Hemodynamic studies in beriberi heart disease

Hemodynamic

Studies in Beriberi Heart Disease*

MOHAMMED AKBARIAN,

M.D.,t

WALTER

NICHOLAS A. YANKOPOULOS, H. ABELMANN,

M.D.$

and

M.D.

Boston, Massachusetts members of the Cardiovascular Division of the Thorndike Memorial Laboratory from November 1954 to June 1965. During these years an average of 336 patients were seen annually in formal cardiac consultation. Hemodynamic studies were carried out in nine of the twenty-five patients. Four did not have coexisting cirrhosis, significant anemia or known heart disease; they form the basis of this report. They were studied within a few days of admission, three before thiamine therapy. All patients were male alcoholics, and their ages ranged from thirty-eight to fifty-eight years. Hemodynamic studies were performed with the patient in a fasting state and recumbent position; no premeditation was given. A 17 gauge Cournand needle was placed in a brachial artery. A polyethylene catheter (internal diameter 1.14 mm.) was inserted percutaneously into an antecubital vein and advanced to the superior vena cava or the right atrium, where it remained for the entire procedure. Three patients (Cases 1, 2 and 4) underwent right heart catheterization, two (Cases 1 and 4) early in the disease and one (Case 2) late in the disease. In one patient (Case 4) left heart catheterization was performed early in the

A

THE only heart disease attributable to deficiency of a single dietary constituent, fully preventable and in general curable, beriberi heart disease has long fascinated clinicians. The classic descriptions of this disease as seen in the Orient and in the West were furnished by Sh~mazono [I], Aalsmeer and Wenckebach [2], Keefer [3], and by Weiss and Wilkins [4]. The high living standard, generally good if not excessive diets, and the practice of adding thiamine to food such as bread, cereals and rice, have made beriberi a relative rarity in the Western world. This disease is seen, or at least recognized, primarily in people with severe nutritional deficiency who have maintained an adequate caloric intake and have remained physically active. Thus most instances of beriberi heart disease recognized in recent years have been among chronic alcoholic patients [5-81. A number of hemodynamic studies of beriberi heart disease have been reported [5,8,9-761 but the pathophysiology of beriberi heart failure remains poorly understood. This report presents four patients with congestive heart failure attributed to beriberi, seen and studied hemodynamically, acutely and after treatment. The studies include observations on the effects of acute digitalization and of a pressor agent. As a specific biochemical test for thiamine deficiency, blood transketolase [77,78] was measured and found to be low in one of these patients. s

MATERIAL

course of his disease. Details of these procedures and calculation of the derived values have been reported previously from this laboratory [79]. The catheters were kept patent by slow infusion of 5 per cent dextrose in water. Plasma volume was determined by injecting approximately 5 mg. of Evans blue dye intravenously and analyzing a single arterial blood sample 10 minutes later. After 10 to 15 minutes of rest, cardiac output was determined in duplicate by the indicator dilution method, using the integrated sample technic [ZO]. A known amount of Evans blue (Cases 1 and 2) or indocyanine green dye (Cases 3 and 4) was injected intravenously through the polyethylene catheter from a calibrated pipette, followed by a 10

AND METHODS

A clinical diagnosis of beriberi heart disease was made in twenty-five patients seen in consultation by

* From the Thorndike Memorial Laboratory and the Second and Fourth (Harvard) Medical Services, Boston City Hospital, and the Department of Medicine, Harvard Medical School, Boston, Massachusetts. This study was supported in part by Research Grant HE 00442 and by Training Grant 5Tl HE 5244 from the National Heart Institute, National Institutes of Health, U. S. Public Health Service. Manuscript received January 3, 1966. t Present address: Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts. 1 This work was carried out during the tenure of a Special Postdoctoral Research Fellowship (5-F3-HE-15,063-02) from the National Heart Institute, National Institutes of Health, U. S. Public Health Service. Present address: Veterans Administration Hospital, 2002 Holcombe Boulevard, Houston, Texas. VOL.

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ml. saline flush. Dye dilution curves were recorded oscillographically (Sanborn) from the output of a densitometer [27] through which blood was drawn from the brachial artery by a constant withdrawal pump at a rate of 35 ml. per minute (Harvard Apparatus Co.). Immediately following each cardiac output, arterial and venous pressures were measured

with strain gauge transducers (Statham P23D or P23G) and recorded oscillographically (Sanborn), the zero reference point being 10 cm. above the back. Mean pressures were obtained by electrical damping. Peripheral vascular resistance was determined by the following formula : mean arterial pressure (mm. Hg) mean central venous pressure (mm. Hg) X 8. cardiac output (L./mm.) and expressed as dynes sec. cm-s. Left ventricular work was expressed as stroke work index and computed as follows: Stroke work index (gm. M. per beat per M2.) = 1.055 X 0.0136 X stroke index (cc. per beat per M2.) >< arterial systolic mean pressure (mm. Hg). * Arteriovenous oxygen difference was calculated from cardiac output and oxygen consumption. The oxygen and carbon dioxide content of expired air collected over 3 minutes were determined by the microtechnic of Scholander. In three patients cardiac output, oxygen consumption, arterial and venous pressures were measured early in the course of the disease as well as after recovery (Cases 2, 3 and 4). In another patient (Case 1) these parameters were measured before and after administration of 100 mg. of thiamine chloride intravenously. Ouabain, 0.5 mg., was given intravenously over a 3 minute period to one patient on two occasions (Case 4). In one patient (Case 4) the response to an intravenous infusion of methoxamine was studied on two occasions. During the first study methoxamine was administered at a rate of 0.32 mg. per kg. per minute for 16 minutes by means of a continuous automatic infusion pump (Harvard Apparatus Co.). The infusion rate was then increased to 0.64 mg. per kg. per minute for 36 minutes. During the second study four days later, methoxamine was given at a rate of 0.64 mg. per kg. per minute for 33 minutes, followed by a rate of 1.2 mg. per kg. per minute for 20 minutes. Brachial arterial and central venous pressures were recorded every 5 minutes during the procedure. One patient (Case 3) exercised on a bicycle ergometer in a supine position at 25 watts energy level for 12 minutes. Hemodynamic measurements were made * In Case 1 mean arterial pressure was used for calcuation of stroke work index.

et al.

at rest and during exercise.

the tenth

CASE

to twelfth

minutes

of

STUDIES

A fifty-four year old white former newspaper writer (B.C.H. No. 1688716) with a history of chronic alcoholism was admitted to the hospital on October 19, 1959, because of syncope. One month previously he had noted the onset of pedal edema, which had progressed to the lower part of the abdomen. He also complained of malaise and fatigue during exertion of several months’ duration. His food intake was limited to one or two meals a day, and he had been drinking large quantities of beer and wine daily for two or three years. Physical examination revealed a blood pressure of 140/90 mm. Hg, an irregular apical pulse of 160 beats per minute and a temperature of 36.7’~. The skin was warm and flushed. The tongue was smooth and red. The neck veins were distended. The heart was enlarged, the apex impulse being felt at _&e’ anterior axillary line. No murmurs or gallops were heard. A few moist r-ales were heard over the base of the right lung. The liver edge was palpable 6 cm. below the right costal margin. There were bilateral inguinal hernias. The scrotal sac was edematous. There was 3f pedal edema extending up to the groins. Vibratory and touch sensation was diminished in the lower extremities, and the deep tendon reflexes were absent in the legs. Urinalysis was within normal limits. Hematocrit was 48 per cent. White blood cell count was 6,100 per cu. mm. with a normal differential. Fasting blood sugar and serum electrolyte levels were normal. Serum total proteins were 6.0 gm. per cent with an albumin of 4.5 gm. per cent. A bromsulfalein test showed 29 per cent retention at 45 minutes. Thymol turbidity was 2.2 units, and serum alkaline phosphatase 1.7 Bodansky units. The venous pressure was 310 mm. of water, and the Decholina arm to tongue circulation time was 10 seconds. The electrocardiogram showed atrial fibrillation with a ventricular response of 146 per minute and T wave inversion in leads I, aVL and Vs through Vs. Repeat electrocardiogram one week later showed atrial fibrillation, a ventricular rate of 105, and reversion of the T waves toward normal. Cardiac fluoroscopy revealed biventricular enlargement and diminished cardiac pulsations. The chest film obtained on admission showed cardiomegaly; on a repeat chest film thirty-two days later the heart was normal. Initial treatment consisted of bed rest and thiamine chloride, 50 mg. daily given intramuscularly. A mercurial diuretic was also given. A massive diuresis resulted in a loss of 30 pounds in six days. On the fifteenth hospital day the patient was digitalized with 1.2 gm. of digitalis leaf and then maintained on 0.1 gm. daily prior to surgery. His condition improved subjectively. Atrial fibrillation persisted, but with a CASE 1.

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SERIAL

HEMGDYNAMIC

DATA

IN FOUR

Case 1

Case

54, M 10/20/59 10/20/59 12:36 P.M. 1:13 P.M. 1 2 Acute 37 minute: after vitamin B1 68.2 68.2 178 178 138 144

number..

status........................... Height (in.). Weight (lb.). Heart rate (beats/min.) Brachial artery pressure (mm. Hg) Systolic. Diastolic....................... Mean.......................... Central venous pressure (mm. Hg) Cardiac output (L./min.). Stroke volume (cc/beat). Stroke work index (pm. M./beat/M*. Peripheral vascular resistance (dym sec.cm-5.). Appearance time (sec.). Oxygen consumption (cc./min. STPD Calculated A-V oxygen difference (vo %), Hematocrit (vol. %). Blood volume (L.).

140 105 125 28 8.01 58 53.6 969 8

46 9.08

140 110 125 33 3.95 27 25.4 1,863 9

47, M 12/31/57 1 Acute

2

nuns

(mm.

2,3 and 4 measurements

HEART

FAILURE

58, M 6/l 6/65

l/3/58 2 Recovety

Case 4

6/25/65

1 Acute

2 COnValeScence

38, M 9/28/64

10/2/64

1 Acute

2 Convalescence

10/6/64

1 l/4/64

3 Convalcscence

4 Recovery

64.5 190.5 97

64.5 172.7 78

64.5 129 80

64.5 120 76

67 163.5 108

67 166.5 100

67 154.5 85

67 147 99

190 95 130 18 12.45 128 150.0

145 75 90 6 7.92 102 86.4

142 68 95 11

151 88 112 4

94 49 82 13 16.39 152 115

132 70 103 19 9.70 97 89.2

181 91 127 10 7.89 93 109.6

142 81 108 4 4.88 49 51.4

728 7 418

846 9 352

337 3 317

693 4.5 336

46

3.40 44 9.48

-6.24 78 83.2

i.86 51 59.1

1,054

2,248

6.1 274

3.90 45 6.17

7.0 262

4.40 39.8 5.78

6.78 47.5 5.28

3.49 34 7.21

1.93 38 6.69

1,186 6 398 5.02 35 6.94

1,714 5.7 205 4.68 38 7.11

are the means of duplicate

determinations

with exception

of blood volume.

Addit; ma1 pressure

measure-

Hz):

Case 2 on l/3/58: &se 3 on 6/16/65: Case 4 on 10/6/64:

Right ventricle 40 systolic, 25 end-diastolic; Right ventricle 55 systolic, 14 end-diastolic. Right ventricle 53 systolic, 17 end-diastolic;

mean

response. Two operations for repair of the hernias were performed on the thirty-first and on the forty-first hospital day and were tolerated well. Hemodynamic studies (Table I, Fig. 1) performed on the second hospital day, during atria1 fibrillation with a ventricular rate of 138 beats per minute, showed a cardiac output of 8.0 L. per minute and a stroke volume of 58 ml. per beat, at a markedly elevated central venous pressure of 28 mm. Hg and a large blood volume of 9.1 L. Thirty-seven minutes after the intravenous administration of 100 mg. thiamine hydrochloride, the studies were repeated. The heart rate remained elevated at 144 beats per minute but the stroke volume had fallen to 27 ml. per beat and the cardiac output to 3.95 L. per minute. The mean arterial blood pressure remained the same at 125 mm. Hg in both states, whereas peripheral vascular resistance increased from 969 to 1,863 dynes sec. cme6.

Comment: A chronic alcoholic patient with recent onset of biventricular congestive heart failure and peripheral neuritis presented himself after an episode of syncope, in atria1 fibrillation with rapid ventricular response, and with evidence of peripheral neuritis. Hemodynamic studies revealed a state of high cardiac output failure, which was converted into a state of low cardiac output failure following the administra41,

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pulmonary

left ventricle

slow ventricular

vol..

BERIBERI

Case 3

NOTE: In Cases

WITH

-

Data

Study

199

I

PATIENTS

-

Age (yr.) and sex. Date.............................

et al.

artery

26;

182 systolic,

pulmonary

wedge

12.

23 end-diastolic.

tion of thiamine. Since the heart rate and blood pressure remained unchanged, the fall in cardiac output was entirely due to a decrease in stroke volume, and the marked increase in peripheral vascular resistance reflects vasoconstriction. CASE 2. This forty-seven year old white male, single laborer (B.C.H. No. 1629522) was admitted to the hospital on December 27, 1957, because of swelling of the legs and dyspnea of two months’ duration. The patient consumed 1 gallon of wine, as well as several high balls and beers daily. For the last four years he had noted dyspnea upon exertion and easy fatigability. During the last four or five months he had noted increasing dyspnea and ankle edema. He had stopped working two or three months before admission. No history of hypertension or prior heart disease could be obtained. Physical examination revealed a blood pressure of 164/85 mm. Hg, pulse rate of 108 per minute, temperature of 38.2”~. and respirations of 20 per minute. The skin was red and warm. An erythematous rash was present over the anterior tibias. The neck veins were distended at 45 degrees. The point of maximum cardiac impulse was palpable at the anterior axillary line. There was a grade 2/4 soft ejection murmur over the apex. The pulmonic closure sound was accentuated. Moist inspiratory rales were heard over the bases of both lungs. The liver edge was palpable 6 cm.

200

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FIG. 1. The systemic circulation in beriberi heart failure (solid symbols) in four patients, with studies after recovery in three patients and immediately after intravenous administration of thiamine in one patient (Case 1). Discussion in text. below the right costal margin. There was 3+ pedal edema. The peripheral pulses were bounding. Pistol shot sounds were heard over both femoral arteries. Pain and touch sensation was decreased over both legs. Deep tendon reflexes were absent in the lower extremities. The urine showed a specific gravity of 1.031, 3+ protein, and many white blood cells on microscopic examination. The hematocrit was 43 per cent, and the white blood count was 13,700 per cu. mm. with a normal differential count. Blood urea nitrogen and serum electrolyte levels were normal. A bromsulfalein test showed 6 per cent retention at 45 minutes. The serum alkaline phosphatase was 1.5 Bodansky units, the thymol turbidity 1.5 units. Prothrombin time was 18 seconds with a control of 16 seconds. Serum protein-bound iodine was 4.8 pg. per cent. The venous pressure measured 260 mm. of water, and the arm to tongue Decholin circulation time was

11 seconds. Chest films on admission showed cardiomegaly and prominent hilar markings. Cardiac fluoroscopy showed biventricular enlargement and diminished cardiac pulsations. Fluid was seen at the right costophrenic angle. The electrocardiogram was within normal limits. A liver biopsy specimen showed minimal fatty metamorphosis but no fibrosis. The patient was treated with bed rest, low sodium diet and mercaptomerin sodium, 2 cc. given intramuscularly. On the third hospital day, treatment with thiamine 60 mg. daily given orally was started. On the fourth hospital day he was given a single oral dose of digitalis leaf 0.8 gm. Over the next five days a massive diuresis ensued, and the patient lost 30 pounds in weight. His edema disappeared and his dyspnea improved. He was treated successfully with sulfadiazine for his urinary tract infection. A repeat chest film obtained ninety-six days after admission showed a decrease in heart size. AMERICAN

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Hemodynamlc studies, on the fifth hospital day, after two days of thiamine therapy (Table I, Fig. l), still showed evidence of high output failure with a central venous pressure of 18 mm. Hg, a cardiac index of 6.5 L. per minute per M2., and an increased stroke volume. The remarkably high cardiac output of 12.4 L. per minute, even at the low peripheral vascular resistance of 728 dynes sec. cm-b., resulted in a high mean arterial pressure of 130 mm. Hg. The narrow arteriovenous oxygen difference of 3.4 volumes per cent indicates that the increased cardiac output was not justified metabolically. The high output state was associated with a large blood volume of 9.5 L. Repeat hemodynamic studies and cardiac catheterization on the eighth hospital day, after further diuresis of 18 pounds, showed a decrease in heart rate to 76 beats per minute, a fall in central venous pressure to 6 mm. Hg, and in cardiac index to 4.2 L. per minute per M2. The stroke volume also decreased. The pulmonary wedge pressure of 12 mm. Hg suggests slight elevation of left ventricular filling pressure. The peripheral vascular resistance had increased to 846 dynes sec. cm-s. alcoholic patient, Comment: This chronic with symptoms and signs of biventricular failure and clinical evidence of hyperactive circulation, on initial study exhibited a high cardiac output and evidence of right ventricular failure with low peripheral vascular resistance. Marked diuresis and clinical improvement were accompanied by decreases in cardiac output and central venous pressure, whereas both left and right ventricular filling pressures at rest still remained elevated, indicating residual myocardial failure on the eighth hospital day. Heart size had not returned to normal. CASE 3. A fifty-eight year old white dishwasher (B.C.H. No. 2038473) was admitted to the hospital on June 14, 1965, because of dyspnea of two weeks’ duration. He consumed large amounts of wine and beer daily. He lived alone, and his food intake was limited to two meals daily, made up mostly of canned soup. For the last five months prior to admission he had noted wheezing and dyspnea on exertion. In the last four weeks he had noted increasing dyspnea and swelling of the ankles, as well as numbness and tingling of the feet. There was no history of heart disease or hypertension. He had been hospitalized here in January 1963. No cardiac symptoms or abnormalities were noted at that time, and a chest film was within normal limits. Physical examination revealed a chronically ill white man. Blood pressure was 110/50 mm. Hg, pulse 104 per minute, temperature 37.7”~. and respirations 24 per minute. There was palmar erythema. The VOL.

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tongue was red and smooth. The eyegrounds were normal. The neck veins were distended at 90 degrees. The heart was enlarged 2 cm. beyond the midclavicular line by percussion. There was a grade 2/6 soft systolic murmur over the base. No gallop was heard. There were moist rales over both lung bases. The liver edge was palpable 2 cm. below the right costal margin. Pin prick sensation and deep tendon reflexes were diminished in both lower extremities. There was 3+ pretibial edema. Hematocrit was 45 per cent. White blood count was 5,800 per cu. mm. with a normal differential count. Serum total bilirubin was 2.3 mg. per cent initially and 0.7 mg. per cent subsequently. Serum glutamic oxalacetic transaminase was 24 units. Blood sugar, blood urea nitrogen, serum electrolyte and creatinine levels, as well as the prothrombin time, were normal. A serum protein-bound iodine level was normal. Venous pressure was 210 mm. of water, and the Decholin arm to tongue circulation time was 10 seconds. The electrocardiogram showed normal sinus rhythm and complete left bundle branch block. A chest film showed cardiomegaly. Cardiac fluoroscopy showed biventricular enlargement. It was thought that the patient had beriberi heart disease, possibly associated with arteriosclerotic heart disease in view of the left bundle branch block. On the day of admission he was digitalized with digoxin and maintained on this drug. He was also given 2 cc. of mercaptomerin intramuscularly and 100 mg. thiamine chloride orally daily. Over the next day he had a diuresis of 2 pounds, and his edema disappeared. In a few days the patient’s dyspnea subsided, and his peripheral edema cleared. Repeat venous pressure eight days later was 58 mm. of water, and Decholin circulation time 20 seconds. A repeat chest film obtained on the eighth hospital day showed the heart to be of normal size. The electrocardiogram remained unchanged. Hemodynamic studies (Table I, Fig. 1 and 2) were performed on the third hospital day, after digitalization, diuretic and thiamine therapy had been followed by a diuresis of 4 pounds. At rest, the elevated right atrial pressure of 13 mm. Hg was associated with a normal cardiac index of 3.8 L. per minute per M2. and a normal arteriovenous oxygen difference of 4.4 volumes per cent. During moderate supine bicycle exercise, right atrial pressure rose to 16 mm. Hg and cardiac index to 4.3 L. per minute per M2. Cardiac output increased only as a result of an increase in heart rate, however, whereas stroke volume actually decreased. The increase in oxygen consumption of 223 cc. per minute STPD was accompanied by an abnormally small increase in cardiac output of 0.7 L. per minute, resulting in an abnormal widening of the arteriovenous oxygen difference to 7.2 volumes per cent. Thus exercise converted the state of high output failure into a state of low output failure. Studies were repeated on the twelfth hospital day,

Beriberi

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200 REST

EXERClSE

REST

EXERCISE

FIG. 2. The hemodynamic response to exercise in a patient with beriberi heart disease (Case 3) in failure and after recovery nine days later. Discussion in text.

after a further weight loss of 9 pounds. At comparable resting heart rate, central venous pressure had fallen to normal, cardiac index had decreased to 2.4 L. per minute per I@., a rather low value as indicated by the somewhat wide arteriovenous oxygen difference of 6.8 volumes per cent. Exercise now was accompanied by a lower cardiac index (3.7 L. per minute) and a wider arteriovenous oxygen difference (9.2 volumes per cent) than comparable exercise during the initial study, whereas central venous pressure remained within normal limits at 6 mm. Hg. Comment: A chronic alcoholic patient with history of poor diet and recent symptoms and signs of biventricular heart failure and peripheral neuritis showed the hemodynamic pattern of high output failure at rest, low output failure during exercise. Cardiac outputs both at rest and during exercise showed a marked decrease in the follow-up study, at which time the out-

put during

exercise

especially

was abnormally

low. CASE 4. A thirty-eight year old white male truck driver (B.C.H. No. 2020683) was admitted to the hospital on September 22, 1964, because of swelling of his legs and shortness of breath of two months’ duration. The patient had started drinking when he was twenty-five years old. He had been admitted to this hospital in 1954 and 1961 for delirium tremens. One year prior to the present admission, following complete extraction of his teeth, he lost his appetite but continued to drink 4 to 6 quarts of beer, several brandies and some whisky daily. He would drink only coffee for breakfast and eat a sandwich for lunch and one for dinner three or four days a week. Three months prior to admission he had noted tenderness and a tingling sensation in both feet. These sensations became worse, and walking became difficult. One month later he noted swelling of the feet and progressive dyspnea on exertion. He stopped AMERICAN

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FIG. 3. Case 4. The chest film (posteroanterior view) obtained on admission shows cardiomegaly and pulmonary congestion. Twenty days later the heart has returned to normal size, and pulmonary congestion has cleared. working two weeks prior to admission. There was no history of prior cardiovascular disease. On physical examination, the patient appeared anxious and tremulous. The blood pressure was 110/40 mm. Hg, the pulse 120 beats per minute, respirations 20 per minute and temperature 37.7’~. The skin of the extremities was warm. The peripheral pulses were bounding. The tongue was tremulous and slightly red. The neck veins were distended at 90 degrees. The thyroid gland was not enlarged. The cardiac apex was palpable in the fifth intercostal space in the anterior axillary line. A grade 2/6 soft systolic murmur was heard over the entire precordium, loudest at the apex. The lungs were clear. The liver edge was palpable 6 cm. below the right costal margin. Deep tendon reflexes were absent in the and vibratory sensation was lower extremities, markedly diminished. No bruit was heard in the neck, abdomen or femoral regions. Urinalysis showed a trace of protein. Hematocrit was 39 per cent, white blood cell count 9,700 per cu. mm. with a normal differential count. Fasting blood sugar was 120 mg. per cent and blood urea nitrogen 14 mg. per cent. Serum sodium was 126 mEq. per L., potassium 3.6 mEq. per L., chloride 88 mEq. per L. and carbon dioxide combining power 22 mEq. per L. Serum glutamic oxalacetic transaminase was 30 units, later 22 units. The serum alkaline phosphatase was 1.7 Bodansky units, total bilirubin 1.3 mg. per cent. Protein-bound iodine and radioactive iodine uptake by the thyroid gland were normal. The electrocardiogram was within normal limits. A chest roentgenogram (Fig. 3) showed cardiomegaly, pulmonary congestion and a left pleural effusion. Venous pressure was 270 mm. of water. Arm to tongue Decholin circulation time was 10 seconds. The blood transketolase level was measured before the patient reVOL.

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ceived therapy* [18]. Blood incubated without thiamine pyrophosphate produced 116 mg. of sedoheptulose-7-phosphate per ml. per hour. Blood incubated with thiamine pyrophosphate produced 173 mg. of sedoheptulose-7-phosphate per ml. per hour, giving a thiamine pyrophosphate (TPP) effect of 33 per cent. This “TPP” effect is significantly elevated and indicates a relatively acute thiamine depletion. The patient was treated with bed rest, low sodium diet and given 2 cc. of mercaptomerin sodium intramuscularly on admission. He never received digitalis. Diuresis failed to develop; instead there was an additional 8 pound gain in weight over the next eight days. At first, thyrotoxicosis or a post-traumatic arteriovenous fistula were considered possible diagnoses. When first seen by us, a clinical diagnosis of beriberi heart disease was made, and a subsequent interview with the patient’s wife revealed that he had indeed been drinking heavily and had had a poor dietary intake for the past year. The patient had denied this originally. Beginning with the twelfth hospital day he was given 50 mg. thiamine chloride intramuscularly daily. He began to improve and had a 30 pound diuresis over the next nine days. At the time of discharge, twenty-three days after admission, the patient’s dyspnea and edema had cleared, and his peripheral neuritis had diminished; the liver was no longer palpable. A repeat chest film (Fig. 3) obtained on the twentieth hospital day showed that the heart size had returned to normal, the pleural effusion had been resorbed, and the lung fields had cleared. The first hemodynamic study (Table I) was performed on the seventh hospital day, after the patient had failed to respond to general therapy for heart * Transketolase level was kindly measured Pierre M. Dreyfus, Department of Neurology, chusetts General Hospital.

by Dr. Massa-

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FIG. 4. The hemodynamic response to methoxamine in a patient with beriberi heart disease (Case 4) during heart failure (total dose 373 ng. per kg. at a rate of 0.32 mg. per mm. for 16 minutes followed by 0.64 mg. per minute for 36 minutes) and four days later during early convalescence (total dose 556 N. per kg. at a rate of 0.64 mg. - .ner minute for 33 minutes and 1.2 mg. per minute for 20 minutes). See text. failure. With a sinus tachycardia of 108 beats per minute and a central venous pressure of 13 mm. Hg, the cardiac index was found to be 9.4 L. per minute per M2., associated with an unusually narrow arteriovenous oxygen difference of 1.9 volumes per cent and an extremely low peripheral vascular resistance of 377 dynes sec. cm-s. The arterial blood pressure was 94/49, with a mean of 82 mm. Hg. Four days later, on the eleventh hospital day, the second hemodynamic study (Table I, Fig. 4), with the patient in about the same clinical state, revealed further increases in central venous pressure to 19 mm. Hg, associated with a heart rate of 100 beats per minute, a decrease in cardiac output, an increase in peripheral vascular resistance to 693 dynes sec. cm-s., and an increase in blood pressure to 132/70, with a mean of 103 mm. Hg. The cardiac index, however, still remained high at 5.2 L. per minute per M2., and the arteriovenous oxygen difference remained narrow

at 3.5 volumes per cent. Intravenous administration of methoxamine at a rate of 0.64 mg. per minute increased arterial pressure only slightly (to 160/80, mean 110 mm. Hg), and resulted in only mild decrease in heart rate (to 93 beats per minute). Cardiac index was maintained at 5.5 L. per minute per M2., and total peripheral resistance increased at most slightly to 863 dynes sec. cm-s. The third hemodynamic study (Table I) was carried out on the fifteenth hospital day, three days after beginning thiamine therapy. Central venous pressure had fallen to 10 mm. Hg, heart rate to 85 beats per minute, and the brachial arterial pressure had increased to 181/91, with a mean of 127 mm. Hg. The cardiac index had decreased to 4.3 L. per minute per M2., and peripheral vascular resistance had increased to 1,186 dynes sec. cm-s. The left ventricular enddiastolic pressure, however, measured for the first time, was found to be elevated (23 mm. Hg). AMERICAN

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FIG. 5. The hemodynamic response to ouabain in a patient failure and after full recovery four weeks later. See text. Thirty minutes after the intravenous administration of 0.5 mg. ouabain (Fig. 5), at a comparable heart rate of 83 beats per minute and a blood pressure of 186/94, mean 126 mm. Hg, the central venous pressure remained unchanged at 12 mm. Hg, left ventricular end-diastolic pressure decreased slightly to 19 mm. Hg, but cardiac index increased strikingly to 5.5 L. per minute per M2., whereas the peripheral vascular resistance decreased. This effect was still being sustained 52 minutes after the administration of ouabain. Methoxamine, given intravenously at a rate of 0.64 mg. per minute, did not affect blood pressure or heart rate. The intravenous administration of methoxamine at a higher rate of 1.2 mg. per minute resulted in a pressor effect to 198/122, 115 mm. Hg mean, with a relative bradycardia of 68 beats per minute. The central venous pressure now rose to 15 mm. Hg, and left ventricular end-diastolic pressure to 30 mm. Hg, whereas cardiac index was 4.04 L. per minute per M*. and peripheral vascular resistance 2,540 dynes sec. cm+. (Fig. 4.) The fourth hemodynamic study was performed forty-four days after admission, when the patient was clinically well. (Table I, Fig. 1.) At a heart rate of 99, the arterial pressure was 142/81, with a mean of 108 mm. Hg, and the central venous pressure was 4 mm. Hg. Cardiac index was 2.8 L. per minute per M2., arteriovenous oxygen difference 4.7 per cent, and peripheral vascular resistance 1,714 dynes sec. cm-s., all values within normal limits.

Comment: with a history VOL.

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This chronic alcoholic of poor diet and recent

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patient onset of

with beriberi

et al.

heart disease (Case 4) in congestive

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symptoms of biventricular failure and peripheral neuritis, did not respond to bed rest, low salt diet or diuretics. The initial study indicated an extremely high cardiac output, with myocardial failure. The low initial blood pressure reflects vasodilatation of such magnitude that a normal blood pressure could not be maintained despite the remarkably high cardiac output. At the time of the second study, peripheral resistance and blood pressure had increased, suggesting some recovery of peripheral vascular tone, but at the same time the lowered cardiac output and widened arteriovenous difference at a higher right ventricular filling pressure appeared to indicate a deterioration in myocardial performance. This was confirmed by the decrease in stroke work index from 115 to 89 gm. M. per beat per M2. in the face of higher blood pressure. The circulation was remarkably resistant to the pressor effect of methoxamine in large dosage. The third study revealed some improvement in the circulation toward normal, after initiation of thiamine treatment. After intravenous administration of ouabain, a positive inotropic effect was observed. The administration of methoxamine in the previous dosage again did not affect either the blood pressure or the heart rate. At a higher dose, a pressor effect and slowing of the heart were noted after 20 minutes,

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whereas cardiac output was maintained and both ventricular filling pressures increased in the face of increased left ventricular work. Study after full clinical recovery, forty-four days after admission to the hospital, revealed a normal hemodynamic profile at rest. COMMENTS

The diagnosis of beriberi heart disease in these four cases may be considered well established, not only by the clinical and hemodynamic data but also by the therapeutic response to thiamine. Other causes of high output failure were ruled out; these patients were not anemic, had normal serum protein-bound iodine levels, and did not have clinical or laboratory evidence of hepatic cirrhosis, Paget’s disease or arteriovenous fistulas. All four patients were chronic alcoholic men, with a history of poor diet and evidence of mild peripheral neuritis, in whom, while physically active, symptoms and physical signs of biventricular congestive heart failure had developed. Roentgenologic examination confirmed biventricular enlargement and pulmonary congestion in all patients. In only two (Cases 3 and 4) did the clinical and roentgenologic examination suggest a hyperkinetic circulation. The electrocardiogram was normal in one patient. It showed nonspecific T wave changes in two patients, diminishing with recovery. One patient had atria1 fibrillation, an.other presented with complete left bundle br&ch block; both abnormalities persisted. Although T wave changes have been the most common abnormalities reported [3,4,7], both atria1 fibrillation and left bundle branch block, although infrequent, have also been observed in beriberi in man [6,7] and in rats with experimentally-induced thiamine deficiency [22]. The possibility of coexisting coronary artery disease has not, however, been ruled out entirely. In all four cases the initial hemodynamic picture (Table I, Fig. 1) was that of high output failure with increased right ventricular pressure and, when measured, left ventricular filling pressure, associated with a low peripheral vascular resistance and increased oxygen consumption, but a cardiac output elevated disproportionately to the metabolic rate, resulting in a narrow arteriovenous oxygen difference. This is the picture generally described in the few hemodynamic studies of beriberi heart disease which have been reported [5,8,9-761. Cardiac output

et al.

was increased to such an extent that, despite the lowered peripheral vascular resistance, ventricular work was significantly increased in all four cases, and arterial blood pressure was raised to an abnormal level in two cases. High output failure was associated with high plasma and blood volumes in all four patients, a finding which is in agreement with measurements made by others [5,8,74,75]. The physiologic studies tended to confirm the clinical evidence of left ventricular failure. This is in agreement with the clinical findings in other series of occidental beriberi [4,6,7]. Furthermore, of the fourteen patients with occidental beriberi studied hemodynamically in whom pulmonary wedge pressures were recorded, thirteen showed elevation of this measure of left ventricular filling pressure [ 72,73,75,76]. Administration of thiamine in one patient (Case 1) restored normal peripheral vascular tone in 37 minutes, decreased left ventricular work, and converted a state of high output cardiac failure into one of low output failure. The only other hemodynamic study of the acute effect of thiamine in a patient with presumptive cardiac beriberi known to us is that of Lahey and associates [ 7 7 1, who found a slight decrease in cardiac output and stroke volume and a slight increase in peripheral vascular resistance 1.5 hours after the administration of thiamine. However, their patient had cirrhosis of the liver with a normal central venous pressure and no cardiac enlargement. Thus the clinical and hemodynamic picture closely resembled that encountered in cirrhosis [23], casting some doubt upon the diagnosis of beriberi heart disease. At the very least, this was not an uncomplicated case, and factors other than thiamine deficiency may have been operative in maintaining peripheral vasodilatation. In this laboratory, Gravallese and Victor [24] studied the hemodynamic response to the intravenous administration of 100 mg. of thiamine in two patients with Wernicke’s encephalopathy. One of these had an initial cardiac index of 5.7 L. per minute per M2. which fell to 4.8 L. per minute per M2. 1 hour after administration of thiamine, whereas total peripheral resistance rose. The second patient studied had a low initial cardiac index, which doubled after thiamine was given, whereas the initially high peripheral resistance decreased markedly. Although both patients clearly suffered from thiamine deficiency, neither had evidence of beriberi heart disease. AMERICAN

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The evidence of increased vascular tone in Case 1 following the administration of thiamine is in full agreement with the hypothesis that thiamine deficiency is directly responsible for the abnormally severe peripheral vasodilatation. The utilization of this acute vascular response to thiamine as a diagnostic test for beriberi merits further exploration. This peripheral response may be inapparent to clinical assessment if the response of the myocardial lesion lags behind, as it did in Case 2. The three patients who received prolonged thiamine therapy showed marked improvement both clinically and in their hemodynamic profile. Uniformly, an increase in peripheral vascular resistance was accompanied by decreases in heart rate, venous pressure, cardiac output, stroke volume and oxygen consumption, whereas oxygen difference increased. arteriovenous Plasma and blood volumes decreased in two of three patients. These results are in agreement with hemodynamic follow-up observations made by others after days to weeks of treatment [5,9, 70,72-761. It must be kept in mind that in addition to thiamine and good diet, therapy invariably included rest, and often diuretics and other nutritional supplements. Furthermore, the late follow-up observations were usually carried out after a diuresis and at a lower blood volume. Thus the hemodynamic response to the prolonged administration of thiamine would appear to have less specific diagnostic value than the acute response. Exercise, as a test of cardiac reserve in Case 3, early in the course of the disease was followed by a slight increase in cardiac index, whereas the central venous pressure and arteriovenous oxygen difference increased. Campbell and associates in 1951 [ 701 studied the response to exercise in two patients with beriberi heart disease. Before treatment, cardiac index failed to increase, but venous pressure rose. The response to exercise became normal with recovery. Wagner [76] also noted that the cardiac index did not increase and mean pulmonary artery pressure rose during exercise in a patient with beriberi heart disease. Blacket and Palmer [75] studied the response to exercise in nine patients with high output heart failure attributed to beriberi, of whom one was studied before treatment only, four were studied before and after treatment, and five only after treatment. In the two patients with the highest cardiac outputs, 26.5 and 17.6 L. per minute, respectively, blood flow did not VOL.

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increase during a moderate degree of exercise sufficient to double their oxygen consumption. In these cases the high initial cardiac output may have represented the maximal cardiac response. The arteriovenous oxygen difference, however, remained well within normal limits. In both patients right atria1 and pulmonary arterial pressures increased significantly during exercise. The other two untreated patients were able to increase cardiac output sufficiently to maintain a normal arteriovenous oxygen difference. Of the five patients whose studies after treatment are reported in detail, including the two whose output remained fixed during exercise before therapy, all showed significant increases in blood flow during exercise. In one patient studied six days after treatment with thiamine (Case 16), however, cardiac output increased only from 5.0 to 6.4 L. per minute whereas oxygen consumption increased from 196 to 590 cc. per minute per STPD, resulting in an abnormal increase in arteriovenous oxygen difference to 9.2 volumes per cent. Right atria1 pressure in this patient increased from a normal value of 3 mm. Hg at rest to 16 mm. Hg during exercise. Here, as in our patient (Case 3), exercise revealed a limited cardiac reserve. The effects of cardiac glycosides have not been fully evaluated in patients with high output failure, such as beriberi heart disease. Aalsmeer and Wenckebach [2], as well as authors of more recent textbooks of cardiology [25,26], state that digitalis is ineffective in beriberi heart disease. Indeed, doubts concerning the usefulness of digitalis in beriberi were so great that a beneficial response to this drug was used to exclude this diagnosis [6]. Some clinicians, however, consider cardiac glycosides beneficial to such patients. Blankenhorn [6] administered digitalis to five patients with beriberi and noted improvement in three. Often patients have been treated simultaneously with thiamine, digitalis, diuretics and bed rest, and it is not possible to evaluate the relative role of these agents in bringing about the therapeutic response. To our knowledge, neither controlled clinical studies nor hemodynamic investigations of the effect of digitalis in beriberi heart disease have been reported previously, except in one case in which the intravenous administration of digoxin was found to have no hemodynamic effect in 2 hours [ 751. The strongly positive inotropic response to ouabain reported here occurred in a patient with clinically evident and biochemically proved

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beriberi heart disease with high output failure and without other underlying cardiovascular disease, confirmed subsequently by his full recovery. The significant increases in stroke volume, cardiac output, stroke work and minute work, at essentially unchanged right and left ventricular pressures, represent a positive inotropic effect of ouabain as great as has been observed in patients with other types of congestive heart failure studied in a similar manner in this laboratory [27]. Furthermore, this effect was considerably greater during the initial study than during the follow-up study four weeks later. If further clinical and hemodynamic studies are confirmatory, cardiac glycosides may no longer be considered ineffective in this disease. In view of the increase in peripheral vascular resistance accompanied by evidence of greater cardiac failure, observed after acute administration of thiamine in Case 1, one may even expect deterioration of the circulatory system after rapid administration of thiamine alone. Indeed, this has been observed clinically by Soma Weiss [28]. The use of digitalis glycosides simultaneously with thiamine in proved beriberi heart disease might prevent such deterioration. The hemodynamic response to methoxamine was studied on two occasions in Case 4, in an attempt to determine if the presumptive peripheral arteriolar dilatation, and with it the high output state, could be reversed by a sympathomimetic amine with a predominantly peripheral action. The hemodynamic response of normal subjects to methoxamine has been reported from this laboratory previously [29]. Eight normal subjects responded to an intravenous infusion of methoxamine at a rate of 0.32 to 0.64 mg. per minute (total dose ranged from 111 to 316 with an average dose of 210.4 pg. per kg.) with an increase in mean arterial pressure of 19 per cent, an increase in central venous pressure of 48 per cent, and a fall in heart rate of 22 per cent, whereas cardiac index remained unchanged. Total peripheral resistance increased by 23 per cent and left ventricular minute work by 17 per cent. Infusion of methoxamine in Case 4 early in the course of the disease, at a dose 1.8 times the average amount required in normal subjects, failed to produce vasoconstriction. At the subsequent study the effective dose of methoxamine was 2.6 times the average amount needed for normal subjects. This lack of response of the patient with high

et al.

output beriberi heart disease to methoxamine is in sharp contrast to the observations made in this laboratory in patients with high output states secondary to chronic anemia [30], who re sponded quite readily, and whose high output state was abolished as peripheral vascular resistance returned toward normal. These findings suggest that the peripheral vasodilatation of beriberi heart disease may not be reversible in the absence of thiamine, and may be difficult to reverse even in its presence. There was a striking contrast between the lack of effect of methoxamine given in large doses in Case 4 and the prompt increase in peripheral resistance and fall in cardiac output observed after the administration of thiamine in Case 1. Inasmuch as methoxamine is thought to produce vasoconstriction by acting directly on the effector cell, i.e., on the smooth muscle cells of the arterioles, one may indeed suspect that thiamine deficiency may interfere with smooth muscle constriction and thus reduce normal vascular tone and block vasoconstriction. Peripheral vasodilatation is not necessarily fixed in beriberi heart disease, however. Wenckebach reported as early as 1934 [37] that he was often able to calm the hyperactive circulation by administration of Pitressin@, which was followed by a rise in diastolic blood pressure and a reduction in pulse pressure. Wenckebach accepted this as proof that arteriolar dilatation was responsible for the accelerated circulation or hyperdynamic state he described so well in oriental beriberi. However, Aalsmeer [32] reported that the administration of 10 units of Pitressin was without effect initially in seven of eleven cases of oriental beriberi. As the patients improved, Pitressin was successful in producing vasoconstriction, indicating recovery from the disease. Although Aalsmeer clearly mentioned his concern “that a rise in peripheral resistance could tax the left heart too heavily” [32], Paul Wood [33] recommended the therapeutic use of Pitressin in fulminating cases of beriberi. The high incidence of coronary disease would seem to contraindicate the use of Pitressin, a known coronary vasoconstrictor, in adult man. The pathophysiology of beriberi heart disease comprises three major physiologic derangements: (1) A state of peripheral vasodilatation leading to a high output state, (2) a state of biventricular myocardial failure, and (3) retention of sodium and water leading to edema and anasarca. AMERICAN

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Pathologic lesions in smooth muscle of the peripheral vessels, or their innervation, have not been described in beriberi. These tissues may, however, be affected by a biochemical lesion of thiamine deficiency. The physiologic evidence for vasodilatation, already discussed in detail, is strong. Measurements of peripheral blood flow [4,75] suggest that the major site of vasodilatation is the skeletal muscle. Generalized vasodilatation in skeletal muscle may account in part for the high levels of cardiac output that have been described. The levels of cardiac output are generally equivalent to those observed during strenuous exercise, in severe anemia, thyrotoxicosis, hepatic cirrhosis and arteriovenous fistulas. In the absence of heart disease or anoxia, high output states are generally well tolerated and only rarely give rise to myocardial failure, especially if intermittent. Indeed, the high output state of thiamine deficiency may be seen without evidence of heart failure [2,24,32]. Thus the occurrence of congestive heart failure in patients with thiamine deficiency without other heart disease constitutes evidence for impaired myocardial function due to thiamine deficiency. Pathologic study of the beriberi heart may reveal dilatation and flabbiness, interstitial myocardial edema, cloudy swelling of myocardial fibers, and hydropic or fatty degeneration [34]. These are all nonspecific changes, and they are not regularly present in human beriberi. It is generally presumed that a biochemical lesion related to thiamine deficiency must account for the myocardial failure in beriberi. Olson and Schwartz [35] suggested that defective energy production in cardiac muscle is the underlying cause of heart failure in this disease. Pyruvate and lactate are important substrates for oxidation in heart muscle. The decarboxylation of pyruvate and its subsequent oxidation in the citric acid cycle require thiamine as the enzyme co-carboxylase (thiamine pyrophosphate). Thiamine deficiency produces tissue depletion of this enzyme and causes a block in the utilization of pyruvate. Therefore, the blood levels of pyruvate and its precursor, lactate, will rise [36]. Although this elevation of pyruvate and lactate levels in the blood has been used as a diagnostic test in beriberi, this test lacks specificity ]37]. Increased blood lactate levels may occur with hyperventilation, anxiety, exercise, agitation, fever, delirium tremens, anemia, liver disease, diabetes and congestive heart failure [38,39]. VOL.

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Many subsequent attempts have been made to devise a test for the detection of thiamine deficiency states. Measurement of urinary excretion of thiamine is a sensitive index of dietary intake of thiamine. Unfortunately, the urinary level of thiamine diminishes to low levels as soon as thiamine intake is reduced and before tissue depletion occurs [do]. The plasma level of thiamine is also an index of thiamine intake; it decreases to low levels before there is any clinical evidence of thiamine deficiency [47]. Moreover, plasma thiamine constitutes only a small fraction (10 per cent) of blood thiamine; the greatest portion of blood thiamine (75 per cent) is in the red blood cells [36]. Whole blood or red blood cell thiamine content has been found to correlate well with the tissue thiamine level [42]. A promising recent development is the demonstration by Brin and associates [77] that transketolase, one of the enzymes of the hexose monophosphate shunt which requires thiamine pyrophosphate as a co-factor, is present and measurable in red blood cell hemolysates. Dreyfus [ 781 found that whole blood transketolase reflects minimal as well as severe degrees of thiamine deficiency. Furthermore, decreased blood transketolase levels in rats were associated with significant reductions in the level of this enzyme in the heart, kidney, liver and brain stem, in that order of severity [43]. Patients with Wernicke’s encephalopathy had decreased blood transketolase levels [ 781. Transketolase activity was found to be low in one of our patients (Case 4), confirming the presence of thiamine deficiency. Peripheral vasodilatation calls for an increase in cardiac output, and this increa,sed volume load in turn results in an increase in cardiac work. In order to maintain blood pressure, the blood flow to certain organs may actually be diminished. Among these may be the skin and the kidneys [ 751. Renal plasma flow and glomerular filtration rate have been found to be diminished in heart failure attributed to beriberi [ 77,72,75]. This may account for the tendency to sodium and water retention, already described by Shimazono [I]. Retention of sodium and water, in turn, will increase plasma volume, which then may participate in maintaining the high output state. It is easily understood that beriberi heart failure is especially prominent in patients who continue hard physical work, thereby maintaining a high cardiac work load [3]. Conversely, the protective action of rest is evident in the rarity of

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heart failure in patients with severe peripheral neuritis [3], and in the salutary effect of bed rest in beriberi heart disease [2,3,7]. Shimazono [I] first noted that adrenalin, the effects of which resemble those of exercise inasmuch as adrenalin accelerates the heart and dilates arterioles in skeletal muscles, may reproduce many of the symptoms and signs of beriberi heart disease. Aalsmeer [32] later used the effect of adrenalin upon the blood pressure as a provocative test in the clinical evaluation of patients with beriberi. Although in the classic case of oriental beriberi heart disease, peripheral vasodilatation, myocardial failure and retention of sodium and water are all present, these three abnormalities do not appear to be obligatory in thiamine deficiency, nor must they occur together. A patient with beriberi may have severe peripheral neuritis with only minimal circulatory abnormalities [24]. Peripheral vasodilatation and hyperkinetic circulation dominate over myocardial failure and fluid retention in the early picture of oriental beriberi [2,32]. This may in part be related to the tropical climate, which itself is known to be associated with peripheral vasodilatation and a high output state [&I, and in part to a prevalence of lower vascular tone and lower sodium intake in the orient. One might thus predict that a form of beriberi in which myocardial failure predominates should also exist. Indeed, earlier clinical studies of both oriental [3] and occidental beriberi heart disease [4] had suggested that the circulation is not uniformly hyperkinetic in this disease. Furthermore, in acute Wernicke’s encephalopathy, another thiamine deficiency state studied in this laboratory [,%I, only four of seven patients were found to have elevated cardiac indices. A number of other heart diseases may be present in the same population exposed to the risk of thiamine deficiency. Among these, coronary artery disease, acute myocarditis and primary cardiomyopathies may present major difficulties in the differential diagnosis. Inasmuch as these diseases are characteristically associated with low output failure, one may be tempted to classify patients according to whether the heart failure is of a hypo- or hyperkinetic type. Such a classification may produce errors in the diagnosis of beriberi heart disease. Thus patients with beriberi and low output failure may escape recognition. Conversely, chronic alcoholic patients with a hyperkinetic circulation secondary to chronic hepatic disease

et al.

or anemia [ 751 may be falsely diagnosed as having beriberi heart disease. Further evidence for the possible dissociation of the peripheral vascular lesion from the cardiac lesion was seen in two patients (Cases 1 and 3) : both showed a marked peripheral response to thiamine, which actually unmasked the myocardial disease by changing volume work into pressure work for a myocardium which was still abnormal. In one patient (Case 4), the third hemodynamic study still showed evidence of left ventricular failure. Thiamine deficiency and its cardiovascular effects may also be superimposed upon other types of heart disease. Anorexia and poor dietary intake often occur in patients with chronic heart disease. Wohl [45] has shown that mercurial diuretics increase the urinary excretion of thiamine. A possible contribution of thiamine depletion to the state of congestive heart failure in such patients also offers a fruitful area for biochemical and hemodynamic studies. SUMMARY

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CONCLUSIONS

To elucidate the pathophysiology of the cir culation in beriberi heart disease, four chronic alcoholic patients in congestive heart failure attributed to thiamine deficiency were studied hemodynamically before and after treatment. The patients, all male alcoholic addicts with a history of poor diet, were thirty-eight, fortyseven, fifty-four and fifty-eight years of age. They were free from other cardiac disease, anemia, hepatic disease or other disease known to be associated with derangements of the circulation, but all had evidence of peripheral neuritis. While working, symptoms and signs of biventricular congestive heart failure developed. Roentgenologic examination showed cardiac enlargement and pulmonary congestion in all patients. The electrocardiogram was normal in one and showed nonspecific changes in the T waves in two patients, whereas one patient had atria1 fibrillation and another had a left bundle branch block. Beriberi heart disease was characterized by tachycardia (mean 106 beats per minute), large stroke index (mean 58 cc. per beat per M2.), increased cardiac index (mean 5.96 L. per minute per M2.), associated with low peripheral vascular resistance (mean 772 dynes sec. cm-b.), narrow arteriovenous oxygen difference (mean 3.24 volumes per cent) and increased right and left ventricular filling pressures. The blood volume AMERICAN

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was increased in all patients. The response to exercise was abnormal in the one patient in whom it was studied. Three patients studied after three to thirtyseven days of treatment showed improvement in their hemodynamic profile. One patient, studied 37 minutes after the intravenous administration of thiamine, showed a marked increase in peripheral vascular resistance and a decrease in cardiac output. In contrast, methoxamine administered to another patient in large doses failed to increase peripheral resistance in the acute stage ; even in convalescence an abnormally large dose was required to produce vasoconstriction. Intravenously administered ouabain produced a significant positive inotropic effect in the same patient. Blood transketolase levels, determined in this patient, confirmed thiamine deficiency. The data suggest that in beriberi heart failure there is both a peripheral vascular lesion and a myocardial lesion, resulting in a state of vasodilatation or loss of peripheral vascular tone, associated with a high cardiac output state and biventricular failure. The poor response of the peripheral lesion to a sympathomimetic amine attests to the severity of the state of vasodilatation. Although the peripheral lesion may respond rapidly to specific treatment with thiamine, the response of the myocardial lesion may be delayed. Thus a state of low output failure may appear during treatment. Attention is directed to the possible therapeutic effect of digitalis glycosides.

Acknowledgment: We acknowledge our indebtedness to Paul Hugenholtz, M.D. and Gordon Katznelson, M.D. for their participation in the earlier studies, to Philip Bornstein and Mary Collins, R.N. and Alba Goodwin, R.N. for technical assistance and to Pierre Dreyfus, M.D. of the Massachusetts General Hospital for performing the transketolase measurement. REFERENCES

1. SHIMAZONO,J. Beriberi. In: Avitaminosen und verwandte Krankheitszustiinde. Edited by Stepp, W. and Gyorgy, P. Berlin, 1927. Julius Springer. 2. AALSMEER, W. C. and WENMEBACH, K. F. The heart and circulatory system in beriberi. Am. Heart J., 4: 630, 1929. 3. KEEFER, C. S. The beriberi heart disease. Arch. Znt. Med., 45: 1, 1930. VOL.

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