ETHYLALCOHOL AS A CARDIAC RISK FACTOR TIMOTHY J. REGAN PHILIP 0. ETTINGER MICHAEL M. LYONS CHRISTOS B. MOSCHOS ALLEN B. WEISSE
Editorial William de Leon,
Board (clockwise C. Roberts, Robert Jr.
EDITORS’
from top): A.
O’Rourke,
W.
Proctor Frank
Harvey, James I. Marcus and
J. Leonard, Antonio C.
PREFACE
It now seems well established that alcohol is one of the causes of cardiomyopathy whereas a couple of decades ago it was not as well appreciated in the United States as compared with the British Isles, where authors such as William Evans were describing this as a separate entity. I remember Doctor Evans describing a group of patients in his practice who developed alcoholic cardiomyopathy, and he mentioned that often it was the successful businessman, who was not known as a drunkard but who consumed a steady daily large amount of alcohol and over a long period of time. Although we in our hospital have had a long interest in cardiomyopathies, we did not at that time have a sizable number of patients who seemed to have this as the etiology of their disease. We started to look more carefully for patients with alcoholic cardiomyopathy and, as is true in all aspects of medicine, we found what we looked for. More patients were found, but they were more likely in our large city hospital or in our Veterans Administration Hospital. It became obvious that the patient population of these hospitals often had more problems related to a larger consumption of alcohol than in our university hospital.
Alcohol can have detrimental effects on the heart, producing toxic damage directly to the myocardium, resulting in congestive heart failure and arrhythmias, some of which-such as ventricular tachycardia and ventricular fibrillation -can be fatal. For a number of years Dr. Timothy Regan and his group at the New Jersey Medical School have had an interest in the relationship between alcohol and the heart, and have done research on this problem. Valuable information as to etiology and mechanism of heart damage has been the result. In addition, practical aspects concerning treatment have also been forthcoming. This issue of CURRENT PROBLEMS IN CARDIOLOGY provides an excellent overview of the interesting problem of alcoholic cardiomyopathy.
Lawrence D. Horwitz, M.D., Guest Editor
Dr. Lawrence D. Horwitz, Associate Professor of Medicine, directs the Cardiology Research Program at the University of Texas Health Science Center in San Antonio. During the past 10 years, Doctor Horwitz has published many important research studies concerning the assessment of left ventricular performance at rest and during exercise in the normal and diseased heart. More recently, he has completed several relevant studies concerning the reduction of ventricular performance by agents that depress myocardial function. Doctor Horwitz has performed several investigative studies concerning the effects of ethyl alcohol on cardiac performance (JAMA 232:959, 1975 and Circulation 49:124, 1974) and for that reason was chosen by the Editorial Board to serve as Guest Editor of this excellent monograph by Doctor Regan and his associates.
r
1 TABLE
EXPERIMENTAL PRECLINICAL
OF CONTENTS
EVIDENCE FOR CHRONIC MYOCARDIAL MALFUNCTION
IN MAN
.
CARDIAC FAILURE AND THE ECG
ILLUSTRATIVE
CASES
.
.
13
.
15 .
.
.
.
.
.
OBSERVATIONS ABOUT THE ARRHYTHMLW
ATYPICAL TREATMENT
MYOCARDIAL
18 18
SUDDEN DEATH
SUMMARY
10
.
ARRH~HMLW
GENERAL
TOXICITY
.
26 .
.
INFARCTION
AND REVERSIBILITY
29 30
.
32
.
33
is Professor of Medicine and Director of the Division of Cardiovascular Diseases at the College of Medicine and Dentistry of New Jersey. He received his M.D. from Boston University School of Medicine and was awarded a fellowship in cardiology by the National Institutes of Health at Wayne State University School of Medicine, Detroit, Michigan. Doctor Regan’s research interests are the interrelations of cardiac metabolism and diseases of heart muscle.
is Clinical Associate Professor of Medicine at the College of Medicine and Dentistry of New Jersey and Attending Cardiologist at Englewood Hospital, Englewood, New Jersey. He received his medical degree from New York University, interned at Lennox Hill Hospital and completed his residency at the Veterans Administration Hospital in the Bronx, New York. Doctor Ettinger was a Cardiac Fellow at New York University Hospital and USPHS Fellow in Cardiology at B. S. Pollack Hospital in Jersey City. He is interested in many aspects of cardiac physiology and pathophysiology, especially in cardiac arrhythmias and myocardial function.
is Associate Professor of Medicine, Department of Pathology, Director of Autopsy Pathology and Anatomical Pathology at the College of Medicine and Dentistry of New Jersey, and Consultant for the Department of Law and Public Safety, Division of Criminal Justice, Office of the Medical Examiner, Newark, New Jersey. Doctor Lyons received his M.D. at the Loyola University of Chicago Stritch School of Medicine and completed his internship at Kings County Hospital, Brooklyn. 6
’ is Professor of Medicine and Director of the r Cardiac Clinic at the College of Medicine and Dentistry of New Jersey. He graduated from f Athens Medical School, completed his postI graduate studies at the University Hospital, Vienna, Austria, and accepted a two-year Fellowship from Boston City Hospital (Tufts). His main research interests are in the cardiovascular field. Doctor Moschos concentrates on the study of the pathophysiology of coronary thrombosis.
is Professor of Medicine at the College of Medicine and Dentistry of New Jersey and Director of the Cardiac Care Unit of the Martland Hospital. He received his M.D. at the State University of New York, Brooklyn, served an internship at Mt. Zion Hospital, San Francisco and took his residency at the VA Hospital, San Francisco. Doctor Weisse’s main research interests are the myocardial function and the coronary collateral circulation in ischemia. Other interests include experimental and human polycythemic states, particularly complicating car pulmonale.
ETHYL ALCOHOL has long been recognized. as.a toxic agent having acute as well as chronic effects on cerebral and hepatic function at certain dose levels. It has been traditional that the heart was not similarly affected. In fact, alcohol, at least in modest amounts, commonly was viewed as a medicinal agent. Appearance of heart disease in an alcoholic individual usually was attributed to underlying heart disease of rheumatic, hypertensive or coronary etiology, often without good supporting evidence. When the specific entity of beriberi heart disease was associated with alcoholism, the patient was treated for thiamine deficiency with frequent success. Consequently, correction of malnutrition was considered the major therapeutic modality in alcoholic patients who had heart disease. In contrast to recent experience, earlier studies of the acute response to ethanol did nothing to dispel this view, since draNOTE: of Alcohol
This investigation was supported by a grant Abuse and Alcoholism. No, AAO0242.
from
the National
Institute 7
matic decreases in cardiac function were not observed consistently. This presumably was related to methodologic difficulties in which the experimental model often was in a nonsteady state, with varying degrees of hypoxia, and the methodology for assessing left ventricular function in a relatively physiologic preparation was not available. The acute response of the myocardium is relevant to the question of the general effects of ethanol and the particular question of its influence in patients with heart disease. Doses that are mildly intoxicating have been shown to adversely affect left ventricular function in some circumstances. This effect is, in part, dependent on prior experience with alcohoi; that is, larger doses are required to demonstrate impaired pumping action of the heart in the chronic alcoholic subject who has no clinical evidence of heart disease’ (cf references l- 9). However, the dose of Scotch, 6 oz, fed to normal individuals over a 2-hour period, has been found to diminish the force of heart muscle contraction at a mildly intoxicating blood level of 75 mg/lOO ml. This effect progresses as blood levels rise and usually is dissipated within a few hours after the drinking is interrupted. Supporting the view that ethanol is acutely depressant to myocardium is the fact that ventricular dysfunction is rapidly reversed after 15- 30 minutes of hemodialysis. b LAWRENCE D. HORWITZ: There has been a widespread misconception
among physicians and laymen alike that alcohol is a cardiac stimulant. In fact, there is strong evidence that alcohol is a myocardial depressant. Since anesthetics themselves impair myocardial function, some of the variation in the results of alcohol studies in anesthetized animals may be due to difficulty in distinguishing superimposed changes in preparations that already are subnormal. However, studies cited by Regan et al. conclude convincingly that under such circumstances a cardiac depressant effect of alcohol usually is demonstrable. In addition, a study of normal conscious dogs has demonstrated markedly reduced myocardial force development at blood alcohol levels below 150 mg/lOO ml, which is the usual legal limit for safe operation of an automobile (Circulation 49:124, 1974).
In contrast to these findings in alcoholics without clinical evidence of heart disease, the patient who already has had at least one episode of heart failure may exhibit a greater sensitivity to the 6-0~ dose of Scotch with substantial elevation of filling pressure. The response in cardiac subjects who are not alcoholics may be qualitatively similar. An important variation of the acute response to ethanol occurs when combined with other pharmacologic agents. Accidental or suicidal deaths have resulted from the combination with barbiturates. Potentiation of the myocardial depressant effect has been observed experimentally with such a combination, which is concurrent with respiratory depression. 8
B LAWRENCE D. HORWITZ: Whether or not they are habitual imbibers of alcoholic beverages, some patients with heart disease may be extraordinarily susceptible to myocardial depression by alcohol. In one study during cardiac catheterization, drinking only 2 ounces of Canadian whiskey reduced cardiac output and stroke volume in patients with a variety of cardiac disorders (JAMA 218:1799,1971). It is my policy to caution cardiac patients to limit their alcohol intake on any given day to no more than one shot (1Yz ounces) of 90-proof whiskey or its equivalent (a 6ounce glass of wine or a 12-ounce can of beer). Even this small quantity may be a prohibitive risk in patients with congestive heart failure. The possibility that other forms of drug abuse, such as barbiturate ingestion, can exacerbate the cardiotoxicity of alcohol is important, since concomitant ingestion of ‘alcohol and other drugs taken for nonmedical reasons is quite common. In addition, little is known concerning the interaction of alcohol with drugs often used for treatment of diseases. Ethacrynic acid, a widely used diuretic, increases the incidence of lethal alcohol toxicity in animals (Proc. Sot. Exp. Biol. Med. 118:970,1965).
The sympathetic nervous system presumably has an important role in modifying the cardiac response. Thus, blockade of the system has been shown to produce greater depression of left ventricular function during ethanol administration. Intensification of the cardiovascular response to ethanol in animals treated with disulfiram, an inhibitor of beta hydroxylation, with resultant lower levels of endogenous norepinephrine, may well be on a similar basis.2 It is noteworthy that the adrenal gland does not appear to respond with greater secretion of epinephrine or norepinephrine, at least in response to moderately intoxicating blood levels,3 so that cardiac catecholamine stores would appear to be the major factor modifying the response to acute ethanol intake. In considering the direct influence of ethanol on cardiac cells when administered acutely, changes of cation transport in the muscle are of major importance. The action in reducing force of contraction may well entail altered calcium mov+nent in the ce11.4 It is known that potassium and phosphate transiently leak out of the muscle cells after a 12-02 dose’; that is not attributable to coronary blood flow reduction. The loss of cation may be related to an inhibitory effect of ethanol on active transport of potassium and sodium across cell membranes, which has beensuggested as a basic mechanism of action of ethanol on most cells.5 Another metabolic change is represented by alteration of lipid transport in the myocardium: the large dose of ethanol reduces the uptake of free fatty acid by the left ventricle whereas the increased triglyceride uptake results in accumulation of lipid in myocardium.’ This response may contribute to pathologic changes observed in human myocardium during postmortem examination; substantial increases in lipid, presumably triglyceride, have been observed in the alcoholic heart6 It is of note that noncardiac striated muscle, including uterus7 and skeletal muscle,* are also depressed acutely by ethanol, al9
though in the diaphragm this follows a period of enhanced contractility. With chronic use, the asymptomatic alcoholic may exhibit modest reduction of lactic dehydrogenase as well as a small reduction in fast twitch glycolytic fibers and volume of mitochondria. The conditions required for acute myopathy and rhabdomyolysis are not well defined, but malnutrition and hypophosphatemia frequently are associated.s EXPERIMENTAL EVIDENCE MYOCARDIAL TOXICITY
FOR CHRONIC
Although histologic abnormalities have been observed in 90% of unselected alcoholics in one postmortem series,‘O uncertainty as to the quantity of ethanol intake, the nutritional status of the patient, including electrolyte deficits, and the possibility of heart disease from other causes have obscured the relationship of excessive ethanol use and cardiomyopathy. Previous chronic experiments with ethanol have yielded conflicting data in terms of the production of a functional deficit, but the negative study used smaller quantities and was relatively short term. To eliminate some of the above variables, a group of young adult male dogs were maintained in a relatively normal nutritional state while receiving up to 36% of calories as ethanol, approximating the quantity reported in many human alcoholics. After an average of 18 months, they were found to have maintained weight, hematocrit, serum proteins, vitamins and electrolytes to an extent similar to normal controls.” When these two groups were studied at similar levels of heart rate and aortic pressure, chronic ethanol animals exhibited a significantly higher end-diastolic pressure at rest despite a lower level of end-diastolic volume. Assessment of left ventricular function was undertaken during afterload increments with angiotensin of similar extent in both groups. Stroke output and work increased moderately but significantly in the controls whereas no such increments occurred in the alcoholic animals, despite a significantly higher end-diastolic pressure. The enddiastolic volume response was significantly less than in controls, and presumably is the basis for the reduced stroke volume. To further analyze the apparent altered stiffness of the ventricle, 6 of the normal animals and 6 of the ethanol group were infused with normal saline via a catheter in the left ventricle. In the ethanol group there was a significantly higher rise of end-diastolic pressure than in the normal, despite an elevation of enddiastolic volume proportionate to that of controls. A potential morphologic basis for the altered diastolic pressure-volume relations was found in sections of the left ventricle. Staining with alcian blue showed distinct accumulation of a glycoprotein-like material in the interstitium of the left ventricular 10
wall in the ethanol group, with virtually no staining in the normal controls. The factors responsible for progression to interstitial collagen accumulation as seen in man are not known. This may limit the rapid accessibility of calcium to intracellular sites and ultimately contribute to the development of heart failure. Whether independent abnormalities of intracellular calcium transport or myosin ATPase are present in long-term experiments has yet to be demonstrated. A difficulty in assessing the importance of these factors is the fact that no animal model has yet been of sufficient duration to produce frank heart failure. As a further assessment of the myocardium in alcoholic aniFig I.-Intercalated ferentiated regions tion 9500x; 4’7,500~
disk of alcoholic are apparent. The final). (Reprinted,
dog. Cystic areas of dilatation of undifnexus region appears normal (magnificawith permission, from Am. Heart J.)
mals, high-speed, high-frequency electrocardiograms were obtained. QRS time was distinctly abnormal in the longer-term animals.‘* Similarly, the conduction time from the His bundle to the onset of ventricular depolarization was significantly prolonged. Dilatation of the intercalated disk by electron microscopy appeared to be the morphologic correlate (Fig. 1). Although plasma lipid concentrations were normal, analyses of left ventricular lipids revealed an increment of triglyceride in the ethanol group, which appeared as fine cytoplasmic droplets on oil red 0 stain. Incorporation of labeled fatty acid into phospholipid was reduced and may represent a process that limits the function of cell membranes, since cation composition of the left ventricle was abnormal.‘4C02 production from 14C-l-oleic acid was decreased and may be secondary to diminished activity of rate-limiting enzymes in the citric acid cycle, demonstrated after chronic ethanol use. l3 Dilatation of the sarcoplasmic reticulum and intercalated disk were the only unequivocal structural abnormalities in the relatively well-nourished animals in this chronic study, findings also observed in patients with alcoholic cardiomyopathy.14 It is problematic whether the extensive abnormalities of myofibrils and mitochondria reported in other human studies are secondary to multiple episodes of heart failure or are due solely to toxicity, coexistent nutritional deficiency, cobalt excess or other complications.15j l6 Although, with time, most species appear to develop myocardial abnormalities, the duration and quantity required to develop functional or morphologic alterations appear to vary. Thus, the rhesus monkey surprisingly has shown focal myocytolysis and early fibrosis after 3 months of ethanol as 40% of calories.” It is possible that the feeding modality, relatively rapid by stomach tube, or the synthetic liquid diet contributed to this response. In the rat, ethanol as 10% of total calories apparently has produced ultrastructural abnormalities as early as 7 weeks.ls Prior experience with rodents and their proclivity for viral infections raises the question of possible conditioning of the myocardium, with sensitization to the early development of lesions at relatively low doses. In considering pathogenesis, one must consider the first metabolite of ethanol. Acetaldehyde can significantly depress left ventricular function when infused at rates that simulate blood levels associated with moderate ethanol ingestion.19 This suggests that acetaldehyde may have a role in the pathogenesis of the cardiomyopathy. An additional consideration involves the role of magnesium ion. Primary magnesium deficiency does produce cardiac lesions in immature experimental animals. Unequivocal disease in adults is difficult to demonstrate, however, although secondary potassium loss could have important conse12
quences. As a general observation, functional and clinical malities of myocardium frequently occur with normal levels of this cation.
abnorserum
LAWRENCE D. HORWITZ: The above studies by Regan and colleagues are important because they are some of the strongest evidence to date that the clinical syndrome of alcoholic cardiomyopathy is caused by a direct toxic e&et of alcohol on the myocardial cells rather than to nutritional deficiencies or the effects of trace metals, as sometimes has been assumed. Although various potentially relevant biochemical or metabolic observations have been made, as summarized above, the mechanism for the adverse effects of alcohol still is an unanswered question. To be fair, it should be pointed out that some efforts to induce a cardiomyopathy type of syndrome in animals induced to ingest alcohol chronically have been unsuccessful (Am. Heart J. 78:770,1969; Jpn. Heart J. 12:242, 1971). It would appear that in animals, as in humans, chronic ingestion of large quantities of alcohol does not inevitably cause myocardial damage but that unknown factors may make certain subjects more susceptible than others.
b
PRECLINICAL
MALFUNCTION
IN MAN
To determine if there was an equivalent functional abnormality in man, studies were undertaken of alcoholic subjects with no symptoms or clinical evidence of heart disease or malnutritionzO Documentation of lo- 15 years of alcoholism and the type of ethanol used was obtained from the patients’ histories or from close relatives. Whiskey was the predominant alcoholic beverage, consumed several times a week, in amounts ranging from 0.5 to 2 pints/day. Liver biopsy revealed fatty liver without fibrosis. Left ventricular performance was studied by increasing afterload with angiotensin. The noncardiac alcoholic exhibited a significantly greater rise of ventricular enddiastolic pressure with minimal increment of stroke volume compared to nonalcoholic controls. Diminished ventricular performance has also been observed during exercise in cirrhotic patients without clear evidence of cardiac disease. Some degree of interstitial fibrosis may be present at this stage, as suggested by postmortem studies of accident victims who were alcoholic.*’ Demonstration of abnormal left ventricular function in alcoholic subjects without clinical evidence of heart involvement has also been reported in noninvasive studies.**, 23 The most significant alterations of the systolic time intervals were found in the prolonged PEP and increased PEP/LVET. This may be attributed to a depressed contractile state or diminished compliance of the left ventricle. The latter interpretation is supported by findings in a canine model of chronic ethanolism. Enhanced diastolic stiffness of the ventricle was associated with glycoprotein accumulation in the interstitium of the experimental model’l and a 13
Fig 2. - Alcian blue-positive glycoproEtim interstitium between muscle fibers. None with permission, from Circulation.)
was
accumulated present
in left in control.
ventricular (Reprinted,
similar histochemical abnormality has been seen in noncardiac alcoholics with cirrhosisz4 (Fig. 2). These studies are in accord with the view that congestive cardiomyopathy is infrequent in patients with cirrhosis but a preclinical abnormality would appear to be common in male cirrhotics. The normal time intervals in females are unlikely to be due to lesser intensity or duration of alcoholism, since the females had cirrhosis of equal or greater severity as judged by prothrombin times. This absence of a functional abnormality in the female suggests that the sex hormones are a determinant in the development of the preclinical entity and presumably the clinical cardiomyopathy. The functional abnormalities in the males are not likely to be due to coronary artery disease, for several reasons. The normals were of similar age, and alcoholics with cirrhosis appear to have less atherosclerosis at postmortem examination than the nonalcoholic population.25 Moreover, patients with angina without cardiac decompensation frequently have normal systolic time intervals. Although some of the cirrhotic patients had clinical evidence of mild malnutrition, particularly in the female group, the normal systolic intervals in the latter suggest that malnutrition was not a determinant of the abnormal systolic time intervals. In addition, the degree of anemia in these patients was not severe enough to cause hemodynamic alterations. This is support14
ed by observations in 5 nonalcoholic patients with moderate anemia, at hematocrit levels between 25% and 30%. No significant difference in systolic time intervals compared to normals was found. More severe chronic anemia apparently is required to evoke hemodynamic change, and these may be evidenced as enhanced rather than reduced ventricular function. b LAWRENCE D. HORWITZ: Although an interesting concept, I do not believe that the evidence presented for a preclinical abnormality in male cirrhotics is very strong. Small differences in systolic time intervals during a single observation in very small groups of subjects are prone to misinterpretation. These measurements could have been influenced by other hemodynamic factors. For example, the possibility that the male cirrhotits studied had reductions in venous return or preload due to extracardisc factors rather than reductions in myocardial contractile force cannot be excluded. The time at which observations are made might also be critical if some factor other than reductions in myocardial contractile force cannot be excluded. The time at which observations are made might also be critical if some factor other than sex were influencing the data. More reliable results could be obtained if much larger numbers of subjects were studied repeatedly over a prolonged period. Not only systolic time intervals but other noninvasive techniques such as echocardiographg could be used.
CARDIAC
FAILURE
To test the thesis that cumulative effects of ethanol over a period of time may result in cardiac abnormality despite adequate nutrition, a well-compensated patient was fed ethanol as Scotch for a period interval
of 5V2 months at a daily of 6 weeks (Fig. 31, resting
dose of 12- 16 OZ.~O After an heart rate began to rise and
there was prolongation of circulation time and elevation of venous pressure without evidence of malnutrition. After 4 months, a ventricular gallop rhythm appeared, which persisted until ethanol was interrupted without evidence of pulmonary congestion.
Subsequently,
without
specific
cardiac
therapy,
there
was
spontaneous restoration to normal. A major role of ethanol in the production of left heart failure in this subject was substantiated by the gradual reversion ity after alcohol ingestion
of the
cardiocirculatory
abnormal-
was interrupted. This observation supports the thesis that the myocardial disease is reversible at certain stages if intake of ethanol is discontinued.
F W. PROCTOR HARVEY: Certainly, as one of the main aspects of treatment, complete abstinence from alcohol must be adhered to in addition to the other aspects of treatment of congestive heart failure, which include rest, digitalization, sodium restriction, diuretics and also the management of specific arrhythmias when they are present. It is encouraging to know that reversibility has been, and can be, accomplished by medical 15
treatment, particularly in their course. It is apparent early treatment are most cardiomyopathy, as is true
those patients whose therapy starts early in that early suspicion, early recognition and important in the management of alcoholic in other etiologies of cardiomyopathy.
In circumstances marked by progression of cardiac dysfunction, pulmonary congestion may lead to exertional or nocturnal dyspnea.26 If long sustained or after repeated episodes, pulmonary hypertension and right heart failure may become evident. Unless there is complicating papillary muscle insufficiency giving rise to mitral regurgitation, cardiomegaly may be moderate in extent and heart size may revert to near normal after central congestion is corrected. In some patients, systemic or pulmonary emboli from mural thrombi may adversely affect the patient’s course. These clinical episodes frequently seem to be precipitated by intensified drinking episodes. Several reports of cardiomyopathy have emphasized the difficulty in obtaining a history of alcoholism. There is a male predominance, and suggestive diagnostic aspects include social disruption, accident proneness and a familial history. Hepatic cirrhosis and clear evidence of peripheral neuritis are not present Fig 3. -Evidence of cardiac decompensation developing during chronic ethanol intake. These are observations in a single,well-nourished patient receiving daily Scotch, which resulted in evidence of heart failure. The failure regressed without medical treatment after interrupting alcohol intake. (Reprinted, with permission, from J. Clin. Invest.)
. CARDIOTHDRACIC a50 RATIO (cm 1 0.45
.
-4
l
.
0
l
.
4
_
.
8
TIME
16
.
.
12
IN
n
.
.
.
l
16
WEEKS
22
26
.
.
frequently in patients with alcoholic cardiomyopathy. The major positive diagnostic feature is the history of ingesting ethanol in intoxicating amounts for many years, frequently with spree episodes. This information often may be obtained only through persistent questioning of the patient or from relatives. Negative aspects include exclusion of other causes of heart disease, namely, hypertension, coronary artery disease, car pulmonale and congenital or valvular disease. Other forms of cardiomyopathy (viral, infiltrative, metabolic, etc.) must be considered also. In addition to the usual lack of specificity of the clinical signs and symptoms, high diastolic-arterial blood pressure not infrequently is found during periods of severe congestive heart failure, which may lead to the false diagnosis of hypertensive heart disease. The blood pressure usually returns to normal following response to therapy for cardiac decompensation. Intoxication itself may contribute to blood pressure rise. Ethanol administration produces vasoconstriction of skeletal muscle vessels associated with dilatation of vessels to the skin. Predominance of the former may account for transient hypertension but there is no evidence that chronic hypertension is produced. Conversely, the net effect on the different vascular regions is not known to produce vasodilatation sufficient to reduce afterload. Modest vasodilatation theoretically would be therapeutic in heart failure if ethanol did not have negative inotropic properties. Not only are quantity, frequency and duration of ethanol intake difficult to assess but their relationship to organ pathology is not straightforward. It is probable that these factors have a similar importance for the varied chronic diseases secondary to alcohol abuse, so that information in relation to liver disease, for which there are more complete data may, in a general way, be applicable to the heart. Alcoholic hepatitis usually develops after years of excessive drinking, although in a ‘few patients it appears within a few years, but may not develop in many even after several decades of drinking.27 More than 80% were drinking 5 years or longer before developing symptoms. The probability of developing alcoholic hepatitis is small in those who drink less than 80 gmlday of ethanol (approximately 8 oz of 86-proof whiskey or 1 liter of wine) or if ethanol provides less than 20% of calories. As the daily ethanol consumption increases to 90- 160 gm/day and the duration of drinking becomes longer, the risk of developing alcoholic liver disease increases. The probability of alcoholic hepatitis or cirrhosis is great if the daily ethanol consumption exceeds 160 gm (for example, two-thirds of a bottle of whiskey, the approximate daily metabolic capacity of an average nondrinking person) and if the drinking-either steady or in sprees-persists for lo- 15 years or longer. It is noteworthy that the rate of ethanol metabolism can be high 17
enough to permit the consumption of large amounts without raising the blood ethanol level over 80 mg/lOO ml, the concentration at which the conventional breath analyzer begins to detect ethanol. b W. PROCTOR HARVEY: As pointed out by the authors, it may be difficult to ascertain the exact amount of alcohol consumed by a patient. When this aspect of his history is obtained, the individual’s intake frequently is minimized, appearing to be a much smaller amount than actually is so. Illustrating this point was a man personally evaluated who held a responsible executive position and had a classic picture of congestive cardiomyopathy. He had cardiomegaly, atria1 and ventricular diastolic gallops, an apical systolic murmur and alternation of heart sounds and murmurs. He had moderately advanced chronic congestive heart failure. When questioned concerning the use of alcohol, he stated that he used it only in moderation and was a “social drinker.” We therefore were about to classify his cardiomyopathy as idiopathic (unknown) etiology; however, when discussing his problem with his wife (the patient was not present), it was determined that he was drinking approximately a fifth of gin per day with increased weekend consumption. He had a long history of a large daily intake of alcohol, starting with “Happy Hour” in World War II. He died several years later, having progressed to an irreversible stage of his disease.
ARRHYTHMIAS
AND
THE ECG
An association between alcohol use and cardiac arrhythmias, particularly atria1 fibrillation, has long been suspected. However, the specific etiologic role of alcohol is difficult to establish and, indeed, doubt may exist as to the presence of any heart disease when overt cardiomyopathy is not present. Over a 4-year period, we have observed or reviewed 32 separate dysrhythmic episodes occurring in 24 patients who drank heavily and habitually. In each instance, hospitalization was deemed necessary for treatment. All patients have histories of prolonged ethanol use, with superimposition of especially heavy ingestion prior to the arrhythmia. Overt alcoholic cardiomyopathy was not present, as only patients with normal or borderline heart size (by x-ray) and normal (or minimally abnormal) ECGs after return
to sinus
ILLUSTRATIVE
rhythm
were
included.2s
CASES
CASE 1. -D. R., a 39-year-old businessman, spent a long weekend drinking heavily in a motel. After 3 days he developed palpitations and was seen at another hospital, where atria1 fibrillation was detected and he was cardioverted. He felt well but gradually resumed consumption of 12- 15 cans of beer daily. Four years later, he presented with palpitaCons. Frequent atria1 extrasystoles (with LBBB aberration) were 18
treated with quinidine. Plasma electrolytes were normal. Since reducing his beer consumption and continuing quinidine, palpitations have lessened, although he has frequent palpitations when he drinks more heavily. CASE 2. -M. H., a 31-year-old woman, drank whiskey in quart quantities daily. She was seen at the emergency room because of palpitations and breathlessness; atria1 fibrillation with ventricular extrasystoles was present (Fig 4, A). Within minutes, the rate accelerated, with runs of beats of uncertain origin, possibly ventricular tachycardia. Cardioversion was performed immediately. Plasma electrolytes were normal. In the next 2 years she was admitted on three additional occasions, each time with atria1 fibrillation and the same drinking history. One each occurred on a Sunday, Monday and Tuesday. CASE 3. -R. G., a 42-year-old woman, was admitted because of palpitations. She drank 6- 12 cans of beer daily. The EGG showed atria1 flutter with 1:l response (Fig. 4, B) and cardioversion was performed. Plasma electrolytes were normal. Fifteen months later, while continuing her beer ingestion, she was readmitted because of the same arrhythmia; treatment with digoxin was begun and sinus rhythm returned. CASE 4. -W. K., a 43-year-old businessman, consumed at least 6 oz of martinis daily for many years. During the month of December he had additional liquor at business luncheons. He “passed out” while seated in a cinema and was taken to the emergency room. Frequent ventricular extrasystoles were present and the plasma K+ was 2.7 mEq/l. Treatment with procainamide and K+ suppressed the arrhythmia. Three weeks later, while asymptomatic and arrhythmia-free at rest, an exercise stress test induced ventricular extrasystoles and runs of ventricular tachycardia to occur after the exercise (Fig. 4, C) and was presumed to be the basis of his presenting symptoms. With abstinence and outpatient treatment with quinidine, the arrhythmia has not recurred.
Twenty patients in the series were male and 4 were female (aged 25-62 years, mean 43 years). All but 3 were between 30 and 60 years of age; 8 patients were in the fourth -decade, 7 in the fifth decade and 6 in the sixth decade. All p+i&nts gave histories of consuming at least 6- 10 drinks daily. The age distribution, beginning mainly after age 30, along with the histories obtained in patient interviews, suggests that at least 10 years of heavy ethanol consumption usually was present as a background. All varieties of beer and whiskey were implicated, alone or in combination. Most patients drank every day of the week but indicated that weekend consumption was higher. We have not yet observed this disorder in anyone who drank wine alone, although this may be a cultural difference, inasmuch as wine drinkers are less frequent in our population than whiskey or beer drinkers. All but 2 patients smoked heavily, but no relation of smoking to arrhythmia was ascertained. Following resolution of the arrhythmias, most patients were asymptomatic, although 1 developed overt alcoholic hepatitis and 2 had delirium tremens. Low plasma potassium, previously 19
Fig 4. -Electrocardiograms of illustrative cases. A, CME 2. - Atria1 fibrillation is seen in top strip with one aberrated (Ashman) beat (the 6th). Within 10 minutes (next two strips), the rate accelerated with runs of wide complexes (?aberration or ventricular tachycardia) at rate of 240/min. B, CASE 3. - Atria1 flutter with 1:l conduction (verified later by carotid massage) at rate of 250/min with RBBB aberration. A single normally conducted beat is seen. C, CASE 4.-Runs of ventricular tachycardia 1 minute following the end of a treadmill stress test 1both strips). (Reprinted, with permission, from Am. Heart J.)
20
1 32
EPISODES,
TO JAN
I
l/2-12/23
12/24-l/1
El
m
1976
1 I J
I
NUMBER OF ADMISSIONS
SUN
ON THU FRI TUE WED SAT Fig 5. -Admitting day for alcoholic arrhythmias. Nineteen admissions were seen Sunday through Tuesday (post-weekend). Of the 13 Wednesday through Saturday admissions, 6 were during the year-end holidays. Therefore, 25 of 32 admissions were holiday-related. (Reprinted, with permission, from Am. Heart J. I
implicated as a possible cause of arrhythmias in alcoholics, was less than 3.5 mEq/l in only 4 of 30 instances, although a wholebody potassium deficit was not excluded. SGOT usually was normal or borderline elevated. Blood alcohol determinations were performed on admission in 8 patients and were positive in 6, ranging from 50 to 430 mg/lOO ml. Plasma sodium, chloride, bicarbonate, lactic dehydrogenase, urea, sugar and cholesterol were normal. Arterial blood gases and pH were normal in all. Figure 5 indicates the admitting day of the week in each instance. Nineteen patients were initially seen between Sunday and Tuesday, with Monday admissions most common. By chisquare testing, 19 of 32 episodes occurring on 3 of the 7 days of the week are significantly greater than the 317 expected. P~0.05. However, further examination of the data was even more revealing, as 6 of the 13 admissions from Wednesday through Saturday were seen between December 24 and January 1. When these holiday admissions are added to the 19 postweekend admissions, fully 25 of the 32 episodes could truly be considered examples of a “holiday heart syndrome,” a name that has been used at our institutions to describe them. In Figure 6, the number of alcoholic arrhythmia admissions per month over the 4-year period is shown. Only 2 patients were seen between May and August whereas the incidence peaked in December and January. In the bottom graph, the mean combined monthly incidence peaked in December and January. In the bottom graph, the mean combined monthly incidence of hos21
JUL
ALCOHOLASSOCIATED ILLNESSES
AUG SEP OCT NOV
DEC JAN
FEB MAR APR
MAY
JUN
30
Fig 6. -Monthly distribution of “holiday heart” hospital compared with mean monthly admissions for “traditional” illnesses (bottom). The apparent year-end peak of alcoholic present for the “traditional” alcoholic illnesses. (Reprinted, from Am. Heart J.)
admissions (top), alcohol-associated arrhythmias is not with permission,
pita1 admissions for all other traditionally accepted alcohol-associated illnesses are tabulated for comparison in 3 years of the 4-year period. These other illnesses did not fall into any seasonal pattern. ECGs in 16 patients were fully normal after resolution of arrhythmia (Table 1) whereas 4 showed mild left axis deviation (up to -3O”), 2 were normal except for a broad P wave and 2 had TABLE l.-ECG IN “HOLIDAY
AND CHEST X-RAYS HEART” PATIENTS
Electrocardiograms (total 24): Fully normal Normal except LAD, - lo” Normal except P wave 0.12 T waves low (not flat), 1-2 (one of these also showed degree AV block) Chest roentgenograms (total Fully normal Cardiothoracic ratio 50%
to -30” set leads first
16 4 2 2
24): 21 3
TABLE
2.-ALCOHOL-ASSOCIATED
RHVTHM ~NORMAUTY
Isolated APCs Atria1 fibrillation Atria1 flutter Paroxysmal atria1 tachycardia Junctional tachycardiat Isolated PVCs Ventricular tachycardia
ARRHYTHMIAS” NO.
4 12 6 3 4 (3 in 1 patient) 6 1 (after treadmill
exercise)
“Several patients had more than one arrhythmia. of atria1 arrhythmias, 6 showed RBBB and 3 LBBB aberration. tone patient with junctional tachycardia showed atrioventricular dissociation.
minimal T wave abnormalities. Many patients had transitory postconversion ECG abnormalities, with evidence of atria1 and/or ventricular extrasystoles, ST-T abnormalities and QT prolongation, but the tracings returned to normal within 48 hours. Some patients were observed to show diminutive or absent Q waves in ECG leads 1 and V, (“absent septal &“I, a finding previously reported to be common in cardiomyopathy. The most commonly seen arrhythmia was atria1 fibrillation, followed by atria1 flutter and isolated ventricular premature beats (Table 2). The last were especially common in association with atria1 fibrillation when the ventricular rate was rapid. Several patients each had isolated multiple supraventricular beats and paroxysmal atria1 tachycardia. Four episodes of junctional tachycardia were observed- three in 1 patient and a fourth associated with transient atrioventricular dissociation in another person. Harder to quantitate was QRS aberration during the arrhythmia. Six instances of right bundle-branch block type of aberration and three of the left bundle-branch block type were observed, but several of these occurred at rapid ventricular rates. Consequently, it was not possible to describe aberration in a quantitative fashion, although it was present unexpectedly in some patients at relatively slow rates. F ANTONIO C. DELEON, JR.: It is of interest that the most frequent arrhythmias noted in this group of patients were supraventricular (atria1 fibrillation and flutter). In patients with idiopathic cardiomyopathy, ventricular premature beats has been the most frequently encountered form of rhythm disturbance.
Treatment of all patients was at the discretion of the admitting physician. All patients survived. Eight episodes went untreated and resolved spontaneously. These included 2 cases of isolated APCs, 1 of isolated VPCs, 1 of mixed APCs and VPCs, 3 of atria1 fibrillation and a case of atrioventricular dissociation 23
and junctional tachycardia. Twelve atria1 arrhythmias (fibrillation, flutter) were treated with digoxin; in 3, cardioversion was required after failure to convert within 24 hours. Four additional supraventricular arrhythmias (flutter, junctional tachycardia, fibrillation) were cardioverted initially. Three episodes of paroxysmal atria1 tachycardia converted to sinus rhythm during metaraminol infusion after carotid sinus massage failed. Procainamide and quinidine were each used in 1 of 2 episodes of multiple APCs and multiple VPCs. Carotid massage was used successfully once to terminate junctional tachycardia; intravenous edrophonium, carotid massage and intravenous Neo-Synephrine were each used several times, unsuccessfully, in attempts to terminate the paroxysmal atria1 and junctional tachycardias. Although no definite “patterns” emerged, at least some of the arrhythmias tended to resolve spontaneously if untreated. b W. PROCTOR HARVEY: I can verify the authors’ observations of the effect of alcohol in relation to arrhythmias. It is well known that in some people an arrhythmia, particularly atria1 fibrillation or atria1 flutter, may result after drinking alcohol. In general, it more likely is related to the apparent concentration of the alcohol, the amount and frequency of ingestion over a more limited period. Ventricular premature contractions likewise are not uncommon, in my experience, in some patients after alcohol ingestion. However, some patients with apparently normal hearts and cardiac function may have an arrhythmia precipitated by small amounts of alcohol, which may be a “trigger” to initiate bothersome arrhythmias such as premature ventricular beats or atria1 arrhythmias (particularly that of atria1 fibrillation). This was also mentioned by the authors, and our own observations attest to this fact. Also, one may see left atria1 enlargement develop, as shown by the x-ray with barium swallow. After a transient period, these findings then may normalize. Along the same lines, and also presumably due to the myocardial depressant effect of alcohol, a patient with coronary artery disease having coronary ischemic pain may have relief from or even disappearance of angina pectoris with abstinence of alcohol. Occasionally, the effect is dramatic, particularly when the alcohol consumption has been high. It often is a neglected aspect of treatment of patients with coronary artery disease having ischemic pain. Although total abstinence from alcohol is prescribed and is best, some patients do not follow this advice. I have seen instances in which the prophylactic use of a single tablet of quinidine taken before the ingestion of alcohol and repeated 4- 6 hours later apparently has been effective in prevention of the arrhythmia, such as atria1 fibrillation, that has been well documented in the nast.
Systolic [PEP], left IPEP/LVETI! 24 patients medication 24
time interval measurements ( pre-ejection period ventricular ejection time [LVETI and their ratio were made in the postabsorptive state in 17 of the at least 3 days after return to sinus rhythm. All had been stopped at least 48 hours earlier. The sys-
tolic time intervals were measured using the method and instrumentation described by Weissler,37 simultaneously recorded ECGs, phonocardiograms and carotid pulse tracings recorded photographically at paper speeds of 150 or 200 mm/set with time markers at 0.02 sec. Ten complexes were measured for each subject. Total electromechanical systole (Q- S,) and left ventricular ejection time (LVET) were measured directly and the PEP was calculated by subtraction ([Q-S&[LVETl). The ratio PEP/LVET was derived for each patient and a mean ratio calculated for the group; the mean PEP/LVET ratio was compared with that of 17 normal age-matched subjects. Because of heart rate differences, corrected values for PEP (PEP11 and LVET (LVETI) in milliseconds were obtained using the following regression formulas: PEP1 = PEP (measured) + 0.40 X HR for women; PEP1 = PEP (measured) + 0.41 X HR for men; LVETI = LVET (measured) + 1.6 X HR for women; LVETI = LVET (measured) + 1.7 x HR for men. PEP and LVET were measured and their ratio calculated in 17 of the 24 patients (Fig. 7). The mean PEP/LVET ratio in the alcoholics, 0.412 2 0.014, was significantly different from that obtained in the age-matched controls, 0.299 + 0.008 (P
Editorial William de Leon,
Board (clockwise C. Roberts, Robert Jr.
EDITORS’
from top): A.
O’Rourke,
W.
Proctor Frank
Harvey, James I. Marcus and
J. Leonard, Antonio C.
PREFACE
It now seems well established that alcohol is one of the causes of cardiomyopathy whereas a couple of decades ago it was not as well appreciated in the United States as compared with the British Isles, where authors such as William Evans were describing this as a separate entity. I remember Doctor Evans describing a group of patients in his practice who developed alcoholic cardiomyopathy, and he mentioned that often it was the successful businessman, who was not known as a drunkard but who consumed a steady daily large amount of alcohol and over a long period of time. Although we in our hospital have had a long interest in cardiomyopathies, we did not at that time have a sizable number of patients who seemed to have this as the etiology of their disease. We started to look more carefully for patients with alcoholic cardiomyopathy and, as is true in all aspects of medicine, we found what we looked for. More patients were found, but they were more likely in our large city hospital or in our Veterans Administration Hospital. It became obvious that the patient population of these hospitals often had more problems related to a larger consumption of alcohol than in our university hospital.
Alcohol can have detrimental effects on the heart, producing toxic damage directly to the myocardium, resulting in congestive heart failure and arrhythmias, some of which-such as ventricular tachycardia and ventricular fibrillation -can be fatal. For a number of years Dr. Timothy Regan and his group at the New Jersey Medical School have had an interest in the relationship between alcohol and the heart, and have done research on this problem. Valuable information as to etiology and mechanism of heart damage has been the result. In addition, practical aspects concerning treatment have also been forthcoming. This issue of CURRENT PROBLEMS IN CARDIOLOGY provides an excellent overview of the interesting problem of alcoholic cardiomyopathy.
Lawrence D. Horwitz, M.D., Guest Editor
Dr. Lawrence D. Horwitz, Associate Professor of Medicine, directs the Cardiology Research Program at the University of Texas Health Science Center in San Antonio. During the past 10 years, Doctor Horwitz has published many important research studies concerning the assessment of left ventricular performance at rest and during exercise in the normal and diseased heart. More recently, he has completed several relevant studies concerning the reduction of ventricular performance by agents that depress myocardial function. Doctor Horwitz has performed several investigative studies concerning the effects of ethyl alcohol on cardiac performance (JAMA 232:959, 1975 and Circulation 49:124, 1974) and for that reason was chosen by the Editorial Board to serve as Guest Editor of this excellent monograph by Doctor Regan and his associates.
r
1 TABLE
EXPERIMENTAL PRECLINICAL
OF CONTENTS
EVIDENCE FOR CHRONIC MYOCARDIAL MALFUNCTION
IN MAN
.
CARDIAC FAILURE AND THE ECG
ILLUSTRATIVE
CASES
.
.
13
.
15 .
.
.
.
.
.
OBSERVATIONS ABOUT THE ARRHYTHMLW
ATYPICAL TREATMENT
MYOCARDIAL
18 18
SUDDEN DEATH
SUMMARY
10
.
ARRH~HMLW
GENERAL
TOXICITY
.
26 .
.
INFARCTION
AND REVERSIBILITY
29 30
.
32
.
33
is Professor of Medicine and Director of the Division of Cardiovascular Diseases at the College of Medicine and Dentistry of New Jersey. He received his M.D. from Boston University School of Medicine and was awarded a fellowship in cardiology by the National Institutes of Health at Wayne State University School of Medicine, Detroit, Michigan. Doctor Regan’s research interests are the interrelations of cardiac metabolism and diseases of heart muscle.
is Clinical Associate Professor of Medicine at the College of Medicine and Dentistry of New Jersey and Attending Cardiologist at Englewood Hospital, Englewood, New Jersey. He received his medical degree from New York University, interned at Lennox Hill Hospital and completed his residency at the Veterans Administration Hospital in the Bronx, New York. Doctor Ettinger was a Cardiac Fellow at New York University Hospital and USPHS Fellow in Cardiology at B. S. Pollack Hospital in Jersey City. He is interested in many aspects of cardiac physiology and pathophysiology, especially in cardiac arrhythmias and myocardial function.
is Associate Professor of Medicine, Department of Pathology, Director of Autopsy Pathology and Anatomical Pathology at the College of Medicine and Dentistry of New Jersey, and Consultant for the Department of Law and Public Safety, Division of Criminal Justice, Office of the Medical Examiner, Newark, New Jersey. Doctor Lyons received his M.D. at the Loyola University of Chicago Stritch School of Medicine and completed his internship at Kings County Hospital, Brooklyn. 6
’ is Professor of Medicine and Director of the r Cardiac Clinic at the College of Medicine and Dentistry of New Jersey. He graduated from f Athens Medical School, completed his postI graduate studies at the University Hospital, Vienna, Austria, and accepted a two-year Fellowship from Boston City Hospital (Tufts). His main research interests are in the cardiovascular field. Doctor Moschos concentrates on the study of the pathophysiology of coronary thrombosis.
is Professor of Medicine at the College of Medicine and Dentistry of New Jersey and Director of the Cardiac Care Unit of the Martland Hospital. He received his M.D. at the State University of New York, Brooklyn, served an internship at Mt. Zion Hospital, San Francisco and took his residency at the VA Hospital, San Francisco. Doctor Weisse’s main research interests are the myocardial function and the coronary collateral circulation in ischemia. Other interests include experimental and human polycythemic states, particularly complicating car pulmonale.
ETHYL ALCOHOL has long been recognized. as.a toxic agent having acute as well as chronic effects on cerebral and hepatic function at certain dose levels. It has been traditional that the heart was not similarly affected. In fact, alcohol, at least in modest amounts, commonly was viewed as a medicinal agent. Appearance of heart disease in an alcoholic individual usually was attributed to underlying heart disease of rheumatic, hypertensive or coronary etiology, often without good supporting evidence. When the specific entity of beriberi heart disease was associated with alcoholism, the patient was treated for thiamine deficiency with frequent success. Consequently, correction of malnutrition was considered the major therapeutic modality in alcoholic patients who had heart disease. In contrast to recent experience, earlier studies of the acute response to ethanol did nothing to dispel this view, since draNOTE: of Alcohol
This investigation was supported by a grant Abuse and Alcoholism. No, AAO0242.
from
the National
Institute 7
matic decreases in cardiac function were not observed consistently. This presumably was related to methodologic difficulties in which the experimental model often was in a nonsteady state, with varying degrees of hypoxia, and the methodology for assessing left ventricular function in a relatively physiologic preparation was not available. The acute response of the myocardium is relevant to the question of the general effects of ethanol and the particular question of its influence in patients with heart disease. Doses that are mildly intoxicating have been shown to adversely affect left ventricular function in some circumstances. This effect is, in part, dependent on prior experience with alcohoi; that is, larger doses are required to demonstrate impaired pumping action of the heart in the chronic alcoholic subject who has no clinical evidence of heart disease’ (cf references l- 9). However, the dose of Scotch, 6 oz, fed to normal individuals over a 2-hour period, has been found to diminish the force of heart muscle contraction at a mildly intoxicating blood level of 75 mg/lOO ml. This effect progresses as blood levels rise and usually is dissipated within a few hours after the drinking is interrupted. Supporting the view that ethanol is acutely depressant to myocardium is the fact that ventricular dysfunction is rapidly reversed after 15- 30 minutes of hemodialysis. b LAWRENCE D. HORWITZ: There has been a widespread misconception
among physicians and laymen alike that alcohol is a cardiac stimulant. In fact, there is strong evidence that alcohol is a myocardial depressant. Since anesthetics themselves impair myocardial function, some of the variation in the results of alcohol studies in anesthetized animals may be due to difficulty in distinguishing superimposed changes in preparations that already are subnormal. However, studies cited by Regan et al. conclude convincingly that under such circumstances a cardiac depressant effect of alcohol usually is demonstrable. In addition, a study of normal conscious dogs has demonstrated markedly reduced myocardial force development at blood alcohol levels below 150 mg/lOO ml, which is the usual legal limit for safe operation of an automobile (Circulation 49:124, 1974).
In contrast to these findings in alcoholics without clinical evidence of heart disease, the patient who already has had at least one episode of heart failure may exhibit a greater sensitivity to the 6-0~ dose of Scotch with substantial elevation of filling pressure. The response in cardiac subjects who are not alcoholics may be qualitatively similar. An important variation of the acute response to ethanol occurs when combined with other pharmacologic agents. Accidental or suicidal deaths have resulted from the combination with barbiturates. Potentiation of the myocardial depressant effect has been observed experimentally with such a combination, which is concurrent with respiratory depression. 8
B LAWRENCE D. HORWITZ: Whether or not they are habitual imbibers of alcoholic beverages, some patients with heart disease may be extraordinarily susceptible to myocardial depression by alcohol. In one study during cardiac catheterization, drinking only 2 ounces of Canadian whiskey reduced cardiac output and stroke volume in patients with a variety of cardiac disorders (JAMA 218:1799,1971). It is my policy to caution cardiac patients to limit their alcohol intake on any given day to no more than one shot (1Yz ounces) of 90-proof whiskey or its equivalent (a 6ounce glass of wine or a 12-ounce can of beer). Even this small quantity may be a prohibitive risk in patients with congestive heart failure. The possibility that other forms of drug abuse, such as barbiturate ingestion, can exacerbate the cardiotoxicity of alcohol is important, since concomitant ingestion of ‘alcohol and other drugs taken for nonmedical reasons is quite common. In addition, little is known concerning the interaction of alcohol with drugs often used for treatment of diseases. Ethacrynic acid, a widely used diuretic, increases the incidence of lethal alcohol toxicity in animals (Proc. Sot. Exp. Biol. Med. 118:970,1965).
The sympathetic nervous system presumably has an important role in modifying the cardiac response. Thus, blockade of the system has been shown to produce greater depression of left ventricular function during ethanol administration. Intensification of the cardiovascular response to ethanol in animals treated with disulfiram, an inhibitor of beta hydroxylation, with resultant lower levels of endogenous norepinephrine, may well be on a similar basis.2 It is noteworthy that the adrenal gland does not appear to respond with greater secretion of epinephrine or norepinephrine, at least in response to moderately intoxicating blood levels,3 so that cardiac catecholamine stores would appear to be the major factor modifying the response to acute ethanol intake. In considering the direct influence of ethanol on cardiac cells when administered acutely, changes of cation transport in the muscle are of major importance. The action in reducing force of contraction may well entail altered calcium mov+nent in the ce11.4 It is known that potassium and phosphate transiently leak out of the muscle cells after a 12-02 dose’; that is not attributable to coronary blood flow reduction. The loss of cation may be related to an inhibitory effect of ethanol on active transport of potassium and sodium across cell membranes, which has beensuggested as a basic mechanism of action of ethanol on most cells.5 Another metabolic change is represented by alteration of lipid transport in the myocardium: the large dose of ethanol reduces the uptake of free fatty acid by the left ventricle whereas the increased triglyceride uptake results in accumulation of lipid in myocardium.’ This response may contribute to pathologic changes observed in human myocardium during postmortem examination; substantial increases in lipid, presumably triglyceride, have been observed in the alcoholic heart6 It is of note that noncardiac striated muscle, including uterus7 and skeletal muscle,* are also depressed acutely by ethanol, al9
though in the diaphragm this follows a period of enhanced contractility. With chronic use, the asymptomatic alcoholic may exhibit modest reduction of lactic dehydrogenase as well as a small reduction in fast twitch glycolytic fibers and volume of mitochondria. The conditions required for acute myopathy and rhabdomyolysis are not well defined, but malnutrition and hypophosphatemia frequently are associated.s EXPERIMENTAL EVIDENCE MYOCARDIAL TOXICITY
FOR CHRONIC
Although histologic abnormalities have been observed in 90% of unselected alcoholics in one postmortem series,‘O uncertainty as to the quantity of ethanol intake, the nutritional status of the patient, including electrolyte deficits, and the possibility of heart disease from other causes have obscured the relationship of excessive ethanol use and cardiomyopathy. Previous chronic experiments with ethanol have yielded conflicting data in terms of the production of a functional deficit, but the negative study used smaller quantities and was relatively short term. To eliminate some of the above variables, a group of young adult male dogs were maintained in a relatively normal nutritional state while receiving up to 36% of calories as ethanol, approximating the quantity reported in many human alcoholics. After an average of 18 months, they were found to have maintained weight, hematocrit, serum proteins, vitamins and electrolytes to an extent similar to normal controls.” When these two groups were studied at similar levels of heart rate and aortic pressure, chronic ethanol animals exhibited a significantly higher end-diastolic pressure at rest despite a lower level of end-diastolic volume. Assessment of left ventricular function was undertaken during afterload increments with angiotensin of similar extent in both groups. Stroke output and work increased moderately but significantly in the controls whereas no such increments occurred in the alcoholic animals, despite a significantly higher end-diastolic pressure. The enddiastolic volume response was significantly less than in controls, and presumably is the basis for the reduced stroke volume. To further analyze the apparent altered stiffness of the ventricle, 6 of the normal animals and 6 of the ethanol group were infused with normal saline via a catheter in the left ventricle. In the ethanol group there was a significantly higher rise of end-diastolic pressure than in the normal, despite an elevation of enddiastolic volume proportionate to that of controls. A potential morphologic basis for the altered diastolic pressure-volume relations was found in sections of the left ventricle. Staining with alcian blue showed distinct accumulation of a glycoprotein-like material in the interstitium of the left ventricular 10
wall in the ethanol group, with virtually no staining in the normal controls. The factors responsible for progression to interstitial collagen accumulation as seen in man are not known. This may limit the rapid accessibility of calcium to intracellular sites and ultimately contribute to the development of heart failure. Whether independent abnormalities of intracellular calcium transport or myosin ATPase are present in long-term experiments has yet to be demonstrated. A difficulty in assessing the importance of these factors is the fact that no animal model has yet been of sufficient duration to produce frank heart failure. As a further assessment of the myocardium in alcoholic aniFig I.-Intercalated ferentiated regions tion 9500x; 4’7,500~
disk of alcoholic are apparent. The final). (Reprinted,
dog. Cystic areas of dilatation of undifnexus region appears normal (magnificawith permission, from Am. Heart J.)
mals, high-speed, high-frequency electrocardiograms were obtained. QRS time was distinctly abnormal in the longer-term animals.‘* Similarly, the conduction time from the His bundle to the onset of ventricular depolarization was significantly prolonged. Dilatation of the intercalated disk by electron microscopy appeared to be the morphologic correlate (Fig. 1). Although plasma lipid concentrations were normal, analyses of left ventricular lipids revealed an increment of triglyceride in the ethanol group, which appeared as fine cytoplasmic droplets on oil red 0 stain. Incorporation of labeled fatty acid into phospholipid was reduced and may represent a process that limits the function of cell membranes, since cation composition of the left ventricle was abnormal.‘4C02 production from 14C-l-oleic acid was decreased and may be secondary to diminished activity of rate-limiting enzymes in the citric acid cycle, demonstrated after chronic ethanol use. l3 Dilatation of the sarcoplasmic reticulum and intercalated disk were the only unequivocal structural abnormalities in the relatively well-nourished animals in this chronic study, findings also observed in patients with alcoholic cardiomyopathy.14 It is problematic whether the extensive abnormalities of myofibrils and mitochondria reported in other human studies are secondary to multiple episodes of heart failure or are due solely to toxicity, coexistent nutritional deficiency, cobalt excess or other complications.15j l6 Although, with time, most species appear to develop myocardial abnormalities, the duration and quantity required to develop functional or morphologic alterations appear to vary. Thus, the rhesus monkey surprisingly has shown focal myocytolysis and early fibrosis after 3 months of ethanol as 40% of calories.” It is possible that the feeding modality, relatively rapid by stomach tube, or the synthetic liquid diet contributed to this response. In the rat, ethanol as 10% of total calories apparently has produced ultrastructural abnormalities as early as 7 weeks.ls Prior experience with rodents and their proclivity for viral infections raises the question of possible conditioning of the myocardium, with sensitization to the early development of lesions at relatively low doses. In considering pathogenesis, one must consider the first metabolite of ethanol. Acetaldehyde can significantly depress left ventricular function when infused at rates that simulate blood levels associated with moderate ethanol ingestion.19 This suggests that acetaldehyde may have a role in the pathogenesis of the cardiomyopathy. An additional consideration involves the role of magnesium ion. Primary magnesium deficiency does produce cardiac lesions in immature experimental animals. Unequivocal disease in adults is difficult to demonstrate, however, although secondary potassium loss could have important conse12
quences. As a general observation, functional and clinical malities of myocardium frequently occur with normal levels of this cation.
abnorserum
LAWRENCE D. HORWITZ: The above studies by Regan and colleagues are important because they are some of the strongest evidence to date that the clinical syndrome of alcoholic cardiomyopathy is caused by a direct toxic e&et of alcohol on the myocardial cells rather than to nutritional deficiencies or the effects of trace metals, as sometimes has been assumed. Although various potentially relevant biochemical or metabolic observations have been made, as summarized above, the mechanism for the adverse effects of alcohol still is an unanswered question. To be fair, it should be pointed out that some efforts to induce a cardiomyopathy type of syndrome in animals induced to ingest alcohol chronically have been unsuccessful (Am. Heart J. 78:770,1969; Jpn. Heart J. 12:242, 1971). It would appear that in animals, as in humans, chronic ingestion of large quantities of alcohol does not inevitably cause myocardial damage but that unknown factors may make certain subjects more susceptible than others.
b
PRECLINICAL
MALFUNCTION
IN MAN
To determine if there was an equivalent functional abnormality in man, studies were undertaken of alcoholic subjects with no symptoms or clinical evidence of heart disease or malnutritionzO Documentation of lo- 15 years of alcoholism and the type of ethanol used was obtained from the patients’ histories or from close relatives. Whiskey was the predominant alcoholic beverage, consumed several times a week, in amounts ranging from 0.5 to 2 pints/day. Liver biopsy revealed fatty liver without fibrosis. Left ventricular performance was studied by increasing afterload with angiotensin. The noncardiac alcoholic exhibited a significantly greater rise of ventricular enddiastolic pressure with minimal increment of stroke volume compared to nonalcoholic controls. Diminished ventricular performance has also been observed during exercise in cirrhotic patients without clear evidence of cardiac disease. Some degree of interstitial fibrosis may be present at this stage, as suggested by postmortem studies of accident victims who were alcoholic.*’ Demonstration of abnormal left ventricular function in alcoholic subjects without clinical evidence of heart involvement has also been reported in noninvasive studies.**, 23 The most significant alterations of the systolic time intervals were found in the prolonged PEP and increased PEP/LVET. This may be attributed to a depressed contractile state or diminished compliance of the left ventricle. The latter interpretation is supported by findings in a canine model of chronic ethanolism. Enhanced diastolic stiffness of the ventricle was associated with glycoprotein accumulation in the interstitium of the experimental model’l and a 13
Fig 2. - Alcian blue-positive glycoproEtim interstitium between muscle fibers. None with permission, from Circulation.)
was
accumulated present
in left in control.
ventricular (Reprinted,
similar histochemical abnormality has been seen in noncardiac alcoholics with cirrhosisz4 (Fig. 2). These studies are in accord with the view that congestive cardiomyopathy is infrequent in patients with cirrhosis but a preclinical abnormality would appear to be common in male cirrhotics. The normal time intervals in females are unlikely to be due to lesser intensity or duration of alcoholism, since the females had cirrhosis of equal or greater severity as judged by prothrombin times. This absence of a functional abnormality in the female suggests that the sex hormones are a determinant in the development of the preclinical entity and presumably the clinical cardiomyopathy. The functional abnormalities in the males are not likely to be due to coronary artery disease, for several reasons. The normals were of similar age, and alcoholics with cirrhosis appear to have less atherosclerosis at postmortem examination than the nonalcoholic population.25 Moreover, patients with angina without cardiac decompensation frequently have normal systolic time intervals. Although some of the cirrhotic patients had clinical evidence of mild malnutrition, particularly in the female group, the normal systolic intervals in the latter suggest that malnutrition was not a determinant of the abnormal systolic time intervals. In addition, the degree of anemia in these patients was not severe enough to cause hemodynamic alterations. This is support14
ed by observations in 5 nonalcoholic patients with moderate anemia, at hematocrit levels between 25% and 30%. No significant difference in systolic time intervals compared to normals was found. More severe chronic anemia apparently is required to evoke hemodynamic change, and these may be evidenced as enhanced rather than reduced ventricular function. b LAWRENCE D. HORWITZ: Although an interesting concept, I do not believe that the evidence presented for a preclinical abnormality in male cirrhotics is very strong. Small differences in systolic time intervals during a single observation in very small groups of subjects are prone to misinterpretation. These measurements could have been influenced by other hemodynamic factors. For example, the possibility that the male cirrhotits studied had reductions in venous return or preload due to extracardisc factors rather than reductions in myocardial contractile force cannot be excluded. The time at which observations are made might also be critical if some factor other than reductions in myocardial contractile force cannot be excluded. The time at which observations are made might also be critical if some factor other than sex were influencing the data. More reliable results could be obtained if much larger numbers of subjects were studied repeatedly over a prolonged period. Not only systolic time intervals but other noninvasive techniques such as echocardiographg could be used.
CARDIAC
FAILURE
To test the thesis that cumulative effects of ethanol over a period of time may result in cardiac abnormality despite adequate nutrition, a well-compensated patient was fed ethanol as Scotch for a period interval
of 5V2 months at a daily of 6 weeks (Fig. 31, resting
dose of 12- 16 OZ.~O After an heart rate began to rise and
there was prolongation of circulation time and elevation of venous pressure without evidence of malnutrition. After 4 months, a ventricular gallop rhythm appeared, which persisted until ethanol was interrupted without evidence of pulmonary congestion.
Subsequently,
without
specific
cardiac
therapy,
there
was
spontaneous restoration to normal. A major role of ethanol in the production of left heart failure in this subject was substantiated by the gradual reversion ity after alcohol ingestion
of the
cardiocirculatory
abnormal-
was interrupted. This observation supports the thesis that the myocardial disease is reversible at certain stages if intake of ethanol is discontinued.
F W. PROCTOR HARVEY: Certainly, as one of the main aspects of treatment, complete abstinence from alcohol must be adhered to in addition to the other aspects of treatment of congestive heart failure, which include rest, digitalization, sodium restriction, diuretics and also the management of specific arrhythmias when they are present. It is encouraging to know that reversibility has been, and can be, accomplished by medical 15
treatment, particularly in their course. It is apparent early treatment are most cardiomyopathy, as is true
those patients whose therapy starts early in that early suspicion, early recognition and important in the management of alcoholic in other etiologies of cardiomyopathy.
In circumstances marked by progression of cardiac dysfunction, pulmonary congestion may lead to exertional or nocturnal dyspnea.26 If long sustained or after repeated episodes, pulmonary hypertension and right heart failure may become evident. Unless there is complicating papillary muscle insufficiency giving rise to mitral regurgitation, cardiomegaly may be moderate in extent and heart size may revert to near normal after central congestion is corrected. In some patients, systemic or pulmonary emboli from mural thrombi may adversely affect the patient’s course. These clinical episodes frequently seem to be precipitated by intensified drinking episodes. Several reports of cardiomyopathy have emphasized the difficulty in obtaining a history of alcoholism. There is a male predominance, and suggestive diagnostic aspects include social disruption, accident proneness and a familial history. Hepatic cirrhosis and clear evidence of peripheral neuritis are not present Fig 3. -Evidence of cardiac decompensation developing during chronic ethanol intake. These are observations in a single,well-nourished patient receiving daily Scotch, which resulted in evidence of heart failure. The failure regressed without medical treatment after interrupting alcohol intake. (Reprinted, with permission, from J. Clin. Invest.)
. CARDIOTHDRACIC a50 RATIO (cm 1 0.45
.
-4
l
.
0
l
.
4
_
.
8
TIME
16
.
.
12
IN
n
.
.
.
l
16
WEEKS
22
26
.
.
frequently in patients with alcoholic cardiomyopathy. The major positive diagnostic feature is the history of ingesting ethanol in intoxicating amounts for many years, frequently with spree episodes. This information often may be obtained only through persistent questioning of the patient or from relatives. Negative aspects include exclusion of other causes of heart disease, namely, hypertension, coronary artery disease, car pulmonale and congenital or valvular disease. Other forms of cardiomyopathy (viral, infiltrative, metabolic, etc.) must be considered also. In addition to the usual lack of specificity of the clinical signs and symptoms, high diastolic-arterial blood pressure not infrequently is found during periods of severe congestive heart failure, which may lead to the false diagnosis of hypertensive heart disease. The blood pressure usually returns to normal following response to therapy for cardiac decompensation. Intoxication itself may contribute to blood pressure rise. Ethanol administration produces vasoconstriction of skeletal muscle vessels associated with dilatation of vessels to the skin. Predominance of the former may account for transient hypertension but there is no evidence that chronic hypertension is produced. Conversely, the net effect on the different vascular regions is not known to produce vasodilatation sufficient to reduce afterload. Modest vasodilatation theoretically would be therapeutic in heart failure if ethanol did not have negative inotropic properties. Not only are quantity, frequency and duration of ethanol intake difficult to assess but their relationship to organ pathology is not straightforward. It is probable that these factors have a similar importance for the varied chronic diseases secondary to alcohol abuse, so that information in relation to liver disease, for which there are more complete data may, in a general way, be applicable to the heart. Alcoholic hepatitis usually develops after years of excessive drinking, although in a ‘few patients it appears within a few years, but may not develop in many even after several decades of drinking.27 More than 80% were drinking 5 years or longer before developing symptoms. The probability of developing alcoholic hepatitis is small in those who drink less than 80 gmlday of ethanol (approximately 8 oz of 86-proof whiskey or 1 liter of wine) or if ethanol provides less than 20% of calories. As the daily ethanol consumption increases to 90- 160 gm/day and the duration of drinking becomes longer, the risk of developing alcoholic liver disease increases. The probability of alcoholic hepatitis or cirrhosis is great if the daily ethanol consumption exceeds 160 gm (for example, two-thirds of a bottle of whiskey, the approximate daily metabolic capacity of an average nondrinking person) and if the drinking-either steady or in sprees-persists for lo- 15 years or longer. It is noteworthy that the rate of ethanol metabolism can be high 17
enough to permit the consumption of large amounts without raising the blood ethanol level over 80 mg/lOO ml, the concentration at which the conventional breath analyzer begins to detect ethanol. b W. PROCTOR HARVEY: As pointed out by the authors, it may be difficult to ascertain the exact amount of alcohol consumed by a patient. When this aspect of his history is obtained, the individual’s intake frequently is minimized, appearing to be a much smaller amount than actually is so. Illustrating this point was a man personally evaluated who held a responsible executive position and had a classic picture of congestive cardiomyopathy. He had cardiomegaly, atria1 and ventricular diastolic gallops, an apical systolic murmur and alternation of heart sounds and murmurs. He had moderately advanced chronic congestive heart failure. When questioned concerning the use of alcohol, he stated that he used it only in moderation and was a “social drinker.” We therefore were about to classify his cardiomyopathy as idiopathic (unknown) etiology; however, when discussing his problem with his wife (the patient was not present), it was determined that he was drinking approximately a fifth of gin per day with increased weekend consumption. He had a long history of a large daily intake of alcohol, starting with “Happy Hour” in World War II. He died several years later, having progressed to an irreversible stage of his disease.
ARRHYTHMIAS
AND
THE ECG
An association between alcohol use and cardiac arrhythmias, particularly atria1 fibrillation, has long been suspected. However, the specific etiologic role of alcohol is difficult to establish and, indeed, doubt may exist as to the presence of any heart disease when overt cardiomyopathy is not present. Over a 4-year period, we have observed or reviewed 32 separate dysrhythmic episodes occurring in 24 patients who drank heavily and habitually. In each instance, hospitalization was deemed necessary for treatment. All patients have histories of prolonged ethanol use, with superimposition of especially heavy ingestion prior to the arrhythmia. Overt alcoholic cardiomyopathy was not present, as only patients with normal or borderline heart size (by x-ray) and normal (or minimally abnormal) ECGs after return
to sinus
ILLUSTRATIVE
rhythm
were
included.2s
CASES
CASE 1. -D. R., a 39-year-old businessman, spent a long weekend drinking heavily in a motel. After 3 days he developed palpitations and was seen at another hospital, where atria1 fibrillation was detected and he was cardioverted. He felt well but gradually resumed consumption of 12- 15 cans of beer daily. Four years later, he presented with palpitaCons. Frequent atria1 extrasystoles (with LBBB aberration) were 18
treated with quinidine. Plasma electrolytes were normal. Since reducing his beer consumption and continuing quinidine, palpitations have lessened, although he has frequent palpitations when he drinks more heavily. CASE 2. -M. H., a 31-year-old woman, drank whiskey in quart quantities daily. She was seen at the emergency room because of palpitations and breathlessness; atria1 fibrillation with ventricular extrasystoles was present (Fig 4, A). Within minutes, the rate accelerated, with runs of beats of uncertain origin, possibly ventricular tachycardia. Cardioversion was performed immediately. Plasma electrolytes were normal. In the next 2 years she was admitted on three additional occasions, each time with atria1 fibrillation and the same drinking history. One each occurred on a Sunday, Monday and Tuesday. CASE 3. -R. G., a 42-year-old woman, was admitted because of palpitations. She drank 6- 12 cans of beer daily. The EGG showed atria1 flutter with 1:l response (Fig. 4, B) and cardioversion was performed. Plasma electrolytes were normal. Fifteen months later, while continuing her beer ingestion, she was readmitted because of the same arrhythmia; treatment with digoxin was begun and sinus rhythm returned. CASE 4. -W. K., a 43-year-old businessman, consumed at least 6 oz of martinis daily for many years. During the month of December he had additional liquor at business luncheons. He “passed out” while seated in a cinema and was taken to the emergency room. Frequent ventricular extrasystoles were present and the plasma K+ was 2.7 mEq/l. Treatment with procainamide and K+ suppressed the arrhythmia. Three weeks later, while asymptomatic and arrhythmia-free at rest, an exercise stress test induced ventricular extrasystoles and runs of ventricular tachycardia to occur after the exercise (Fig. 4, C) and was presumed to be the basis of his presenting symptoms. With abstinence and outpatient treatment with quinidine, the arrhythmia has not recurred.
Twenty patients in the series were male and 4 were female (aged 25-62 years, mean 43 years). All but 3 were between 30 and 60 years of age; 8 patients were in the fourth -decade, 7 in the fifth decade and 6 in the sixth decade. All p+i&nts gave histories of consuming at least 6- 10 drinks daily. The age distribution, beginning mainly after age 30, along with the histories obtained in patient interviews, suggests that at least 10 years of heavy ethanol consumption usually was present as a background. All varieties of beer and whiskey were implicated, alone or in combination. Most patients drank every day of the week but indicated that weekend consumption was higher. We have not yet observed this disorder in anyone who drank wine alone, although this may be a cultural difference, inasmuch as wine drinkers are less frequent in our population than whiskey or beer drinkers. All but 2 patients smoked heavily, but no relation of smoking to arrhythmia was ascertained. Following resolution of the arrhythmias, most patients were asymptomatic, although 1 developed overt alcoholic hepatitis and 2 had delirium tremens. Low plasma potassium, previously 19
Fig 4. -Electrocardiograms of illustrative cases. A, CME 2. - Atria1 fibrillation is seen in top strip with one aberrated (Ashman) beat (the 6th). Within 10 minutes (next two strips), the rate accelerated with runs of wide complexes (?aberration or ventricular tachycardia) at rate of 240/min. B, CASE 3. - Atria1 flutter with 1:l conduction (verified later by carotid massage) at rate of 250/min with RBBB aberration. A single normally conducted beat is seen. C, CASE 4.-Runs of ventricular tachycardia 1 minute following the end of a treadmill stress test 1both strips). (Reprinted, with permission, from Am. Heart J.)
20
1 32
EPISODES,
TO JAN
I
l/2-12/23
12/24-l/1
El
m
1976
1 I J
I
NUMBER OF ADMISSIONS
SUN
ON THU FRI TUE WED SAT Fig 5. -Admitting day for alcoholic arrhythmias. Nineteen admissions were seen Sunday through Tuesday (post-weekend). Of the 13 Wednesday through Saturday admissions, 6 were during the year-end holidays. Therefore, 25 of 32 admissions were holiday-related. (Reprinted, with permission, from Am. Heart J. I
implicated as a possible cause of arrhythmias in alcoholics, was less than 3.5 mEq/l in only 4 of 30 instances, although a wholebody potassium deficit was not excluded. SGOT usually was normal or borderline elevated. Blood alcohol determinations were performed on admission in 8 patients and were positive in 6, ranging from 50 to 430 mg/lOO ml. Plasma sodium, chloride, bicarbonate, lactic dehydrogenase, urea, sugar and cholesterol were normal. Arterial blood gases and pH were normal in all. Figure 5 indicates the admitting day of the week in each instance. Nineteen patients were initially seen between Sunday and Tuesday, with Monday admissions most common. By chisquare testing, 19 of 32 episodes occurring on 3 of the 7 days of the week are significantly greater than the 317 expected. P~0.05. However, further examination of the data was even more revealing, as 6 of the 13 admissions from Wednesday through Saturday were seen between December 24 and January 1. When these holiday admissions are added to the 19 postweekend admissions, fully 25 of the 32 episodes could truly be considered examples of a “holiday heart syndrome,” a name that has been used at our institutions to describe them. In Figure 6, the number of alcoholic arrhythmia admissions per month over the 4-year period is shown. Only 2 patients were seen between May and August whereas the incidence peaked in December and January. In the bottom graph, the mean combined monthly incidence peaked in December and January. In the bottom graph, the mean combined monthly incidence of hos21
JUL
ALCOHOLASSOCIATED ILLNESSES
AUG SEP OCT NOV
DEC JAN
FEB MAR APR
MAY
JUN
30
Fig 6. -Monthly distribution of “holiday heart” hospital compared with mean monthly admissions for “traditional” illnesses (bottom). The apparent year-end peak of alcoholic present for the “traditional” alcoholic illnesses. (Reprinted, from Am. Heart J.)
admissions (top), alcohol-associated arrhythmias is not with permission,
pita1 admissions for all other traditionally accepted alcohol-associated illnesses are tabulated for comparison in 3 years of the 4-year period. These other illnesses did not fall into any seasonal pattern. ECGs in 16 patients were fully normal after resolution of arrhythmia (Table 1) whereas 4 showed mild left axis deviation (up to -3O”), 2 were normal except for a broad P wave and 2 had TABLE l.-ECG IN “HOLIDAY
AND CHEST X-RAYS HEART” PATIENTS
Electrocardiograms (total 24): Fully normal Normal except LAD, - lo” Normal except P wave 0.12 T waves low (not flat), 1-2 (one of these also showed degree AV block) Chest roentgenograms (total Fully normal Cardiothoracic ratio 50%
to -30” set leads first
16 4 2 2
24): 21 3
TABLE
2.-ALCOHOL-ASSOCIATED
RHVTHM ~NORMAUTY
Isolated APCs Atria1 fibrillation Atria1 flutter Paroxysmal atria1 tachycardia Junctional tachycardiat Isolated PVCs Ventricular tachycardia
ARRHYTHMIAS” NO.
4 12 6 3 4 (3 in 1 patient) 6 1 (after treadmill
exercise)
“Several patients had more than one arrhythmia. of atria1 arrhythmias, 6 showed RBBB and 3 LBBB aberration. tone patient with junctional tachycardia showed atrioventricular dissociation.
minimal T wave abnormalities. Many patients had transitory postconversion ECG abnormalities, with evidence of atria1 and/or ventricular extrasystoles, ST-T abnormalities and QT prolongation, but the tracings returned to normal within 48 hours. Some patients were observed to show diminutive or absent Q waves in ECG leads 1 and V, (“absent septal &“I, a finding previously reported to be common in cardiomyopathy. The most commonly seen arrhythmia was atria1 fibrillation, followed by atria1 flutter and isolated ventricular premature beats (Table 2). The last were especially common in association with atria1 fibrillation when the ventricular rate was rapid. Several patients each had isolated multiple supraventricular beats and paroxysmal atria1 tachycardia. Four episodes of junctional tachycardia were observed- three in 1 patient and a fourth associated with transient atrioventricular dissociation in another person. Harder to quantitate was QRS aberration during the arrhythmia. Six instances of right bundle-branch block type of aberration and three of the left bundle-branch block type were observed, but several of these occurred at rapid ventricular rates. Consequently, it was not possible to describe aberration in a quantitative fashion, although it was present unexpectedly in some patients at relatively slow rates. F ANTONIO C. DELEON, JR.: It is of interest that the most frequent arrhythmias noted in this group of patients were supraventricular (atria1 fibrillation and flutter). In patients with idiopathic cardiomyopathy, ventricular premature beats has been the most frequently encountered form of rhythm disturbance.
Treatment of all patients was at the discretion of the admitting physician. All patients survived. Eight episodes went untreated and resolved spontaneously. These included 2 cases of isolated APCs, 1 of isolated VPCs, 1 of mixed APCs and VPCs, 3 of atria1 fibrillation and a case of atrioventricular dissociation 23
and junctional tachycardia. Twelve atria1 arrhythmias (fibrillation, flutter) were treated with digoxin; in 3, cardioversion was required after failure to convert within 24 hours. Four additional supraventricular arrhythmias (flutter, junctional tachycardia, fibrillation) were cardioverted initially. Three episodes of paroxysmal atria1 tachycardia converted to sinus rhythm during metaraminol infusion after carotid sinus massage failed. Procainamide and quinidine were each used in 1 of 2 episodes of multiple APCs and multiple VPCs. Carotid massage was used successfully once to terminate junctional tachycardia; intravenous edrophonium, carotid massage and intravenous Neo-Synephrine were each used several times, unsuccessfully, in attempts to terminate the paroxysmal atria1 and junctional tachycardias. Although no definite “patterns” emerged, at least some of the arrhythmias tended to resolve spontaneously if untreated. b W. PROCTOR HARVEY: I can verify the authors’ observations of the effect of alcohol in relation to arrhythmias. It is well known that in some people an arrhythmia, particularly atria1 fibrillation or atria1 flutter, may result after drinking alcohol. In general, it more likely is related to the apparent concentration of the alcohol, the amount and frequency of ingestion over a more limited period. Ventricular premature contractions likewise are not uncommon, in my experience, in some patients after alcohol ingestion. However, some patients with apparently normal hearts and cardiac function may have an arrhythmia precipitated by small amounts of alcohol, which may be a “trigger” to initiate bothersome arrhythmias such as premature ventricular beats or atria1 arrhythmias (particularly that of atria1 fibrillation). This was also mentioned by the authors, and our own observations attest to this fact. Also, one may see left atria1 enlargement develop, as shown by the x-ray with barium swallow. After a transient period, these findings then may normalize. Along the same lines, and also presumably due to the myocardial depressant effect of alcohol, a patient with coronary artery disease having coronary ischemic pain may have relief from or even disappearance of angina pectoris with abstinence of alcohol. Occasionally, the effect is dramatic, particularly when the alcohol consumption has been high. It often is a neglected aspect of treatment of patients with coronary artery disease having ischemic pain. Although total abstinence from alcohol is prescribed and is best, some patients do not follow this advice. I have seen instances in which the prophylactic use of a single tablet of quinidine taken before the ingestion of alcohol and repeated 4- 6 hours later apparently has been effective in prevention of the arrhythmia, such as atria1 fibrillation, that has been well documented in the nast.
Systolic [PEP], left IPEP/LVETI! 24 patients medication 24
time interval measurements ( pre-ejection period ventricular ejection time [LVETI and their ratio were made in the postabsorptive state in 17 of the at least 3 days after return to sinus rhythm. All had been stopped at least 48 hours earlier. The sys-
tolic time intervals were measured using the method and instrumentation described by Weissler,37 simultaneously recorded ECGs, phonocardiograms and carotid pulse tracings recorded photographically at paper speeds of 150 or 200 mm/set with time markers at 0.02 sec. Ten complexes were measured for each subject. Total electromechanical systole (Q- S,) and left ventricular ejection time (LVET) were measured directly and the PEP was calculated by subtraction ([Q-S&[LVETl). The ratio PEP/LVET was derived for each patient and a mean ratio calculated for the group; the mean PEP/LVET ratio was compared with that of 17 normal age-matched subjects. Because of heart rate differences, corrected values for PEP (PEP11 and LVET (LVETI) in milliseconds were obtained using the following regression formulas: PEP1 = PEP (measured) + 0.40 X HR for women; PEP1 = PEP (measured) + 0.41 X HR for men; LVETI = LVET (measured) + 1.6 X HR for women; LVETI = LVET (measured) + 1.7 x HR for men. PEP and LVET were measured and their ratio calculated in 17 of the 24 patients (Fig. 7). The mean PEP/LVET ratio in the alcoholics, 0.412 2 0.014, was significantly different from that obtained in the age-matched controls, 0.299 + 0.008 (P
