Brain-Eart Interactions the Neurocardiology of Arrhythmia and Sudden Cardiac Death

Behavioral Aspects ofHeart Disease Brain-eart Interactions The Neurocardiology of Arrhythmia and Sudden Cardiac Death

Alan M. Davis, MD Neuroanatomic connections between the brain and the heart provide links that allow Benjamin H. Natelson, MD cardiac arrhythmias to occur in response to brain activation. Recognition and analysis of such links in the pathogenesis of malignant cardiac arrhythmia are emphasized in this review Neurocardiac links have been shown to produce arrhythmia both experimentally and clinically; specific examples, including stroke, epilepsy, and environmental stress are presented. We hypothesize that the individual with a diseased heart has a greater likelihood of experiencing cardiac arrhythmia and sudden cardiac death when the neurocardiac axis is activated. Reviewing possible mechanisms of brain-related arrhythmias, we suggest that the nervous system directs the events leading to cardiac damage by raising catecholamine levels and potentially inducing arrhythmia. (Texas Heart Insti- tute Journal 1993;20:158-69)

N | eurocardiology investigates the interactions between the brain and the heart that are not generally taught during specialty training within either neurology or cardiology. Cardiology primarily evaluates the end-organ; neurology traditionally evaluates the nervous system. A case study of a neurologist's wife who had migraines and palpitations illustrates how neglecting brain- heart interactions can lead to delayed diagnosis and treatment.' In this case, an Key words: Arrhythmia; otherwise healthy young woman experienced sudden onset of palpitations, shaki- autonomic nervous system; ness, tremor, sweating, lightheadedness, and feelings of dread. She had episodes brain; catecholamines; of palpitations while falling asleep and awakening. These symptoms suggested cerebrovascular disorders; death, sudden; epilepsy; epilepsy, which her husband, the neurologist, evaluated by electroencephalog- heart rate; myocardial raphy. Finding the results to be normal, he requested a cardiac evaluation. Consul- infarction; neural pathways; tations by 3 cardiologists and an internist revealed mitral valve prolapse and the stress, psychological possibility of a psychiatric disorder. Holter monitor electrocardiography revealed frequent runs of sinus tachycardia and one 15-beat series of unifocal ventricular From: The Department beats. The patient was treated with quinidine, digoxin, and verapamil, propran- of Physical Medicine and Rehabilitation (Dr. Davis), olol, and nadolol; only the latter 2-the 5-blockers-suppressed the tremor, sweat- and the Department of ing, and the magnitude of the tachycardia. Although diminished, the bursts of Neurosciences (Drs. Davis tachycardia and the feelings of dread continued, prompting treatment for sus- and Natelson), UMDNJ-NJ Medical School and Grad- pected visceral epilepsy. Her symptoms initially abated with clonazepam admin- uate School of Biomedical istration; when the efficiency of the benzodiazepine waned, her symptoms abated Sciences, Newark, New with carbamazepine. Finally, a computed tomographic scan was ordered, which Jersey; and East Orange Veterans'Administration documented a large, partially calcified, right frontal mass lesion despite the pa- Hospital (Drs. Davis and tient's normal results on neurological examination. At surgery, a large glioma was Natelson), East Orange, found and removed. New Jersey This case report epitomizes the deficiency of our nonintegrated specialty training process. The individual physicians responded to the patient's symptoms with Work by Dr. Davis is treatment from their specific system of interest without considering the ways in supported by NIDRR Dept. of Education Grant which the central nervous system interacts with the heart to produce arrhythmia; H133P10002-93 consequently, correct diagnosis and treatment were delayed. A 1985 neurocardiology review from our laboratory2 examined the neuro- Section editors: anatomy of brain-heart interactions, presented animal models demonstrating these Francisco Fernandez, MD interactions, and cited clinical studies showing brain-heart interactions occurring Virendra S. Mathur, MD within patient populations frequently seen in medical practice. The present review includes additional neuroanatomic findings that have appeared in the litera- Address for reprints: ture more recently. We review the anatomy of the connections between the brain Benjamin H. Natelson, MD, and the heart and discuss how activation of this neurocardiologic axis can pro- New Jersey Medical School, 88 Ross St., East Orange, duce arrhythmia. We hypothesize that the heart, particularly when diseased, is NJ 07018 more likely to develop arrhythmia when central nervous system structures are

158 Neurocardiology of Arrhythmia and Sudden Cardiac Death Volume 20, Number 3, 1993 activated. We show how the neuroanatomic brain- The underlying cause of sudden cardiac death heart links that produce arrhythmia can be activated remains unclear despite several proposed mecha- experimentally by diseases commonly seen in prac- nisms. Early research emphasized heart disease as tice, such as stroke and epilepsy, as well as by envi- the cause of the arrhythmias that produce sudden ronmental stress. cardiac death. Indeed, the patient who has cardiac disease does have a higher risk of sudden cardiac Sudden Cardiac Death death; congestive heart failure'7 and complex ven- Sudden cardiac death epitomizes the most devastat- tricular activity'8 both increase the risk. In 25% to ing arrhythmia and is responsible for nearly one-half 30% of individuals who have multiple-vessel ath- million deaths annually in the United States. Smith3 erosclerotic coronary artery disease, no recognized defines arrhythmia as any disturbance in the cardiac symptoms of heart disease precede sudden cardiac activation sequence or any deviation from accepted death. limits of rate or regularity of the normal impulse, Alternative hypotheses focus on the compromised which is formed in the sinus node and conducted heart as fertile ground for the development of through a specialized system to the endocardial arrhythmia. One such hypothesis proposes that the Purkinje network and the myocardium. The main premature ventricular beat may trigger ventricular types of arrhythmia leading to sudden cardiac death fibrillation, particularly in the presence of myocardial are tachyarrhythmias and bradyarrhythmias. The ischemia. Within this framework, individuals who tachyarrhythmias associated with sudden cardiac have ischemic heart disease would be considered at death include ventricular fibrillation, ventricular greater risk for sudden cardiac death due to an in- tachycardia, and torsade de pointes. The bradyar- creased frequency of premature ventricular beats.'9 rhythmias include sinus bradycardia, complete atrio- The hypothesis of autonomic balance20'2' suggests ventricular block, and sudden asystole. Holter that the heart maintains normal activity when sym- monitor recordings in patients with cardiac disease pathetic and parasympathetic activities are in bal- frequently demonstrate ventricular tachycardia lead- ance; cardiac arrhythmias result from the loss of ing to ventricular fibrillation and, less frequently, autonomic balance. In studies using the balanced bradyarrhythmic heart block leading to asystole.49 autonomic animal model,2' parasympathetic block- Elevation of the ST segment often precedes brady- ade has resulted in tachyarrhythmias, and sinoatrial arrhythmic asystole,4'5'8 although 1 series10 has doc- node removal has produced brady-tachyarrhythmia umented an equal frequency of ST segment ab- similar to that which accompanies the sick sinus syn- normalities in both the tachyarrhythmias and the drome seen in clinical practice. Lown22 described the bradyarrhythmias that lead to sudden cardiac death. heart as a target and the brain as the trigger. Sudden Autopsy studies performed after sudden cardiac cardiac death in this context is triggered by an "elec- death usually lack evidence of new myocardial in- trical accident,"23 which can be treated with ventricu- farction.11"2 Whether an acute arterial lesion forms lar defibrillation; in such cases, patients generally during the period just before sudden cardiac death return to their prior state of health. remains controversial. In an autopsy study of 100 individuals after sudden cardiac death, Davies and Neuroanatomy Thomas'3 defined major luminal occlusion as >500/o Review of neuroanatomy facilitates recognition and of the cross-sectional area, and found that 44% of the analysis of the neurocardiologic links in the patho- individuals with ischemic heart disease had a recent genesis of malignant cardiac arrhythmia. Since our thrombosis of that magnitude. When all cases of in- 1985 article on neurocardiology,2 more recent lit- traluminal thrombosis were included (1% to 100% erature has described influences on the heart from luminal occlusion), 74 of 100 hearts tested had additional brainstem nuclei, the amygdaloid com- thrombosis. Davies'4 performed pathologic evalua- plex, and the cortex.2433 Figure 1 depicts a complex tion on the hearts of 168 individuals who died of of higher nervous influences that descend to the ambulatory sudden cardiac death. Of these, 73.3% heart in cascade fashion, innervating key autonomic showed a recent coronary thrombotic lesion, and structures affecting heart rate and rhythm within the the remainder showed chronic high-grade coronary brainstem and modifying the efferent information stenosis. Study of the cardiac neural elements has relayed to the heart. The heart receives neural input yielded results suggesting that autonomic damage is through parasympathetic ganglia and the intermedi- associated with sudden death. James'5 demonstrated olateral gray column of the spinal cord, both of that a variety of inflammatory and degenerative le- which are influenced by multiple medullary nuclei. sions can affect the intracardiac nerves and ganglia, With few exceptions, most of the higher centers as well as the coronary chemoreceptor. Another provide descending efferent connections with med- group'6 documented catecholamine depletion in ad- ullary nuclei. The cortex and amygdaloid complexes renergic elements of the cardiac nerve plexi. have many connections with all of the lower levels.

Texas Hea?l Instituteiournal Neurocardiology of Arrhythmia and Sudden Cardiac Death 159 C IoLrA -4

AMYGDALOID 'COMPLEX

-HYPOTHALAMUS

BRAIN STEM

SPEALCORD & GANmJI

HEART

Fig. 1 Neuroanatomic links producing arrythmia. DVN = dorsal vagal nucleus; LC = locus coeruleus; NA = nucleus ambiguus; NTS = nucleus tractus solitarius; PAG = periaqueductal gray matter; PVN = paraventricular nucleus; VLM = ventrolateral medulla (Modified from Natelson BH,2 with permission. Copyright 1985, American Medical Association.)

Hypothalamic nuclei send descending connections tractus solitarius (NTS) connects reciprocally with to brainstem, spinal cord, and ganglia. The nucleus both the paraventricular nucleus (PVN) and the area

160 Neurocardiology of Arrhythmia and Sudden Cardiac Death Volume 20, Number 3, 1993 postrema. As part of the parasympathetic efferent frequently in the nontransmural infarction group motor system, the NTS provides afferent information with sympathetic fiber interruption. The group that to the parabrachial nucleus, which sends fibers to the had transmural myocardial infarction and interrupted ventrolateral medulla (VLM). Depending on the spe- sympathetic fibers showed denervation supersensi- cies studied, vagal and sympathetic nerves leading tivity; however, programmed stimulation did not in- to the heart may be confluent rather than discrete. crease their vulnerability to ventricular fibrillation. Afferent nerves from the heart stretch, and chemore- These researchers suggested that the dyshomoge- ceptors ascend via the spinal cord or the 9th or 10th nous nontransmural myocardial infarction might cranial nerve to terminate in the NTS and the dorsal produce nonuniform depression of excitability and vagal nucleus (DVN). conduction. The incidence of ventricular fibrillation increased most in those dogs with sympathetic den- Peripheral Nerve Activity and Arrhythmia ervation, and during norepinephrine infusion. Pro- Animals with Normal Hearts. We now examine pranolol attenuated both the shortening of the the conditions that contribute to malignant arrhyth- effective refractory period and the induction of ven- mias, or "electrical accidents" in the case of sudden tricular fibrillation. cardiac death. Studies of neurocardiac axis activation In a similar cat model, Schwartz and colleagues42 in animals have documented that stimulating the evaluated the effectiveness of antiarrhythmic agents. peripheral nervous system can produce both ar- Class I antiarrhythmics (lidocaine, mexiletine, and rhythmia and pathologic changes within the heart. propafenone) did not protect the animals from lethal Stimulating either the ventrolateral34 or the ventro- arrhythmias, and in some cases were proarrhyth- median35 sympathetic cardiac nerve in dogs elicits mogenic. Prazosin and propranolol (Class II anti- nodal arrhythmias and, less often, ventricular ar- arrhythmics), however, were 60% and 800/o effective, rhythmias. Randall and co-authors20 developed a respectively. The calcium channel blocker verapamil canine model of autonomic imbalance leading to (Class III) protected completely against induced ven- cardiac arrhythmias; they surgically denervated the tricular tachycardia and ventricular fibrillation, as did heart, sparing only the ventrolateral nerve. During amiodarone (Class IV). Effectiveness seemed related strenuous exercise, the dogs manifested multiple ab- to the ability of the drug to decrease both sympa- normal rhythms, including ventricular tachycardia thetic outflow and coronary ischemia through vaso- and premature ventricular beats. dilation. Using left ansae stimulation and right ansae Programmed ventricular stimulation is a method transection in an ischemic canine model, Euler and of testing for sensitivity to the development of ven- associates43 demonstrated that the sympathetic ner- tricular arrhythmias. The ventricle is stimulated for vous system has a direct arrhythmogenic effect (on a short series of beats, and additional stimulation is ventricular fibrillation) independent of heart rate. administered in an attempt to elicit ventricular ec- In contrast to sympathetic stimulation, parasympa- topy. One group of investigators3 used programmed thetic stimulation appears to protect the heart against ventricular stimulation combined with either bilater- arrhythmia. In studies of previously infarcted dogs, al ansa subclaviae stimulation or norepinephrine in- direct stimulation of the right vagus nerve provided fusion, which produced ventricular arrhythmias after 900/o protection against ventricular fibrillation during regional sympathetic denervation in dogs. Pathologic exercise.44 Decreasing vagal activity with atropine changes due to arrhythmia after peripheral nerve increased the incidence of arrhythmias, including stimulation include subendocardial hemorrhage with ventricular fibrillation, in approximately 75% of ex- myofibrillar degeneration and necrosis, which have ercising dogs tested.45 Low levels of intravenous been noted after stellate ganglion stimulation in acetylcholine were found to augment the duration healthy dogs,37 after peripheral stimulation and aor- of ventricular fibrillation in rats; higher doses pro- tic arch stimulation, M and after norepinephrine infu- duced the opposite effect.46 sion.6 Risk of exercise-induced ventricular fibrillation Animals with Abnormal Hearts. Arrhythmias may can also be assessed by measuring baroreceptor re- develop in an ischemic or infarcted heart during pe- flex sensitivity, which is the change in heart rate that ripheral nervous system stimulation. Sympathetic hy- occurs as blood pressure is manipulated pharmaco- peractivity due to ischemia39 and dyshomogeneity of logically. Integrating sympathetic and parasympa- sympathetic innervation due to infarction40 are asso- thetic reflexes, Schwartz and coworkers47 measured ciated with malignant ventricular arrhythmia. Inoue baroreceptor reflex sensitivity in previously infarcted and Zipes41 developed a canine model of myocar- dogs to evaluate susceptibility to ventricular fibrilla- dial infarction with sympathetic or parasympathetic tion during the sympathetic stimulation caused by denervation, or both. Using programmed ventricu- ischemia and strenuous exercise. Dogs with a lower lar stimulation, they measured the incidence of ven- baroreceptor reflex sensitivity had a significantly tricular fibrillation and found that it occurred most higher risk of exercise-induced ventricular fibrilla-

Texas Heart Institutejournal Neurocardiology of Arrhythmia and Sudden Cardiac Death 161 tion. These studies support the hypothesis that there pathetic nerve discharge.57 Kindled seizures in rats58 is a critical autonomic balance that prevents cardiac generated by subthreshold electrical stimulation of arrhythmia. Ischemia and myocardial infarction ap- the amygdala induced cardiac arrhythmias, including pear to upset this balance, which predisposes the premature ventricular complexes, profound brady- diseased animal heart to a higher risk of arrhythmia. cardia, and increased PR interval during seizure activity. Hypothalamic chemical stimulation producing Central Nervous System focal epilepsy in hemispherectomized rats59 resulted Activity and Cardiac Dysfunction in bradyarrhythmias, sinus arrest, and ventricular bi- Animals with Normal Hearts. Animal models of geminy. These results show that epilepsy also acti- human central nervous system disease demonstrate vates the neurocardiac axis and disrupts autonomic that electrocardiographic changes, cardiac arrhyth- balance, leading to potentially fatal cardiac arrhythmias, and sudden death may arise from the effects mias. of central nervous system activation. Spinal cord Stimulation of specific brain areas activates the compression and head trauma have both produced brain-heart links and results in cardiac arrhythmia cardiac arrhythmias in monkeys.4849 In a study by and morphologic cardiac changes. Administering McNair and coworkers,50 subarachnoid blood in lateral hypothalamic stimulation in cats6O has pro- mice produced myocardial necrosis in 48% of the duced subendocardial damage. In a study by Evans animals. This cardiac damage was prevented by pre- and Gillis,61 sinoatrial node denervation prior to treatment with reserpine and attenuated by atro- hypothalamic stimulation consistently allowed the pine.50'51 Raising intracranial pressure in rats resulted occurrence of stimulus-bound nodal arrhythmias, in increased plasma catecholamine levels and myo- presumably due to unmasking of the subatrial pace- cardial damage.52 Uchida and associates" injected makers. Propranolol and phenytoin each prevented rabbits with prostaglandin PGF2a intracisternally these arrhythmias and the concomitant sympathetic and recorded electrocardiographic changes, includ- hyperactivity. Oppenheimer and associates62 used ing bradycardia, premature beats, ventricular tachy- phasic electrical stimulation of the insula locked to cardia, and ventricular fibrillation. Middle cerebral specific times in the cardiac cycle of rats, producing artery stroke in the rat resulted in subendocardial electrocardiographic changes and progressive heart damage, increased pulse and arterial pressures, and block leading to ventricular ectopy and death in increased plasma catecholamines.54 Smith's group55 asystole. Plasma norepinephrine levels were raised measured plasma levels of norepinephrine, epineph- markedly and myocardial damage was documented. rine, and dopamine in cats during occlusion of the Animals with Abnormal Hearts. Similarly, expe- left middle cerebral artery; these plasma levels were rimental studies demonstrate that central nervous elevated significantly when the stroke involved the system stimulation of the abnormal heart through insular cortex, but not when sham-operated or cere- anatomic links can also affect the production of bral infarction spared the insula. This finding sug- malignant arrhythmias. Digitalis toxicity, a common- gests that the sympathetic stimulation occurring after ly seen cardiac problem, may cause ventricular ar- stroke may be specific to the insula. rhythmias. Sympathetic blockade prevents these Animal models of epilepsy also demonstrate that arrhythmias in guinea pigs.63 The brain site for digi- central nervous system dysfunction may result in talis-related cardiac arrhythmias has not been clearly cardiac arrhythmias and sudden death. Using a cat identified. In their work with rabbits, Markgraf and model of epilepsy induced by pentylenetetrazol, Kapp' administered digitalis and then electrically Lathers and co-authors56 observed that preganglionic stimulated the amygdaloid central nucleus, which sympathetic and vagal discharges were correlated in elicited bradycardia followed by ventricular ecto- time with both ictal and interictal spikes on the con- py, premature ventricular beats, and bundle-branch current electroencephalogram. This synchroniza- block. These investigators then used Pavlovian con- tion of electroencephalographic activity with cardiac ditioning to reproduce the arrhythmias with an aver- neural discharge occurred more frequently with sym- sive conditioned stimulus in the rabbits64 as had been pathetic than with vagal neural discharge. The au- done previously in guinea pigs.65 Experimentally- thors suggested this synchronization of epileptiform induced bilateral lesions in the amygdaloid central spikes with cardiac sympathetic neural discharge as nuclei attenuated the conditioned-stimulus arrhyth- a possible explanation of sudden unexplained epi- mias.k In cats, the anterior hypothalamus66 and the leptic death without overt seizure activity. Various midbrain67 are other sites that have been shown to doses of pentylenetetrazol56'57 produced differential attenuate the production of digitalis-related arrhyth- autonomic imbalance without overt epileptiform ac- mias. The area postrema has been disproved as a tivity. Moderate doses (50 mg/kg) resulted in more facilitating area for these arrhythmias.68 parasympathetic variability in discharge, whereas Using the infarcted animal heart enables inves- higher doses (100 mg/kg) resulted in increased sym- tigators to examine the ways in which the central

162 Neurocardiology of Arrhythmia and Sudden Cardiac Death Volume 20, Nu m ber 3, 199-3 nervous system contributes to arrhythmogenesis. In toxicity occurred earlier and more frequently in the such studies, a coronary artery is usually ligated to rabbits conditioned to expect a shock after hearing a predispose the heart to arrhythmia before specific tone than in those that were given randomly admin- areas of the central nervous system are stimulated or istered shocks and tones. ablated. Somberg and colleagues69 ligated the left The 2nd model uses a coronary infarct to sensi- coronary artery and recorded a lower incidence of tize the heart to arrhythmia. Randall and Hasson78 arrhythmias in cats after brainstem transection at the applied classical aversive conditioning in monkeys obex. Skinner's group functionally blocked the fron- after left anterior descending coronary artery oc- tal lobes70 and the amygdaloid central nucleus71 in clusion. Although the aversive situations did not pigs, which decreased the incidence of ventricular necessarily cause more arrhythmia, the investiga- fibrillation. tors noted that ventricular arrhythmias occurred most Recently, investigators using animal models of ar- frequently when the heart rate of an animal was rhythmia caused by drugs or infarction have modi- within a specific range. This finding was attributed to fied arrhythmias with a variety of drugs administered the underlying sympathetic and parasympathetic bal- by intracerebroventricular injection. In 1 study in- ance. In dogs with healed, experimentally-induced volving guinea pigs,72 both morphine and dynorphin myocardial infarction, stress caused a re-emergence were found to increase the dose at which digoxin- of the early ventricular arrhythmias seen in the acute induced arrhythmias occurred; this attenuation was infarction period.7980 In a study of pigs70 having tem- reversed by atropine sulfate, which crosses the porary occlusion of the left anterior descending cor- blood-brain barrier. These results support evidence onary artery, ventricular fibrillation occurred when that central cholinergic parasympathetic mechanisms the animals were stressed by having their feet taped influence the production of arrhythmias. Central together. Bilateral cryoblockade of the amygdala nervous system activation, superimposed upon the blocked this lethal effect in 5 of 8 animals. Kirby's compromised heart, provides a fertile setting for group8l used a porcine model with previous myo- arrhythmogenesis. cardial infarction and noted that increased behavioral arousal or social stress enhanced the induci- Environmental Stress bility and rate of ventricular tachycardia; metopro- and Cardiac Dysfunction lol blocked this enhancement. In another study82 Animals with Normal Hearts. Stress alone does using pigs with recent experimentally-induced myo- not produce potentially lethal arrhythmias in studies cardial infarction, researchers noted a decreased of animals with normal hearts.2 However, stress does extrasystole threshold during repetitive stimulation appear to cause cardiac damage that may lead to in comparison with normal controls. Ninety minutes arrhythmia. A study in which monkeys were given after administration of the catecholamine precur- a high-cholesterol diet and then subjected to social sor tyrosine, the threshold increased to near-control disruption73 revealed development of microscopic levels. endothelial damage, the precursor of coronary artery The 3rd method uses animals with genetic predis- disease. To test whether sympathetic arousal and the position to heart disease. Cardiomyopathic hamsters, resulting increase in heart rate led to these changes, for example, develop congestive cardiomyopathy the researchers administered the ,13-adrenergic with focal sites of micronecrosis and die early. When blocking agent metoprolol and noted inhibition of cold and immobilization83 were used as stressors to the endothelial injury.73 When pharmacologically activate the sympathetic nervous system, healthy paralyzed pigs were subjected to occasional electric hamsters were not affected by the stress, but cardio- shocks74 over a 15- to 20-minute period, malignant myopathic hamsters died. Alprazolam significantly arrhythmias developed in 16 of 23. Two days later reduced the stress-induced mortality.83 Verapamil the 20 surviving animals were killed, and pathologic sensitized the hamsters to stress,84 causing arrhyth- heart changes were noted in all. mic death, presumably due to verapamil's inhibition Animals with AbnormalHearts. Researchers have of atrioventricular nodal conduction. As opposed to formulated 3 basic animal paradigms to evaluate those with normal hearts, animals with abnormal the contribution of stress to arrhythmogenesis in the hearts frequently died of arrhythmia when subjected compromised heart: drug administration, coronary to environmental stress. infarction, and genetic predisposition to heart disease. Drug administration may increase the suscep- Laterality of Function tibility of the normal heart to arrhythmia. In our Animal Hearts. Both the sympathetic and the laboratory,75'76 psychological stress sensitized guinea parasympathetic branches of the central nervous sys- pigs to digitalis-induced arrhythmias due to changes tem that influence cardiac rhythms demonstrate lat- in peripheral cholinergic function. In a learned fear erality of function. In our earlier review,2 we noted a model using rabbits,77 arrhythmias due to digitalis right-sided predominance for the control of heart

Texas Hea?l Instituteiournal Neurocardiology of Arrhythmia and Sudden Cardiac Death 163 rate and a left-sided predominance in the genesis of is mediated by the parasympathetic nervous system arrhythmias. The work with animals85 showed that through the vagus nerve and can be diminished by stimulating the left stellate ganglion lowered the atropine.92 Because this variability can be measured threshold for ventricular fibrillation; in contrast, stim- electrocardiographically, investigators have a non- ulating the right stellate ganglion raised the thresh- invasive method to determine the level of cardiac old.85 The left stellate ganglion was ablated in parasympathetic activity. experiments designed to reduce the risk of arrhyth- This approach has been used by Kleiger and co- mogenesis. Because animal studies showed that workers93 to calculate the relative risk of cardiac stimulation of the left stellate ganglion produced mortality after myocardial infarction. They found that ventricular fibrillation and its ablation protected the patients with reduced heart rate variability (<50 animal from this arrhythmia,6386 similar studies were msec) had 5 times the mortality of individuals whose developed for application in human beings. heart rate variability was more than 100 msec. Rich Human Hearts. Individuals with idiopathic long and co-authors94 extended the study of heart rate Q-T syndrome87 have prolonged Q-T interval and variability to include 100 individuals without recent syncopal episodes due to ventricular fibrillation; myocardial infarction who were undergoing coro- these usually result in sudden death during the first nary angiography. Using baseline Holter monitor re- 2 decades of life. Death often occurs under condi- cordings and observing these individuals for 1 year, tions that increase sympathetic activity, such as the investigators noted a markedly higher mortality strong emotions or physical exertion. I-Adrenergic rate in those with reduced heart rate variability (<50 blocking agents markedly decrease the syncopal msec, 36%; >50 msec, 2%). episodes; however, a subgroup of individuals with Recently, more sophisticated methods of measur- long Q-T syndrome continue to experience syncope. ing interbeat interval change during respiration have Fifty-seven patients who did not respond to 3- led to clearer insights into the factors contributing blockers underwent neurosurgical treatment with to heart rate variability. Power spectrum analysis of high left thoracic stellectomy, a surgical approach heart rate variability serves as a very sensitive tool that removes the first 4 to 5 thoracic ganglia. This for understanding cardiac control. This statistical approach markedly decreased the mortality rate of technique allows greater precision in finding sources this high-risk subgroup from 700/o in the first 5 years of interbeat variability, breaking them down into to less than 7% after 7 years of this ongoing study.87 specific frequencies. A peak on the frequency spec- In a clinical trial88 enrolling patients with anterior trum occurring at about 0.2 cycles/sec represents myocardial infarction complicated by ventricular the variability due to respiration and has been shown fibrillation, high thoracic left sympathectomy de- to be purely parasympathetic.9295 Other sources of creased the mortality rate from 21.3% to 3.6%. cardiac rhythm control such as sympathetic activity, Consistent with previous findings regarding lat- parasympathetic-sympathetic interaction, and hor- eralization of rhythm control, a review of the Hol- monal release can also be analyzed with power ter monitor recordings of patients with lateralized spectrum analysis. In addition, this method has been stroke89 documented sinus tachyarrhythmias only in used to demonstrate a circadian rhythm in heart rate patients with right-sided strokes. These results dem- variability,% to show abnormal autonomic heart rate onstrate a loss of right-sided predominance of para- influences in patients with Alzheimer's disease,97 to sympathetic control in addition to the increased provide a marker of vulnerability to stress,98 and to sympathetic tone associated with stroke. calculate the likelihood of surviving sudden cardiac arrest.99 Spectrum analysis has also enabled investi- Noninvasive Assessment of Nerves gators to measure reproducible differences in the to the Heart and Risk of Sudden Death heart rate variability of individuals who have con- Parasympathetic activity generally provides an anti- gestive heart failure compared with those who have arrhythmic effect by slowing heart rate, antagonizing normal heart function.'00 The heart rate spectrum sympathetic activity, and effecting electrophysiologic has been correlated with mortality to determine the changes in the myocardium.Y0 Vagal overstimulation prognosis of patients with end-stage heart failure.10' rarely causes arrhythmias.9' Measuring the level of Baroreceptor reflex sensitivity measurement eval- parasympathetic activity may therefore provide a uates vagal reflexes and has also been used to as- rational basis for assessing risk of sudden cardiac sess the risk of sudden death. Baroreceptor reflex death. Heart rate variability results from the coupling sensitivity (BRS) represents the change in heart rate of respiration to the duration of time between heart that occurs as blood pressure is manipulated phar- beats, which produces the commonly observed res- macologically. Low BRS indicates that heart rate piratory sinus arrhythmia seen during electrocardio- changes minimally in response to such changes; high graphic evaluation of young healthy individuals. BRS indicates that the heart rate responds readily to This coupling, which results in heart rate variability, changes in blood pressure. In a prospective clinical

164 Neurocardiology of Arrhythmia and Sudden Cardiac Death Volume 20, Number 3, 1993 study of patients enrolled 1 month after myocardial been reported. Earnest and associates'09 retrospec- infarction, Schwartz and colleagues102 assessed the tively studied patients who died of epileptic sudden correlation between BRS and cardiac mortality. Dur- death in comparison with those who had epilepsy ing the course of the study, mortality was 50% in the but were otherwise healthy. These investigators group having absent or low BRS compared with 3% measured a significantly prolonged Q-Tc (corrected in the group having higher BRS. for rate) interval-a known risk for sudden death- in the group that died; their risk appears to be com- Human Studies Implicating the Nervous parable with that of individuals who have idiopathic System in the Pathogenesis of Arrhythmias long Q-T syndrome. Prolonged Q-Tc interval may be After reviewing neuroanatomy and animal studies a marker for electrical instability resulting from cen- that show the existence and function of brain-heart tral nervous system stimulation or instability.'09 The links leading to cardiac arrhythmias, we examine tachycardia and elevated catecholamines"8 associ- whether commonly encountered neurologic syn- ated with sudden unexpected epileptic death may be dromes also lead to arrhythmia. Stroke, epilepsy, and a result of sympathetic activation or autonomic im- environmental stress all provide clinical examples balance brought on by the same brain-heart links of how the neurocardiac axis may be activated. that lead to sudden cardiac death. Stroke. Stroke activates the neurocardiac axis, Stress. The lay community would not argue that producing arrhythmia, cardiac damage, and sudden emotional stress contributes to mortality. The expres- death. Electrocardiographic abnormalities and cardi- sion that someone "died of a broken heart" does ac arrhythmias following stroke have been reported. have epidemiologic support. In a prospective Fin- Andreoli and associates103 systematically evaluated nish study of 95,647 widowed individuals,"19 the 70 patients during the 1st acute phase of subarach- highest mortality occurred during the 1st week of noid hemorrhage using continuous Holter monitor- bereavement with more than double the expected ing. They found that 41% of the individuals studied risk. The presence of ischemic heart disease further had severe cardiac arrhythmias, including ventric- increased this rate to 2.3 times the risk for men and ular fibrillation, successive ventricular premature 3.5 for women.'19 The influence of psychosocial complexes, supraventricular tachycardia, and brady- factors on mortality after myocardial infarction has arrhythmias. They noted no correlation between age been explored extensively. and the occurrence or severity of heart disease. Con- Lown's group'20 suggested that stress is a precipi- tinuous electrocardiographic monitoring after sub- tant of ventricular premature contractions with ven- arachnoid hemorrhage'10 documented more cardiac tricular fibrillation, both in patients with normal arrhythmias (except for sinus bradycardias and asys- hearts'20 and in those with heart disease.19 In a group tole) in a subgroup of patients with midbrain symp- of patients with frequent ventricular premature beats toms, which may provide clinical evidence of lost but no previous myocardial infarction,'2' psychologi- hypothalamic-medullary integration at a midbrain cal profiles described higher hysteria scores and synapse. Overactivity of the parasympathetic ner- more anxiety, depression, and social isolation when vous system may also cause sudden death with asys- compared with the profiles of general medical and tole after stroke.'05 Oppenheimer and Hachinski'06 surgical patients. In a study of 2,320 men enrolled in have suggested that an increase in catecholamines is the n-Blocker Heart Attack Trial, Ruberman'22 noted 1 possible mediator of electrocardiographic changes that a high degree of life stress and social isolation and heart damage. occurred with greater frequency in the individuals Epilepsy. Sudden unexplained death in patients with less education, and these factors correlated with with epilepsy occurs at a rate of about 2 per thou- a fivefold increased risk of sudden death for the 3 sand.'07 According to their clinical histories, death years following myocardial infarction. One study of occurs in young patients who have generalized sei- arrhythmia after myocardial infarction'23 revealed zures with subtherapeutic serum levels of anticon- that the level of self-reported psychological stress vulsant medication and have a history of alcohol or predicted an increased risk of ventricular ectopy and substance abuse.108-10 Susceptibility to sudden car- malignant arrhythmias. Frasure-Smith and Prince'24 diac death in a person having epilepsy might be monitored life stress intermittently in 453 male myo- due to a brain focus that is stimulating arrhythmia. cardial infarction patients and used stress reduction Simultaneous recordings during seizures"' "-13 have techniques when the stress score passed a critical demonstrated an association between electrocardio- level. During a 1-year period, fewer deaths occurred graphic abnormalities and electroencephalograph- in the monitored group receiving treatment for stress ic changes. Typical electrocardiographic changes than in the group not monitored. Tavazzi and asso- include the onset of tachycardia just before the sei- ciates'25 used programmed ventricular stimulation to zure with both atrial and ventricular ectopy. Sinus study the stress of mental arithmetic in patients after arrest 114-117 and ventricular tachycardial" have also myocardial infarction; their results suggested that this

Texas Hea?l Instituteiournal Neurocardiology of Arrhythmia and Sudden Cardiac Death 165 stressor lowers the fibrillation threshold in such pa- 8. Bayes-de Luna A, Coumel P, Leclercq JF. Ambulatory sud- tients. den cardiac death: mechanisms of production of fatal arrhythmia on the hasis of data from 157 cases. Am Heart J 1989;1 17:151-9. Conclusions 9. Olshausen KV, Witt T, Pop T, Treese N, Bethge KP, Meyer J. Sudden cardiac death while wearing a Holter monitor. Am J This paper maps the nervous system anatomy affect- Cardiol 1991;67:381-6. ing the genesis of cardiac arrhythmias, reviews ex- 10. Pepine CJ, Morganroth J, McDonald JT, Gottlieb SO. Sudden perimental studies showing these interactions, and death during ambulatory electrocardiographic monitoring. presents typical clinical examples of brain-heart in- AmJ Cardiol 1991;68:785-8. 11. Friedman M, Manwaring JH, Rosenman RH, Donlon G, teractions. The diseased heart is more sensitive to the Ortega P, Grube SM. Instantaneous and sudden deaths: clini- development of arrhythmias than is the normal heart. cal and pathological differentiation in coronary artery dis- Hypothetical mechanisms through which the neuro- ease. JAMA 1973;225:1319-28. cardiac links become activated include autonomic 12. Spain DM, Bradess VA. Sudden death from coronary heart imbalance, premature ventricular beats leading to disease: survival time, frequency of thrombi, and cigarette smoking. Chest 1970;58:107-10. malignant arrhythmias, or heart disease itself. The 13. Davies MJ, Thomas A. Thrombosis and acute coronary- role of catecholamines presents a unifying hypoth- artery lesions in sudden cardiac ischemic death. N Engl J esis involving such diverse entities as stroke, epi- Med 1984;310:1137-40. lepsy, and environmental stress and how they result 14. Davies MJ. Anatomic features in victims of sudden coronary in arrhythmia and cardiac damage.126-128 death: coronary artery pathology. Circulation 1992;85(Suppl However, I):I-19-24. catecholamine release stems from neural activation; 15. James TN. Degenerative lesions of a coronary chemorecep- therefore, it is the nervous system that plays the cru- tor and nearby neural elements in the hearts of victims of cial role in determining whether arrhythmias will sudden death. J Am Coll Cardiol 1986;8(Suppl A):12A-21A. occur in the compromised heart, and for this reason 16. Shvalev VN, Vikhert AM, Stropus RA, et al. Changes in neu- we place the nervous system at the top of a cascade ral and humoral mechanisms of the heart in sudden death due to myocardial abnormalities. J Am Coll Cardiol 1986;8 of pathophysiologic events that can end in sudden (Suppl A):55A-64A. cardiac death. 17. Stambler BS, Wood MA, Ellenbogen KA. Sudden death in Clinicians evaluating patients who have been ex- patients with congestive heart failure: future directions. PACE periencing arrhythmia under conditions that stimu- Pacing Clin Electrophysiol 1992;15:451-70. late the central nervous system should consider the 18. Abdalla ISH, Prineas RJ, Neaton JD, Jacobs DR Jr, Crow RS. Relation between ventricular premature complexes and sud- neurocardiac links described. Medical training pro- den cardiac death in apparently healthy men. Am J Cardiol grams in the United States emphasize expertise in 1987;60: 1036-42. single systems at the expense of interdisciplinary 19. Lown B, DeSilva RA, Lenson R. Roles of psychologic stress skills. Growing recognition of this deficiency means and autonomic nervous system changes in provocation of that the physicians of the future are more likely to ventricular premature complexes. Am J Cardiol 1978;41:979- 85. have a working knowledge of integrated systems, 20. Randall WC, Kaye MP, Hageman GR, Jacobs HK, Euler DE, which will provide them with a broader perspective Wehrmacher W. Cardiac dysrhythmias in the conscious dog when evaluating and treating patients. after surgically induced autonomic imbalance. Am J Cardiol 1976;38: 178-83. 21. Wehrmacher WH, TalanoJV, Kaye MP, Randall WC. The un- balanced heart: animal models of cardiac dysrhythmias. Car- References diology 1979;64:65-74. 22. Lown B. Sudden cardiac death: the major challenge con- 1. Natelson BH. Need for an integrative approach to medical fronting contemporary cardiology. AmJ Cardiol 1979;43:313- diagnosis. Am J Med 1986;80:1017-8. 28. 2. Natelson BH. Neurocardiology: an interdisciplinary area for 23. Lown B, Verrier RL, Rabinowitz SH. Neural and psychologic the 80s. Arch Neurol 1985;42:178-84. mechanisms and the problem of sudden cardiac death. Am 3. Smith WM. Mechanisms of cardiac arrhythmias and conduc- J Cardiol 1977;39:890-902. tion disturbances. In: Hurst JW, Schlant RC, Rackley CE, 24. Ruggiero DA, Mraovitch S, Granata AR, Anwar M, Reis DJ. A Sonneblick EH, Wenger NK, eds. The heart, arteries and role of insular cortex in cardiovascular function. J Comp veins. 7th ed. New York: McGraw-Hill, 1990:473-89. Neurol 1987;257:189-207. 4. Clark MB, Dwyer EM Jr, Greenberg H. Sudden death during 25. Oppenheimer SM, Cechetto DF. Cardiac chronotropic orga- ambulatory monitoring: analysis of six cases. Am J Med 1983; nization of the rat insular cortex. Brain Res 1990;533:66-72. 75:801-6. 26. Yasui Y, Breder CD, Saper CB, Cechetto DF. Autonomic re- 5. Savage HR, KissaneJQ, Becher EL, Maddocks WQ, Murtaugh sponses and efferent pathways from the insular cortex in the JT, Dizadji H. Analysis of ambulatory electrocardiograms in rat. J Comp Neurol 1991;303:355-74. 14 patients who experienced sudden cardiac death during 27. Cassell MD, Gray TS. The amygdala directly innervates ad- monitoring. Clin Cardiol 1987;10:621-32. renergic (Cl) neurons in the ventrolateral medulla in the rat. 6. Greenberg HM. Bradycardia at onset of sudden death: po- Neurosci Lett 1989;97:163-8. tential mechanisms. Ann N Y Acad Sci 1984;427:241-52. 28. Cechetto DF, Chen SJ. Subcortical sites mediating sympa- 7. Schmidinger H, Weber H. Sudden death during ambulatory thetic responses from insular cortex in rats. Am J Physiol Holter monitoring. Int J Cardiol 1987; 16:169-76. 1990;258:R245-55.

166 Neurocardiology of Arrhythmia and Sudden Cardiac Death Volume 20, Number 3, 199-3 29. Allen GV, Cechetto DF. Functional and anatomical organiza- 50. McNair JL, Clower BR, Sanford RA. The effect of reserpine tion of cardiovascular pressor and depressor sites in the lat- pretreatment on myocardial damage associated with simu- eral hypothalamic area: I. Descending projections. J Comp lated intracranial hemorrhage in mice. EurJ Pharmacol 1970; Neurol 1992;315:313-32. 9:1-6. 30. Mastrianni JA, Palkovits M, Kunos G. Activation of brainstem 51. Hawkins WE, Clower BR. Myocardial damage after head endorphinergic neurons causes cardiovascular depression trauma and simulated intracranial haemorrhage in mice: the and facilitates baroreflex bradycardia. Neuroscience 1989;33: role of the autonomic nervous system. Cardiovasc Res 1971; 559-66. 5:524-9. 31. Sved AF, Felsten G. Stimulation of the locus coeruleus de- 52. Shanlin RJ, Sole MJ, Rahimifar M, Tator CH, Factor SM. In- creases arterial pressure. Brain Res 1987;414:119-32. creased intracranial pressure elicits hypertension, increased 32. Ferguson AV, Smith P. Autonomic mechanisms underlying sympathetic activity, electrocardiographic abnormalities and area postrema stimulation-induced cardiovascular responses myocardial damage in rats. J Am Coll Cardiol 1988;12:727- in rats. AmJ Physiol 1991;261:R1-8. 36. 33. Barraco RA, el-Ridi MR. Cardiorespiratory responses follow- 53. Uchida M, Saito K, Niitsu T, Okuda H. Model of electrocar- ing electrical stimulation of caudal sites in the rat medulla. diographic changes seen with subarachnoid hemorrhage in Brain Res Bull 1989;23:299-310. rabbits. Stroke 1989;20:112-8. 34. D'Agrosa LS. Cardiac arrhythmias of sympathetic origin in the 54. Cechetto DF, Wilson JX, Smith KE, Wolski D, Silver MD, dog. Am J Physiol 1977;233:H535-40. Hachinski VC. Autonomic and myocardial changes in middle 35. Gillis RA, Pearle DL, Hoekman T. Failure of beta-adrenergic cerebral artery occlusion: stroke models in the rat. Brain Res receptor blockade to prevent arrhythmias induced by sym- 1989;502:296-305. pathetic nerve stimulation. Science 1974;185:70-2. 55. Smith KE, Hachinski VC, Gibson CJ, Ciriello J. Changes in 36. Inoue H, Zipes DP. Results of sympathetic denervation in the plasma catecholamine levels after insula damage in experi- canine heart: supersensitivity that may be arrhythmogenic. mental stroke. Brain Res 1986;375:182-5. Circulation 1987;75:877-87. 56. Lathers CM, Schraeder PL, Weiner FL. Synchronization of car- 37. Klouda MA, Randall WC. Subendocardial hemorrhages dur- diac autonomic neural discharge with epileptogenic activity: ing stimulation of the sympathetic cardiac nerves. In: Raab the lockstep phenomenon. Electroencephalogr Clin Neuro- W, ed. Prevention of ischemic heart disease: principles and physiol 1987;67:247-59. practice. Springfield, Illinois: Charles C Thomas, 1966:49-56. 57. Lathers CM, Schraeder PL. Autonomic dysfunction in 38. Zavodskaya IS, Moreva EV, Novikova NA. Neurogenic heart epilepsy: characterization of autonomic cardiac neural dis- lesions. Oxford: Pergamon Press, 1980. charge associated with pentylenetetrazol-induced epilepto- 39. De Ferrari GM, Schwartz PJ. Autonomic nervous system and genic activity. Epilepsia 1982;23:633-47. arrhythmias. Ann N Y Acad Sci 1990;601:247-62. 58. Goodman JH, Homan RW, Crawford IL. Kindled seizures 40. Barber MJ, Mueller TM, Henry DP, Felten SY, Zipes DP. elevate blood pressure and induce cardiac arrhythmias. Epi- Transmural myocardial infarction in the dog produces sym- lepsia 1990;31:489-95. pathectomy in noninfarcted myocardium. Circulation 1983; 59. Mameli P, Mameli 0, Tolu E, et al. Neurogenic myocardial 67:787-96. arrhythmias in experimental focal epilepsy. Epilepsia 1988; 41. Inoue H, Zipes DP. Time course of denervation of efferent 29:74-82. sympathetic and vagal nerves after occlusion of the coronary 60. Blum B. Hypothalamic etiology in sympathetically induced artery in the canine heart. Circ Res 1988;62:1111-20. pathogenic cardiovascular changes in the cat. Isr J Med Sci 42. Schwartz PJ, Vanoli E, Zaza A, Zuanetti G. The effect of anti- 1992;28:81-5. arrhythmic drugs on life-threatening arrhythmias induced by 61. Evans DE, Gillis RA. Effect of diphenylhydantoin and lido- the interaction between acute myocardial ischemia and sym- caine on cardiac arrhythmias induced by hypothalamic pathetic hyperactivity. Am Heart J 1985;109:937-48. stimulation. J Pharmacol Exp Ther 1974;191:506-17. 43. Euler DE, Nattel S, Spear JF, Moore EN, Scanlon PJ. Effect of 62. Oppenheimer SM, Wilson JX, Guiraudon C, Cechetto DF. sympathetic tone on ventricular arrhythmias during circum- Insular cortex stimulation produces lethal cardiac arrhyth- flex coronary occlusion. Am J Physiol 1985;249:H1045-50. mias: a mechanism of sudden death? Brain Res 1991;550:115- 44. Vanoli E, De Ferrari GM, Stramba-Badiale M, Hull SSJr, Fore- 21. man RD, Schwartz PJ. Vagal stimulation and prevention of 63. Kujime K, Natelson BH. Effects of stellectomy on cardiac sudden death in conscious dogs with a healed myocardial rhythm disturbances induced by ouabain in guinea pigs. J infarction. Circ Res 1991;68:1471-81. Pharmacol Exp Ther 1984;229:113-7. 45. De Ferrari GM, Vanoli E, Stramba-Badiale M, Hull SSJr, Fore- 64. Markgraf CG, Kapp BS. Lesions of the amygdaloid central man RD, Schwartz PJ. Vagal reflexes and survival during nucleus block conditioned cardiac arrhythmias in the rabbit acute myocardial ischemia in conscious dogs with healed receiving digitalis. J Auton Nerv Syst 1991;34:37-45. myocardial infarction. Am J Physiol 1991;261(1):H63-9. 65. Natelson BH. Stress, predisposition and the onset of serious 46. Amitzur G, Manoach M, Weinstock M. The influence of car- disease: implications about psychosomatic etiology. Neuro- diac cholinergic activation on the induction and maintenance sci Biobehav Rev 1983;7:511-27. of ventricular fibrillation. Basic Res Cardiol 1984;79:690-7. 66. Chinn C, Natelson BH. Termination of ouabain-induced car- 47. Schwartz PJ, Vanoli E, Stramba-Badiale M, De Ferrari GM, diac arrhythmias by anterior hypothalamic stimulation. Res Billman GE, Foreman RD. Autonomic mechanisms and sud- Commun Chem Pathol Pharmacol 1984;43:203-8. den death: new insights from analysis of baroreceptor re- 67. Somberg JC, Smith TW. Localization of the neurally medi- flexes in conscious dogs with and without a myocardial ated arrhythmogenic properties of digitalis. Science 1979; infarction. Circulation 1988;78:969-79. 204:321-3. 48. Evans DE, Alter WA III, Shatsky SA, Gunby EN. Cardiac ar- 68. Thron CD, Riancho JA, Borison HL. Lack of protection rhythmias resulting from experimental head injury. J Neuro- against ouabain cardiotoxicity after chronic ablation of the surg 1976;45:609-16. area postrema in cats. Exp Neurol 1984;85:574-83. 49. Evans DE, Kobrine AI, Rizzoli HV. Cardiac arrhythmias ac- 69. Somberg JC, Nosta JJ, Knox S. Localization of the neurally companying acute compression of the spinal cord. J Neuro- mediated facilitation of post infarction arrhythmias [abstracti. surg 1980;52:52-9. Circulation 1981;64(Suppl IV):IV-140.

Texas Heart Instituteiournal Neurocardiology of Arrhythmia and Sudden Cardiac Death 167 70. Skinner JE, Reed JC. Blockade of frontocortical-brain stem 90. Schwartz PJ, Stone HL. The analysis and modulation of au- pathway prevents ventricular fibrillation of ischemic heart. tonomic reflexes in the prediction and prevention of sudden Am J Physiol 1981;240:H156-63. death. In: Zipes DP, Jalife J, eds. Cardiac electrophysiology 71. Carpeggiani C, Landisman C, Montaron MF, Skinner JE. and arrhythmias. Orlando, Florida: Grune & Statton, Inc., Cryoblockade in limbic brain (amygdala) prevents or delays 1985: 165-76. ventricular fibrillation after coronary artery occlusion in psy- 91. Zipes DP, Ben-David J. Autonomic neural modulation of car- chologically stressed pigs. Circ Res 1992;70:600-6. diac rhythm: Part 2: Mechanisms and examples. Mod Con- 72. Rabkin SW. Morphine and the endogenous opioid dynor- cepts Cardiovasc Dis 1988;57:47-52. phin in the brain attenuate digoxin-induced arrhythmias in 92. Tapp WN, Knox FS III, Natelson BH. The heart rate spec- guinea pigs. Pharmacol Toxicol 1992;71:353-60. trum in simulated flight: reproducibility and effects of atro- 73. Strawn WB, Bondjers G, Kaplan JR, et al. Endothelial dys- pine. Aviat Space Environ Med 1990;61:887-92. function in response to psychosocial stress in monkeys. Circ 93. Kleiger RE, Miller JP, Bigger JT Jr, Moss AJ, Multicenter Post- Res 1991;68:1270-9. Infarction Research Group. Decreased heart rate variability 74. Johansson G, Jonsson L, Lannek N, Blomgren L, Lindberg P, and its association with increased mortality after acute myo- Poupa 0. Severe stress-cardiopathy in pigs. Am Heart j 1974; cardial infarction. Am J Cardiol 1987;59:256-62. 87:451-7. 94. Rich MW, Saini JS, Kleiger RE, Carney RM, teVelde A, 75. Natelson BH, Cagin NA. The role of shock predictability Freedland KE. Correlation of heart rate variability with clini- during aversive conditioning in producing psychosomatic cal and angiographic variables and late mortality after coro- digitalis toxicity. Psychosom Med 1981;43:191-7. nary angiography. Am J Cardiol 1988;62:714-7. 76. Cagin NA, Natelson BH. Cholinergic activation produces psy- 95. Akselrod S, Gordon D, Ubel FA, Shannon DC, Barger AC, chosomatic digitalis toxicity. J Pharmacol Exp Ther 1981;218: Cohen RJ. Power spectrum analysis of heart rate fluctuation: 709-11. a quantitative probe of beat-to-beat cardiovascular control. 77. Natelson BH, Grover E, Cagin NA, OttenwellerJE, Tapp W'N. Science 1981;213:220-2. Learned fear: a cause of arrhythmia onset in the presence of 96. Cornelissen G, Bakken E, Delmore P, et al. From various digitalis. Pharmacol Biochem Behav 1989;33:431-4. kinds of heart rate variability to chronocardiology. Amj Car- 78. Randall DC, Hasson DM. Cardiac arrhythmias in the mon- diol 1990;66:863-8. key during classically conditioned fear and excitement. 97. Aharon-PeretzJ, Harel T, Revach M, Ben-Haim SA. Increased Pavlov J Biol Sci 1981;16:97-107. sympathetic and decreased parasympathetic cardiac inner- 79. Corbalan R, Verrier R, Lown B. Psychological stress and ven- vation in patients with Alzheimer's disease. Arch Neurol tricular arrhythmias during myocardial infarction in the con- 1992;49:919-22. scious dog. Am J Cardiol 1974;34:692-6. 98. Porges SW. Vagal tone: a physiologic marker of stress vul- 80. Rosenfeld J, Rosen MR, Hoffman BF. Pharmacologic and nerability. Pediatrics 1992;90:498-504. behavioral effects on arrhythmias that immediately follow 99. Dougherty CM, Burr RL. Comparison of heart rate variability abrupt coronary occlusion: a canine model of sudden coro- in survivors and nonsurvivors of sudden cardiac arrest. Am nary death. Am J Cardiol 1978;41:1075-82. J Cardiol 1992;70:441-8. 81. Kirby DA, Pinto JMB, Hottinger S, Johnson DA, Lown B. 100. Van Hoogenhuyze D, Weinstein N, Martin GJ, et al. Repro- Behavioral arousal enhances inducibility and rate of ven- ducibility and relation to mean heart rate of heart rate vari- tricular tachycardia. Am J Physiol 1991;261:H1734-9. ability in normal subjects and in patients with congestive 82. Pinto JM, Kirby DA, Maher TJ, Lown B. Decreases in repeti- heart failure secondary to coronary artery disease. Am J Car- tive extrasystole threshold in the conscious pig with myo- diol 1991;68:1668-76. cardial infarct were reversed by tyrosine. Life Sci 1991;49: 101. Binder T, Frey B, Porenta G, et al. Prognostic value of heart 419-26. rate variability in patients awaiting cardiac transplantation. 83. Tapp WN, Natelson BH, Creighton D, Khazam C, Ottenwel- PACE Pacing Clin Electrophysiol 1992;15:2215-20. ler JE. Alprazolam reduces stress-induced mortality in car- 102. Schwartz PJ, La Rovere MT, Vanoli E. Autonomic nervous diomyopathic hamsters. Pharmacol Biochem Behav 1989;32: system and sudden cardiac death. Experimental basis and 331-6. clinical observations for post-myocardial infarction risk strati- 84. Tapp WN, Natelson BH. Verapamil sensitizes cardiomyo- fication. Circulation 1992;85(Suppl I):I-77-91. pathic hamsters to the effects of stress. Res Commun Chem 103. Andreoli A, di Pasquale G, Pinelli G, Grazi P, Tognetti F, Testa Pathol Pharmacol 1988;62:511-4. C. Subarachnoid hemorrhage: frequency and severity of car- 85. Verrier RL. Neural factors and ventricular electrical instabil- diac arrhythmias. A survey of 70 cases studied in the acute ity. In: Kulbertus HE, Wellens HJJ, eds. Sudden death. The phase. Stroke 1987;18:558-64. Hague: Martinus Nijhoff, 1980:137-55. 104. Stober T, Sen S, Anstatt T, Bette L. Correlation of cardiac ar- 86. Schwartz PJ, Stone HL. Unilateral stellectomy and sudden rhythmias with brainstem compression in patients with in- death. In: Schwartz PJ, Brown AM, Malliani A, Zanchetti A, tracerebral hemorrhage. Stroke 1988; 19:688-92. eds. Neural mechanisms in cardiac arrhythmias. New York: 105. Bashour TT, Cohen MS, Ryan C, Antonini C Sr. Sinus node Raven Press, 1978:107-22. suppression in acute strokes-case reports. Angiology 1988; 87. Schwartz PJ. Idiopathic long QT syndrome: progress and 39: 1048-55. questions. Am Heart J 1985; 109;399-411. 106. Oppenheimer SM, Hachinski VC. The cardiac consequences 88. Schwartz PJ, Randall WC, Anderson EA, et al. Task Force 4: of stroke. Neurol Clin 1992;10:167-76. Sudden cardiac death. Nonpharmacologic interventions. In: 107. Terrence CF Jr, Wisotzkey HM, Perper JA. Unexpected, un- ShepherdJT, Weiss SM, eds. Conference on Behavioral Medi- explained death in epileptic patients. Neurology 1975;25: cine and Cardiovascular Disease, sponsored by the Ameri- 594-8. can Heart Association and the National Heart, Lung, and 108. Leestma JE, Walczak T, Hughes JR, Kalelkar MB, Teas SS. A Blood Institute; 1985 Feb 3-7; Sea Island, Georgia. Circula- prospective study on sudden unexpected death in epilepsy. tion 1987;76(Suppl I):I-215-29. Ann Neurol 1989;26:195-203. 89. Lane RD, Wallace JD, Petrosky PP, Schwartz GE, Gradman 109. Earnest MP, Cohen JA, Hossack KF, Woods JP. Cardiac QTc AH. Supraventricular tachycardia in patients with right hemi- interval is prolonged in epilepsy patients with clinical fea- sphere strokes. Stroke 1992;23:362-6.

168 Neurocardiology of Arrhythmia and Sudden Cardiac Death Voltime 20, Number3, 199.3 tures associated with sudden death [abstract]. Neurology 120. Lown B, TemteJV, Reich P, Gaughan C, Regestein Q, Hai H. 1990;40(Suppl 1):298. Basis for recurring ventricular fibrillation in the absence of 110. Oppenheimer S. Cardiac dysfunction during seizures and coronary heart disease and its management. N Engl J Med the sudden epileptic death syndrome. J R Soc Med 1990;83: 1976;294:623-9. 134-6. 121. Katz C, Martin RD, Landa B, Chadda KD. Relationship of 111. Marshall DW, Westmoreland BF, Sharbrough FW. Ictal psychologic factors to frequent symptomatic ventricular ar- tachycardia during temporal lobe seizures. Mayo Clin Proc rhythmia. Am J Med 1985;78:589-94. 1983;58:443-6. 122. Ruberman W, Weinblatt E, Goldberg JD, Chaudhary BS. 112. GilchristJM. Arrhythmogenic seizures: diagnosis by simulta- Psychosocial influences on mortality after myocardial infarc- neous EEG/ECG recording. Neurology 1985;35:1503-6. tion. N Engl J Med 1984;311:552-9. 113. Keilson MJ, Hauser WA, Magrill JP, Goldman M. ECG ab- 123. Follick Mj, Gorkin L, Capone RJ, et al. Psychological distress normalities in patients with epilepsy. Neurology 1987;37: as a predictor of ventricular arrhythmias in a post-myocar- 1624-6. dial infarction population. Am Heart J 1988;1 16:32-6. 114. Phizackerley PJR, Poole EW, Whitty CWM. Sino-auricular 124. Frasure-Smith N, Prince R. The ischemic heart disease life heart block as an epileptic manifestation: a case report. Epi- stress monitoring program: impact on mortality. Psychosom lepsia 1954;3:89-91. Med 1985;47:431-45. 115. Haslam RHA, Jameson HD. Cardiac standstill simulating 125. Tavazzi L, Zotti AM, Rondanelli R. The role of psychologic repeated epileptic attacks: a case report. JAMA 1973;224: stress in the genesis of lethal arrhythmias in patients with 887-9. coronary artery disease. Eur HeartJ 1986;7(Suppl A):99-106. 116. Stern S, Tzivoni D. Atrial and ventricular asystole for 19 sec- 126. Eliot RS, Buell JC. Role of emotions and stress in the genesis onds without syncope: report of a case. Isr J Med Sci 1976; of sudden death. J Am Coll Cardiol 1985;5:95B-98B. 12:28-33. 127. Samuels MA. Neurogenic heart disease: a unifying hypoth- 117. Kiok MC, Terrence CF, Fromm GH, Lavine S. Sinus arrest in esis. Am J Cardiol 1987;60:15J-19J. epilepsy. Neurology 1986;36:115-6. 128. Oppenheimer S. The insular cortex and the pathophysiol- 118. Terrence CF, Rao GR, Perper JA. Neurogenic pulmonary ogy of stroke-induced cardiac changes. Can J Neurol Sci edema in unexpected, unexplained death of epileptic pa- 1992;19:208-1 1. tients. Ann Neurol 1981;9:458-64. 119. KaprioJ, Koskenvuo M, Rita H. Mortality after bereavement: a prospective study of 95,647 widowed persons. Am J Pub- lic Health 1987;77:283-7.

Texas Hea?l Institutefournal Neurocardiology of Arrhythmia and Sudden Cardiac Death 169