer).**

#### **3.3. Arrhythmogenic cardiomyopathy**

contribute to the causation of ventricular arrhythmias in patients with HCM. HCM is charac‐ terized pathologically by hypertrophied myocardium along with increased fibrosis and myocardial disarray (figure 2). [8-10] Apart from these histopathological features that predis‐ pose to ventricular arrhythmias, there are also abnormalities of calcium handling at molecular level. Cardiomyocytes in patients with systolic and diastolic heart failure have impaired ability of calcium cycling due to altered expression and phosphorylation of sarcoplasmic calcium ATPase 2(SERCA 2) and ryanodine receptor 2, key proteins involved in intracellular calcium handling. [11], [12] Perturbed calcium fluxes have also been seen in HCM. [13], [14] Inefficient energy utilization in some of the HCM associated mutations of troponin lead to insufficient energy for the cardiomyocytes to maintain cellular calcium hemostasis, leading to increased risk of arrhythmia especially during exercise. [15], [16] Microvascular dysfuction with myocardial ischemia along with increased energy needs is another important factor contribu‐ ting to the arrhythmogenicity in HCM. [17], [18] Left ventricular outflow tract obstruction (LVOTO) and altered systolic blood pressure response to exercise may mechanistically predispose to SCD by electromechanical dissociation and demand ischemia. Hence arrhyth‐ mogenic substrates in HCM potentially include altered cellular handling of calcium, with myocardial ischemia, patchy myocardial fibrosis and hypertrophy maintaining the arrhyth‐ mias. Moreover, presence of systolic or diastolic heart failure itself may contribute to the risk by neuro-humoral activation. Apart from these intrinsic predispositions to arrhythmogenesis in the natural course of disease, there has been recent concern of iatrogenic arrhythmias in patients undergoing alcohol septal ablation, which leaves a large ventricular septal scar

170 Cardiomyopathies

predisposing to scar-related re-entrant ventricular arrhythmias. [19]-[21]

**Figure 2.** Photomicrographs showing hematoxyline and eosin-stained section with florid myocyte disarray and fibrosis in familial HCM. Disarray is characterized by hypertrophic myocytes with enlarged and pleomorphic nuclei aligned at odd angles to one another (panel A). Photomicrograph showing Masson's trichrome stain with marked increase in interstitial fibrosis, a hallmark of HCM (panel B). **Adapted with permission from chapter 'Cardiomyopathy' by Sian Hughes from the book 'Cardiac Pathololgy: A Guide to Current Practice' eds' S. Kim Suvarna ISBN:**

**978-1-4471-2406-1 (Print) 978-1-4471-2407-8 (Online) (Springer).**

The hallmark of arrhythmogenic cardiomyopathy (previously called arrhythmogenic right ventricular cardiomyopathy) is a defect in cell-cell adhesion caused by genetic defects most commonly affecting the desmosomal proteins. Such defects lead to myocyte loss with fibrofatty replacement of the myocardial tissue (figure 3), most commonly involving the right ventricle, with left ventricular and biventricular involvement less commonly. This provides a substrate for ventricular tachycardia from re-entry around the fibrous scar. [22] Reports of ventricular arrhythmia in subjects harboring the genes of arrhythmogenic cardiomyopathy even in the absence of detectable histopathological and MRI changes in the myocardium suggest an additional electrical substrate distinct from simple reentry involving perhaps intracellular signaling process or heterogeneity in conduction. Gap junction remodeling with paucity of gap junctions in the myocardial cells of affected patients may also provide a substrate for arrhythmia. [23]

**Figure 3.** Fibroadipose infiltration of the right ventricle, seen in the inset macroscopically top right, arrowed. Histology shows the adipose and fibrous tissue replacement of the myocyte architecture (hematoxylin & eosin). **Adapted with** **permission from chapter 'Cardiomyopathy' by Sian Hughes from the book 'Cardiac Pathololgy: A Guide to Cur‐ rent Practice' eds' S. Kim Suvarna ISBN: 978-1-4471-2406-1 (Print) 978-1-4471-2407-8 (Online) (Springer).**

#### **3.4. Dilated cardiomyopathy**

Dilated cardiomyopathy is characterized by loss of myocardial cells with interstitial, perivascu‐ lar and replacement fibrosis, which provide an arrhythmogenic substrate (figure 4). [24], [25] Frequently the reentry circuits of these arrhythmias exit on the epicardial aspect of the myocar‐ dium,asdistinctfromischemiccardiomyopathywhereendocardialcircuitsaretherule.[25]This is related to the differences in the pathogenetic mechanism of scar formation in the two groups of patients, patients with ischemic cardiomyopathy having predisposition to endocardial scar duetosubendocardialischemiaandacutecoronaryevents,whilepatientswithdilatedcardiomy‐ opathy having epicardial scar more often than ischemic cardiomyopathy. This also has implica‐ tionsontherapeuticapproachaspatientswithnonischemiccardiomyopathywithVTfrequently require epicardial approach for catheter ablation. [26] Arrhythmic events occurring in patients with idiopathic dilated cardiomyopathy are nonsustained and sustained VT and ventricular fibrillation in addition to isolated ventricular ectopy. [27], [28] Bundle branch reentry VT is relatively commoner form of VT in patients with dilated cardiomyopathy, constituting 6-11% of patients referredfor cathetermappingofmonomorphicVT.[26],[29]Spontaneous sustainedVT is rare in DCM and this diagnosis should raise the suspicion of other types of cardiomyopa‐ thiesthatdocommonlycausescarrelatedventriculararrhythmias,includingsarcoidosis,Chagas disease and left dominant arrhythmogenic cardiomyopathy. Spontaneous sustained VTs are caused by scar-related related reentry or bundle branch reentry. [25], [29] Neurohumoral activation, myocardial stretch secondary to mechanical overload and electrolyte disturbance all can contribute to arrhythmogenesis by a non-reentrant mechanism facilitating focal mecha‐ nisms of arrhythmogenesis like triggered activity and focal automaticity. [28]

#### **3.5. Left Ventricular noncompaction**

Left ventricular noncompaction is a recently recognized form of cardiomyopathy. Also referred to as left ventricular hypertrabeculation, LV myocardium in these patients shows increased trabeculation, unlike normal compact structure of the LV. Imaging with echocar‐ diography or cardiac MRI, showing thick endocardial noncompact layer of myocardium and relatively thin epicardial compact myocardium, usually makes the diagnosis. Apart from heart failure and thromboembolic events, patients with ventricular noncompaction are known to be at an increased risk of sudden cardiac death due to ventricular arrhythmias. Life-threatening ventricular tachycardias are reported in almost one fifth of the patient. The arrhythmogenic substrate is in the form of subdendocardial fibrosis due to microcirculatory dysfunction (figure 5). [30], [31]

developing a conduction system abnormality due to involvement of basal part of the inter‐ ventricular septum and this may result in complete heart block [32], [33] and potentially sudden cardiac death. Ventricular arrhythmia is another mechanism of sudden cardiac death in patients with cardiac sarcoidosis. Resolving inflammation and resulting scarring of the

**Figure 4.** Photomicrographs of the myocardium from a 35-year-old female. (A) Shows evidence of myofibre hypertro‐ phy, interstitial fibrosis (\*) and areas of lymphocytic infiltration (arrows) consistent with resolving myocarditis (H&E). (B) While some myocytes are hypertrophied with enlarged nuclei (black arrow), others are thinned and elongated with nuclei that occupy almost the entire width of the myocyte (white arrow). Some myocytes appear "empty"; likely due to diminished numbers of myofibrils. Areas of interstitial fibrosis (\*) and fat infiltration (F) can also be seen (H&E). (C) Photomicropgraph showing evidence of interstitial fibrosis (\*), subendocardial fibrosis (arrows) and endocardial fi‐ broelastic changes (arrowheads) (H&E). (D) Microphotograph of myocardium showing degenerative changes in the left bundle (dotted line). These changes may appear as a bundle branch block on ECG. Areas of interstitial fibrosis (\*) and lymphocytic infiltration (arrows) are also seen (elastic trichrome stain). **Adapted with permission from Luk et al,**

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Cardiac amyloid infiltration is another disorder associated with increased risk of sudden cardiac death. Amyloid infiltration with perivascular fibrosis and small vessel ischemia [36] is instrumental in pathology of cardiac conduction system and myocardium. These patholog‐ ical changes lead to the electrophysiological abnormalities responsible for sudden cardiac

myocardium provides substrate for reentrant ventricular arrhythmias. [34], [35]

**Dilated cardiomypathy : a review. J Clin Pathol 2009;62:219-225.**

#### **3.6. Other cardiomyopathies**

Sarcoidosis frequently involves the myocardium, causing infiltration and scarring. Although at least 25% of patients with sarcoidosis have cardiac involvement based on autopsy data, only 5% have cardiac symptoms. Patients with sarcoid cardiomyopathy are at an increased risk of

**permission from chapter 'Cardiomyopathy' by Sian Hughes from the book 'Cardiac Pathololgy: A Guide to Cur‐ rent Practice' eds' S. Kim Suvarna ISBN: 978-1-4471-2406-1 (Print) 978-1-4471-2407-8 (Online) (Springer).**

Dilated cardiomyopathy is characterized by loss of myocardial cells with interstitial, perivascu‐ lar and replacement fibrosis, which provide an arrhythmogenic substrate (figure 4). [24], [25] Frequently the reentry circuits of these arrhythmias exit on the epicardial aspect of the myocar‐ dium,asdistinctfromischemiccardiomyopathywhereendocardialcircuitsaretherule.[25]This is related to the differences in the pathogenetic mechanism of scar formation in the two groups of patients, patients with ischemic cardiomyopathy having predisposition to endocardial scar duetosubendocardialischemiaandacutecoronaryevents,whilepatientswithdilatedcardiomy‐ opathy having epicardial scar more often than ischemic cardiomyopathy. This also has implica‐ tionsontherapeuticapproachaspatientswithnonischemiccardiomyopathywithVTfrequently require epicardial approach for catheter ablation. [26] Arrhythmic events occurring in patients with idiopathic dilated cardiomyopathy are nonsustained and sustained VT and ventricular fibrillation in addition to isolated ventricular ectopy. [27], [28] Bundle branch reentry VT is relatively commoner form of VT in patients with dilated cardiomyopathy, constituting 6-11% of patients referredfor cathetermappingofmonomorphicVT.[26],[29]Spontaneous sustainedVT is rare in DCM and this diagnosis should raise the suspicion of other types of cardiomyopa‐ thiesthatdocommonlycausescarrelatedventriculararrhythmias,includingsarcoidosis,Chagas disease and left dominant arrhythmogenic cardiomyopathy. Spontaneous sustained VTs are caused by scar-related related reentry or bundle branch reentry. [25], [29] Neurohumoral activation, myocardial stretch secondary to mechanical overload and electrolyte disturbance all can contribute to arrhythmogenesis by a non-reentrant mechanism facilitating focal mecha‐

nisms of arrhythmogenesis like triggered activity and focal automaticity. [28]

Left ventricular noncompaction is a recently recognized form of cardiomyopathy. Also referred to as left ventricular hypertrabeculation, LV myocardium in these patients shows increased trabeculation, unlike normal compact structure of the LV. Imaging with echocar‐ diography or cardiac MRI, showing thick endocardial noncompact layer of myocardium and relatively thin epicardial compact myocardium, usually makes the diagnosis. Apart from heart failure and thromboembolic events, patients with ventricular noncompaction are known to be at an increased risk of sudden cardiac death due to ventricular arrhythmias. Life-threatening ventricular tachycardias are reported in almost one fifth of the patient. The arrhythmogenic substrate is in the form of subdendocardial fibrosis due to microcirculatory dysfunction (figure

Sarcoidosis frequently involves the myocardium, causing infiltration and scarring. Although at least 25% of patients with sarcoidosis have cardiac involvement based on autopsy data, only 5% have cardiac symptoms. Patients with sarcoid cardiomyopathy are at an increased risk of

**3.4. Dilated cardiomyopathy**

172 Cardiomyopathies

**3.5. Left Ventricular noncompaction**

5). [30], [31]

**3.6. Other cardiomyopathies**

**Figure 4.** Photomicrographs of the myocardium from a 35-year-old female. (A) Shows evidence of myofibre hypertro‐ phy, interstitial fibrosis (\*) and areas of lymphocytic infiltration (arrows) consistent with resolving myocarditis (H&E). (B) While some myocytes are hypertrophied with enlarged nuclei (black arrow), others are thinned and elongated with nuclei that occupy almost the entire width of the myocyte (white arrow). Some myocytes appear "empty"; likely due to diminished numbers of myofibrils. Areas of interstitial fibrosis (\*) and fat infiltration (F) can also be seen (H&E). (C) Photomicropgraph showing evidence of interstitial fibrosis (\*), subendocardial fibrosis (arrows) and endocardial fi‐ broelastic changes (arrowheads) (H&E). (D) Microphotograph of myocardium showing degenerative changes in the left bundle (dotted line). These changes may appear as a bundle branch block on ECG. Areas of interstitial fibrosis (\*) and lymphocytic infiltration (arrows) are also seen (elastic trichrome stain). **Adapted with permission from Luk et al, Dilated cardiomypathy : a review. J Clin Pathol 2009;62:219-225.**

developing a conduction system abnormality due to involvement of basal part of the inter‐ ventricular septum and this may result in complete heart block [32], [33] and potentially sudden cardiac death. Ventricular arrhythmia is another mechanism of sudden cardiac death in patients with cardiac sarcoidosis. Resolving inflammation and resulting scarring of the myocardium provides substrate for reentrant ventricular arrhythmias. [34], [35]

Cardiac amyloid infiltration is another disorder associated with increased risk of sudden cardiac death. Amyloid infiltration with perivascular fibrosis and small vessel ischemia [36] is instrumental in pathology of cardiac conduction system and myocardium. These patholog‐ ical changes lead to the electrophysiological abnormalities responsible for sudden cardiac

limitations in several groups of patients, most notably in those with ICM but also in hyper‐

trophic cardiomyopathy and arrhythmogenic cardiomyopathy. Attempts to identify features

predicting higher risk of sudden cardiac death have helped in management decisions. In this

section we will discuss available knowledge about risk of sudden death and risk stratification

· Prior cardiac arrest

· History of syncope · Genetic factors · NYHA functional class · Prolongation of QRS · QT dynamicity · QRS fragmentation

heart rate recovery, · Baroreflex sensitivity · T-wave alternans

Ischemic cardiomyopathy

coronary syndrome · LV systolic function · NYHA fuctional class · QRS duration

· QT dispersion, · T-wave alternans · Abnormal SAECG

heart rate recovery, · Baroreflex sensitivity

· QT interval prolongation

· Left Ventricular systolic function

· Heart rate variability, heart rate turbulence and

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· Myocardial fibrosis: serum markers, cardiac MRI

· Prior cardiac arrest outside the setting of acute

· Heart rate variability, heart rate turbulence and

**Hypertrophic cardiomyopathy Dilated cardiomyopathy**

in patients with cardiomyopathy.

· Nonsustained VT (≥3consecutive beats at ≥120 bpm) · Failure of systolic BP to rise by ≥20 mm Hg during maximal

**Major risk factors** · Prior cardiac arrest · Spontaneous sustained VT · Family history of 1 or more

· instances of SCD

upright exercise testing · Unexplained syncope

· Microvascular ischemia · Diffuse late gadolinium · enhancement on cardiovascular

· magnetic resonance

· Burnt out disease · High-risk mutation

· Prior cardiac arrest · History of syncope · RV dilatation/dysfunction

· LV involvement · QRS dispersion

· Paced electrogram fractionation

Arrhythmogenic right ventricular cardiomyopathy

**Table 1.** Risk predictors for SCD in cardiomyopathies

· Right precordial QRS prolongation and late potentials on SAECG

· Prior alcohol septal ablation

**Other risk factors** · Resting LV outflow tract

· obstruction

· analysis

· Maximum LV wall thickness ≥30 mm

**Figure 5.** Photomicrographs of myocardium from a patient with LV noncompaction. Panel A shows low-power hema‐ toxylin- and eosin-stained photograph from noncompacted layer shoing 'fingerlike' projections. Panel B has a photo‐ micrograph with Masson's t trichrome stain showing prominent endocardial and subendocardial fibrosis, which is a feature of this disease due to abnormal myocardial microperfusion. **Adapted from chapter 'Cardiomyopathy' by Sian Hughes from the book 'Cardiac Pathololgy: A Guide to Current Practice' eds' S. Kim Suvarna ISBN: 978-1-4471-2406-1 (Print) 978-1-4471-2407-8 (Online) (Springer).**

death due to bradyarrhythmia or ventricular tachyarrhythmia. [37] Frequently the cause of sudden death in these patients is pulseless electrical activity, presumably resulting from the severe diastolic dysfunction associated with amyloidosis. [38]

Inherited muscular dystrophies like Duchenne and Becker muscular dystrophies have skeletal and cardiac muscle involvement and cardiac pathology essentially manifests as dilated cardiomyopathy with associated heart failure and risk of sudden cardiac death. However, muscular dystrophies like Emery-Dreifuss (X-linked and autosomal variants), limb girdle muscular dystrophy type 1B, entity of DCM with conduction system disease (associated with lamin A/C mutations) and myotonic dystrophy are associated with high risk of sudden cardiac death. In these conditions sudden cardiac death was traditionally thought to be primarily due to conduction system disease and bradyarrhythmia. However, after routine implantation of pacemakers, it has been recognized that ventricular arrhythmias also contribute to sudden cardiac death in these patients. These conditions are associated with cardiomyopathy, with LV dysfunction as a late feature in the natural course of disease; sudden cardiac death is an early feature of cardiac involvement. The molecular pathogenesis of cardiac arrhythmias and conduction system disease in these patients is an area of active research. [39]
