Sudden Arrhythmia Death Syndrome: Importance of the Long QT Syndrome JOHN S. MEYER, M.D., St. Luke’s Hospital, Chesterfield, Missouri ALI MEHDIRAD, M.D., Midwest Heart Rhythm, St. Louis, Missouri BAKR I. SALEM, M.D., and WIT A. JAMRY, M.D., St. Luke’s Hospital, Chesterfield, Missouri AGNIESZKA KULIKOWSKA, M.D., St. Louis Children’s Hospital, St. Louis, Missouri PIOTR KULIKOWSKI, M.D., St. Mary’s Hospital, St. Louis, Missouri In approximately 5 percent of sudden cardiac deaths, no demonstrable anatomic abnormality is found. Some cases are caused by sudden arrhythmia death syndrome. A prolonged QT interval is a common thread among the various entities associated with sudden arrhythmia death syndrome. A number of drugs are known to cause QT prolongation (e.g., terfenadine), as are hypokalemia, hypomagnesemia, myocardi- tis, and endocrine and nutritional disorders. Recently, attention has focused on a group of inherited gene mutations in cardiac ion channels that cause long QT syndrome and carry an increased risk for sudden death. Some of the highest rates of inherited long QT syndrome occur in Southeast Asian and Pacific Rim countries. The median age of persons who die of long QT syndrome is 32 years; men are predominately affected. In addition to a prolonged QT interval, which occurs in some but not all persons with long QT syndrome, another characteristic electrocardiographic abnormality is the so-called Brugada sign (an upward deflection of the terminal portion of the QRS complex). Most cardiac events are precipitated by vigorous exercise or emotional stress, but they also can occur during sleep. Torsades de pointes and ven- tricular fibrillation are the usual fatal arrhythmias. Long QT syndrome should be suspected in patients with recurrent syncope during exertion and those with family histories of sudden, unexpected death. Unfortu- nately, not all persons with long QT syndrome have premonitory symptoms or identifiable electrocardio- graphic abnormalities, and they may first present with sudden death. Beta blockers, potassium supple- ments, and implantable defibrillators have been used for treatment of long QT syndrome. Identifying the specific gene mutation in a given patient with long QT syndrome can help guide prophylactic therapy. (Am Fam Physician 2003;68:483-8. Copyright© 2003 American Academy of Family Physicians.) udden death from cardiac arrest occurs in approximately 300,000 TABLE 1 persons per year in the United Causes of Sudden Cardiac Death States. Coronary artery disease accounts for the majority of cases, More common Swhile most of the others are associated with Coronary atherosclerosis anatomic abnormalities and are presaged by Cardiomyopathies clinical signs and symptoms (Table 1).Occa- Aortic valvular stenosis sionally, the underlying heart disease remains Drug-induced electrolyte imbalance undiagnosed, and death comes suddenly and Viral myocarditis unexpectedly, but the postmortem examina- Less common Sudden arrhythmia death syndrome tion reveals a cause. In 1 to 5 percent of Anomalous coronary artery origin deaths, however, no anatomic abnormality Mitral ball-valve thrombus or myxoma can be found, and this group constitutes the Tumors of atrioventricular node region newly described “sudden arrhythmia death Hepatic steatosis-induced arrhythmia 1,2 syndrome” (SADS). Wolff-Parkinson-White syndrome SADS encompasses a number of clinical High-degree atrioventricular heart block entities, including congenital long QT syn- (Stokes-Adams syndrome) drome, Wolff-Parkinson-White syndrome, Sick sinus syndrome idiopathic ventricular fibrillation, and coro- Idiopathic ventricular fibrillation nary artery spasm (e.g., from cocaine intoxi- AUGUST 1, 2003 / VOLUME 68, NUMBER 3 www.aafp.org/afp AMERICAN FAMILY PHYSICIAN 483 atine kinase MB levels were attributed to pro- The various causes of sudden arrhythmia death syndrome longed CPR. A second cardiac arrest that have in common a prolongation of the QT interval. began with asystole was followed by ventricu- lar fibrillation. Junctional bradycardia oc- curred several hours after a second cardiac resuscitation, followed by electromechanical cation). Some cases of sudden infant death dissociation, lactic acidosis, and death 11 hours syndrome also have been attributed to fatal after the initial event. arrhythmias during sleep. Arrhythmias may Autopsy demonstrated a heart of normal be induced in normal hearts by drugs (e.g., weight with no anatomic abnormalities. terfenadine [Seldane]); electrolyte abnor- Coronary arteries were examined at 0.5-cm malities (e.g., hypokalemia or hypomagne- intervals and were found to be without signif- semia); myocarditis; and endocrine, central icant luminal narrowing. Examination of nervous system, or nutritional disorders. other organs, including the brain, showed These arrhythmias are associated with prolon- only old scarring of the middle lobe of the gation of the electrocardiographic QT inter- right lung. val.3 Another class of arrhythmias that is often associated with long QT syndrome includes Historical Background of SADS hereditary genetic defects that affect the car- A sudden, unexpected nocturnal death syn- diac ion channels; this article focuses on this drome has been known in Southeast Asian and emerging entity. Pacific Rim countries for decades. The fatal event typically is accompanied by labored res- Illustrative Case piration, gasping, or groaning. It is called “ban- During the night, the screams of a 57-year- gungut” in the Philippines,“pokkuri” in Japan, old Taiwanese woman awakened her husband, and “lai tai” in Thailand, all meaning “sleep who found her in bed cyanotic, unresponsive, death.”In these areas it is recognized as a lead- and pulseless. He called for help and adminis- ing cause of death in young men, with the tered cardiopulmonary resuscitation (CPR). highest mortality rate occurring in northeast- On arrival, emergency medical personnel ern Thailand (40 per 100,000 persons per found the patient to be in ventricular fibrilla- year).4 The degree of familial expression can be tion. They administered defibrillatory shocks, devastating. One report5 documented 25 sud- and after a period of asystole, the patient’s den deaths in one family, with 16 of them heart returned to sinus rhythm. occurring during the night. A U.S. study4 of The patient’s medical history was signifi- 82 instances of SADS among refugees from cant for several episodes of syncope. A previ- Southeast Asia showed an age range of 16 to ous work-up had discovered frequent prema- 63 years, with a median age of 32 years. All but ture ventricular complexes and runs of one of the victims were men. bigeminy on a Holter monitor examination. Discovery of a characteristic hereditary Quinidine and a beta-adrenergic blocker were ECG abnormality, the Brugada sign, in right prescribed, but at some point the patient had precordial leads resulted in classification of stopped taking them. this condition as a right ventricular repolar- On arrival in the hospital emergency ization defect.6,7 The Brugada sign consists of department, examination revealed signs of a prominent upward deflection at the end of decerebration with dilation of both pupils. the QRS complex, which may be associated Electrocardiography (ECG) showed no ab- with right bundle branch block (Figure 1).7 normality, with normal PR and QT intervals. Hereditary prolongation of the QT interval Slight elevations of serum troponin I and cre- (Figure 2) also has been associated with SADS. 484 AMERICAN FAMILY PHYSICIAN www.aafp.org/afp VOLUME 68, NUMBER 3 / AUGUST 1, 2003 Sudden Cardiac Death FIGURE 1. Electrocardiogram showing Brugada sign, or elevation of terminal deflection of QRS in precordial leads (arrows). The latter is not associated with prolongation of the QT interval but may be associated with right bundle branch block (although not in this patient). Reprinted with permission from Gussak I, Antzelevitch C, Bjerregaard P, Towbin JA, Chaitman BR. The Brugada syndrome: clinical, electrophysiologic and genetic aspects. J Am Coll Cardiol 1999;33:7. FIGURE 2. Long QT interval shown in all electrocardiographic leads. The interval is measured from the beginning of the QRS complex to the end of the T wave. In this patient, the QT inter- val is 560 msec. The normal upper limit for the QT interval is 440 msec in men and 460 msec in women. This electrocardiogram compares with Figure 1 showing a normal QT interval. AUGUST 1, 2003 / VOLUME 68, NUMBER 3 www.aafp.org/afp AMERICAN FAMILY PHYSICIAN 485 FIGURE 3. Electrocardiogram showing torsades de pointes. Note the more or less symmetric vari- ation in the ventricular tachycardia waves. Torsades de pointes may resolve into sinus rhythm or progress into ventricular fibrillation. The most common type of SADS associated A number of known genetic errors are associ- with hereditary long QT syndrome is the ated with this syndrome. The affected genes autosomally dominant Romano-Ward syn- make proteins that are involved in the func- drome (syncope, seizures, and sudden tion of cardiac cell membrane sodium and death).8,9 While the syndrome may first man- potassium ion channels. ifest as syncope or seizures, sudden death is the only event in 30 to 40 percent of patients.6 ECG Manifestations of Inherited Long QT Syndrome When ECGs could be obtained during SADS events, they have always shown the The Authors polymorphic ventricular tachyarrhythmia JOHN S. MEYER, M.D., is emeritus chief pathologist and director of laboratories at St. termed “torsades de pointes” (Figure 3),or Luke’s