life-threatening arrhythmias in the mitral valve prolapse syndrome

Life-Threatening Arrhythmias in the Mitral Valve

Prolapse Syndrome

ROGER A. WINKLE, M.D.

MARIO G. LOPES, M.D.”

RICHARD L. POPP, M.D.+

E. WILLIAM HANCOCK, M.D.

Stanford, California

From the Cardiology Division, Stanford Univer- sity School of Medicine, Stanford, California 94305. This work was supported in part by N.I.H. Grants No. HL-5888 and Program Project Grant No. l-POl-HL-15833. Requests for re- prints should be addressed to Dr. E. William Hancock, Cardiology Division, Stanford Univer- sity School of Medicine, Stanford, California 94305. Manuscript accepted November 19, 1975.

l Supported by a grant from the lnstituto de Alta Cultura, Portuguese Department of Nation- al Education, Lisbon, Portugal.

+ Present address: Faculdade de Medicina de Lisboa, Lisbon, Portugal.

This study describes seven patients wlth the mitral valve prolapse or click-murmur syndrome who have survived one or more episodes of life-threatening ventricular arrhythmias. These arrhythmias include cardiac arrest due to ventricular fibrillation, re- current ventricular tachycardia causing syncope or sustained ventricular tachycardia requiring electroversion. These patients were seen over a two-year period in a single medical center. Five of the seven had repolarization abnormalities in the resting electrocardiogram. Premature ventricular contractions were present in the routine resting electrocardiograms of six of the seven patients and were frequent during treadmill testing and ambulatory electrocardiographic monitoring in all six tested. There were electrolyte abnormalities or changes in medtcattons known to affect myocardial repolarization during the week be- fore the episode in three of the four patients with cardiac arrest. The diagnosis of mitral valve prolapse click-murmur syndrome was made prior to the episode of life-threatening arrhythmia In only two of the seven patients. Varying forms of antiarrhythmic therapy were given to these patients,during follow-up periods of five to 26 months. Although the incidence of fatal arrhythmias In the mitral prolapse syndrome is probably small, we suggest that such arrhythmias may not be extremely rare, particularly among those patients who have repolarization abnormalities in the red- ing electrocardiogram and frequent premature beats. Patients with unexplained ventricular arrhythmias should be screened for mitral valve prolapse.

Patients with the mitral valve prolapse or click-murmur syndrome frequently have cardiac arrhythmias of various types. Ambulatory electrocardiographic monitoring demonstrates frequent premature ventricular contractions in up to 85 per cent and brief episodes of ventricular tachycardia in up to 50 per cent of these patients [l- 31. These arrhythmias are frequently well-tolerated [4], although occasional instances of sudden death [5-g], presumably arrhythmia related, do occur. Published reports of severe life-threatening arrhythmias in these patients have been infrequent [ 10,111. In this study we report the findings in seven patients with the mitral valve prolapse syndrome, with either prolonged symptomatic ventricular tachycardia, frequently requiring cardioversion for termination, or cardiac arrest from which they were successfully resuscitated. These patients illustrate the fact that severe and life-threatening

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LIFE-THREATENING ARRHYTHMIAS-WINKLE ET AL

arrhythmias can occur occasionally in patients with

this syndrome.

MATERIALS AND METHODS

This study includes all patients seen by members of the Cardiology Division of Stanford University Medical Center, between December 1972 and December 1974, in whom life-threatening arrhythmias were associated with the mitral valve prolapse syndrome.

Life-threatening arrhythmias were defined as episodes of cardiac arrest or of ventricular tachycardia which were sustained and associated with severe symptoms or which required cardioversion for termination. Patients with non- sustained ventricular tachycardia were not included. Pa- tients with other cardiac disorders which could account for the arrhythmias were also excluded. Four of the seven patients had coronary arteriograms, and none showed significant coronary artery disease; coronary artery disease was excluded on the basis of clinical findings in the re- maining patients. During this period, the majority of other patients seen at Stanford with life-threatening arrhythmias underwent echocardiographic evaluation; in most coronary arteriograms and left ventricular angiograms were performed in an effort to determine the etiology of their arrhythmias. Clinical records were reviewed in all patients, and follow-up’was obtained in February 1975 by di- rect contact with either the patients and/or their referring physicians.

RESULTS

Table I summarizes the findings in these patients. Five were women and two were men, ranging in age from 21 to 61 years at the time of evaluation at Stan- ford. Three of the seven experienced a single cardiac arrest, and one patient had multiple cardiac arrests, each with successful resuscitation. One patient had a single episode and another multiple episodes of sustained ventricular tachycardia requiring cardioversion, and one patient experienced multiple episodes of ventricular tachycardia, each lasting several minutes and resulting in presyncope. The following are brief clinical summaries of these patients:

Case 1. A 42 year old woman (SMC 2-85-38) had a murmur which was first detected at age 10. In 1987, a mid- systolic click and a grade l/6 systolic murmur were detected on routine examination. An electrocardiogram at that time revealed multifocal premature ventricular contractions, ventricular pairs and runs of three ventricular beats in a row. In 1970 she began treatment with 1.600 mg of quinidine a day for the ectopic beats, and potassium chloride because of a serum potassium of 3.7 meqiliter. She continued to experience daily palpitations on these medications, and in May 1973 the potassium supplement was discontinued and 40 mg of propranolol/day was added to the quinidine. Four days later she collapsed while driving her car, and cardiopulmonary resuscitation was initiated when the life squad found her apneic and pulseless. On arrival at the hospital she was in sinus rhythm. Serum

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LIFE-THREATENING ARRHYTHMIAS-WINKLE ET AL

tests for alcohol, barbiturates and other drugs were nega- tive, and the serum potassium was 4.3 meq/liter. Neuro- logic examination was compatible with hypoxic encephalopathy with diffuse abnormalities on the electroencepha- logram. She gradually made a complete neurologic recov- ery. Therapy with propranolol, 320 mg/day, was initiated in November 1973 for control of her premature ventricular contractions. She has had no further episodes of syncope or cardiac arrest.

Case 2. A 60 year old male mechanical engineer (SMC 42-40-68) with moderately severe chronic obstructive pul- monary disease had a murmur and intermittent palpitation, self-treated with occasional quinidine, for 15 years. In June 1973, while at work and not taking quinidine, he noted the sudden onset of a rapid heartbeat, associated with symptoms of low output. Upon arrival in the emergency room he was in ventricular tachycardia, at a rate of 200 beats/min. The rhythm was unresponsive to lidocaine therapy and required cardioversion. Blood gases shortly after cardioversion showed a pH of 7.40, an oxygen tension (~0~) of 109 and a carbon dioxide tension (pCO*) of 49. During the next two months, despite trials of propran- 0101, quinidine, procainamide, and a combination of quinidine and propranolol therapy, he had nine more episodes of ventricular tachycardia (Figure I), all associated with mild hypotension and all requiring cardioversion. In Sep- tember 1973, the administration of 1,200 mg of quinidine and 300 mg of Dilantin@/day was started, and he had no further episodes of ventricular tachycardia until October 1974. From October 1974 until January 1975, he had four more episodes of sustained ventricular tachycardia, all requiring cardioversion.

Case 3. A 21 year old housewife (SMC 40-65-15) had a cyanotic spell at age 3 for which she required mouth-to- mouth resuscitation. In June 1970 she collapsed at home and was taken immediately to a nearby emergency room, where she was cyanotic, apneic, pulseless and had dilated pupils. An electrocardiogram showed ventricular fibrillation which responded to cardioversion. Her mental status returned towards normal by the following morning, and monitoring revealed frequent bigeminy and runs of ventricular tachycardia and sinus bradycardia. The following day she had two more episodes of ventricular fibrillation, each requiring cardioversion. Serum potassium levels as low as 2.9 meq/liter were recorded during this period. Shortly after this cardiac arrest an intermittent mid-systolic click was first noted. During the subsequent year, trials of propranolol, quinidine. diphenylhydantoin, lidocaine and a combination of quinidine and propranolol therapy were unsuccessful in suppressing her premature ventricular contractions, and she was ultimately treated with potassium chloride and triamterene. A complete metabolic work- up did not determine the etiology of her hypokalemia. In December 1972, she noted a week of severe fatigue cul- minating in ventricular fibrillation requiring cardioversion (Figure 2). Her serum potassium was 2.3+ meq/liter at that time. She has remained on potassium chloride, triamterene and intermittent propranolol therapy and has had no further episodes of ventricular fibrillation, although frequent premature ventricular contractions persist.

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LIFE-THREATENING ARRHYTHMIAS-WINKLE ET AL.

Figure 1. Case 2. 124ead electrocardiogram showing one of many episodes of ventricular tachycardia, all of which required cardioversion.

Figure 2. Case 3. Electrocardiographic strips, obtained on patient’s arrival in the Emer- gency Room, demonstrating ventricular fibrillation which reverts to sinus rhythm following electroversion. The abnormal S-T segments promptly returned toward normal following resuscitation. The patient had normal coronary arteries.

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Figure 3. Case 6. Electrocardiographic strip obtained on patient’s arrival in the Emergency Room. These tracings demonstrate ventricular standstill, ventricular fibrillation and ventricular flutter. The words “Ft. alone” refer to the patient’s spontaneous rhythm and the strips labeled “CM” for cardiac massage demonstrate electrocardiographic artifact caused by closedkhest massage.

Case 4. A 44 year old housewife (SMC 43-17-57) had the onset of multiple episodes of exertional dizziness and blurred vision in June 1973. In September 1973 episodes of self-limited ventricular tachycardia at a rate of 200 beats/min were documented to be the cause of these episodes, which occasionally lasted several minutes. Multiple episodes were recorded during treadmill exercise tests and ambulatory electrocardiographic monitoring. Her serum potassium was 4.1 meq/liter and she was not taking medication at the time of these episodes. She has taken propranolol in doses up to 320 mg/day and has remained asymptomatic since September 1973. Follow-up ambulatory monitoring has confirmed the suppression of her arrhythmias by propranolol.

Case 5. This 53 year old airline mechanic (WC 10-71-13) first noted chest pain with radiation to the neck in 1970. These pains usually occurred in the evening and were not related to exertion. They often occurred several times in a week and then disappeared for several months. Inhospital monitoring revealed no blood pressure or electrocardiographic changes during resting chest pain. In March 1973 the patient experienced a severe episode of chest pain

and was hospitalized without electrocardiographic or en- zyme changes. He was readmitted to the hospital less than 24 hours after discharge with chest discomfort, dysbnea and heart pounding. An electrocardiogram showed ventricular tachycardia at a rate of 200 beats/ min, associated with moderate hypertension. The arrhythmia was unresponsive to, the administration of lidocaine and required cardioversion. Serial electrocardiograms and enzymes were again normal. In late March 1973, T wave inversion was noted in leads VI through Vs. Coronary arteriograms were normal except for a small iatrogenic inti- mal flap in the distal circumflex coronary artery. The patient has had no further ventricular tachycardia and no chest pain on 320 mg of propranolol/day.

Case 6. A 59 year old housewife (WC 46-54-63) had a life-long history of a heart murmur and frequent ectopic beats, first documented in the early 1940’s. In August 1973 she was again noted to have premature ventricular contractions, a late systolic murmur and late systolic mitral valve prolapse on echocardiogram. Her only medication was chlorothiazide for chronic mild ankle edema. She collapsed in January 1974 while at home, and was



promptly taken to a nearby hospital, where her electrocardiogram showed ventricular standstill (Figure 3). During her resuscitation she had multiple runs of ventricular fibrillation and tachycardia requiring defibrillation. Subsequent- ly hypoxic encephalopathy developed, from which she re- covered fully. Following discharge she was treated with procainamide, 2 g/day, and propranolol, 60 to 60 mg/day. She subsequently had two further hospitalizations for lightheadedness associated with runs of 3 to 5 beats of ventricular tachycardia. Since September 1974 she has been taking propranolol, 80 mg, and quinidine. 1,200 mg/day, and has had no further hospitalizations.

Case 7. In this 61 year old saleslady (SMC 41-21-16) paroxysmal supraventricular tachycardia first developed in 1968; initially she was treated with digoxin, 0.25 mg/day; ultimately she required quinidine and propranolol. In April 1972 she discontinued all medications, except digoxin, which she took on an intermittent basis for palpitation. On September 16, 1972, therapy was started with chlorothiazide for hypertension and on September 25 digoxin, 0.5 mgfday, for two days, followed by a maintenance dose of 0.25 mg/day. Quinidine therapy was resumed on Septem- ber 29 because of premature ventricular contractions. Two days later she had a syncopal episode at home and was brought to the emergency room. Frequent premature ventricular contractions were noted at the time of her arrival but soon ventricular fibrillation developed and she required cardiopulmonary resuscitation. After 6 hours her neurologic status was normal. Serial enzymes and electrocardiograms were unchanged. She has continued to have episodic paroxysmal atrial arrhythmias and premature ventricular contractions and has been treated with propranolol for one and a half years. A pacemaker was also inserted because of marked sinus bradycardia recorded transiently.

Documentation of the Mitral Valve Prolapse Syn- drome. In six of the seven patients auscultatory

findings were suggestive of this syndrome. In all seven patients, echocardiograms were performed.

Four showed consistent late systolic mitral valve

prolapse, two showed intermittent late systolic mitral valve prolapse and one had a technically poor echocardiogram which was suggestive, but not absolutely diagnostic, of mitral valve prolapse. Three of the patients had left ventricular angiograms, and all demon-

strated systolic prolapse of the mitral valve into the left atrium. One of these three had a moderate de- gree of mitral regurgitation. These findings are sum- marized in Table I. 12-Lead, Exercise and Ambulatory Electrocardlo- grams. All patients had at least one 12-lead electrocardiogram, and six of the seven had treadmill exercise tests and 12- or 24-hour ambulatory electrocardiograms available for analysis. The 1 P-lead electrocardiograms demonstrated a variety of abnormal findings, including premature ventricular contractions on at least one tracing in six of the seven patients. Repolarization abnormalities, either S-T segment, T

wave abnormalities or prominent U waves, were present in five of the seven. All the exercise tread-

mill tests and ambulatory electrocardiographic re-

cordings demonstrated frequent premature ventricular contractions. In only one patient did the premature ventricular contractions fall near the peak of the

T wave. Consecutive pairs of premature ventricular contractions occurred in the ambulatory electrocar-

diograms in four patients. Short bursts of ventricular

tachycardia occurred in two patients on both the

treadmill exercise test and the ambulatory electrocardiogram.

Events Preceding the Episodes of Life-Threatenlng Arrhythmia. The episodes of life-threatening arrhythmia were associated with exertion in only one

patient (Case 4). In all the other patients, the episodes occurred either at rest or during routine daily activities. Of the four patients with cardiac arrest,

one had profound idiopathic hypokalemia as the pre-

cipitating factor, two had changes in medications known to affect myocardial repolarization in the

week preceding their cardiac arrest, and the fourth

was receiving intermittent diuretic therapy for idio-

pathic pedal edema of many years’ duration (although it is uncertain whether or not the patient was taking the medication prior to the arrest).

Therapy and Follow-Up. All patients are currently alive an average of 25 months after the initial epi-

sode of life-threatening arrhythmia. The patient with the hypokalemia has remained asymptomatic for 26 months and has been receiving large doses of potas-

sium supplement, triamterene and intermittent propranolol. Propranolol, in doses up to 320 mg, has

been successfully used alone in four patients and in combination with quinidine in another. One patient in whom ventricular tachycardia developed while he was receiving 160 mg of propranolol/day had no re-

currences for 13 months with a combination of quini-

dine and diphenylhydantoin therapy; but subsequently he had four episodes of ventricular tachycardia, all requiring cadioversion, while taking this combination

of drugs.

COMMENTS

This study emphasizes the occurrence of life-threatening ventricular tachyarrhythmias in patients with the mitral valve prolapse syndrome. Previous reports of such severe arrhythmias in these patients have been infrequent. The evaluation of seven patients at one medical center over a two-year period suggests that these severe arrhythmias are not extremely rare. The incidence of such arrhythmias among patients with the mitral prolapse-click-murmur syndrome cannot be estimated from our study, since each of our patients was preselected by the occurrence of the life-threatening arrhythmia, and the pop-

966 June 1976 The American Journal of Medlclne Volume 60

ulation base from which they were drawn, although assumed to be large, is unknown.

Sudden arrhythmic death is seen in the mitral valve prolapse syndrome, although the number of documented instances is small [5-lo]. The diagnosis of this syndrome prior to the occurrence of the life-threatening arrhythmia in only two of our seven patients suggests that many arrhythmic sudden deaths occur among patients with undiagnosed mitral valve prolapse. Accurate assessment of both the incidence of this syndrome in the population and the incidence of sudden death in these patients will re- quire a long-term prospective follow-up of a large number of patients, and a better definition of their condition. It is likely that several etiotogies may be associated with either the clicks and murmurs or with the echocardiographic and angiocardiographic mitral valve prolapse. Although the incidence of sudden death in this syndrome is unknown, we assume that it must be low, in view of the recognition of this condition in a large number of the apparently healthy population.

All of our patients with life-threatening arrhythmias demonstrated frequent premature ventricular contractions. With the exception of two patients de- scribed by Shappell [ 7, IO], frequent premature ventricular contractions occurred in all previously de- scribed patients with sudden death [5,6,8] or revers- ible ventricular fibrillation [ 111, when this informa- tion was available. This suggests that sudden death is a risk primarily in those patients with mitral valve prolapse who show frequent premature ventricular contractions. However, since frequent premature ventricular contractions are common in the mitral valve prolapse syndrome, the incidence of sudden death must be low even in this subgroup.

Although the relationship between the medication changes and the cardiac arrests in our group may have been coincidental, it would seem prudent to

LIFE-TXREATENING ARRHYTHMIAS-WINKLE ET AL.

carefully consider the use of digitalis, antiarrhythmic drugs and potassium-wasting diuretics in patients with mitral valve prolapse, and to be particularly alert to the possible role of hypokalemia in these patients. At the present time, routine antiarrhythmic therapy is difficult to justify for the entire group of mitral prolapse patients who show frequent premature ventricular contractions, or perhaps even for all those who show consecutive pairs or brief parox- ysms of ventricular tachycardia, since such therapy often produces unacceptable side effects and fails to adequately suppress these arrhythmias. If antiarrhythmic therapy can be documented to suppress the arrhythmia and does not produce side effects, it should probably be given when the arrhythmias are considered to be life-threatening or when they are symptomatic or distressing to the patient. We choose propranolol as initial therapy, rather than quinidine or procainamide, because the latter drugs are more likely to increase the frequently existing myocardial repolarization abnormality. Long-term follow-up studies will be required to answer the question of the advisability of antiarrhythmic drug therapy for all patients with frequent premature ventricular contractions.

Our study suggests that most patients who survive episodes of life-threatening arrhythmias have a favorable intermediate term prognosis. Whether or not the therapy given to our patients accounts for their favorable clinical course is difficult to determine. However, it appears to have played a role in several of them.

In our experience, the mitral valve prolapse or click-murmur syndrome accounts for a significant minority of patients with life-threatening ventricular tachyarrhythmias not associated with coronary artery disease, and this syndrome should be considered in all patients with unexplained serious ventricular arrhythmias.

REFERENCES

1. Winkle RA, Lopes MG, Fitzgerald JW, Goodman DJ, Cardiovasc Dis 15: 623, 1973. Schroeder JS, Harrison DC: Arrhythmias in patients with 7. Shappell SD, Marshall CE, Brown RE, Bruce TA: Sudden mitral valve prolapse. Circulation 52: 73, 1975. death and the familial occurrence of mid-systolic click,

2. DeMaria AN, Amsterdam EZ, Vismara LA, Markson W, late systolic murmur syndrome. Circulation 48: 1128, Brocchini R, Mason DT: The variable spectrum of 1973. rhythm disturbances in the mitral valve prolapse syn- 8. Trent JK, Adelman AG, Wigle ED, Silver MD: Morphology drome (abstract). Circulation 49 8 50 (suppl lll):lll-222, of a prolapsed posterior mitral valve leaflet. Am Heart J 1974. 79: 539, 1970.

3. Kreisman K, Kleiger R, Schad N, Aker U. Parker B: Ar- 9. Barlow JB, Bosman CK. Pocock WA, Marchand P: Late rhythmia in prolapse of the mitral valve (abstract). Circu- systolic murmurs and non-ejection (“mid-late”) systolic lation 43 & 44 (suppl II): k-44, 1971. clicks. An analysis of 90 patients. Br Heart J 30: 203.

4. Gooch AS, Vicencio F, Maranhao V, Goldberg H: Arrhyth- 1968. mias and left ventricular asynergy in the prolapsing mi- 10. Shappell SD, Marshall CE: Ballooning posterior leaflet syn- tral leaflet syndrome. Am J Cardiol 29: 611, 1972. drome. Arch Intern Med 135: 664, 1975.

5. Hancock EW. Cohn K: The syndrome associated with mid- 11. Cobbs BW Jr, King SB Ill: Mechanism of abnormal ventric- systolic click and late systolic murmur. Am J Med 41: ulogram (VGM) and ECG associated with prolapsing mi- 183, 1966. tral valve (PMV) (abstract). Circulation 49 & 50 (suppl Ill):

6. Jeresaty RM: Mitral valve prolapse-click syndrome. Progr 111-7, 1974.


life-threatening arrhythmias in the mitral valve prolapse syndrome

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