Handbook of Clinical Neurology, Vol. 119 (3rd series) Neurologic Aspects of Systemic Disease Part I Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 2

Sudden cardiac death ALEJANDRO A. RABINSTEIN* Department of Neurology, Mayo Clinic, Rochester, MN, USA

INTRODUCTION That people can die of a “broken heart,” be “scared to death,” or be killed by an attack of anger have probably been common notions for centuries. However, it is only within the last few decades that medicine has recognized the conceptual truth behind these popular sayings. Sudden death can occur as a consequence of neurocardiogenic injury related to extreme emotional stress, and a similar phenomenon may cause fatalities after acute, severe brain insults. This chapter will summarize current knowledge about the history, definition, histopathology, presumed pathophysiology, precipitants, clinical manifestations, and potential preventive treatments of neurocardiogenic injury and sudden cardiac death (SCD).

HISTORY Walter B. Cannon was the first to bring the topic of sudden death to the forum of scientific medical literature, in 1942, in a publication entitled “‘Voodoo’ Death” (Cannon, 1942). In this piece, Cannon compiled examples from anthropology research into fatal events induced by an absolute belief that a powerful external force (such as sorcery or black magic) completely beyond the control of the victim would cause irrevocably the victim’s death. Cannon postulated that the death was due to the “lasting and intense action of the sympathico-adrenal system” and thus opened a line of research that continues even today. Less visionary was his conviction that these phenomena were confined to human groups plagued by ignorance and dominated by primitive superstition. In fact, there are much older written accounts of emperors, kings, and popes said to have died after a sudden emotion, and the idea that sudden death could be provoked by psychological stress was accepted by prominent physicians until the 19th century (Engel, 1971). Subsequent

research would confirm that reason and intelligence do not make people immune to sudden cardiac death. George L. Engel further moved the concept of sudden death from the realm of folk wisdom to that of scientific medicine in a remarkable paper published in 1971 in which he described 170 cases and classified them into eight categories according to the “life settings” (i.e., precipitants) in which death occurred (Engel, 1971): collapse or death of someone close, acute grief (within 16 days of the loss), threat of loss of someone close, during mourning or anniversary, loss of status or self-esteem, real or symbolic personal danger or threat of injury, after danger is over, and at the time of a happy ending. Settings of loss accounted for nearly two-thirds of cases and danger for another third, while happy settings were much more rarely the trigger (10 cases, 6%). People of all ages and social extractions formed this series. The clinical detail presented in this paper remains unsurpassed. The following 40 years brought us much useful information leading to our current understanding that acute cardiac injury produced by catecholamine toxicity is probably responsible for at least some cases of unexplained sudden death. We have also learned that cardiac arrest related to acute, severe brain insults may share a common mechanism with the cases of sudden death after emotional stress. Less severe forms of neurocardiogenic injury, such as apical ballooning syndrome, have been identified. Yet, the precise pathophysiology underlying these events remains incompletely elucidated.

DEFINITION Research on SCD has been hampered by the lack of a uniformly accepted definition. Perhaps the most used is an unexpected natural death due to cardiac cause and heralded by abrupt loss of consciousness within 1 hour of onset of acute symptoms (Priori et al., 2002).

*Correspondence to: Professor Alejandro A. Rabinstein, 200 First Street SW, Mayo W8B, Rochester, MN 55905, USA. E-mail: [email protected]

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By stating that the event should be natural, the aim is to exclude death by violent or traumatic causes. The time criterion attempts to focus on arrhythmic deaths, as this is the mechanism considered most often causative. Yet, it is important to be mindful that instantaneous death can follow various acute diseases which neither necessarily induce fatal arrhythmias nor share the mechanisms and characteristics of SCD to be discussed in this chapter. Examples include ruptured aortic aneurysm, massive pulmonary embolism, and cardiac tamponade, to mention just a few. Furthermore, the most common cause of SCD is myocardial infarction from coronary disease. Cardiomyopathy, with or without left ventricular dysfunction, and various arrhythmogenic disorders (prominently including the Wolff–Parkinson–White syndrome and inherited channelopathies, such as congenital long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, and short QT syndrome) are also relatively common primary cardiac causes of SCD (Priori et al., 2002; Camm et al., 2006). In fact, it is estimated that only 5–10% of cases of SCD occur in subjects without coronary disease or heart failure (Priori et al., 2002). It is these cases that are the focus of the following sections.

PATHOPHYSIOLOGY AND HISTOPATHOLOGY The prevailing concept is that neurocardiogenic injury is caused by catecholamine toxicity, mainly related to sympathetic hyperactivity (Samuels, 2007). It has been known for decades that electrocardiographic changes and myocardial fiber damage can be induced by hypothalamic stimulation in experimental models (Melville et al., 1963). Similar abnormalities have been reported in patients succumbing to strokes that involve the insular cortex (Oppenheimer et al., 1992), another brain structure that participates in the control of central autonomic responses. It is also known that direct stimulation of the heart by catecholamines released by the nerves reaching the myocardium is more toxic than high levels of circulating catecholamines. This notion is supported by experiments demonstrating that the toxicity can be blocked by direct intramyocardial catecholamine depletion with drugs such as reserpine, but less effectively by adrenalectomy (Samuels, 2007). A potential contributing role from simultaneous parasympathetic (vagal) activation has been discussed (Corr et al., 1987), but remains more speculative. The pathologic hallmark of neurocardiogenic injury found in necropsies of patients who suffered sudden cardiac death without pre-existing heart disease (coronary artery disease, cardiomyopathy, or myocarditis) is the myofibrillary degeneration (also known by the more

descriptive terms coagulative myocytolysis or contraction band necrosis) (Reichenbach and Benditt, 1969; Karch and Billingham, 1986; Fineschi et al., 2010). The dead myocardial fibers are widely distributed and they are characterized by a hypercontracted state with abnormal, irregular cross-band structures and associated mononuclear infiltrates. The predominant subendocardial localization (i.e., in close proximity to the electrical conduction system) may contribute to the higher propensity to induce serious cardiac arrhythmias. Calcifications are common. In fact, excessive calcium entry into the myocardial fiber has been postulated to be a key factor in the sequence of molecular changes leading to sudden muscle fiber contraction before cell death (Samuels, 2007). Toxicity mediated by reactive oxygen species may also play a major role. Catecholamines might generate these reactive intermediaries from their auto-oxidation, which in turn could cause loss of intracellular potassium and high-energy phosphates, calcium overload, and local activation of cytokines (Fineschi et al., 2010). Vasospasm and reperfusion injury have also been proposed as alternative mechanisms for the occurrence of neurocardiogenic injury and neurogenic SCD. These mechanisms could be a component of the catecholamine toxicity rather than a separate process. Coronary (macrovascular) vasospasm of epicardial arteries has been conspicuously absent in most series of patients with apical ballooning syndrome (Wittstein et al., 2005; Prasad et al., 2008) and there is no solid documentation of epicardial vasospasm in cases of SCD. Indirect evidence of microvascular spasm in patients with apical ballooning syndrome does exist, but the clinical significance of these findings remains uncertain (Prasad et al., 2008).

PRECIPITANTS Neurogenic triggers of SCD include intense psychological stress and severe acute brain disease (Table 2.1). The role of intense emotions in the generation of neurocardiogenic injury has been pointed out in the historical Table 2.1 Main precipitants of neurocardiogenic injury Emotional stress Fear Anger Acute grief Acute brain disease Aneurysmal subarachnoid hemorrhage Ischemic stroke (insular involvement) Epilepsy with poorly controlled seizures Exposure to extrinsic adrenergic agents

SUDDEN CARDIAC DEATH section of this chapter. More recent literature has confirmed the association between anger, fear, or sudden personal loss with the occurrence of ventricular arrhythmias and myocardial stunning, even in persons without coronary artery disease (Lampert et al., 2002; Wittstein et al., 2005). Extreme versions of these phenomena could produce SCD, which would explain the spikes in SCD observed after natural disasters or in the midst or the aftermath of terrorist attacks (Meisel et al., 1991; Leor et al., 1996; Steinberg et al., 2004). Examples of brain disease that can result in SCD include aneurysmal subarachnoid hemorrhage, acute ischemic stroke (especially when involving the insula), intracerebral hemorrhage, and epilepsy (Ozdemir and Hachinski, 2008; Baranchuk et al., 2009; Schuele, 2009). As emotional stressors, these conditions can also produce nonfatal manifestations of neurogenic heart syndrome, such as repolarization changes, ventricular arrhythmias, and apical ballooning syndrome (Khechinashvili and Asplund, 2002; Prasad et al., 2008).

CLINICAL MANIFESTATIONS Little is known of the events immediately preceding cardiac arrest in patients with neurogenic SCD. It is often assumed that a ventricular arrhythmia would be the final event. Yet, the histopathology of muscle fibers in contraction is not seen in usual cases of death from fatal arrhythmia. Therefore, direct myocardial damage is the primary mechanism of neurogenic SCD. The typical semiology of cardiac failure is not observed before the arrest because of the suddenness of the event. Many more data exist on nonfatal cases of neurocardiogenic injury. The main manifestations are electrical conduction abnormalities and left ventricular stunning (stress cardiomyopathy).

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Electrical conduction abnormalities Electrocardiographic changes are very prevalent after various forms of acute stroke. In a systematic review, it was concluded that electrical conduction abnormalities can be observed in three-quarters of patients with subarachnoid hemorrhage regardless of whether they had pre-existent heart disease. They were present in one-third to nearly one-half of patients with acute ischemic stroke and intracerebral hemorrhage without known heart disease and over 90% of those with this antecedent (Khechinashvili and Asplund, 2002). The incidence of electrocardiographic changes in general and ventricular arrhythmias in particular is much higher when cerebral infarctions affect the insular cortex (Cheung and Hachinski, 2000; Abboud et al., 2006; Ay et al., 2006; Laowattana et al., 2006). The most common abnormalities are repolarization changes, and they may mimic myocardial ischemia. While QT prolongation and ST segment depression or elevation are most frequently noted, diffuse T-wave inversion throughout the precordial leads (often referred to as “cerebral T waves”) are the most characteristic (Fig. 2.1). Q waves may also appear, especially in V1 to V3 leads (Wittstein et al., 2005). When in doubt about the possibility of acute myocardial ischemia, cardiac enzymes and echocardiography should be obtained to determine whether coronary angiography is necessary. Electrophysiologic studies have shown that mental stress can increase the T-wave alternans, a validated measure of heterogeneity of repolarization, in patients with known ventricular arrhythmias treated with implantable cardioverter-defibrillators (Lampert et al., 2009). Polymorphic ventricular arrhythmias can be triggered by emotional stress and acute brain disease, especially (but not exclusively) in patients known to be prone to arrhythmogenesis (Lampert, 2010).

Fig. 2.1. Electrocardiographic changes in a patient with aneurysmal subarachnoid hemorrhage on an electrocardiogram obtained 36 hours after symptom onset. Notice the deep negative T waves in the anterolateral precordial leads and the prolongation of the QT interval.

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Neurogenic electrocardiographic changes are typically transient. Resolution may start within 1–2 days of their appearance, but full normalization may take days or even weeks and occasionally minor repolarization changes may become permanent (Wittstein et al., 2005).

Stress cardiomyopathy Stress cardiomyopathy is a reversible form of primary, acquired cardiomyopathy due to neurogenic myocardial stunning (Prasad et al., 2008). It is also known as takotsubo cardiomyopathy (after the similarity of the left ventriculogram during systole in patients with this condition to an octopus-trapping pot (tako tsubo) used in Japan) or apical ballooning syndrome (for its preferential involvement of the left ventricular apex). It usually occurs in postmenopausal women and it is very rare in patients younger than 50 years (Bybee et al., 2004; Wittstein et al., 2005; Lee et al., 2006). In addition to acute emotional stress, documented precipitants include acute intracranial events (e.g., subarachnoid hemorrhage, ischemic stroke), physical stress, and exposure to exogenous catecholaminergic agents (e.g., high-dose inhaled b-agonists, epinephrine, dobutamine, cocaine) (Arora et al., 2006; Abraham et al., 2009). It has also been exceptionally reported as a complication of acute severe medical illness and after noncardiac surgery (Prasad et al., 2008). Its presentation may mimic an acute coronary event. Angina-like chest pain and acute dyspnea are the most common symptoms. Electrocardiographic changes may include ST elevation in the precordial leads, most often followed by deep, diffuse T-wave inversion; prolongation of the PR and especially the QTc intervals is characteristically present (Wittstein et al., 2005; Prasad et al., 2008). These changes are often associated with modest elevation of troponin levels. Normal R-wave progression gets restored within days. The diagnosis is established by the echocardiographic findings. The typical pattern features preserved or hypercontractile basal function, moderate or severe midventricular dysfunction, and apical akinesis or severe dyskinesis. These wall motion abnormalities extend beyond the distribution of any single coronary artery. Left ventricular ejection fraction is acutely diminished (often to 20–30%), but recovers within 2–4 weeks as all segments regain normal contractility. Rarely, variants of the syndrome with atypical echocardiographic presentations can be encountered. These include concurrent right ventricular involvement (in which signs of congestive heart failure can be pronounced), the apical sparing variant (i.e., wall motion abnormalities limited to the midventricular segments), and the inverted takotsubo (i.e., basal hypokinesis with normal apical function) (Wittstein et al., 2005; Prasad et al., 2008). These four patterns – apical,

Table 2.2 Criteria for the diagnosis of apical ballooning syndrome (adapted from Prasad et al., 2008) Transient akinesis, hypokinesis, or dyskinesis of the left ventricular mid-segments, with or without apical dysfunction, extending beyond the territory of any single coronary distribution Presence of a recognized trigger (not indispensable) No evidence of coronary plaque rupture on angiography New transient electrographic changes and modest elevation of serum cardiac troponin concentration Absence of pheochromocytoma or myocarditis

biventricular, midventricular, and basal – can also be documented by cardiovascular magnetic resonance imaging, which also shows myocardial edema, some myocardial inflammation, and no significant necrosis/fibrosis (Eitel et al., 2011). Pericardial effusion is not infrequent, but usually not severe (Eitel et al., 2011). If performed, coronary angiography shows normal or only mildly atherosclerotic coronary arteries. The absence of delayed gadolinium hyperenhancement on cardiac magnetic resonance imaging may be useful to differentiate stress cardiomyopathy from myocardial ischemia and myocarditis. Criteria for the diagnosis of stress cardiomyopathy are presented in Table 2.2. It is thought that this condition is caused by the effects of excessive sympathetic stimulation of the myocardium. Markers of increased sympathoneural and adrenomedullary activity have been identified in patients with stress cardiomyopathy and endomyocardial biopsies have often shown typical changes of myofibrillary degeneration (Wittstein et al., 2005). Experiments in animal models indicate that high concentrations of epinephrine could change b2-receptor agonism from cardiostimulant (mediated by Gs protein and seen with low concentrations of epinephrine) to cardioinhibitory (mediated by Gi protein) (Paur et al., 2012). Direct myocardial injury would be the main cause of the stunning, but microvascular spasm could play a contributory role. Although the density of sympathetic nerves is greater at the base of the ventricle, the apex may be more responsive to adrenergic stimulation (Mori et al., 1993) and consequently more vulnerable to the detrimental effects of sympathetic surges. It has been proposed that the vulnerability of postmenopausal women to this syndrome could be related to the loss of protective estrogen actions (Prasad et al., 2008).

SPECIFIC CLINICAL SCENARIOS Sudden unexplained death in epilepsy The pathophysiology of sudden unexplained death in epilepsy (SUDEP) remains speculative (So et al., 2009).

SUDDEN CARDIAC DEATH Potential mechanisms include cardiac, respiratory, and autonomic abnormalities. Seizures have various effects on cardiac function which are primarily mediated by ictal activation and postictal suppression of the autonomic nervous system (Schuele, 2009; Sevcencu and Struijk, 2010). Ictal sympathetic activation could lead to myocardial ischemia in patients with coronary disease and fatal arrhythmias. Meanwhile, ictal vagal activation could produce severe bradycardia or asystole, which has been occasionally documented in patients undergoing electroencephalographic monitoring, and this mechanism could explain some cases of SUDEP (So, 2008). Alternatively, postictal suppression of cerebral and brainstem function could provoke a rapid sequence of events mediated by extreme autonomic dysfunction and culminating in respiratory arrest (So, 2008; Schuele, 2009). Reduction in heart rate variability has been documented in patients with refractory epilepsy (Ansakorpi et al., 2002); however, it is not known whether this sign of autonomic dysfunction could represent a marker of patients at high risk for SUDEP. Stress cardiomyopathy can occur after seizures and it has been implicated as a potential mechanism of SUDEP (Dupuis et al., 2012). Numerous risk factors for the occurrence of SUDEP have been identified. Principal among these are frequent generalized tonic-clonic seizures, subtherapeutic anticonvulsant levels, young age, early epilepsy onset, long epilepsy duration, combination of multiple antiepileptic drugs, and low intelligence quotient (So, 2008; Hughes, 2009; Hesdorffer et al., 2011). Currently recommended preventive strategies focus on correcting modifiable risk factors: optimize seizure control (especially reducing the number of generalized tonic-clonic seizures), evaluate for epilepsy surgery immediately after two antiepileptics have failed to control the seizures, emphasize the importance of compliance with medications, and use the lowest possible number of drugs (So et al., 2009; Hesdorffer et al., 2011).

Sudden death after stroke A higher risk of cardiac arrhythmias and sudden death has been observed in patients with infarction involving the insular cortex (Cheung and Hachinski, 2000). It is less clear whether the side of infarction makes a major difference in this risk. While some investigators have found a greater risk in patients with right insular strokes (Abboud et al., 2006; Ay et al., 2006), others have reported a higher risk with left insular infarctions, especially among patients with coronary artery disease (Laowattana et al., 2006). Hence, the validity of the concept of cerebral lateralization of autonomic function and differential risk of cardiac depending on the side of brain damage remain unproven.

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The significance of the finding in a large populationbased study of an association between parietal lobe infarction (but not insular infarction) and higher risk of cardiac events and death over a median follow-up of 4 years cannot presently be elucidated (Rincon et al., 2008).

POTENTIAL PREVENTIVE STRATEGIES Given the unexpected nature of the problem, there are no known strategies to prevent neurogenic SCD. However, it is conceivable that certain pharmacologic interventions could alter the sequence of events responsible for acute neurocardiogenic injury. For instance, b-blockers could diminish the myocardial damage induced by excessive adrenergic stimulation, calcium channel blockers could reduce calcium entry into the cells, and antioxidants and free radical scavengers could minimize the toxicity mediated by reactive oxygen species (Samuels, 2007). Studies evaluating these alternatives could be conducted in selected high-risk populations, such as patients with severe aneurysmal subarachnoid hemorrhage.

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Sudden cardiac death.

Sudden cardiac death can occur after exposure to extreme stress and sometimes as a complication of acute neurologic disease. Excessive adrenergic stim...
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