Sudden Cardiac Death 
Introduction
Sudden cardiac death (SCD) is the sudden, abrupt loss of heart function (i.e. cardiac arrest) in a person who may or may not have diagnosed heart disease, the time and mode of death are unexpected, and it occurs instantly or shortly after the onset of symptoms1. While previous heart disease is a risk factor for SCD, an individual may have no history or symptoms of heart disease prior to the onset of SCD. SCD is the end result of untreated rapid ventricular tachycardia or ventricular fibrillation2, or an extreme slowing of the heart1. Estimates of the number of SCDs that occur in the United States each year range from 250,000 to 500,0001,.3 Reduction in the mortality from SCD involves two issues: prevention and treatment of underlying risk factors, and interruption of SCD events through rapid defibrillation of the heart.
The underlying causes for SCD are varied, and sometimes unknown. Some of the known causes include cardiac ischemia, abnormal electrical conduction in the heart, structural abnormalities of the heart, atherosclerosis of the coronary arteries, or changes in the heart due to long-standing hypertension. Risk factors generally accepted as associated with heart disease include a family history of heart disease, increased age, being male, hypertension, increased blood cholesterol, cigarette smoking, and diabetes. The main three risk factors that increase an individual's risk of SCD are history of a previous myocardial infarction (MI), depressed left ventricular ejection fraction, and the presence of complex ventricular ectopy4.
Escobedo and Caspersen5 looked at modifiable risk factors of SCD. They split SCD into two types: unexpected SCD (occurs in individuals without a history of coronary heart disease) and sudden coronary heart disease death (occurs in individuals with a history of coronary heart disease). Cigarette smoking was the only factor that showed an increased risk for unexpected SCD. Diabetes, cigarette smoking, and hypertension all were associated with an increased risk of sudden coronary heart disease death. Sexton et al.6 conducted a population-based case-control study with 306 men in Tasmanian and found that independent risk factors for sudden unexpected cardiac death were a history of diabetes mellitus (OR=4.2; 95% CI, 1.39-12.81), current smoking (OR=3.5; 95% CI, 1.80-6.82), and family history of IHD (OR=2.6; 95% CI, 1.34-4.92). As research into this area increases, more is being discovered concerning other possible causes or predisposing factors for SCD. Results of some of the most recent research will now be reviewed.
Structural
abnormalities
There appear to be a number of structural conditions that may predispose an individual to SCD. Mitral valve prolapse (MVP) is a usually benign condition in which there is redundant tissue on one or both leaflets of the mitral valve. It can, however, be associated with some potentially serious complications7. Burke et al.8 found that when they compared the hearts of 24 patients with MVP who had suddenly died with the hearts of 16 patients who died of trauma that there was significantly more dysplasia of the atrioventricular nodal artery, luminal narrowing, and fibrosis in the base of the ventricular septum in the former group. They concluded that arterial dyplasia in MVP may contribute to sudden cardiac death mediated by ventricular fibrosis.
Patients with hypertrophic cardiomyopathy (HC) often die suddenly. Risk factors for SCD in these patients appear to be youth, a family history of SCD, ventricular tachycardia, and possibly syncope. Maki et al.9 followed 309 patients with HC and found that those who suffered exercise-related SCD were younger and had smaller increases in systolic blood pressure during exercise testing than those without exercise-related SCD. Those HC patients who experience exercise-unrelated SCD were older and had higher left ventricular outflow tract pressure gradients.
Coronary artery anomalies have been associated with an increased risk of SCD. Frescura et al.10 examined causes of death in 27 patients with anomalous coronary arteries, most often from the aorta itself. They determined that in 59% sudden death had occurred. In 50% of these individuals sudden death was the first manifestation of the disease, and in 50% sudden death was precipitated by effort. Another study was done by Taylor et al.11 to look at which anomalies might be associated with SCD. These researchers, however, found no simple relationship between variations in the initial artery course and outcome. They did conclude that an age of 30 years or greater was associated with a decreased incidence of SCD in these patients.
Patients with congenital heart defects remain at risk for SCD even after surgical correction of the defect. Incidence ranges from 1 to 6%12. Silka et al.13 conducted a prospective study of patients who had undergone surgery for correction of a congenital heart defect in Oregon prior to the age of 19 years. They concluded that the risk of SCD is 25 to 100 times greater in these patients than in an age-matched control population. The increased risk was greatest for patients who had had cyanotic or left heart obstructive lesions, and the risk increased primarily after the second postoperative decade.
Hearts that have been structurally affected by disease also can be at risk for SCD. Case reports of patients with sarcoidosis have associated sarcoid heart involvement with SCD. Reuhl et al.14 reported on two young women who died suddenly of myocardial sarcoidosis, and been previously entirely free of symptoms. Autopsy examination showed infiltration of the ventricular septum by fibrous tissue. Boglioli et al.15 reports another case of SCD due to myocardial sarcoidosis, as well as Veinot and Johnston16, who report on a 33 year old male. The latter patient had a history of surgically repaired congenital heart disease, yet on autopsy it was found that he had cardiac sarcoid with prominent involvement of the conduction system. Veinot and Johnston also report that cardiac involvement is found in 20-50% of autopsied patients with sarcoidosis, with the interventricular septum base the most common site. However, sarcoidosis only gives rise to clinical manifestations in about 5% of patients.
Electrocardiographic
patterns
Certain EKG patterns appear to be associated with an increased incidence of SCD. Such patterns could be enormously helpful in determining which individuals might be at risk for SCD. Brugada et al.17 analyzed data on individuals without demonstrable heart disease who had an EKG pattern of right bundle-branch block (RBBB) and ST-segment elevation in leads V1 through V3. Some of these patients had been symptomatic (an episode of aborted SCD or syncope of unknown origin) and some had been asymptomatic (EKG pattern caught by chance or due to screening secondary to a SCD of a relative) prior to recognition of this pattern on their EKGs. The authors determined that patients with this EKG pattern are at increased risk of SCD. They also analyzed treatments received after discovery of this pattern, and found that amiodarone (an anti-arrhythmic) and/or beta-blockers did not protect these patients against SCD (26% mortality from SCD versus 31% in those with no treatment) and that an automatic implantable cardioverter-defibrillator (AICD) appeared to be the best treatment for this group (0% mortality from SCD).
Nademanee et al.18 studied an interesting group of patients. Between 1981 and 1989 the Centers for Disease Control and Prevention reported a very high incidence of sudden death among young male Southeast Asians who died unexpectedly during sleep. The pattern of death had long been prevalent in this region. These investigators studied 27 Thai men referred because they either had had cardiac arrest due to ventricular fibrillation or were suspected to have had symptoms similar to the clinical presentation of sudden unexpected cardiac death. These men were determined to have either a normal EKG or to have a RBBB and ST-segment elevation in V1 through V3. As in the previous study, the latter group was found to have a much greater risk of dying suddenly (p=.05).
Long QT syndrome is a disorder in which patients are at increased risk of sudden death (71% if untreated), and often have syncope associated with emotional, physical, or auditory stress. The EKG usually shows a prolonged QT interval. The syndrome may be autosomal-dominant or autosomal-recessive (and associated with congenital deafness), or sporadic with no familial linkage4. Vincent19 reviewed patients with the autosomal-dominant syndrome and determined that QT presentation on EKG may be normal or borderline some of the time, making diagnosis difficult. Zareba et al.20 analyzed risks of SCD in individuals related to patients with long QT syndrome. They found that female first-degree relatives of patients with long QT syndrome have a higher risk of cardiac events than male first- or second-degree relatives, although this was not specific to SCD.
QTc (QT corrected for sinus cycle length) dispersion is another electrocardiographic pattern that has been associated with SCD in some populations.
deBruyne et al.21 did a prospective analysis with an older population (men and women > or = 55 years), categorizing degree of QTc dispersion into tertiles. Those in the highest tertile relative to the lowest tertile had a hazard ratio of 1.9 (95% CI, 1.0-3.7) for SCD. Another examination of QT dispersion as a risk factor was completed by Manttari et al.22. These investigators conducted a prospective study of middle aged men and found that those having a QTPEAK (up to the peak of the T wave) dispersion in the highest tertile were 6.2 times as likely (95% CI, 1.7 to 23.5) to experience SCD as those in the lowest tertile. They remained 4.9 times as likely (1.2 to 19.5) after adjustment for the presence of left ventricular hypertrophy.
As noted earlier, patients who have experienced a myocardial infarction are at increased risk of SCD. Yi et al.23 retrospectively examined both QTc dispersion and QT interval on the exercise test EKGs of two groups of post-MI patients (one group experienced SCD and one group were event-free) plus a control group. They found that while exercise-induced changes in QTc dispersion were not predictive of SCD, exercise-induced prolongation of the QTc interval could differentiate those post-MI patients at high risk of SCD from those post-MI patients at low risk of SCD.
Finally, in a two-year study of patients with severe congestive heart failure (CHF) by Doval et al.24 it was determined that couplets and/or nonsustained ventricular tachycardia (NSVT) on 24-hour Holter monitor were predictive for SCD (RR 10.1; 95% CI, 1.91 to 52.7; p<.01). However, Singh et al.25 when studied patients with heart failure, they only found that NSVT may be associated with worsened survival in univariate analysis. After adjusting for other variables, only ejection fraction was an independent predictor of SCD, not NSVT. They questioned whether suppression of arrhythmias such as NSVT improves survival in these patients.
Heart
rate variability
Heart rate variability has been connected with risk of SCD. Researchers are finding that a decrease in heart rate variability may be associated with increased risk. Jiang et al.26 also studied a group of patients with advanced CHF. They determined that those patients with a life-threatening cardiac event or death had a significantly lower heart rate variability than those who did not experience such an event. Patients with dilated cardiomyopathy are also at risk for SCD. Przibille et al.27 found in these patients that parameters influenced by low- and mid-frequent oscillations of the heart rate were significantly lower in patients who died suddenly or received adequate shocks from an AICD. Hathaway et al.28 prospectively studied a group of patients with end-stage renal disease (ESRD) and healthy controls. 24-hour measures of autonomic function and heart rate variability were collected. They found that all groups of ESRD patients had severely compromised autonomic function, with diabetic patients having the greatest degree of dysregulation. They felt that heart rate variability tests could be useful in identifying those in this population at increased risk of SCD.
Decreased heart rate variability diagnosed from a 24-hour EKG recording has also been associated with SCD in post-MI patients. Kautzner et al.29 studied 30 minute resting short-term EKGs collected on patients 2 and 5 days after admission for MI. The patients were followed for one year, and it was found that subjects who died of SCD had significantly depressed heart rate variability. The predictive value of the short-term EKG was strengthened when combined with results of echocardiogram. Depressed heart rate variability and depressed left ventricular ejection fraction together was most predictive of SCD. Faber et al.30 also determined that a short-term (5 minute) heart rate variability test could be efficiently used to select those post-MI patients that needed to be further evaluated with a long-term (24 hour) assessment in order to identify those patients with the highest likelihood of future cardiac events.
On the treatment side, Kontopoulos et al.31 compared the effects of various angiotensin-converting enzyme (ACE) inhibitors on heart rate variability in post-MI patients, patients with stable coronary artery disease (CAD), and normal volunteers. They found that some but not all of the ACE-inhibitors tested increased heart rate variability related to vagal tone, and concluded that these might be beneficial in reducing the risk of SCD in post-MI patients.
Circadian
rhythm
Levi32 explores the intersection of circadian rhythms and pharmacology. He discusses that biologic functions of mammals vary according to a circadian rhythm of about 24 hours which is governed by the hypothalamus, and circadian rhythm genes have been cloned in mice. These rhythms can be altered by disease and the actions of drugs can be affected by the time of day at which they are administered. He relates that the morning peak of MI in man is due to the combination of certain circadian changes occurring together. Flack and Yunis33 indicate that the morning peak from 6 am to 12 noon of such occurrences as MI, thrombotic stroke, transient myocardial ischemia, and SCD is due to the high levels of coronary vasomotor tone, plasma catecholamines, and platelet aggregability, and the low levels of coronary blood flow and plasma fibrinolytic activity. At this same time, there is a rapid increase in blood pressure during the early morning hours. He also feels that it is important to maintain control of blood pressure throughout the early morning to try to avoid adverse events. A study in Auckland, New Zealand, by Vanderpalen et al.34 had some slightly different findings on circadian rhythm. They report an afternoon peak in SCD (32.5%) and a secondary morning peak (27.6%). Also, they found a Saturday high (18.6%) for SCD.
Yi et al.35 examined circadian variation of the QT interval in post MI patients and normal controls and its relation to SCD. They found the SCD victims did not show a significantly longer QT interval at night when compared to day as the normal subjects and MI survivors did, and the SCD victims did show a significantly longer QTc averaged over 24 hours. So, the circadian variation of the QT interval did vary when compared to normal subjects and those who survived the year following a MI.
Medication
effects on SCD
Medications can have significant effects on the incidence of SCD. Warner et al. investigated an association between neuroleptic medication and EKG changes predictive of malignant cardiac arrhythmias. They found prolonged QTc intervals to be more common in patients receiving neuroleptic medication than unmedicated controls, but no significant increase in QTc dispersion. They suggest this may be a link between neuroleptic medication and SCD.
Hoes et al.37 reported on the antihypertensive treatment of diuretics and beta-blockers and SCD. It was found that a pooled risk-ratio of sudden death of 1.5 (95% CI, 1.1-2.0) was observed when non-potassium sparing diuretics were compared with placebo in seven trials. They also state that two recent case-control studies have strongly indicated that the use of thiazides increases the risk of sudden death. The use of beta-blockers and an increased risk of SCD is also an area that has been questioned and requires further study.
Kenneback et al.38 report that sudden unexpected death has been associated with low or undetectable concentrations of antiepileptic drugs in patients with epilepsy, suggesting that a sudden fall in plasma levels of these drugs might be a critical factor for the occurrence of these sudden deaths. The authors studied changes in arrhythmia profile and heart rate variability during abrupt withdrawal of carbamazepine and phenytoin in ten patients with side effects to these drugs. Three patients had a 10-fold increase in ventricular premature beats, and there was a significant reduction in heart rate variability. This holds implications not only for patients who stop medications under physician supervision, but also for seizure patients who may intermittently stop medication on their own.
Other
various possible risk factors
Current research is still exploring many other associations between various possible risk factors and SCD. One of the more intriguing areas is the relationship between emotions and SCD. Glassman39 reports on multiple studies that show evidence of a link between depression and cardiovascular death. Piccirillo et al.40 reported findings that suggest that persons with high anxiety scores have baseline cardiac sympathetic hyperactivity and low heart rate variability, as well as a susceptibility to SCD. Kowachi et al.41 studied a group of more than 2000 men over a 32 year period and concluded that there was a significant correlation between between high anxiety SCD. They hypothesize that this might be due to intense stress interrupting the activity of nerves controlling the heart. Leier et al.42 report on an interesting and possibly related phenomenon. They followed the outcome of 10 patients who were removed from the waiting list for a heart transplant because of significant improvement in clinical status and exercise capacity (n=9) or criteria violation (n=1). 40% of those removed experienced SCD within four months, resulting in a 60% survival rate during six months, whereas there was a 80% survival rate among newly listed patients. The four who died could only be distinguished from the other patients by an elevated pulmonary capillary wedge pressure.
The benefits and risk of physical activity have been debated. Bartels et al.43 investigated the effects of regular physical activity and sudden strenuous situations on the incidence of SCD. The population they studied was divided into groups dependent on level of regular physical activity. The incidence of SCD dropped as regular physical activity increased. Also, the relative risk of SCD during strenuous activity compared with inactivity was 150 in the sedentary group and only 4 in the most active group. These results were independent of the preexisting illness status of the individuals. The authors concluded that the protective effect of regular physical activity for SCD far exceeds the risk increase of the actual strenuous situation.
Diet has been investigated for years in its possible relationship to diseases of the heart. Albert et al.44 reported on a study of 20,551 male physicians who completed an abbreviated, semiquantitative food frequency questionnaire on fish consumption and were then followed for up to 11 years. They found that consumption of fish at least once a week was associated with a reduced risk of SCD. Daviglus et al.45 also reported on fish in the diet. They examined data on 1822 middle-aged men, with fish consumption determined on the basis of a detailed dietary history. They found an inverse relationship between fish conumption and nonsudden death from MI. Apparently, the relationship for SCD, however, was not as strong. Another possible dietary factor that has been examined is nut consumption. Albert et al.46 used data from the Physicians Health Study, in which participants completed a diet questionnaire one year after enrollment. They found that as nut consumption increased, the risk of total cardiac death and sudden death decreased in a linear fashion. They hypothesize that this might be due to the alpha-linolenic acid found in some nuts that may have antiarrhythnic properties.
In another study that could possibly be related to diet, Kovanen et al.47 followed dyslipidemic men (non-HDL cholesterol >201 mg/dL) and controls for five years. Levels of IgA, IgE, IgG, and IgM, were drawn at study entry. In the dyslipidemic men, the levels of all immunoglobulins except M were significantly higher than in the controls. Hypertriglyceridemia and a low level of HDL cholesterol were associated with an increased risk of a coronary end point (these included SCD) only if the levels of IgA, IgE, or IgG were also elevated. The investigators hypothesized that an immune response might be necessary for dyslipidemia to cause coronary atherothrombosis.
Impacting
the incidence of CVD
Various treatments are currently in use to attempt to decrease an individual's risk of CVD. They include preventive lifestyle changes, such as diet, exercise, stress reduction, and smoking cessation, as well as treatments such as medications, cardiac angioplasty, coronary artery bypass surgery, electrophysiologic ablation, implantable pacemaker, automatic implantable cardioverter-defibrillator, and heart transplant1. AICDs are now considered to be more effective against SCD than medication2. However, at present such treatment is concentrated on the most high-risk patients. Per Fogoros4, "To make a significant impact in decreasing the yearly toll of sudden death, then, we will ultimately need to address our efforts toward patients in the moderate-risk group...there is currently no generally accepted approach for reducing the risk of sudden death in these patients".
With approximately 400,000 victims in the United States each year4, SCD is obviously a major health problem. Since the majority of those who experience SCD are not successfully resuscitated2, there often is no chance for treatment after it strikes, as there is in most other diseases. It would appear that to reach the majority of those individuals at risk for SCD and make a meaningful intervention, it is necessary to better identify those at moderate as well as high risk. As has been shown, the etiology of SCD can be quite varied, although the major risks remain history of a MI, depressed left ventricular ejection fraction, and presence of complex ventricular ectopy. Since heart rate variability has been shown to be a possible predictor of future SCD26,27,28, it would seem that this is an area in which more research is needed. As a screening test it is non-invasive, the technology appears to be within reach of most medical institutions, and the predictability is fairly good and could probably be made even stronger. The short-term heart rate variability test29,30 would be the most advantageous, since it would involve only a 5 or 30 minute test rather than a 24 hour test, thus reducing cost and inconvenience, and increasing the number of people who could be tested. It might also prove to be a way to test the efficacy of new anti-arrhythmic drugs.