Several cardiac problems have been reported in patienst with *liver cirrhosis*, including chro‐ notrope incompetence, cardiomyopathy and prolonged QT intervals, proportional to the Child-Pugh class [46]. A prolonged QT interval represents the most common electrocardio‐ graphic (ECG) finding in patients with liver cirrhosis and is the electrophysiological hallmark of "cirrhotic cardiomyopathy" [47, 48, 49 ]. Cirrhotic cardiomyopathy can appear in all forms of cirrhosis and includes systolic and diastolic dysfunction and electrophysiological abnor‐ malities, in the absence of any known cardiac disease [48]. Cardiac ion channels remodeling has been noticed in patients with liver cirrhosis, with impaired K and Ca channels, due to endotoxins and increased biliary acids, which alter beta-adrenoreceptor, G protein and ionic channels in patients with cholestasis [46].

stroke patients [63]. Atrial fibrillation, the most common arrhythmia in clinical practice, is a major risk factor for embolic stroke [60, 64]. Stroke and *subarachnoid hemorrhage* cause other cerebrogenic ECG findings as well, prolong the QT interval, increase QT dispersion and ventricular arrhythmia risk, mainly due to an autonomic nervous system dysregulation [1, 61, 65, 66 ]. Large, inverted T waves following a prolonged QTc interval, common after subar‐ achnoid hemorrhage, are often termed as "cerebral" or "neurogenic" [67]. Brady- and tachyar‐ rhythmia, including polymorphic ventricular tachycardia (PVT), have been also described in the setting of neurologic injury [68]. The greatest risk of arrhythmias is, probably, within the first 24 h after stroke, with a marked decline in time [69]. Activation of both sympathetic and parasympathetic systems has cumulative effect in the development of arrhythmias and myocardial damage after cerebral incidents, and the damage of the hypothalamic, insular, and brainstem region is crucial for the genesis of cardiac arrhythmias, due to neural connections with other cortical sites and the autonomic nervous system [61]. Sander et al, found increased norepinephrine levels in patients with insular infarction, significantly related to adverse outcome and QTc [70]. The sympathetic system has a major role in the pathogenesis of hypokalemia and may indirectly result in QTc prolongation after subarachnoid hemorrhage [61]. Probably constant catecholamine stimulation of beta-adrenoreceptors linked to mem‐

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itating ventricular arrhythmias [62]. Both reduced heart-rate variability (HRV) and impaired baroreceptor reflex sensitivity (BRS) suggest impaired physiological central and cardiac autonomic reflex function [62]. Ventricular arrhythmogenesis following stroke, related to the cardiac autonomic imbalance is explained by two hypotheses [62]. The first involves damage to central nervous structures controlling the autonomic nervous system, resulting in sympa‐ thetic amplification or parasympathetic inhibition, with subsequent ECG changes, without permanent myocardium damage, and the second hypothesis proposes an augmented sympa‐ thetic discharge, resulting in increased secretion of catecholamine, causing myocytolysis [62]. The insula plays an important role in autonomic nervous function imbalance after stroke [62, 71]. Involvement of the right insula decreases basal sympathetic tone and may result in parasympathetic hyperactivity, and left insular lesions decrease parasympathetic activity and augment cardiac sympathetic tone [71]. Sympathetic hyperactivity prolongs repolarization

A concomitant myocardial ischemia or necrosis, elevated blood pressure and heart failure may be also considered [1]. Autopsy of stroke patients, who developed repolarization abnormalities, revealed no obvious coronary artery atherosclerosis in most of them, and the only findings were petechial subendocardial hemorrhages and focal myofibrillar degenera‐ tion, reproducible with intravenous administration of catecholamines or electrical stimula‐ tion of the vagus nerve in laboratory animals [61]. Sudden calcium influx, mediated by catecholamines, impairs myocardial relaxation, leads to myocytolysis, myofibrillar degener‐ ation, coronary vasoconstriction, myocardial ischemia and ECG changes, and is proarrhyth‐ mic [61, 62]. Elevated serum uric acid, direct neural interventions, inflammation, reactive oxygen species, electrolyte imbalances, the structural and electrophysiological changes of a senescent heart and comorbities can increase sudden cardiac death risk in stroke [61, 66]. Stroke survivors with a prolonged QT in V6, were identified to have an increased sud‐

brane Na+

/K+

duration and increases arrhythmogenesis [62].

QT prolongation in liver pathology was first described in alcoholic liver diseases [50]. Alcohol effects on life-threatening arrhythmias correlate directly with the amount and duration of alcohol intake; even small quantities are significant in susceptible individuals [35]. Further studies reported prolonged QT intervals in patients with *primary biliary cirrhosis* and other *chronic non-alcoholic liver diseases,* related to the severity of the autonomic neuropathy, and could detect patients with increased cardiovascular risk [51]. QT interval prolongation was related to the pathophysiology of cirrhosis itself and not to a specific cause of cirrhosis [52]. Prolonged QTc intervals were related to the presence of portal hypertension, including mild portal hypertension, and liver dysfunction [53]. Genovesi et al. reported significant correla‐ tions between QTc and each of the following: plasma calcium level, portal hypertension, and the hepatic venous pressure gradient [47]. Liver disease severity, alcoholic etiology, and serum uric acid were associated with prolonged QT interval in patients with liver cirrhosis, according to another study [48]. *Liver transplantation* may revert cardiac dysfunction [54] and prolonged QTc returns to normal values, in most of the patients, after liver transplantation, suggesting that liver disease may not be the only factor in the pathogenesis of prolonged QTc [52, 55]. Acute gastrointestinal bleeding was found to further prolong QTc in patients with liver cirrhosis, and QTc prolongation predicted bleeding induced mortality [56].

Concluding, the mechanisms by which liver cirrhosis affects ventricular repolarization are as follows: electrolyte imbalances, impaired autonomic function, subclinical cardiomyopathy, reduced β-adrenoreceptor function, postreceptor pathway defects, altered physical properties of myocyte plasma membrane, elevated levels of cardiotoxins, ion channel remodeling, portosystemic shunting and systemic circulatory disturbances [46-48, 53, 54, 57].

The clinical significance of QT prolongation in liver cirrhosis is unclear, considering that sudden cardiac death and torsades de pointes are rare [58].

QTc interval was also measured in patients with *chronic hepatitis C*, showing non-significant increases six months after starting combination therapy with pegylated interferon and ribavirin, in order to achieve sustained virological response [59].

### **7. Cerebrogenic arrhythmias and ventricular arrhythmia risk in neurologic diseases**

Cardiac diseases are a well-known *stroke* risk factors and complicate stroke outcome [60]. Cardiac arrhythmias and electrocardiographic abnormalities are frequently observed after acute cerebrovascular events, even in the absence of structural heart disease [61]. With improved survival after major cardiovascular events and aging of the population, stroke followed by myocardial infarction and arrhythmias will be an increasing clinical entity in the coming decades [60]. The neurologic event is the main cause of death only in the first week after stroke [62]. After the first year, cardiovascular diseases are the main cause of death in stroke patients [63]. Atrial fibrillation, the most common arrhythmia in clinical practice, is a major risk factor for embolic stroke [60, 64]. Stroke and *subarachnoid hemorrhage* cause other cerebrogenic ECG findings as well, prolong the QT interval, increase QT dispersion and ventricular arrhythmia risk, mainly due to an autonomic nervous system dysregulation [1, 61, 65, 66 ]. Large, inverted T waves following a prolonged QTc interval, common after subar‐ achnoid hemorrhage, are often termed as "cerebral" or "neurogenic" [67]. Brady- and tachyar‐ rhythmia, including polymorphic ventricular tachycardia (PVT), have been also described in the setting of neurologic injury [68]. The greatest risk of arrhythmias is, probably, within the first 24 h after stroke, with a marked decline in time [69]. Activation of both sympathetic and parasympathetic systems has cumulative effect in the development of arrhythmias and myocardial damage after cerebral incidents, and the damage of the hypothalamic, insular, and brainstem region is crucial for the genesis of cardiac arrhythmias, due to neural connections with other cortical sites and the autonomic nervous system [61]. Sander et al, found increased norepinephrine levels in patients with insular infarction, significantly related to adverse outcome and QTc [70]. The sympathetic system has a major role in the pathogenesis of hypokalemia and may indirectly result in QTc prolongation after subarachnoid hemorrhage [61]. Probably constant catecholamine stimulation of beta-adrenoreceptors linked to mem‐ brane Na+ /K+ -ATPases causes a potassium influx, resulting in hypokalemia, and thus precip‐ itating ventricular arrhythmias [62]. Both reduced heart-rate variability (HRV) and impaired baroreceptor reflex sensitivity (BRS) suggest impaired physiological central and cardiac autonomic reflex function [62]. Ventricular arrhythmogenesis following stroke, related to the cardiac autonomic imbalance is explained by two hypotheses [62]. The first involves damage to central nervous structures controlling the autonomic nervous system, resulting in sympa‐ thetic amplification or parasympathetic inhibition, with subsequent ECG changes, without permanent myocardium damage, and the second hypothesis proposes an augmented sympa‐ thetic discharge, resulting in increased secretion of catecholamine, causing myocytolysis [62]. The insula plays an important role in autonomic nervous function imbalance after stroke [62, 71]. Involvement of the right insula decreases basal sympathetic tone and may result in parasympathetic hyperactivity, and left insular lesions decrease parasympathetic activity and augment cardiac sympathetic tone [71]. Sympathetic hyperactivity prolongs repolarization duration and increases arrhythmogenesis [62].

endotoxins and increased biliary acids, which alter beta-adrenoreceptor, G protein and ionic

QT prolongation in liver pathology was first described in alcoholic liver diseases [50]. Alcohol effects on life-threatening arrhythmias correlate directly with the amount and duration of alcohol intake; even small quantities are significant in susceptible individuals [35]. Further studies reported prolonged QT intervals in patients with *primary biliary cirrhosis* and other *chronic non-alcoholic liver diseases,* related to the severity of the autonomic neuropathy, and could detect patients with increased cardiovascular risk [51]. QT interval prolongation was related to the pathophysiology of cirrhosis itself and not to a specific cause of cirrhosis [52]. Prolonged QTc intervals were related to the presence of portal hypertension, including mild portal hypertension, and liver dysfunction [53]. Genovesi et al. reported significant correla‐ tions between QTc and each of the following: plasma calcium level, portal hypertension, and the hepatic venous pressure gradient [47]. Liver disease severity, alcoholic etiology, and serum uric acid were associated with prolonged QT interval in patients with liver cirrhosis, according to another study [48]. *Liver transplantation* may revert cardiac dysfunction [54] and prolonged QTc returns to normal values, in most of the patients, after liver transplantation, suggesting that liver disease may not be the only factor in the pathogenesis of prolonged QTc [52, 55]. Acute gastrointestinal bleeding was found to further prolong QTc in patients with liver

cirrhosis, and QTc prolongation predicted bleeding induced mortality [56].

portosystemic shunting and systemic circulatory disturbances [46-48, 53, 54, 57].

sudden cardiac death and torsades de pointes are rare [58].

**diseases**

ribavirin, in order to achieve sustained virological response [59].

Concluding, the mechanisms by which liver cirrhosis affects ventricular repolarization are as follows: electrolyte imbalances, impaired autonomic function, subclinical cardiomyopathy, reduced β-adrenoreceptor function, postreceptor pathway defects, altered physical properties of myocyte plasma membrane, elevated levels of cardiotoxins, ion channel remodeling,

The clinical significance of QT prolongation in liver cirrhosis is unclear, considering that

QTc interval was also measured in patients with *chronic hepatitis C*, showing non-significant increases six months after starting combination therapy with pegylated interferon and

**7. Cerebrogenic arrhythmias and ventricular arrhythmia risk in neurologic**

Cardiac diseases are a well-known *stroke* risk factors and complicate stroke outcome [60]. Cardiac arrhythmias and electrocardiographic abnormalities are frequently observed after acute cerebrovascular events, even in the absence of structural heart disease [61]. With improved survival after major cardiovascular events and aging of the population, stroke followed by myocardial infarction and arrhythmias will be an increasing clinical entity in the coming decades [60]. The neurologic event is the main cause of death only in the first week after stroke [62]. After the first year, cardiovascular diseases are the main cause of death in

channels in patients with cholestasis [46].

94 Cardiac Arrhythmias - Mechanisms, Pathophysiology, and Treatment

A concomitant myocardial ischemia or necrosis, elevated blood pressure and heart failure may be also considered [1]. Autopsy of stroke patients, who developed repolarization abnormalities, revealed no obvious coronary artery atherosclerosis in most of them, and the only findings were petechial subendocardial hemorrhages and focal myofibrillar degenera‐ tion, reproducible with intravenous administration of catecholamines or electrical stimula‐ tion of the vagus nerve in laboratory animals [61]. Sudden calcium influx, mediated by catecholamines, impairs myocardial relaxation, leads to myocytolysis, myofibrillar degener‐ ation, coronary vasoconstriction, myocardial ischemia and ECG changes, and is proarrhyth‐ mic [61, 62]. Elevated serum uric acid, direct neural interventions, inflammation, reactive oxygen species, electrolyte imbalances, the structural and electrophysiological changes of a senescent heart and comorbities can increase sudden cardiac death risk in stroke [61, 66]. Stroke survivors with a prolonged QT in V6, were identified to have an increased sud‐

den cardiac death risk [72]. Prolonged QT intervals were associated with decreased survival rates and worse neurological outcomes at hospital discharge [73]. The prevalence of cardiac arrhythmias after acute stroke may reach 28%, higher after subarachnoid hemorrhage (37.5%) and in right sided lesions [61].  Independent risk factors for the development of ventricular arrhythmias in patients with aneurysmal subarachnoid hemorrhage were prolonged QTc and decreased heart rate, and therapy with angiotensin converting enzyme inhibitors and angiotensin receptor blockers was protective [74]. Literature data are insufficient to support the hypothesis that subarach‐ noid hemorrhage and stroke cause ventricular arrhythmias, considering that in most patients additional QT prolonging causes were mentioned, including hypokalemia, hypomagnesaemia, and congenital long QT syndrome, and patients with stroke usually have risk factors for coronary artery disease, such as hypertension, diabetes mellitus, and smoking, or advanced age, or left ventricular hypertrophy [61, 62, 75]. Several studies did not control pre-existing arrhythmias, were of short duration and did not explore the longterm consequences of ventricular arrhythmogenesis [62]. Another important limitation of most of the studies is the use of single surface ECG, because it may underestimate arrhythmia incidence in the acute phase of a stroke [62]. Holter monitoring revealed a higher incidence of ventricular arrhythmias after transient ischemic attacks, cerebral infarction and intracerebral hemorrhage compared to patients who were not continuously monitored (56% vs. 8%) [76].

It is uncertain whether ECG abnormalities are caused by the cerebrovascular event itself, considering that in the majority of studies patients' previous ECG data were unavailable [61]. Current management after stroke focuses mostly on the neurological function [62]. The QT interval and electrolyte levels should be monitored, and QT prolonging drugs should be avoided in patients with acute cerebrovascular events, especially for female patients with insular cortex lesions [61]. Multiple studies recommend continuous ECG monitoring, however, others believe that only severely QTc interval prolongation predicts cardiac complications [62]. Follow up studies with large sample sizes, considering previous arrhythmias and coronary heart disease, are needed, to establish the incidence of ventricular arrhythmias after stroke, and clear guidelines for clinicians approaching stroke patients with increased ventricular

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Goldberger et al. reported an unusual case of idiopathic acute *encephalopathy*, with persistent fever, refractory seizure, marked ventricular repolarization with bursts of torsade de pointes,

Two mechanisms connecting cardiomyopathies and neurological diseases have been descri‐ bed: cardiomyopathies may either secondarily cause neurological disease or may represent the cardiac manifestation of a neurological disease, especially neuromuscular disorders [2]. Sudden cardiac death and ventricular arrhythmias occur mainly in neurological diseases causing hypertrophic cardiomyopathy (in adolescents and young adults), or dilated cardio‐ myopathy (among which syncope is a common clinical manifestation), or arrhythmogenic right ventricular dysplasia [2]. Takotsubo cardiomyopathy ("the broken heart" syndrome) was reported after stroke, subarachnoid bleeding, spontaneous intracerebral bleeding, *spinal injury and head trauma*, and the patients are prone to arrhythmias, heart failure or thrombus formation within the left ventricle during the acute phase [2]. *Inherited neuromuscular disorders* may predispose to premature ventricular contractions, monomorphic and polymorphic ventricular tachycardia and sudden cardiac death, due to degenerative changes in the myocardium [35]. Electrical abnormalities, including QTc and JTc dispersion (the difference between the longest and shortest JT interval duration), may be the earliest manifestation of cardiomyopathy in patients with *Emery-Dreifuss muscular dystrophy*, a hereditary muscle disorder characterized by slowly progressive muscle wasting and weakness, with humero-peroneal distribution [84]. QTc and JTc dispersions (QTcd, JTcd) reflect ventricular repolarization heterogeneities, due to diffuse fibrosis and fatty acid infiltration in Emery-Dreifuss muscular dystrophy, and if elevated, increase the risk of development of malignant ventricular arrhythmias via early afterdepolarization and reentry (polymorphic ventricular tachyarrhythmia), facilitated by intramural functional conduction blocks [84]. The mechanisms underlying sudden cardiac death in *myotonic dystrophy type 1* are: bradyarrhythmias due to cardiac conduction abnormal‐ ities, and the increased values of the QT variability index, demonstrating an important heart involvement, extended beyond the conduction system [85]. *Duchenne muscular dystrophy*, related to a mutation in the dystrophin gene, the most common neuromuscular disease, causes progressive proximal muscle weakness of the legs and pelvis and a loss of muscle mass. It affects also the heart (myocyte degeneration, fibrosis and fatty infiltration), impairing ventric‐ ular repolarization, causing autonomic dysfunction, QTc prolongation and increase of QT

diffuse ST elevations and Brugada-like pattern, treated with propofol [68].

arrhythmia risk [62].

It is also possible that in some cases, prolonged QTc actually existed before the development of stroke and it could be used as a *predictor of future stroke* in the general population [75]. The association of QTc with cardiovascular risk factors does not fully explain the prognostic significance of QTc as a stroke predictor, but it is possible, that prolonged QTc interval is a marker of silent undetected atherosclerotic vascular disease [75]. QTc was previously associ‐ ated with markers of subclinical atherosclerosis, including carotid intima media thickness, arterial stiffness and endothelial dysfunction [77-80]. Probably, QTc prolongation may be a surrogate indicator of subclinical atherosclerosis and subsequently can be predictive of future atherosclerotic vascular events such as stroke, but it is not clear if it represents a marker, a limited adaptive or pathological process [75].

The ECG abnormalities observed in *intracranial hemorrhage* may also influence clinical outcome. QTc prolongation correlated with insular cortex involvement, presence of intraventricular blood, and hydrocephalus on admission CT scans in patients with intracranial hemorrhage [81]. A case of a 58-year-old woman, with several episodes of self-terminating torsade de pointes (TdP) following nonspecific ST-T changes, and prolonged QT after brainstem hemor‐ rhage, has been reported in the literature [82]. Maramattom et al. found premature ventricular contractions and QTc prolongation at 24 hours from admission, not related with the location, volume and side of the hemorrhage, nor with the presence of hydrocephalus, extraparenchy‐ mal extension or troponin T elevation [83].

It is uncertain whether ECG abnormalities are caused by the cerebrovascular event itself, considering that in the majority of studies patients' previous ECG data were unavailable [61]. Current management after stroke focuses mostly on the neurological function [62]. The QT interval and electrolyte levels should be monitored, and QT prolonging drugs should be avoided in patients with acute cerebrovascular events, especially for female patients with insular cortex lesions [61]. Multiple studies recommend continuous ECG monitoring, however, others believe that only severely QTc interval prolongation predicts cardiac complications [62]. Follow up studies with large sample sizes, considering previous arrhythmias and coronary heart disease, are needed, to establish the incidence of ventricular arrhythmias after stroke, and clear guidelines for clinicians approaching stroke patients with increased ventricular arrhythmia risk [62].

den cardiac death risk [72]. Prolonged QT intervals were associated with decreased survival rates and worse neurological outcomes at hospital discharge [73]. The prevalence of cardiac arrhythmias after acute stroke may reach 28%, higher after subarachnoid hemorrhage (37.5%) and in right sided lesions [61].  Independent risk factors for the development of ventricular arrhythmias in patients with aneurysmal subarachnoid hemorrhage were prolonged QTc and decreased heart rate, and therapy with angiotensin converting enzyme inhibitors and angiotensin receptor blockers was protective [74]. Literature data are insufficient to support the hypothesis that subarach‐ noid hemorrhage and stroke cause ventricular arrhythmias, considering that in most patients additional QT prolonging causes were mentioned, including hypokalemia, hypomagnesaemia, and congenital long QT syndrome, and patients with stroke usually have risk factors for coronary artery disease, such as hypertension, diabetes mellitus, and smoking, or advanced age, or left ventricular hypertrophy [61, 62, 75]. Several studies did not control pre-existing arrhythmias, were of short duration and did not explore the longterm consequences of ventricular arrhythmogenesis [62]. Another important limitation of most of the studies is the use of single surface ECG, because it may underestimate arrhythmia incidence in the acute phase of a stroke [62]. Holter monitoring revealed a higher incidence of ventricular arrhythmias after transient ischemic attacks, cerebral infarction and intracerebral hemorrhage compared to patients who were not continuously monitored (56%

96 Cardiac Arrhythmias - Mechanisms, Pathophysiology, and Treatment

It is also possible that in some cases, prolonged QTc actually existed before the development of stroke and it could be used as a *predictor of future stroke* in the general population [75]. The association of QTc with cardiovascular risk factors does not fully explain the prognostic significance of QTc as a stroke predictor, but it is possible, that prolonged QTc interval is a marker of silent undetected atherosclerotic vascular disease [75]. QTc was previously associ‐ ated with markers of subclinical atherosclerosis, including carotid intima media thickness, arterial stiffness and endothelial dysfunction [77-80]. Probably, QTc prolongation may be a surrogate indicator of subclinical atherosclerosis and subsequently can be predictive of future atherosclerotic vascular events such as stroke, but it is not clear if it represents a marker, a

The ECG abnormalities observed in *intracranial hemorrhage* may also influence clinical outcome. QTc prolongation correlated with insular cortex involvement, presence of intraventricular blood, and hydrocephalus on admission CT scans in patients with intracranial hemorrhage [81]. A case of a 58-year-old woman, with several episodes of self-terminating torsade de pointes (TdP) following nonspecific ST-T changes, and prolonged QT after brainstem hemor‐ rhage, has been reported in the literature [82]. Maramattom et al. found premature ventricular contractions and QTc prolongation at 24 hours from admission, not related with the location, volume and side of the hemorrhage, nor with the presence of hydrocephalus, extraparenchy‐

vs. 8%) [76].

limited adaptive or pathological process [75].

mal extension or troponin T elevation [83].

Goldberger et al. reported an unusual case of idiopathic acute *encephalopathy*, with persistent fever, refractory seizure, marked ventricular repolarization with bursts of torsade de pointes, diffuse ST elevations and Brugada-like pattern, treated with propofol [68].

Two mechanisms connecting cardiomyopathies and neurological diseases have been descri‐ bed: cardiomyopathies may either secondarily cause neurological disease or may represent the cardiac manifestation of a neurological disease, especially neuromuscular disorders [2]. Sudden cardiac death and ventricular arrhythmias occur mainly in neurological diseases causing hypertrophic cardiomyopathy (in adolescents and young adults), or dilated cardio‐ myopathy (among which syncope is a common clinical manifestation), or arrhythmogenic right ventricular dysplasia [2]. Takotsubo cardiomyopathy ("the broken heart" syndrome) was reported after stroke, subarachnoid bleeding, spontaneous intracerebral bleeding, *spinal injury and head trauma*, and the patients are prone to arrhythmias, heart failure or thrombus formation within the left ventricle during the acute phase [2]. *Inherited neuromuscular disorders* may predispose to premature ventricular contractions, monomorphic and polymorphic ventricular tachycardia and sudden cardiac death, due to degenerative changes in the myocardium [35]. Electrical abnormalities, including QTc and JTc dispersion (the difference between the longest and shortest JT interval duration), may be the earliest manifestation of cardiomyopathy in patients with *Emery-Dreifuss muscular dystrophy*, a hereditary muscle disorder characterized by slowly progressive muscle wasting and weakness, with humero-peroneal distribution [84]. QTc and JTc dispersions (QTcd, JTcd) reflect ventricular repolarization heterogeneities, due to diffuse fibrosis and fatty acid infiltration in Emery-Dreifuss muscular dystrophy, and if elevated, increase the risk of development of malignant ventricular arrhythmias via early afterdepolarization and reentry (polymorphic ventricular tachyarrhythmia), facilitated by intramural functional conduction blocks [84]. The mechanisms underlying sudden cardiac death in *myotonic dystrophy type 1* are: bradyarrhythmias due to cardiac conduction abnormal‐ ities, and the increased values of the QT variability index, demonstrating an important heart involvement, extended beyond the conduction system [85]. *Duchenne muscular dystrophy*, related to a mutation in the dystrophin gene, the most common neuromuscular disease, causes progressive proximal muscle weakness of the legs and pelvis and a loss of muscle mass. It affects also the heart (myocyte degeneration, fibrosis and fatty infiltration), impairing ventric‐ ular repolarization, causing autonomic dysfunction, QTc prolongation and increase of QT dispersion, as an independent risk factor for ventricular arrhythmias of Lown grade III or higher [86-88]. Late ventricular potentials were reported in patients with Duchenne muscular dystrophy (31%), indicating the presence of a substrate for reentry ventricular arrhythmias, associated with local myocardial fibrosis, and identifying patients at high risk for sudden cardiac death [89]. Cardiac involvement was also mentioned in other dystrophinopathies, due to the replacement of myocardium by connective tissue or fat, but it remains subclinical in Duchenne and *Becker muscular dystrophy* [86]. Patients with primary and secondary neuro‐ muscular disorders need to be obligatorily screened for cardiac disease and ventricular arrhythmia risk, as soon as the neurological diagnosis is established, and cardiac investigations should be regularly repeated, especially in the case of severe cardiac involvement [2]. Once cardiac involvement occurs, the clinician should consider invasive electrophysiological studies and ICD implantation [35].

abnormalities [98]. Rejdak et al. reported abnormal SAECGs and late ventricular potentials in epilepsy patients, associated with disease duration, higher monthly seizure frequency, refractory epilepsy and tendency for higher number of generalized tonic-clonic seizures, polytherapy [99]. Data about intercritical QT intervals in epileptic patients are contradictory; it was found within normal limits, shorter or longer, and antiepileptic drugs and the ketogenic diet are potential confounders [96]. Transient dysfunction of cortical networks, as interictal epileptiform electroencephalographic discharges, can impair cardiac repolarization causing transient QTc prolongation [100]. Potential mechanisms of periictal QTc prolongation include cerebral dysregulation, ictal hypoxemia and hypercapnia, cardiorespiratory interactions, sympathetic stimulation, release of stress hormones and cardiac dysfunction [96, 101]. Generalized tonic-clonic seizures are a risk factor for sudden cardiac death, and cause QTc shortening due probably to seizure-related release of catecholamines, hyperkalemia, and acidosis [96]. The increased QT dispersion is explained by autonomic dysfunction with increased sympathetic tone, and subtle perivascular and interstitial fibrosis, which have been

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In order to reduce the risk of, or prevent, sudden cardiac death, 12-lead ECG should be performed in every patient with epilepsy, in order to identify those at high risk, and, therapy may include antiarrhythmic medication and implantation of cardiac combined pacemaker– defibrillator devices [96]. Cardiogenic syncope is often a difficult differential diagnosis for seizures, and long QT with recurrent syncope has been mistaken for epilepsy, and, epileptic seizures, probably due to cerebral hypoperfusion, have been described in patients with congenital long QT [96, 104]. Mutations of ionic channels could affect both heart and brain

function, thereby leading to a susceptibility to epilepsy and cardiac arrhythmias [96].

Anemia and red blood cells transfusions have been associated with arrhythmias. Several electrocardiographic changes were previously mentioned in patients with *anemia*, including prolonged QT intervals, ST segment depression, inverted T waves, increased R amplitude after stress test [105]. Anemia was associated with prolonged QT intervals in hypertensive [106] and end stage renal disease patients [107], as well. Associations between the QT interval and serum ferritin level [108] and anisocytosis [106], respectively, were mentioned. Scheller et al. [109] reported a gradual prolongation of the QT and QTc interval in normovolemic anemia. Anemia may increase cardiac output and heart rate, may lead to eccentric left ventricular hypertrophy, activation of the sympathetic nervous system, stimulation of the renin angiotensin aldosterone system, and is closely associated with chronic inflammation and increased oxidative stress [106, 110]. Tissue hypoxia and changes in blood flow patterns due to low hemoglobin may play an atherogenic role [110]. The pathophysiological link between anemia and prolonged QT intervals and ventricular arrhythmia risk is, probably, hypoxia and decreased myocardial

Jaja et al [111] reported a blunted autonomic cardiovascular response to changes in posture in patients with *sickle cell anemia*. Left ventricular systolic and diastolic dysfunction, increased

**8. Hematologic diseases and ventricular arrhythmia risk**

described in epilepsy [102, 103].

oxygen supply [106].

In *Parkinson's disease* factors affecting cardiac conduction may include intrinsic or iatrogenic autonomic disturbances, cardiovascular comorbidities (cardiac ischemia, ventricular hyper‐ trophy), and electrolyte imbalances due to diuretics [90]. The most common prescribed drugs with QT prolonging effect were: Dromperidone, with antiemetic effect and also used to treat symptomatic postural hypotension, Citalopram, an antidepressant, and some antimicrobial agents (macrolides, azoles and fluoroquinolones) in a study conducted by Malek et al. [90]. Combining such drugs with some antipsychotics, tricyclic antidepressants, antihistamines and anti-retrovirals has additive influence on QT interval prolongation [90]. Large epidemiological studies emphasized the difficulties in detecting transient drug-induced ventricular arrhythmia in outpatient clinics, due to too few events, despite frequent syncope [91]. Oka et al considered that QTc intervals are closely related to autonomic nervous system dysfunction in patients with Parkinson's disease, related to the progression of the disease [92, 93]. Deguchi et al. found prolonged QTc intervals in patients with Parkinson's disease, reflecting the degeneration of cardioselective sympathetic and parasympathetic neurons [94]. Artifacts related to muscle tremor may affect ECGs in patients with Parkinson's disease, but methods were found to reduce noise and variance of QTc [95]. Drugs known to prolong the QT interval are often prescribed in patients with Parkinson's disease, and therapy should consider additional risk factors, especially comorbidities, autonomic dysfunction and degeneration of cardioselective neurons [90, 94].

Sudden unexpected death in *epilepsy* is probably caused by periictal cardiorespiratory alterations, such as central apnea, bradyarrhythmia, and neurogenic pulmonary edema, and ventricular arrhythmias [96, 97]. Sudden cardiac death in patients with seizure disorders is facilitated by associated cardiovascular diseases, pathologic cardiac repolarization, sympa‐ thovagal imbalance and therapy used to treat the disease [35, 96, 97]. A pathologic cardiac repolarization has been described in epileptic patients, with prolonged intercritical and periictal QT intervals, increased QT dispersion and shortened QTc after generalized tonicclonic seizures, but fatal seizure-related ventricular arrhythmias are very rare [96]. On the other hand, no LVPs and significant standard ECG abnormalities were recorded in patients with newly diagnosed epilepsy, without clinical evidence of heart disease, three to nine months after therapy start, demonstrating lack of antiepileptic drugs induced electrocardiographic abnormalities [98]. Rejdak et al. reported abnormal SAECGs and late ventricular potentials in epilepsy patients, associated with disease duration, higher monthly seizure frequency, refractory epilepsy and tendency for higher number of generalized tonic-clonic seizures, polytherapy [99]. Data about intercritical QT intervals in epileptic patients are contradictory; it was found within normal limits, shorter or longer, and antiepileptic drugs and the ketogenic diet are potential confounders [96]. Transient dysfunction of cortical networks, as interictal epileptiform electroencephalographic discharges, can impair cardiac repolarization causing transient QTc prolongation [100]. Potential mechanisms of periictal QTc prolongation include cerebral dysregulation, ictal hypoxemia and hypercapnia, cardiorespiratory interactions, sympathetic stimulation, release of stress hormones and cardiac dysfunction [96, 101]. Generalized tonic-clonic seizures are a risk factor for sudden cardiac death, and cause QTc shortening due probably to seizure-related release of catecholamines, hyperkalemia, and acidosis [96]. The increased QT dispersion is explained by autonomic dysfunction with increased sympathetic tone, and subtle perivascular and interstitial fibrosis, which have been described in epilepsy [102, 103].

dispersion, as an independent risk factor for ventricular arrhythmias of Lown grade III or higher [86-88]. Late ventricular potentials were reported in patients with Duchenne muscular dystrophy (31%), indicating the presence of a substrate for reentry ventricular arrhythmias, associated with local myocardial fibrosis, and identifying patients at high risk for sudden cardiac death [89]. Cardiac involvement was also mentioned in other dystrophinopathies, due to the replacement of myocardium by connective tissue or fat, but it remains subclinical in Duchenne and *Becker muscular dystrophy* [86]. Patients with primary and secondary neuro‐ muscular disorders need to be obligatorily screened for cardiac disease and ventricular arrhythmia risk, as soon as the neurological diagnosis is established, and cardiac investigations should be regularly repeated, especially in the case of severe cardiac involvement [2]. Once cardiac involvement occurs, the clinician should consider invasive electrophysiological studies

In *Parkinson's disease* factors affecting cardiac conduction may include intrinsic or iatrogenic autonomic disturbances, cardiovascular comorbidities (cardiac ischemia, ventricular hyper‐ trophy), and electrolyte imbalances due to diuretics [90]. The most common prescribed drugs with QT prolonging effect were: Dromperidone, with antiemetic effect and also used to treat symptomatic postural hypotension, Citalopram, an antidepressant, and some antimicrobial agents (macrolides, azoles and fluoroquinolones) in a study conducted by Malek et al. [90]. Combining such drugs with some antipsychotics, tricyclic antidepressants, antihistamines and anti-retrovirals has additive influence on QT interval prolongation [90]. Large epidemiological studies emphasized the difficulties in detecting transient drug-induced ventricular arrhythmia in outpatient clinics, due to too few events, despite frequent syncope [91]. Oka et al considered that QTc intervals are closely related to autonomic nervous system dysfunction in patients with Parkinson's disease, related to the progression of the disease [92, 93]. Deguchi et al. found prolonged QTc intervals in patients with Parkinson's disease, reflecting the degeneration of cardioselective sympathetic and parasympathetic neurons [94]. Artifacts related to muscle tremor may affect ECGs in patients with Parkinson's disease, but methods were found to reduce noise and variance of QTc [95]. Drugs known to prolong the QT interval are often prescribed in patients with Parkinson's disease, and therapy should consider additional risk factors, especially comorbidities, autonomic dysfunction and degeneration of cardioselective

Sudden unexpected death in *epilepsy* is probably caused by periictal cardiorespiratory alterations, such as central apnea, bradyarrhythmia, and neurogenic pulmonary edema, and ventricular arrhythmias [96, 97]. Sudden cardiac death in patients with seizure disorders is facilitated by associated cardiovascular diseases, pathologic cardiac repolarization, sympa‐ thovagal imbalance and therapy used to treat the disease [35, 96, 97]. A pathologic cardiac repolarization has been described in epileptic patients, with prolonged intercritical and periictal QT intervals, increased QT dispersion and shortened QTc after generalized tonicclonic seizures, but fatal seizure-related ventricular arrhythmias are very rare [96]. On the other hand, no LVPs and significant standard ECG abnormalities were recorded in patients with newly diagnosed epilepsy, without clinical evidence of heart disease, three to nine months after therapy start, demonstrating lack of antiepileptic drugs induced electrocardiographic

and ICD implantation [35].

98 Cardiac Arrhythmias - Mechanisms, Pathophysiology, and Treatment

neurons [90, 94].

In order to reduce the risk of, or prevent, sudden cardiac death, 12-lead ECG should be performed in every patient with epilepsy, in order to identify those at high risk, and, therapy may include antiarrhythmic medication and implantation of cardiac combined pacemaker– defibrillator devices [96]. Cardiogenic syncope is often a difficult differential diagnosis for seizures, and long QT with recurrent syncope has been mistaken for epilepsy, and, epileptic seizures, probably due to cerebral hypoperfusion, have been described in patients with congenital long QT [96, 104]. Mutations of ionic channels could affect both heart and brain function, thereby leading to a susceptibility to epilepsy and cardiac arrhythmias [96].

#### **8. Hematologic diseases and ventricular arrhythmia risk**

Anemia and red blood cells transfusions have been associated with arrhythmias. Several electrocardiographic changes were previously mentioned in patients with *anemia*, including prolonged QT intervals, ST segment depression, inverted T waves, increased R amplitude after stress test [105]. Anemia was associated with prolonged QT intervals in hypertensive [106] and end stage renal disease patients [107], as well. Associations between the QT interval and serum ferritin level [108] and anisocytosis [106], respectively, were mentioned. Scheller et al. [109] reported a gradual prolongation of the QT and QTc interval in normovolemic anemia. Anemia may increase cardiac output and heart rate, may lead to eccentric left ventricular hypertrophy, activation of the sympathetic nervous system, stimulation of the renin angiotensin aldosterone system, and is closely associated with chronic inflammation and increased oxidative stress [106, 110]. Tissue hypoxia and changes in blood flow patterns due to low hemoglobin may play an atherogenic role [110]. The pathophysiological link between anemia and prolonged QT intervals and ventricular arrhythmia risk is, probably, hypoxia and decreased myocardial oxygen supply [106].

Jaja et al [111] reported a blunted autonomic cardiovascular response to changes in posture in patients with *sickle cell anemia*. Left ventricular systolic and diastolic dysfunction, increased QTc intervals and QT dispersions and late ventricular potentials were found in patients with *beta-thalassemia*, a genetic cause of anemia, due to reduced synthesis of beta-globin chains [112, 113]. Several mechanisms explain increased sudden cardiac death in patients with thalassemia, including iron overload thalassemic cardiomyopathy, with patchy cardiac iron depostition (due to intensive blood transfusions), changes in calcium homeostasis, elevated prostaglandin E2 to prostacyclin ratio, increased interleukin 1 level and lipid peroxidation [106, 113, 114].

Selected patients could benefit from electrocardiographic monitoring, specific therapy and avoidance of QT prolonging drugs, decreasing the burden of sudden cardiac death. Large follow up studies are needed, controlling for previous QT interval durations, arrhythmias, coronary heart disease and cardiovascular risk factors, in order to assess the prevalence of ventricular arrhythmias in noncardiac diseases, to identify further mechanisms and risk factors for arrhythmogenesis, and to elaborate clear guidelines for clinicians approaching the men‐

Ventricular Arrhythmia Risk in Noncardiac Diseases

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101

"Victor Babes" University of Medicine and Pharmacy, Department of Functional Sciences,

[1] Pollack ML. ECG Manifestations of Selected Extracardiac Diseases. Emerg MedClin.

[2] Finsterer J, Stöllberger C, Wahbi K. Cardiomyopathy in neurological disorders. Car‐ diovascular Pathology 2013; http://dx.doi.org/10.1016/j.carpath.2012.12.008

[3] Tereshchenko LG. Electrocardiogram as a screening tool in the general population: A strategic review. J Electrocardiol. 2013;doi:10.1016/j.jelectrocard.2013.07.005

[4] Rautaharju PM, Surawicz B, Gettes LS, et al. AHA/ACC/HRS recommendations for the standardization and interpretation of the electrocardiogram. Part IV: The ST seg‐ ment, T and U waves, and the QT interval: A scientific statement from the American Heart association Electrocardiography and Arrhythmias Committee, Council on Clinical Cardiology; the American College of Cardiology Foundation; and the Heart Rhythm Society; Endorsed by the International Society for Computerized Electro‐

[5] Mozoş I, Şerban C and Mihăescu R. Late Ventricular Potentials in Cardiac and Ex‐ tracardiac Diseases. In: Breijo- Marquez FR (ed). Cardiac Arrhythmias - New Consid‐ erations. Rjeka:InTech; 2012, p227-256. Available from: http://www.intechopen.com/ books/cardiac-arrhythmias-new-considerations/late-ventricular-potentials-in-car‐

diac-and-extracardiac-diseases (accessed 15 September, 2013).

tioned pathology.

**Author details**

Timisoara, Romania

2006;24:133-143.

**References**

Address all correspondence to<EMAIL_ADDRESS>
cardiology. Circulation 2009;119:e241-e250.

Ioana Mozos\*

Athar et al. reported that packed red blood cells (PRBC) *transfusions* were independently associated with an increased risk of new onset cardiac arrhythmias and conduction abnor‐ malities in patients with acute myocardial infarction [64]. Multiple factors contributed to the development of atrial fibrillation in the setting of acute myocardial infarction, including pericarditis, atrial ischemia, infarction, changes in autonomic tone, metabolic abnormalities, increased atrial pressures and inflammation [64]. The inflammatory process, exacerbated by PRBC transfusion, tissue hypoxia, exacerbations of cardiac ischemia and reinfarctions result‐ ing from deficiencies in the ability of stored packed red blood cells to deliver oxygen to tissue, may explain the appearance of ventricular arrhythmias [64].

A significant correlation was found between QT dispersion and *platelet count* in healthy centenarians, hypothesizing that a reduced number of platelets and the maintenance of normal QT dispersion may contribute to the extreme longevity and protects centenarians from cardiovascular events [115].

Anthracyclines, used in therapy of patients with *hematological malignancies*, may have cardio‐ toxic effects, and the typical cardiac manifestations include cardiomyopathy, QT prolongation, ventricular ectopy and torsade de pointes [35, 116]. High intermittent doses and excessive cumulative doses increase the risk of cardiomyopathy and fatal arrhythmias, risk factors including age, female gender, hypertension, preexisting cardiac diseases, electrolyte imbalan‐ ces, associated therapy with other QT prolonging drugs [35, 117]. Long term cardiac monitor‐ ing of patients is needed, in order to prevent sudden cardiac death and cardiac decompensation.

#### **9. Conclusions**

Sudden cardiac death, due to fatal ventricular arrhythmias, continues to be an important public health problem in developed countries. A high ventricular arrhythmia risk has been reported in several noncardiac diseases, including metabolic, liver, blood, neurological and psychiatric disorders. The most common mechanisms were: autonomic and electrolyte imbalances, ion channel remodeling, cardiomyopathies, increased oxidative stress and QT prolonging drugs. Most of the mentioned studies used standard 12-lead ECG and surrogate markers of ventric‐ ular arrhythmia risk (QT interval duration, QT dispersion and signal averaged ECG), but several papers reported ventricular arrhythmias, as well.

Considering that there are no guidelines for the prevention and therapy of arrhythmias appearing in most of extracardiac disorders, the present review highlighted important epidemiological and pathophysiological issues related to this topic.

Selected patients could benefit from electrocardiographic monitoring, specific therapy and avoidance of QT prolonging drugs, decreasing the burden of sudden cardiac death. Large follow up studies are needed, controlling for previous QT interval durations, arrhythmias, coronary heart disease and cardiovascular risk factors, in order to assess the prevalence of ventricular arrhythmias in noncardiac diseases, to identify further mechanisms and risk factors for arrhythmogenesis, and to elaborate clear guidelines for clinicians approaching the men‐ tioned pathology.

#### **Author details**

Ioana Mozos\*

QTc intervals and QT dispersions and late ventricular potentials were found in patients with *beta-thalassemia*, a genetic cause of anemia, due to reduced synthesis of beta-globin chains [112, 113]. Several mechanisms explain increased sudden cardiac death in patients with thalassemia, including iron overload thalassemic cardiomyopathy, with patchy cardiac iron depostition (due to intensive blood transfusions), changes in calcium homeostasis, elevated prostaglandin E2 to prostacyclin ratio, increased interleukin 1 level and lipid peroxidation [106, 113, 114]. Athar et al. reported that packed red blood cells (PRBC) *transfusions* were independently associated with an increased risk of new onset cardiac arrhythmias and conduction abnor‐ malities in patients with acute myocardial infarction [64]. Multiple factors contributed to the development of atrial fibrillation in the setting of acute myocardial infarction, including pericarditis, atrial ischemia, infarction, changes in autonomic tone, metabolic abnormalities, increased atrial pressures and inflammation [64]. The inflammatory process, exacerbated by PRBC transfusion, tissue hypoxia, exacerbations of cardiac ischemia and reinfarctions result‐ ing from deficiencies in the ability of stored packed red blood cells to deliver oxygen to tissue,

A significant correlation was found between QT dispersion and *platelet count* in healthy centenarians, hypothesizing that a reduced number of platelets and the maintenance of normal QT dispersion may contribute to the extreme longevity and protects centenarians from

Anthracyclines, used in therapy of patients with *hematological malignancies*, may have cardio‐ toxic effects, and the typical cardiac manifestations include cardiomyopathy, QT prolongation, ventricular ectopy and torsade de pointes [35, 116]. High intermittent doses and excessive cumulative doses increase the risk of cardiomyopathy and fatal arrhythmias, risk factors including age, female gender, hypertension, preexisting cardiac diseases, electrolyte imbalan‐ ces, associated therapy with other QT prolonging drugs [35, 117]. Long term cardiac monitor‐ ing of patients is needed, in order to prevent sudden cardiac death and cardiac

Sudden cardiac death, due to fatal ventricular arrhythmias, continues to be an important public health problem in developed countries. A high ventricular arrhythmia risk has been reported in several noncardiac diseases, including metabolic, liver, blood, neurological and psychiatric disorders. The most common mechanisms were: autonomic and electrolyte imbalances, ion channel remodeling, cardiomyopathies, increased oxidative stress and QT prolonging drugs. Most of the mentioned studies used standard 12-lead ECG and surrogate markers of ventric‐ ular arrhythmia risk (QT interval duration, QT dispersion and signal averaged ECG), but

Considering that there are no guidelines for the prevention and therapy of arrhythmias appearing in most of extracardiac disorders, the present review highlighted important

may explain the appearance of ventricular arrhythmias [64].

100 Cardiac Arrhythmias - Mechanisms, Pathophysiology, and Treatment

several papers reported ventricular arrhythmias, as well.

epidemiological and pathophysiological issues related to this topic.

cardiovascular events [115].

decompensation.

**9. Conclusions**

Address all correspondence to<EMAIL_ADDRESS>
"Victor Babes" University of Medicine and Pharmacy, Department of Functional Sciences, Timisoara, Romania

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**Chapter 5**

**Treatment of Ventricular Arrhythmias**

The presence of 3 or more consecutive ventricular premature complexes (VPCs) on an elec‐ trocardiogram is ventricular tachycardia (VT) [1, 2]. VT is sustained if it lasts ≥30 seconds and nonsustained if its lasts <30 seconds [2]. Complex ventricular arrhythmias (VA) are VT or paired, multiform, or frequent VPCs. This author diagnoses frequent VPCs if there are an average of ≥30/hour on a 24-hour ambulatory electrocardiogram (AECG) or ≥6/minute on a 1-minute rhythm strip of an electrocardiogram (ECG) [2, 3]. Simple VA are infrequent VPCs

The prevalence of nonsustained VT diagnosed by 24-hour AECGs varied from 2% to 13% in older persons without cardiovascular disease [1, 4-7], was 9% in 385 older men and 8% in 806 older women with hypertension, valvular disease, or cardiomyopathy [7], and was 16% in 395 older men and 15% in 771 older women with coronary artery disease (CAD) [7]. The prevalence of complex VA in older persons in these studies varied from 16% to 50% in older persons without cardiovascular disease [1, 4-7], was 54% in older men and 55% in older women with hypertension, valvular disease, or cardiomyopathy [7], and was 69% in older

In 104 older persons without cardiovascular disease, complex VA were present on 24-hour AECGs in 33% of persons and on 1-minute rhythm strips in 2% of persons [3]. In 843 older persons, with cardiovascular disease, complex VA were present on 24-hour AECGs in 55%

In persons with cardiovascular disease, those with an abnormal left ventricular (LV) ejection fraction [8], with echocardiographic LV hypertrophy [9], or with silent myocardial ischemia [10] have a higher prevalence of VT and of complex VA than those with normal LV ejection

> © 2014 Aronow; licensee InTech. This is a paper distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Additional information is available at the end of the chapter

Wilbert S. Aronow

**1. Introduction**

and no complex forms.

men and 68% in older women with CAD [7].

of persons and on 1-minute rhythm strips in 4% of persons [3].

fraction, normal LV mass, and no myocardial ischemia.

http://dx.doi.org/10.5772/57545

## **Treatment of Ventricular Arrhythmias**

Wilbert S. Aronow

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/57545

#### **1. Introduction**

The presence of 3 or more consecutive ventricular premature complexes (VPCs) on an elec‐ trocardiogram is ventricular tachycardia (VT) [1, 2]. VT is sustained if it lasts ≥30 seconds and nonsustained if its lasts <30 seconds [2]. Complex ventricular arrhythmias (VA) are VT or paired, multiform, or frequent VPCs. This author diagnoses frequent VPCs if there are an average of ≥30/hour on a 24-hour ambulatory electrocardiogram (AECG) or ≥6/minute on a 1-minute rhythm strip of an electrocardiogram (ECG) [2, 3]. Simple VA are infrequent VPCs and no complex forms.

The prevalence of nonsustained VT diagnosed by 24-hour AECGs varied from 2% to 13% in older persons without cardiovascular disease [1, 4-7], was 9% in 385 older men and 8% in 806 older women with hypertension, valvular disease, or cardiomyopathy [7], and was 16% in 395 older men and 15% in 771 older women with coronary artery disease (CAD) [7]. The prevalence of complex VA in older persons in these studies varied from 16% to 50% in older persons without cardiovascular disease [1, 4-7], was 54% in older men and 55% in older women with hypertension, valvular disease, or cardiomyopathy [7], and was 69% in older men and 68% in older women with CAD [7].

In 104 older persons without cardiovascular disease, complex VA were present on 24-hour AECGs in 33% of persons and on 1-minute rhythm strips in 2% of persons [3]. In 843 older persons, with cardiovascular disease, complex VA were present on 24-hour AECGs in 55% of persons and on 1-minute rhythm strips in 4% of persons [3].

In persons with cardiovascular disease, those with an abnormal left ventricular (LV) ejection fraction [8], with echocardiographic LV hypertrophy [9], or with silent myocardial ischemia [10] have a higher prevalence of VT and of complex VA than those with normal LV ejection fraction, normal LV mass, and no myocardial ischemia.

© 2014 Aronow; licensee InTech. This is a paper distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

#### **2. Prognosis of ventricular arrhythmias**

In the Baltimore Longitudinal Study of Aging, nonsustained VT or complex VA were not as‐ sociated with new

drugs. The serum low-density lipoprotein (LDL) cholesterol level should be reduced ≥ 50% by high-dose statins (atorvastatin 40to 80 mg daily or rosuvastatin 20 to 40 mg daily) [40].

Treatment of Ventricular Arrhythmias http://dx.doi.org/10.5772/57545 113

Age-related physiologic changes may affect absorption, distribution, metabolism, and excre‐ tion of cardiovascular drugs [41]. Numerous physiologic changes with aging affect pharma‐ codynamics with alterations in end-organ responsiveness to cardiovascular drugs [41]. Drug interactions between antiarrhythmic drugs and other cardiovascular drugs are common [41]. There are also important drug-disease interactions [41]. Class I antiarrhythmic drugs have an unacceptable proarrhythmia rate in patients with heart disease and should be avoided. Class III antiarrhythmic drugs should also be used with caution in patients with heart disease since multiple factors may increase proarrhythmia. Except for beta blockers, all antiarrhythmic drugs may cause torsades de pointes (VT with polymorphous appearance

Class I antiarrhythmic drugs are sodium channel blockers. Class Ia antiarrhythmic drugs have intermediate channel kinetics and prolong repolarization. These drugs include quini‐ dine, procainamide, and disopyramide. Class Ib antiarrhythmic drugs have rapid channel kinetics and slightly shorten repolarization. These drugs include lidocaine, mexilitine, tocai‐ nide, and phenytoin. Class Ic drugs have slow channel kinetics and have little effect on repo‐ larization. These drugs include encainide, flecainide, moricizine, propafenone, and lorcainide. None of the Class I antiarrhythmic drugs have been found in controlled, clinical

The International Mexilitine and Placebo Antiarrhythmic Coronary Trial (IMPACT) was a prospective, double-blind, randomized study in survivors of myocardial infarction (MI) in whom 317 persons were randomized to mexilitine and 313 persons to placebo [42]. At 1-year follow-up, mortality was 7.6% for mexilitine-treated patients versus 4.8% for placebo-treated

The Cardiac Arrhythmia Suppression Trial (CAST) I was a prospective, double-blind, randomized study in survivors of MI with asymptomatic or mildly symptomatic VA in which 730 patients were randomized to encainide or flecainide and 725 patients to placebo [43]. Adequate suppression of VA by encainide or flecainide was needed before randomiza‐ tion. Despite adequate suppression of VA, at 10-month follow-up, encainide and flecainide significantly increased mortality from arrhythmia or cardiac arrest 3.6 times and significant‐ ly increased total mortality 2.5 times[43). Older age increased the likelihood of adverse

CAST II was a prospective, double-blind, randomized study in survivors of MI with asymp‐ tomatic or mildly symptomatic VA in which 581 patients were randomized to moricizine and 574 patients to placebo. [45]. Adequate suppression of VA by moricizine was required before randomization. At 18-month follow-up, the mortality from arrhythmia or cardiac ar‐ rest was 8.4% for patients treated with moricizine and 7.3% for patients treated with placebo [45]. The 2-year survival rate was 81.7% for patients treated with moricizine and 85.6% for patients treated with placebo [45]. Older age increased the likelihood of adverse events, in‐

trials to reduce sudden cardiac death, total cardiac death, or total mortality.

events, including death, in patients treated with encainide and flecainide[44].

cluding death, in patients receiving moricizine [44].

associated with prolonged QT interval).

patients [42].

coronary events at 10-year follow-up of 98 persons without heart disease [11]. In this study, exercise-induced nonsustained VT was not associated with new coronary events at 2-year follow-up in persons without heart disease [12]. At 5.6-year follow-up in this study, exer‐ cise-induced frequent or repetitive VPCs also were not associated with new coronary events in persons without heart disease [13].

Nonsustained VT or complex VA diagnosed by 24-hour AECGs were not associated with new coronary events at 2-year follow-up in 76 persons without heart disease [14] and were not associated with primary ventricular fibrillation (VF) or sudden cardiac death in 86 per‐ sons without heart disease [15]. Complex VA diagnosed by 24-hour AECGs or by 12-lead ECGs with 1-minute rhythm strips were also not associated with new coronary events at 39 month follow-up in 104 persons without heart disease [3]. Nonsustained VT or complex VA diagnosed by 24-hour AECGs were not associated with new coronary events at 45-month follow-up of 135 men and at 47-month follow-up of 297 women without cardiovascular dis‐ ease [7].

Because nonsustained VT or complex VA are not associated with new coronary events in persons without heart disease, asymptomatic nonsustained VT or complex VA in persons without heart disease should not be treated with antiarrhythmic drugs. Because simple VA in persons with heart disease are not associated with new coronary events [3, 7, 11, 14, 15], simple VA in older persons with heart disease should not be treated with antiarrhythmic drugs.

However, patients with VT (sustained or nonsustained) or with complex VA associated with heart disease are at increased risk for developing new coronary events, primary VF, and sudden cardiac death [3, 7, 11, 14-19].

#### **3. Medical therapy**

Underlying causes of complex VA should be treated, if possible. Therapy of congestive heart failure (CHF), digitalis toxicity, hypokalemia, hypomagnesemia, hypertension, LV dysfunc‐ tion, LV hypertrophy, myocardial ischemia by anti-ischemic drugs such as beta blockers or by coronary revascularization, hypoxia, and other conditions may abolish or decrease com‐ plex VA. Persons should not smoke or drink alcohol and should avoid drugs that may cause or increase complex VA.

CAD should be treated with aspirin [20-23], with beta blockers [23-28], with angiotensinconverting enzyme (ACE) inhibitors [23, 28-33], and with 3-hydroxy-3-methylglutaryl coen‐ zyme A reductase inhibitors (statins) [23, 34-40] unless there are contraindications to these drugs. The serum low-density lipoprotein (LDL) cholesterol level should be reduced ≥ 50% by high-dose statins (atorvastatin 40to 80 mg daily or rosuvastatin 20 to 40 mg daily) [40].

**2. Prognosis of ventricular arrhythmias**

112 Cardiac Arrhythmias - Mechanisms, Pathophysiology, and Treatment

in persons without heart disease [13].

sudden cardiac death [3, 7, 11, 14-19].

**3. Medical therapy**

or increase complex VA.

sociated with new

ease [7].

drugs.

In the Baltimore Longitudinal Study of Aging, nonsustained VT or complex VA were not as‐

coronary events at 10-year follow-up of 98 persons without heart disease [11]. In this study, exercise-induced nonsustained VT was not associated with new coronary events at 2-year follow-up in persons without heart disease [12]. At 5.6-year follow-up in this study, exer‐ cise-induced frequent or repetitive VPCs also were not associated with new coronary events

Nonsustained VT or complex VA diagnosed by 24-hour AECGs were not associated with new coronary events at 2-year follow-up in 76 persons without heart disease [14] and were not associated with primary ventricular fibrillation (VF) or sudden cardiac death in 86 per‐ sons without heart disease [15]. Complex VA diagnosed by 24-hour AECGs or by 12-lead ECGs with 1-minute rhythm strips were also not associated with new coronary events at 39 month follow-up in 104 persons without heart disease [3]. Nonsustained VT or complex VA diagnosed by 24-hour AECGs were not associated with new coronary events at 45-month follow-up of 135 men and at 47-month follow-up of 297 women without cardiovascular dis‐

Because nonsustained VT or complex VA are not associated with new coronary events in persons without heart disease, asymptomatic nonsustained VT or complex VA in persons without heart disease should not be treated with antiarrhythmic drugs. Because simple VA in persons with heart disease are not associated with new coronary events [3, 7, 11, 14, 15], simple VA in older persons with heart disease should not be treated with antiarrhythmic

However, patients with VT (sustained or nonsustained) or with complex VA associated with heart disease are at increased risk for developing new coronary events, primary VF, and

Underlying causes of complex VA should be treated, if possible. Therapy of congestive heart failure (CHF), digitalis toxicity, hypokalemia, hypomagnesemia, hypertension, LV dysfunc‐ tion, LV hypertrophy, myocardial ischemia by anti-ischemic drugs such as beta blockers or by coronary revascularization, hypoxia, and other conditions may abolish or decrease com‐ plex VA. Persons should not smoke or drink alcohol and should avoid drugs that may cause

CAD should be treated with aspirin [20-23], with beta blockers [23-28], with angiotensinconverting enzyme (ACE) inhibitors [23, 28-33], and with 3-hydroxy-3-methylglutaryl coen‐ zyme A reductase inhibitors (statins) [23, 34-40] unless there are contraindications to these Age-related physiologic changes may affect absorption, distribution, metabolism, and excre‐ tion of cardiovascular drugs [41]. Numerous physiologic changes with aging affect pharma‐ codynamics with alterations in end-organ responsiveness to cardiovascular drugs [41]. Drug interactions between antiarrhythmic drugs and other cardiovascular drugs are common [41]. There are also important drug-disease interactions [41]. Class I antiarrhythmic drugs have an unacceptable proarrhythmia rate in patients with heart disease and should be avoided. Class III antiarrhythmic drugs should also be used with caution in patients with heart disease since multiple factors may increase proarrhythmia. Except for beta blockers, all antiarrhythmic drugs may cause torsades de pointes (VT with polymorphous appearance associated with prolonged QT interval).

Class I antiarrhythmic drugs are sodium channel blockers. Class Ia antiarrhythmic drugs have intermediate channel kinetics and prolong repolarization. These drugs include quini‐ dine, procainamide, and disopyramide. Class Ib antiarrhythmic drugs have rapid channel kinetics and slightly shorten repolarization. These drugs include lidocaine, mexilitine, tocai‐ nide, and phenytoin. Class Ic drugs have slow channel kinetics and have little effect on repo‐ larization. These drugs include encainide, flecainide, moricizine, propafenone, and lorcainide. None of the Class I antiarrhythmic drugs have been found in controlled, clinical trials to reduce sudden cardiac death, total cardiac death, or total mortality.

The International Mexilitine and Placebo Antiarrhythmic Coronary Trial (IMPACT) was a prospective, double-blind, randomized study in survivors of myocardial infarction (MI) in whom 317 persons were randomized to mexilitine and 313 persons to placebo [42]. At 1-year follow-up, mortality was 7.6% for mexilitine-treated patients versus 4.8% for placebo-treated patients [42].

The Cardiac Arrhythmia Suppression Trial (CAST) I was a prospective, double-blind, randomized study in survivors of MI with asymptomatic or mildly symptomatic VA in which 730 patients were randomized to encainide or flecainide and 725 patients to placebo [43]. Adequate suppression of VA by encainide or flecainide was needed before randomiza‐ tion. Despite adequate suppression of VA, at 10-month follow-up, encainide and flecainide significantly increased mortality from arrhythmia or cardiac arrest 3.6 times and significant‐ ly increased total mortality 2.5 times[43). Older age increased the likelihood of adverse events, including death, in patients treated with encainide and flecainide[44].

CAST II was a prospective, double-blind, randomized study in survivors of MI with asymp‐ tomatic or mildly symptomatic VA in which 581 patients were randomized to moricizine and 574 patients to placebo. [45]. Adequate suppression of VA by moricizine was required before randomization. At 18-month follow-up, the mortality from arrhythmia or cardiac ar‐ rest was 8.4% for patients treated with moricizine and 7.3% for patients treated with placebo [45]. The 2-year survival rate was 81.7% for patients treated with moricizine and 85.6% for patients treated with placebo [45]. Older age increased the likelihood of adverse events, in‐ cluding death, in patients receiving moricizine [44].

Aronow et al [46] performed a prospective study in 406 persons with heart disease (58% with prior MI) and asymptomatic complex VA diagnosed by 24-hour AECGs. The preva‐ lence of nonsustained VT was 20%. The prevalence of an abnormal ejection fraction was 32%. The incidence of adverse effects causing cessation of drug was 48% for quinidine and 55% for procainamide. At 24-month follow-up, the incidences of sudden cardiac death, total cardiac death, and of total death were not significantly different in persons treated with qui‐ nidine or procainamide or with no antiarrhythmic drug [46]. The incidence of total mortality was 65% for persons treated with quinidine or procainamide and 63% for persons treated with no antiarrhythmic drug. Quinidine or procainamide did not decrease sudden cardiac death, total cardiac death, or total death in comparison with no antiarrhythmic drug in older patients with ischemic or nonischemic heart disease, abnormal or normal LV ejection frac‐ tion, and presence versus absence of VT [46].

Teo et al [52] analyzed 59 randomized controlled trials of 23, 229 patients that investigated use of Class I antiarrhythmic drugs after MI. The Class I drugs investigated included quini‐ dine, procainamide, disopyramide, imipramine, moricizine, lidocaine, tocainide, phenytoin, mexiletine, aprindine, encainide, and flecainide. Mortality was 14% higher in patients re‐ ceiving Class I antiarrhythmic drugs than in patients receiving no antiarrhythmic drugs. None of the 59 studies demonstrated that use of a Class I antiarrhythmic drug decreased mortality in postinfarction patients [52].On the basis of these data, no Class I antiarrhythmic

Treatment of Ventricular Arrhythmias http://dx.doi.org/10.5772/57545 115

Calcium channel blockers are not useful in treatment of complex VA. Although verapamil can terminate a left septal fascicular VT, hemodynamic collapse can occur if intravenous ve‐ rapamil is given to patients with the more common forms of reentry VT. Teo et al [52] ana‐ lyzed randomized controlled trials of 20, 342 patients that investigated the use of calcium channel blockers after MI. Mortality was insignificantly 4% higher in patients receiving cal‐ cium channel blockers than in patients receiving no antiarrhythmic drugs [52]. On the basis of these data, no calcium channel blockers should be used in the treatment of VT or complex

Teo et al [52] analyzed 55 randomized controlled trials comprising 53, 268 patients that in‐ vestigated use of beta blockers after MI. Mortality was significantly reduced 19% in patients receiving beta blockers [52]. The decrease in mortality after MI in persons treated with beta blockers was due to both a reduction in sudden cardiac death and recurrent MI [24-27, 53]. The Beta Blocker Heart Attack Trial was a double-blind, randomized study of 3, 290 patients after MI [53-55]. At 25-month follow-up, propranolol decreased sudden cardiac death by 28% in patients with complex VA and by 16% in patients without complex VA. Propranolol significantly reduced total mortality by 34% in patients aged 60 to 69 years (p=0.01) and in‐

significantly reduced total mortality by 19% in patients aged 30 to 59 years [53-55].

cardiac death in patients treated with propranolol for 1 year [58].

Beta blockers decrease complex VA including VT [55-57]. Beta blockers also increase VF threshold in animal models and have been found to decrease VF in patients with acute MI [58] A randomized, double-blind, placebo-controlled study of propranolol in high-risk sur‐ vivors of acute MI at 12 Norwegian hospitals showed a 52% significant reduction in sudden

Beta blockers decrease myocardial oxygen demand and myocardial ischemia, which may re‐ duce the likelihood of VF. Stone et al [59] showed by 48-hour AECGs in 50 patients with sta‐ ble angina pectoris that propranolol, but not diltiazem or nifedipine, caused a significant decrease in mean number of episodes of myocardial ischemia and in mean duration of myo‐ cardial ischemia compared with placebo. Beta blockers also decrease sympathetic tone, in‐ crease vagal tone, and stabilize cardiac membrane potentials which reduces the likelihood of VF. In addition, beta blockers are antithrombotic [60] and may prevent atherosclerotic pla‐

In the retrospective study by Hallstrom et al [48] in 941 patients resuscitated from prehospi‐ tal cardiac arrest attributed to VF, beta blockers were given to 28% of patients and no antiar‐ rhythmic drug to 39% of patients. At 108-month follow-up, patients treated with beta

drugs should be used for the treatment of VT or complex VA.

VA.

que rupture [61].

Moosvi et al [47] performed a retrospective analysis of the effect of empiric antiarrhythmic therapy in 209 resuscitated out-of-hospital cardiac arrest patients with CAD. Of the 209 pa‐ tients, 48 received quinidine, 45 received procainamide, and 116 received no antiarrhythmic drug. The 2-year sudden death survival was 69% for quinidine-treated patients, 69% for pro‐ cainamide-treated patients, and 89% for patients treated with no antiarrhythmic drug [47]. The 2-year total survival was 61% for quinidine-treated patients, 57% for procainamidetreated patients, and 71% for patients treated with no antiarrhythmic drug [47].

Hallstrom et al [48] performed a retrospective analysis of the effect of antiarrhythmic drug use in 941 patients resuscitated from prehospital cardiac arrest attributable to VF between 1970 and 1985. Quinidine was given to 19% of patients, procainamide to 18% of patients, be‐ ta blockers to 28% of patients, and no antiarrhythmic drug to 39% of patients. There was a 17% increased incidence of death or recurrent cardiac arrest in patients treated with quini‐ dine or procainamide versus no antiarrhythmic drug. Survival was 57% worse for patients treated with procainamide than for patients treated with quinidine [48].

A meta-analysis of 6 double-blind studies of 808 patients with chronic atrial fibrillation who underwent direct-current cardioversion to sinus rhythm showed that the mortality at one year was higher in patients treated with quinidine (2.9%) than in patients treated with place‐ bo (0.8%) [49]. Of 1, 330 patients in the Stroke Prevention in Atrial Fibrillation Study, 127 were receiving quinidine, 57 procainamide, 15 disopyramide, 34 flecainide, 20 encainide, and 7 amiodarone [50]. The adjusted relative risk of cardiac mortality was 1.8 times higher and the adjusted relative risk of arrhythmic death was 2.1 times higher in patients receiving antiarrhythmic drugs [50]. In patients with a history of CHF, the adjusted relative risk of cardiac death was 3.3 times higher and the adjusted relative risk of arrhythmic death was 5.8 times higher in patients receiving antiarrhythmic drugs[50].

Morganroth and Goin [51] performed a meta-analysis of 4 randomized, double-blind con‐ trolled trials lasting 2 to 12 weeks in which quinidine (n=502) was compared with flecainide (n=141), mexiletine (n=246), tocainide (n=67), and propafenone (n=53) in the treatment of complex VA. There was an increased risk of mortality in patients treated with quinidine compared with patients treated with the other antiarrhythmic drugs (absolute risk increase = 1.6%) [51].

Teo et al [52] analyzed 59 randomized controlled trials of 23, 229 patients that investigated use of Class I antiarrhythmic drugs after MI. The Class I drugs investigated included quini‐ dine, procainamide, disopyramide, imipramine, moricizine, lidocaine, tocainide, phenytoin, mexiletine, aprindine, encainide, and flecainide. Mortality was 14% higher in patients re‐ ceiving Class I antiarrhythmic drugs than in patients receiving no antiarrhythmic drugs. None of the 59 studies demonstrated that use of a Class I antiarrhythmic drug decreased mortality in postinfarction patients [52].On the basis of these data, no Class I antiarrhythmic drugs should be used for the treatment of VT or complex VA.

Aronow et al [46] performed a prospective study in 406 persons with heart disease (58% with prior MI) and asymptomatic complex VA diagnosed by 24-hour AECGs. The preva‐ lence of nonsustained VT was 20%. The prevalence of an abnormal ejection fraction was 32%. The incidence of adverse effects causing cessation of drug was 48% for quinidine and 55% for procainamide. At 24-month follow-up, the incidences of sudden cardiac death, total cardiac death, and of total death were not significantly different in persons treated with qui‐ nidine or procainamide or with no antiarrhythmic drug [46]. The incidence of total mortality was 65% for persons treated with quinidine or procainamide and 63% for persons treated with no antiarrhythmic drug. Quinidine or procainamide did not decrease sudden cardiac death, total cardiac death, or total death in comparison with no antiarrhythmic drug in older patients with ischemic or nonischemic heart disease, abnormal or normal LV ejection frac‐

Moosvi et al [47] performed a retrospective analysis of the effect of empiric antiarrhythmic therapy in 209 resuscitated out-of-hospital cardiac arrest patients with CAD. Of the 209 pa‐ tients, 48 received quinidine, 45 received procainamide, and 116 received no antiarrhythmic drug. The 2-year sudden death survival was 69% for quinidine-treated patients, 69% for pro‐ cainamide-treated patients, and 89% for patients treated with no antiarrhythmic drug [47]. The 2-year total survival was 61% for quinidine-treated patients, 57% for procainamide-

Hallstrom et al [48] performed a retrospective analysis of the effect of antiarrhythmic drug use in 941 patients resuscitated from prehospital cardiac arrest attributable to VF between 1970 and 1985. Quinidine was given to 19% of patients, procainamide to 18% of patients, be‐ ta blockers to 28% of patients, and no antiarrhythmic drug to 39% of patients. There was a 17% increased incidence of death or recurrent cardiac arrest in patients treated with quini‐ dine or procainamide versus no antiarrhythmic drug. Survival was 57% worse for patients

A meta-analysis of 6 double-blind studies of 808 patients with chronic atrial fibrillation who underwent direct-current cardioversion to sinus rhythm showed that the mortality at one year was higher in patients treated with quinidine (2.9%) than in patients treated with place‐ bo (0.8%) [49]. Of 1, 330 patients in the Stroke Prevention in Atrial Fibrillation Study, 127 were receiving quinidine, 57 procainamide, 15 disopyramide, 34 flecainide, 20 encainide, and 7 amiodarone [50]. The adjusted relative risk of cardiac mortality was 1.8 times higher and the adjusted relative risk of arrhythmic death was 2.1 times higher in patients receiving antiarrhythmic drugs [50]. In patients with a history of CHF, the adjusted relative risk of cardiac death was 3.3 times higher and the adjusted relative risk of arrhythmic death was 5.8

Morganroth and Goin [51] performed a meta-analysis of 4 randomized, double-blind con‐ trolled trials lasting 2 to 12 weeks in which quinidine (n=502) was compared with flecainide (n=141), mexiletine (n=246), tocainide (n=67), and propafenone (n=53) in the treatment of complex VA. There was an increased risk of mortality in patients treated with quinidine compared with patients treated with the other antiarrhythmic drugs (absolute risk increase =

treated patients, and 71% for patients treated with no antiarrhythmic drug [47].

treated with procainamide than for patients treated with quinidine [48].

times higher in patients receiving antiarrhythmic drugs[50].

1.6%) [51].

tion, and presence versus absence of VT [46].

114 Cardiac Arrhythmias - Mechanisms, Pathophysiology, and Treatment

Calcium channel blockers are not useful in treatment of complex VA. Although verapamil can terminate a left septal fascicular VT, hemodynamic collapse can occur if intravenous ve‐ rapamil is given to patients with the more common forms of reentry VT. Teo et al [52] ana‐ lyzed randomized controlled trials of 20, 342 patients that investigated the use of calcium channel blockers after MI. Mortality was insignificantly 4% higher in patients receiving cal‐ cium channel blockers than in patients receiving no antiarrhythmic drugs [52]. On the basis of these data, no calcium channel blockers should be used in the treatment of VT or complex VA.

Teo et al [52] analyzed 55 randomized controlled trials comprising 53, 268 patients that in‐ vestigated use of beta blockers after MI. Mortality was significantly reduced 19% in patients receiving beta blockers [52]. The decrease in mortality after MI in persons treated with beta blockers was due to both a reduction in sudden cardiac death and recurrent MI [24-27, 53].

The Beta Blocker Heart Attack Trial was a double-blind, randomized study of 3, 290 patients after MI [53-55]. At 25-month follow-up, propranolol decreased sudden cardiac death by 28% in patients with complex VA and by 16% in patients without complex VA. Propranolol significantly reduced total mortality by 34% in patients aged 60 to 69 years (p=0.01) and in‐ significantly reduced total mortality by 19% in patients aged 30 to 59 years [53-55].

Beta blockers decrease complex VA including VT [55-57]. Beta blockers also increase VF threshold in animal models and have been found to decrease VF in patients with acute MI [58] A randomized, double-blind, placebo-controlled study of propranolol in high-risk sur‐ vivors of acute MI at 12 Norwegian hospitals showed a 52% significant reduction in sudden cardiac death in patients treated with propranolol for 1 year [58].

Beta blockers decrease myocardial oxygen demand and myocardial ischemia, which may re‐ duce the likelihood of VF. Stone et al [59] showed by 48-hour AECGs in 50 patients with sta‐ ble angina pectoris that propranolol, but not diltiazem or nifedipine, caused a significant decrease in mean number of episodes of myocardial ischemia and in mean duration of myo‐ cardial ischemia compared with placebo. Beta blockers also decrease sympathetic tone, in‐ crease vagal tone, and stabilize cardiac membrane potentials which reduces the likelihood of VF. In addition, beta blockers are antithrombotic [60] and may prevent atherosclerotic pla‐ que rupture [61].

In the retrospective study by Hallstrom et al [48] in 941 patients resuscitated from prehospi‐ tal cardiac arrest attributed to VF, beta blockers were given to 28% of patients and no antiar‐ rhythmic drug to 39% of patients. At 108-month follow-up, patients treated with beta blockers had a significant 38% decreased incidence of death or recurrent cardiac arrest com‐ pared to patients treated with no antiarrhythmic [48].

ACE inhibitors have been shown to cause a significant reduction in complex VA in patients with CHF in some studies [68, 69] but not in other studies [70, 71]. ACE inhibitors have also been shown to reduce sudden cardiac death in some studies of patients with CHF [32, 72]. ACE inhibitors should be given to reduce total mortality in older and younger patients with CHF [30, 32, 72, 73], an anterior MI [31], an MI with a LV ejection fraction ≤40% [28, 29, 32], and in all patients with atherosclerotic cardiovascular disease [23, 33]. ACE inhibitors should be used to treat patients with CHF with abnormal LV ejection fraction [30, 32, 72, 73]

Treatment of Ventricular Arrhythmias http://dx.doi.org/10.5772/57545 117

On the basis of available data, ACE inhibitors should be used to treat patients with VT or complex VA associated with CHF, an anterior MI, an MI with LV systolic dysfunction, or atherosclerotic cardiovascular disease if there are no contraindications to use of ACE inhibi‐ tors. Beta blockers should be used in addition to ACE inhibitors in treating these patients. Class III antiarrhythmic drugs are potassium channel blockers which prolong repolarization manifested by an increase in QT interval on the electrocardiogram. These drugs suppress VA by increasing the refractory period. However, prolonging cardiac repolarization and re‐

In the Survival With Oral d-Sotalol (SWORD) Trial, 3, 121 survivors of MI with a LV ejection fraction ≤40% were randomized to d-sotalol, a pure potassium channel blocker with no beta blocking activity, or to double-blind placebo [76]. At 148-day follow-up, mortality was 5.0% in patients treated with d-sotalol versus 3.1% in patients treated with placebo [76]. Pre‐ sumed arrhythmic deaths accounted for the 77% increased mortality (relative risk = 1.77;

Studies comparing the effect of d, l-sotalol, a Class III antiarrhythmic drug with beta block‐ ing activity, versus placebo or beta blockers in patients with VT or complex VA have not been performed. In a study of 1, 486 patients with prior MI, compared with placebo, d, l-

In the Electrophysiologic Study versus Electrocardiographic Monitoring (ESVEM) study of 486 patients, Holter monitor-guided therapy significantly predicted antiarrhythmic drug ef‐ ficacy more often than did the electrophysiologic study in patients with sustained VT or sur‐ vivors of cardiac arrest (77% versus 45% of patients) [78]. However, there was no significant difference in the success of drug therapy selected by the two methods in preventing recur‐

In the ESVEM study, d, l-sotalol was more effective than the other 6 antiarrhythmic drugs [imipramine, mexiletine, pirmenol, procainamide, propafenone, and quinidine] used in re‐ ducing recurrence of arrhythmia, death from arrhythmia, death from cardiac causes, and death from any cause [79]. However, 7 of 10 episodes of torsade de pointes during this study occurred in patients receiving d, l-sotalol [79]. In 481 patients with VT, d, l-sotalol caused torsade de pointes (12 patients) or an increase in VT episodes (11 patients) in 23 pa‐ tients (4.9%) [80]. Women had a significantly higher risk for drug-induced VF. On the basis of available data, use of beta blockers is recommended over the use of d, l-sotalol in treating

fractory period can trigger afterdepolarizations and resultant torsade de pointes.

sotalol did not reduce mortality in patients followed for 1 year [77].

patients with VT or complex VA associated with heart disease.

or with normal LV ejection fraction [74, 75].

95% CI, 1.15 to 2.74) [76].

rences of ventricular tachyarrhythmias.

Aronow et al [62] performed a prospective study in 245 persons with heart disease (64% with prior MI and 36% with hypertensive heart disease) and complex VA diagnosed by 24 hour AECGs and a LV ejection fraction ≥40%. Nonsustained VT occurred in 32% of patients. Silent myocardial ischemia occurred in 33% of patients. Of 245 patients, 123 were random‐ ized to propranolol and 122 to no antiarrhythmic drug. Follow-up was 29 months. Propra‐ nolol was stopped because of adverse effects in 14 of 123 patients (11%).

Follow-up 24-hour AECGs were obtained at a median of 6 months in 91% of patients treated with propranolol and in 89% of patients treated with no antiarrhythmic drug [62]. Proprano‐ lol was significantly more effective than no antiarrhythmic drug in reducing VT >90% (71% versus 25% of patients) and in decreasing the average number of VPCs/hour >70% (71% ver‐ sus 25% of patients) [62]. The prevalence of silent myocardial ischemia on follow-up 24-hour AECGs was insignificantly higher on no antiarrhythmic drug. However, silent ischemia was significantly abolished by propranolol, with 37% of patients with silent ischemia on their baseline 24-hour AECGs having no silent ischemia on their follow-up 24-hour AECGs [62].

Multivariate Cox regression analyses showed that propranolol caused a 47% significant re‐ duction in sudden cardiac death, a 37% significant decrease in total cardiac death, and a 20% insignificant decrease in total death [62]. Univariate Cox regression analysis showed that among patients taking propranolol, suppression of complex VA caused a 33% insignificant reduction in sudden cardiac death, a 27% insignificant decrease in total cardiac death, and a 30% insignificant reduction in total death [63]. Among patients taking propranolol, abolition of silent myocardial ischemia caused a 70% significant decrease in sudden cardiac death, a 70% significant reduction in total cardiac death, and a 69% significant decrease in total death [63].

There was also a circadian distribution of sudden cardiac death or fatal MI with the peak incidence occurring from 6 AM to 12 PM (peak hour was 8 AM and a secondary peak occur‐ red around 7 PM) in patients treated with no antiarrhythmic drug [64] Propranolol abolish‐ ed this circadian distribution of sudden cardiac death or fatal MI [64]. In this study, propranolol markedly decreased the circadian variation of complex VA [65] and abolished the circadian variation of myocardial ischemia [66].

In a retrospective analysis of data from the CAST study, Kennedy et al [67] showed that 30% of patients with a LV ejection fraction ≤40% were receiving beta blockers. Patients on beta blockers had a significant decrease in all-cause mortality of 43% at 30 days, of 46% at 1 year, and of 33% at 2 years [67]. Patients treated with beta blockers had a significant reduction in arrhythmic death or cardiac arrest of 66% at 30 days, of 53% at 1 year, and of 36% at 2 years [67]. Multivariate analysis showed that beta blockers were an independent factor for de‐ creasing arrhythmic death or cardiac arrest by 40%, for reducing all-cause mortality by 33%, and for decreasing new or worsened CHF by 32% [67].

ACE inhibitors have been shown to cause a significant reduction in complex VA in patients with CHF in some studies [68, 69] but not in other studies [70, 71]. ACE inhibitors have also been shown to reduce sudden cardiac death in some studies of patients with CHF [32, 72].

blockers had a significant 38% decreased incidence of death or recurrent cardiac arrest com‐

Aronow et al [62] performed a prospective study in 245 persons with heart disease (64% with prior MI and 36% with hypertensive heart disease) and complex VA diagnosed by 24 hour AECGs and a LV ejection fraction ≥40%. Nonsustained VT occurred in 32% of patients. Silent myocardial ischemia occurred in 33% of patients. Of 245 patients, 123 were random‐ ized to propranolol and 122 to no antiarrhythmic drug. Follow-up was 29 months. Propra‐

Follow-up 24-hour AECGs were obtained at a median of 6 months in 91% of patients treated with propranolol and in 89% of patients treated with no antiarrhythmic drug [62]. Proprano‐ lol was significantly more effective than no antiarrhythmic drug in reducing VT >90% (71% versus 25% of patients) and in decreasing the average number of VPCs/hour >70% (71% ver‐ sus 25% of patients) [62]. The prevalence of silent myocardial ischemia on follow-up 24-hour AECGs was insignificantly higher on no antiarrhythmic drug. However, silent ischemia was significantly abolished by propranolol, with 37% of patients with silent ischemia on their baseline 24-hour AECGs having no silent ischemia on their follow-up 24-hour AECGs [62].

Multivariate Cox regression analyses showed that propranolol caused a 47% significant re‐ duction in sudden cardiac death, a 37% significant decrease in total cardiac death, and a 20% insignificant decrease in total death [62]. Univariate Cox regression analysis showed that among patients taking propranolol, suppression of complex VA caused a 33% insignificant reduction in sudden cardiac death, a 27% insignificant decrease in total cardiac death, and a 30% insignificant reduction in total death [63]. Among patients taking propranolol, abolition of silent myocardial ischemia caused a 70% significant decrease in sudden cardiac death, a 70% significant reduction in total cardiac death, and a 69% significant decrease in total death

There was also a circadian distribution of sudden cardiac death or fatal MI with the peak incidence occurring from 6 AM to 12 PM (peak hour was 8 AM and a secondary peak occur‐ red around 7 PM) in patients treated with no antiarrhythmic drug [64] Propranolol abolish‐ ed this circadian distribution of sudden cardiac death or fatal MI [64]. In this study, propranolol markedly decreased the circadian variation of complex VA [65] and abolished

In a retrospective analysis of data from the CAST study, Kennedy et al [67] showed that 30% of patients with a LV ejection fraction ≤40% were receiving beta blockers. Patients on beta blockers had a significant decrease in all-cause mortality of 43% at 30 days, of 46% at 1 year, and of 33% at 2 years [67]. Patients treated with beta blockers had a significant reduction in arrhythmic death or cardiac arrest of 66% at 30 days, of 53% at 1 year, and of 36% at 2 years [67]. Multivariate analysis showed that beta blockers were an independent factor for de‐ creasing arrhythmic death or cardiac arrest by 40%, for reducing all-cause mortality by 33%,

pared to patients treated with no antiarrhythmic [48].

116 Cardiac Arrhythmias - Mechanisms, Pathophysiology, and Treatment

the circadian variation of myocardial ischemia [66].

and for decreasing new or worsened CHF by 32% [67].

[63].

nolol was stopped because of adverse effects in 14 of 123 patients (11%).

ACE inhibitors should be given to reduce total mortality in older and younger patients with CHF [30, 32, 72, 73], an anterior MI [31], an MI with a LV ejection fraction ≤40% [28, 29, 32], and in all patients with atherosclerotic cardiovascular disease [23, 33]. ACE inhibitors should be used to treat patients with CHF with abnormal LV ejection fraction [30, 32, 72, 73] or with normal LV ejection fraction [74, 75].

On the basis of available data, ACE inhibitors should be used to treat patients with VT or complex VA associated with CHF, an anterior MI, an MI with LV systolic dysfunction, or atherosclerotic cardiovascular disease if there are no contraindications to use of ACE inhibi‐ tors. Beta blockers should be used in addition to ACE inhibitors in treating these patients.

Class III antiarrhythmic drugs are potassium channel blockers which prolong repolarization manifested by an increase in QT interval on the electrocardiogram. These drugs suppress VA by increasing the refractory period. However, prolonging cardiac repolarization and re‐ fractory period can trigger afterdepolarizations and resultant torsade de pointes.

In the Survival With Oral d-Sotalol (SWORD) Trial, 3, 121 survivors of MI with a LV ejection fraction ≤40% were randomized to d-sotalol, a pure potassium channel blocker with no beta blocking activity, or to double-blind placebo [76]. At 148-day follow-up, mortality was 5.0% in patients treated with d-sotalol versus 3.1% in patients treated with placebo [76]. Pre‐ sumed arrhythmic deaths accounted for the 77% increased mortality (relative risk = 1.77; 95% CI, 1.15 to 2.74) [76].

Studies comparing the effect of d, l-sotalol, a Class III antiarrhythmic drug with beta block‐ ing activity, versus placebo or beta blockers in patients with VT or complex VA have not been performed. In a study of 1, 486 patients with prior MI, compared with placebo, d, lsotalol did not reduce mortality in patients followed for 1 year [77].

In the Electrophysiologic Study versus Electrocardiographic Monitoring (ESVEM) study of 486 patients, Holter monitor-guided therapy significantly predicted antiarrhythmic drug ef‐ ficacy more often than did the electrophysiologic study in patients with sustained VT or sur‐ vivors of cardiac arrest (77% versus 45% of patients) [78]. However, there was no significant difference in the success of drug therapy selected by the two methods in preventing recur‐ rences of ventricular tachyarrhythmias.

In the ESVEM study, d, l-sotalol was more effective than the other 6 antiarrhythmic drugs [imipramine, mexiletine, pirmenol, procainamide, propafenone, and quinidine] used in re‐ ducing recurrence of arrhythmia, death from arrhythmia, death from cardiac causes, and death from any cause [79]. However, 7 of 10 episodes of torsade de pointes during this study occurred in patients receiving d, l-sotalol [79]. In 481 patients with VT, d, l-sotalol caused torsade de pointes (12 patients) or an increase in VT episodes (11 patients) in 23 pa‐ tients (4.9%) [80]. Women had a significantly higher risk for drug-induced VF. On the basis of available data, use of beta blockers is recommended over the use of d, l-sotalol in treating patients with VT or complex VA associated with heart disease.

Amiodarone is very effective in suppressing VT and complex VA associated with heart dis‐ ease [81-83]. However, the incidence of adverse effects from amiodarone approaches 90% af‐ ter 5 years of therapy [84]. In the Cardiac Arrest in Seattle: Conventional Versus Amiodarone Drug Evaluation study, the incidence of pulmonary toxicity was 10% at 2 years in patients receiving an amiodarone dose of 158 mg daily [81]. Amiodarone can also cause cardiac adverse effects, gastrointestinal adverse effects including hepatitis, hyperthyroidism, hypothyroidism, and neurologic, dermatologic, and ophthalmologic adverse effects.

**4. Invasive intervention**

tery bypass graft surgery [91].

**4.1. Automatic implantable cardioverter-defibrillator**

fraction [99].

[100].

If patients have life-threatening recurrent VT or VF resistant to antiarrhythmic drugs, inva‐ sive intervention should be performed. Patients with critical coronary artery stenosis and se‐ vere myocardial ischemia should undergo coronary artery bypass graft surgery to reduce mortality [90]. In the Coronary Artery Bypass Graft (CABG) Patch Trial, there was no evi‐ dence of improved survival among patients with CAD, LV ejection fraction <36%, and an abnormal signal-averaged electrocardiogram undergoing complete coronary revasculariza‐ tion in whom an AICD was implanted prophylactically at the time of elective coronary ar‐

Treatment of Ventricular Arrhythmias http://dx.doi.org/10.5772/57545 119

Surgical ablation of the arhythmogenic focus in patients with life-threatening ventricular ta‐ chyarrhythmias can be curative. This treatment includes aneurysectomy or infarctectomy and endocardial resection with or without adjunctive cryoablation based on activation map‐ ping in the operating room [92-94]. However, the perioperative mortality rate is high. En‐ doaneurysmorrhaphy with a pericardial patch combined with mapping-guided subendocardial resection frequently cures recurrent VT with a low operative mortality and improvement of LV systolic function [95]. Radiofrequency catheter ablation of VT has been beneficial in the therapy of selected patients with arrhythmogenic foci of monomorphic VT [96-98]. Catheter ablation has been effectively used to treat patients with right ventricular outflow tract VT and LV fascicular VT. Prophylactic VT ablation should be considered be‐ fore implantation of an AICD in patients with stable VT, prior MI, and reduced LV ejection

However, the AICD is the most effective treatment for patients with life-threatening VT or VF. [93-110]. The Multicenter Automatic Defibrillator Implantation Trial (MADIT) random‐ ized 196 patients, with a prior MI, a LV ejection fraction ≤35%, a documented episode of asymptomatic nonsustained VT, and inducible nonsuppressible ventricular tachyarrhyth‐ mia on electrophysiologic study to an AICD or conventional medical therapy [100]. At 27 month follow-up, patients receiving an AICD had a 54% significant reduction in mortality

In the Antiarrhythmics versus Implantable Defibrillators (AVID) Trial, 1, 016 patients were randomized to an AICD or class III antiarrhythmic drug therapy [101]. Forty-five percent of patients had been resuscitated from near-fatal VF. The other 55% of patients had sustained VT with syncope or sustained VT with a LV ejection fraction ≤40% and symptoms suggest‐ ing severe hemodynamic compromise due to the arrhythmia (near-syncope, CHF, and angi‐ na pectoris). The 1-year survival was 89.3% for patients who had the AICD versus 82.3% for patients treated with drug therapy (39% reduction by AICD) [101]. The 2-year survival was 81.6% for patients who had the AICD versus 74.7% for patients treated with drug therapy (27% reduction by AICD) [101]. The 3-year survival was 75.4% for patients who had the AICD versus 64.1% for patients treated with drug therapy (31% reduction by AICD) [101].

A double-blind study randomized 674 patients with CHF and complex VA to amiodarone or placebo [82]. Compared with placebo, amiodarone significantly decreased the number of episodes of VT and the frequency of complex VA. Twenty-seven percent of patients discon‐ tinued amiodarone in this study. At 2-year follow-up, survival was not different in patients treated with amiodarone or placebo [82].

The Canadian Amiodarone Myocardial Infarction Arrhythmia Trial (CAMIAT) randomized 1, 202 survivors of MI with nonsustained VT or complex VA to amiodarone or placebo [83] Early permanent discontinuation of amiodarone for reasons other than adverse events oc‐ curred in 36% of patients taking this drug [83]. At 1.8-year follow-up, amiodarone caused no significant reduction in mortality [83].

The European Myocardial Infarction Amiodarone Trial (EMIAT) randomized 1, 486 survi‐ vors of MI with a LV ejection fraction ≤40% to amiodarone or placebo [85]. Early permanent discontinuation of amiodarone occurred in 38.5% of patients taking this drug. At 21-month follow-up, mortality was similar in patients treated with amiodarone or with placebo [85].

In the Sudden Cardiac Death in Heart Failure Trial (SCD-HEFT), 2, 521 patients with New York Heart Association (NYHA) class II or III CHF due to ischemic or nonischemic heart disease, a LV ejection fraction of 35% or less, and a mean QRS duration on the resting ECG of 120 msec were randomized to placebo, amiodarone, or an automatic implantable cardi‐ overter-defibrillator (AICD) [86]. At 45.5-month median follow-up, compared with placebo, amiodarone insignificantly increased mortality by 6% [86]. At 45.5-month median follow-up, compared with placebo, AICD therapy significantly reduced all-cause mortality by 23%, with an absolute reduction in mortality of 7.2% after 5 years [86].

Since amiodarone has not been found to reduce mortality in patients with VT or complex VA associated with MI or CHF and has a very high incidence of toxicity, beta blockers should be used rather than amiodarone in treating these patients. A meta-analysis of 10 randomized trials showed that the use of beta blockers significantly reduced 2-year mortali‐ ty in patients receiving AICD therapy [87]. In a study of 965 patients with AICDs, at 32 month mean follow-up, use of beta blockers significantly reduced all-cause mortality by 46%, whereas use of amiodarone or sotalolol did not affect mortality [88]. During 33-month mean follow-up of 1, 038 patients with AICDs, use of beta blockers significantly reduced ap‐ propriate AICD shocks [89]. Use of amiodarone plus a beta blocker was not more effective than beta blocker therapy alone in reducing AICD shocks for any reason [89]. In this study, use of sotalol did not reduce appropriate AICD shocks [89].

#### **4. Invasive intervention**