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RELATION BETWEEN SERUM-FREE-FATTY-ACIDS AND ARRHYTHMIAS AND DEATH AFTER ACUTE MYOCARDIAL INFARCTION
710
RELATION BETWEEN SERUM-FREE-FATTYACIDS AND ARRHYTHMIAS AND DEATH AFTER ACUTE MYOCARDIAL INFARCTION M.D.
M. F. OLIVER Edin., F.R.C.P.E., M.R.C.P.
PHYSICIAN, ROYAL INFIRMARY, EDINBURGH, AND SENIOR LECTURER IN MEDICINE, UNIVERSITY OF EDINBURGH
CONSULTANT
V. A. KURIEN Mysore, M.R.C.P.E.
M.B. Edin., B.Sc.
SENIOR HOUSE-OFFICER, ROYAL INFIRMARY,
EDINBURGH *
T. W. GREENWOOD M.A., M.B. Cantab. SENIOR
HOUSE-OFFICER, CORONARY CARE UNIT, INFIRMARY, EDINBURGH †
ROYAL
From the Departments of Cardiology and Clinical Chemistry, and the Coronary Care Unit, Royal Infirmary, Edinburgh 3
Serum-free-fatty-acid (F.F.A.) levels measured in 200 patients during the first fortyeight hours after an acute myocardial infarction have been related to the prevalence of arrhythmias detected by continuous monitoring of the electrocardiogram, to the clinical state of the patients, and to serum-enzyme and blood-glucose levels. Maximum elevation of serum F.F.A. occurred within four to eight hours in most patients after acute myocardial infarction. Those with a striking elevation (above 1200 µeq. per litre) had an increased prevalence of serious arrhythmias and disorders of conduction. Both early and late deaths were more frequent among these patients compared with those with less elevated levels. There was no correlation between serum-F.F.A. and the clinical state of the patients, except for cardiogenic shock; nor between serum-F.F.A. and serum-creatine-kinase or serum-aspartate-aminotransferase levels; nor between these serum-enzyme levels and the prevalence of arrhythmias. Serum-F.F.A. and bloodglucose levels did not show significant correlation, except in cardiogenic shock. It is concluded that measurement of serum-F.F.A. is a new and valuable early predictive index of the vulnerability of patients with acute myocardial infarction to serious arrhythmias. This relationship between serum-F.F.A. levels and arrhythmias could result from increased catecholamine activity, particularly that of noradrenaline, or it could be due directly to an increase in myocardial oxygen consumption caused by the utilisation of F.F.A. as the major energy substrate. Both mechanisms would intensify myocardial hypoxia in an already ischæmic heart. Summary
with very high serum-F.F.A. levels. Therefore, the present study was established in order to examine whether there is any relationship in patients with acute myocardial infarction between serum-F.F.A. levels and arrhythmias and death. Patients and Methods Selection of Patients The clinical material consisted of 200 patients admitted with acute myocardial infarction to the coronary care unit of the Royal Infirmary of Edinburgh. The electrocardiogram (E.C.G.) of each patient was monitored continuously by a SanbomVisomonitor ’ and on an oscilloscope from the time of admission for at least forty-eight hours, according to the policy of the coronary care unit (Lawrie, Greenwood, Goddard, Harvey, Donald, Julian, and Oliver 1967, Oliver et al. 1967). A permanent record could be made at any time and a strip was recorded automatically at least hourly and often half or quarter hourly. Male and female patients were accepted into the series on a consecutive basis providing they conformed to the following criteria:
(1) Age under seventy. (2) Onset of symptoms within the preceding twenty-four hours. (3) E.C.G. signs of myocardial infarction. The Minnesota code (Rose and Blackburn 1966) was used for classifying electrocardiograms and categories 1-1, 1-2, 1-3 with 4-1 or 5-1, and 7-1 were accepted. (4) Elevation of either serum-creatine-kinase (C.K.) or serumaspartate-aminotransferase (S.G.O.T.), or both. (5) No pre-existing diabetes mellitus. (6) No prior administration of heparin, catecholamines, steroids, antihypertensive drugs, or clofibrate (’ Atromid-S ’), all of which can influence serum-levels of F.F.A. (7) An arrhythmia was not known to have preceded the first venepuncture for serum-F.F.A. analysis. Patients with high-grade block on admission were included provided they had no preceding or associated tachycardia. (8) Serial serum-F.F.A. estimations were obtained according to the requirements described below.
Serum-F.F.A. Estimations Requirements.-One blood specimen had to be obtained within twenty-four hours of the onset of symptoms of acute myocardial infarction: this was usually not a fasting specimen unless the patient had been admitted during the night. A second blood specimen had to be obtained in the fasting state on the morning after admission. Usually three specimens were obtained from each patient and the first two were taken within twenty-four hours of the onset of symptoms. A patient from whom a single blood specimen was taken was accepted only if he had died before a second specimen could be obtained.
Introduction
SERUM-LEVELS of free-fatty-acids (F.F.A.) are elevated after acute myocardial infarction (Kurien and Oliver 1966). This rise is more than after a meal, whether predominantly fatty or carbohydrate in content, or after prolonged fasting. It is not due to the anxiety and stress of being admitted to hospital as an emergency, and is only partly related to pain. We suggested that it is most probably a consequence of mobilisation of F.F.A. from adipose tissue by noradrenaline (Kurien and Oliver 1966). During the course of this earlier work, a few patients who died after acute myocardial infarction had particularly high levels of serum-F.F.A., and we gained the impression that arrhythmias developed more frequently in patients *
Present appointment: physician, Holdsworth Memorial Hospital, Mysore, India. t Present appointment: medical registrar, Harold Wood Hospital, Harold Wood, Essex.
Fig. 1-Distribution of serum-F.F.A. levels in- 100 normal men (fasting) and 200 patients after acute myocardial infarction (maximum recorded levels).
711 with the criteria for normal and abnormal values, has been described by Smith (1967): a level of 80 I.U. per litre was taken as the limit separating myocardial infarction from coronary insufficiency. S.G.O.T. was measured by an autoanalyser adaptation of the method of Reitman and Frankel (1957); a value of 40 Reitman-Frankel units per litre was regarded as the upper limit of normal. Serum-triglycerides were estimated by the method of Carlson (1963) for determination of glyceride-glycerol. Results
Fig. 2-Serum-F.F.A.
response in 50
patients after acute myocardial
infarction.
In all patients three or more serial measurements were obtained: the first was usually not taken in the fasting state. The 95% confidence limits for the control population are shown in broken lines.
Method.-All blood-samples were centrifuged at 1000 g for fifteen minutes within one hour of withdrawal. A lipid extract was prepared without delay using the Trout modification of the Dole procedure (Dole 1956, Trout et al. 1960). Total F.F.A. were then measured from duplicate extracts using a modification (Kurien and Oliver 1966) of the colorimetric method of Mosinger (1965). The mean fasting level in 100 healthy male controls age between eighteen and sixty-two was 521 (±129) .eq. per litre giving an upper 95% confidence limit of 779 eq. per litre. No sex differences in serum-F.F.A. have been observed in our normal population. The controls were mostly members of the medical and laboratory staffs but included non-obese convalescent patients without vascular disease. The patients had normal blood-pressures and were mostly admitted for gastrointestinal diseases, mainly peptic ulceration. The distribution of serum-F.F.A. levels in these controls is shown in fig. 1. Method of expressing results.-Serum-F.F.A. levels reported here are maximum levels obtained; the only exception is the study of serial blood specimens during the first forty-eight hours (fig. 2). Usually the maximum rise after acute myocardial infarction was seen in the first specimen obtained. This observed maximum may be appreciably lower than the real maximum, but short of obtaining blood hourly from each patient, no closer approximation was possible. Other Laboratory Investigations Blood-glucose was measured on a Technicon Autoanalyser’ using a ferri-ferro-cyanide oxidation-reduction reaction. Serum-creatine-kinase was measured by a method based on that of Oliver (1955). The experience using serum-creatinekinase in the Royal Infirmary coronary care unit, together
Serum-F.F.A. Levels In fig. 1 the distribution of maximum observed serumF.F.A. levels from 200 patients with acute myocardial infarction is contrasted with the distribution of fasting serum-F.F.A. levels from 100 healthy male controls. The mean age of the patients (fifty-eight years) was higher than that of the controls (thirty-nine years); no age differences have been observed in our normal population. In fig. 2 the response after acute myocardial infarction is illustrated from serial changes in 50 patients from whom three or more blood specimens were obtained. Most of the specimens taken within the first twelve hours were not obtained in the fasting state since patients were admitted to the coronary care unit at all times during the day or night. Specimens obtained twenty-four or more hours after the onset of symptoms were taken after an overnight fast. The striking elevation of serumF.F.A. levels at six hours after the onset of symptoms compared with the levels at twenty-four hours and fortyeight hours is obvious, but the degree to which serumF.F.A. are elevated during the first six hours is less certain since it has not been possible to make sufficient observations so soon after the onset. For the presentation of results, serum-F.F.A. levels in the 200 patients with acute myocardial infarction have been grouped into four categories of approximately equal numerical size 500-799, 800-999, 1000-1199, and 1200 or more eq. per litre: the highest level recorded was 2186 (.Leq. per litre. The numbers, age, sex, and severity of response to myocardial infarction in each serumF.F.A. group are shown in table i. Unfortunately none of the existing systems for scoring severity take arrhythmias into account adequately, and, since we were primarily concerned with the development of arrhythmias in relation to initial serum-F.F.A. levels, we have restricted our grading of severity to the presence on admission of left ventricular failure (fourth-sound gallop and basal crepitations), congestive failure (jugular venous pressure raised 3 cm. or more), and shock (systolic blood-pressure of less than 90 mm. Hg with patients restless, confused, and sweating). No patient appears more than once in table I. The only significant correlation between severity and serum-F.F.A. was in shocked patients. It is important to emphasise that the presence of left ventricular failure or congestive failure is not significantly associated with or a reliable guide to high serum-F.F.A. levels.
TABLE I-MAXIMUM RECORDED SERUM-F.F.A. LEVELS AND SEVERITY OF MYOCARDIAL INFARCTION
712 TABLE II-MAXIMUM RECORDED SERUM-F.F.A. LEVELS AND ARRHYTHMIAS
TABLE III-MAXIMUM RECORDED SERUM-F.F.A. LEVELS AND DEATHS
Arrhythmias Table 11 shows how the incidence of the major arrhythmias which follow acute myocardial infarction varied with serum-F.F.A. The incidence of all arrhythmias is greater in patients with serum-F.F.A. above 1200 eq. per litre compared with those with lower levels. Two statistical analyses have been performed for each arrhythmia. One is a test of significance comparing the incidence of each arrhythmia in patients with serum-F.F.A. levels of 1200 p-eq. per litre or more with those in patients with lower levels, and the other is a test of homogeneity and shows a progressive increase in arrhythmias from the lowest through to the highest serum-F.F.A. group. The E.c.G.s of all patients were monitored continuously and displayed on oscilloscopes for at least forty-eight hours after admission; but continuous recording was not attempted, so the observed arrhythmias will be an under-
estimate of the time incidence. The term atrial arrhythmias is used to describe persistent or recurring arrhythmias and not just an occasional supraventricular premature beat. We have arbitrarily used v.p.B. to describe ventricular premature beats which occurred at a frequency of four in every ten seconds. In most instances, the knowledge of the arrhythmias was obtained from paper records of the E.C.G., although occasionally we had to rely on the written account of events seen on oscilloscopes. The descriptive terms of primary and complicating ventricular fibrillation (v.F.) or ventricular asystole (v.A.) have been used to describe cardiac arrest occurring unexpectedly in relatively well patients (primary) or in patients already ill from heartfailure or shock (complicating) (Oliver et al. 1967). Patients in terminal cardiac arrest or arrest induced by drugs or catheter electrodes have not been included in these cate-
gories.
TABLE IV-MAXIMUM RECORDED SERUM-CREATINE-KINASE LEVELS AND ARRHYTHMIAS
TABLE V-MAXIMUM RECORDED S.G.O.T. LEVELS AND ARRHYTHMIAS
713
Mortality Table in shows the relation between maximum serumlevel and mortality. Considering all deaths, whether in the coronary care unit or after transfer, significantly 1200 eq. more patients with very high serum-F.F.A. (> per litre) died compared with the rest. While the chief cause of death in the coronary care unit was cardiogenic shock, more deaths from cardiac arrest would have been expected outside an intensive monitoring unit. Thus, there were 18 additional patients with V.F. and 1 with asystole who survived during the period of study as a consequence of admission to the coronary care unit. The relation between high serum-F.F.A. levels and sudden death after transfer from the coronary care unit to general medical wards is also shown in table in. All these late deaths happened unexpectedly between the ninth and twenty-fourth days after admission. In 3 9 of the E.C.G. tracings showed ventricular fibrillation. 12 patients had been allowed out of bed, although only 3 were ambulant at the time of death. F.F.A.
Other
Findings
Neither serum-creatine-kinase nor s.G.o.T. were related to serum-F.F.A. Scatter diagrams were constructed; they showed no correlation. The incidence of arrhythmias is not related to serumcreatine-kinase (table iv ); and, except for high-grade block (P< 0-05), the same is true for s.G.o.T. levels (table v). The mortality-rate was significantly higher in patients with S.G.o.T. levels greater than 120 l.u., both in the coronarycare unit and after transfer (p < 0-005). Fig. 3 shows the serum-F.F.A. and the maximum observed blood-glucose levels (usually non-fasting) for 150 patients. No firm trend can be derived. Of 11
Fig.
3-A scatter diagram showing the relationship of maximum recorded blood-sugar and maximum recorded serum-F.F.A. in 150 patients. 8 patients with blood-sugar levels greater than 148 mg. per 100 ml. died in the coronary care unit and 7 of these deaths were due to
cardiogenic
shock.
deaths in the coronary care unit, 8 patients had bloodglucose levels above 140 mg. per 100 ml. and 7 of these 8 died from cardiogenic shock; this confirms the finding reported by MacKenzie et al. (1964) of hyperglycaemia in cardiogenic shock. Triglyceride levels were estimated on the first fasting serum specimen (see earlier) in most patients in this series. No correlation was evident between serum-triglyceride and serum-F.F.A. levels. We did not attempt to follow serum triglyceride levels serially in order to disclose a late change in relation to initial serum-F.F.A. levels. Discussion
Serious
arrhythmias and both early and late deaths were more common in cases of acute myocardial infarction where serum-F.F.A levels were notably raised. These observations amplify and support our preliminary results (Kurien, Greenwood, and Oliver 1967). Serum-F.F.A. levels and clinical state were not correlated, except for cardiogenic shock which was more common in patients with higher serum-F.F.A. levels; nor were serum-F.F.A levels and the size of the infarct, as estimated by enzyme levels. These findings suggest that measurement of serum-F.F.A. is a new and valuable early predictive index of vulnerability after acute myocardial infarction. We cannot explain the relationship between high serum-F.F.A. levels soon after infarction and late deaths. Most of these late deaths were sudden and unexpected and probably due to arrhythmias. If initially high levels of F.F.A. or of catecholamines sensitise the myocardium to further rises, anxiety, resumption of cigarette smoking and mobilisation may all be adverse influences since they can raise F.F.A. and catecholamines. Elsewhere (Kurien and Oliver 1966) we suggested that myocardial hypoxia and severe pain could be responsible for this rise in serum-F.F.A. by leading to release of noradrenaline from the myocardium and postganglionic sympathetic nerve-endings causing mobilisation of F.F.A. from adipose tissue. Carlson, Boberg, and Hogstedt (1965) have reviewed fully the factors influencing lipid mobilisation from adipose tissue. The speculation that hypoxia rather than myocardial infarction might be the explanation is strengthened by the lack of correlation between serum-F.F.A. levels and serum-creatine-kinase and S.G.o.T. The observation that the prevalence of serious arrhythmias correlated positively with the height of the serum-F.F.A. levels but not with serum-enzyme levels also suggests that it is not the extent of myocardial infarction but the metabolic disturbances resulting from hypoxia and sympathetic stimulation that may lead to serious arrhythmias and death. There are at least two mechanisms through which this relationship between serum-F.F.A. levels and arrhythmias and deaths can be explained. One is stimulation of the hypoxic and infarcted myocardium by increased circulating catecholamines. Another is an increase in myocardial oxygen requirements as a result of the utilisation of increased amounts of circulating F.F.A. as an energy substrate. Both of these explanations require examination. That there is an increase in urinary catecholamine excretion after tissue injury is not in doubt. In patients with severe burns, the degree of urinary excretion of catecholamines estimated by the ethylenediamine method (Birke et al. 1959) and of elevation of serum-F.F.A. (Birke et al. 1965) correlate well with the extent of tissue necrosis.
714
trihydroxyindole method, Wallace (1968) twenty-four-hour urinary excretion in 9 healthy people, in 9 patients with chest pain but no infarction, and in 26 patients for the first ten days after acute myocardial infarction. There was no difference in catecholamine excretion in the first two groups but nearly a fourfold increase during the first twenty-four hours in the myocardial infarct group; during the ten-day period
Using
the measured
catecholamine excretion remained elevated with a stepwise decrease each day. In patients whose myocardial infarction was uncomplicated, the increase in excretion was noradrenaline only. In patients with shock or heart block, the urinary levels of noradrenaline and adrenaline were both increased and there was a greater relative increase in adrenaline; the excretion of both catecholamines was highest in those with heart block. Noradrenaline and adrenaline were most strikingly elevated in those with the highest incidence of serious arrhythmias, but relative values are not given in these patients. This detailed study amplifies the earlier reports by Forssman et al. (1952), Gazes et al. (1959), who studied plasma levels, and Valori et al. (1967). Catecholamine increase after myocardial infarction could come from the myocardium, the postganglionic sympathetic nerve-endings, and the adrenal medulla. There is no evidence to apportion the importance of these three sources, although postganglionic nerve-endings are likely to contribute most to the catecholamine rise. Initially the first source may be the myocardium, which is rich in noradrenaline (a normal-sized heart probably contains between 400 and 600 fLg.). On the basis of the concentrations of intravenous noradrenaline required to raise serum-F.F.A., it can be calculated that depletion of 50% of this store would be sufficient to elevate circulating F.F.A. for about an hour. This depletion probably begins immediately after occlusion and is supplemented soon by catecholamine release from the sympathetic system. It is well known that catecholamines can induce disorders of rhythm after myocardial infarction and increase myocardial oxygen consumption and that prolonged sympathetic stimulation may be harmful to the myocardium (Raab 1966 a, b). Increased catecholamine levels could therefore aggravate the hypoxia of the infarcted myocardium predisposing to arrhythmias and failure. Sympathetic stimulation and catecholamines increase the susceptibility of the ventricles to disorganised behaviour and the likelihood of ectopic beats in the vulnerable period of the cardiac cycle (Daggett and Wallace 1966). Since increased sympathetic activity (Cardon and Gordon 1959) and catecholamines (Dole 1956, Gordon and Cherkes 1956, 1958, Havel and Goldfien 1959) cause mobilisation of F.F.A. from adipose tissue with elevation of circulating albumin-bound F.F.A., the correlation between arrhythmias and elevated serumF.F.A. levels observed in this study may merely be an indirect indication of increased circulating catecholamines. But another explanation of this correlation is that increase in the circulating F.F.A. could in itself lead to arrhythmias. Under normal conditions the myocardium can use up large amounts of F.F.A. as an energy source. Elevated F.F.A. concentrations have been shown, in the isolated perfused rat heart, to increase the oxygen consumption of the myocardium (Challoner and Steinberg 1966). This is independent of flow-rate suggesting a metabolic effect and is accompanied by an increase in extraction and oxidation of F.F.A. (Ballard et al. 1960,
Evans et al. 1963). In an adequately perfused heart with normal oxygen supply, this places no burden on the heart. In conditions of ischxmia, elevated plasma-F.F.A. levels may intensify myocardial hypoxia. This is particularly likely since the extraction of F.F.A. is already increased in myocardial ischasmia (Scheuer and Brachfield 1966). Lipids accumulate in the myocardium of dogs made ischxmic (Scheuer and Brachfield 1966) and after excessive F.F.A. mobilisation by noradrenaline (Carlson, Liljedahl, and Wirsen 1965), and this is probably due to stimulation of triglyceride synthesis as a result of increased F.F.A. levels and extraction. Whether increased catecholamines or F.F.A. or both are responsible for increasing myocardial oxygen requirements soon after acute infarction, the situation is probably aggravated further by an increase in adrenocortical steroids (Klein and Palmer 1963, Logan and Murdoch 1966, Bailey et al. 1967). It is interesting to note that the rise in plasma-hydrocortisone, which may be as much as in patients with Cushing’s syndrome, precedes that of serum-enzymes and is very similar in time to the rise in serum-F.F.A.-viz., within the first twelve hours (Logan and Murdoch 1966). Corticoids can " sensitise" the myocardium to the necrotising effects of catecholamines (Selye 1961), are necessary in dogs for the lipid-mobilising activity of catecholamines (Shafrir and Steinberg 1960), and cause potassium loss from the myocardium (Berger
1966). There are at least three possible therapeutic approaches elevation of serum-F.F.A. after acute myocardial infarction. One is to suppress the stimuli responsible by attempting to block noradrenaline release. Suppression of sympathetic stimuli, while achieved easily by3 or blocking drugs, may be clinically disastrous because it could deprive the myocardium of the inotropic and chronotropic effects indispensable after acute myocardial damage. Another is to block the release of F.F.A. from adipose tissue by nicotinic acid, but this might also tilt the balance hxmodynamically against survival by decreasing peripheral resistance. A third approach, and perhaps the most promising, is to present the hypoxic myocardium with a source of energy which will not increase oxygen requirements to the same degree, namely an adequate and continuous supply of glucose. We thank Mr. W. Lutz, senior lecturer in statistics, department of social medicine, for undertaking the statistical analysis; Prof. L. G. Whitby for advice and providing laboratory help; Mrs. Sandra Conrad, Miss Janice Yuill, and Mr. T. Healy for skilled technical assistance; and the medical and nursing staff of the coronary care unit. This research programme has been supported by a grant to
from the Scottish Hospital Endowments Research Trust. Requests for reprints should be addressed to M. F. 0., ment of Cardiology, Royal Infirmary, Edinburgh 3.
Depart-
REFERENCES
Bailey, R. R., Abernethy, M. H., Beaven, D. W. (1967) Lancet, i, 970. Ballard, F. B., Dandorth, W. H., Naegle, S., Bing, R. J. (1960) J. clin. Invest. 39, 717. Berger, H. (1966) in Electrolytes and Cardiovascular Diseases (edited by E. Bajusz); vol. II, p. 17. Basle. Birke, G., Carlson, L. A., Liljedahl, S-O. (1965) Acta med. scand. 178, 337. Liljedahl, S-O., Linderholm, H. (1959) Acta chir. scand. 114, 87. Cardon, P. V., Gordon, R. S. (1959) J. psychosom. Res. 4, 5. Carlson, L. A. (1963) J. Atheroscler. Res. 3, 334. Boberg, J., Hogstedt, B. (1965) in Adipose Tissue (edited by A. E. Renold and G. F. Cahill). Handbook of Physiology, section 5, p. 625. Liljedahl, S-O., Wirsen, C. (1965) Acta med. scand. 17, 81. Challoner, D. R., Steinberg, D. (1966) Am. J. Physiol. 210, 280. Daggett, W. H., Wallace, A. G. (1966) in Mechanisms and Therapy of Cardiac Arrhythmias (edited by L. S. Dreifus and W. Likoff); p. 64. —
—
—
New York.
Dole, V. P. (1956) J. clin. Invest. 35, 150. Evans, J. R., Opie, L. H., Shipp, J. C. (1963) Am. J. Physiol. 205, 766.
References continued
at
foot of next column
715
BONE DISEASE AND CALCIUM ABSORPTION IN PRIMARY BILIARY CIRRHOSIS With
Special Reference *
to
Vitamin-D
Therapy
M.D. Athens
C. D. HOLDSWORTH &dag er; M.D. Leeds, M.R.C.P.
RESEARCH FELLOW
LECTURER IN MEDICINE
A. K. KEHAYOGLOU
B.A. Cantab., M.Sc. Lond.
M. J. WHELTON M.B., B.Sc. N.U.I., M.R.C.P.,
ASSISTANT PHYSICIST
MEDICAL REGISTRAR
J. E. AGNEW
M.R.C.P.I.
SHEILA SHERLOCK M.D. Edin., F.R.C.P., F.R.C.P.E., F.A.C.P. (Hon.) From the
Department of Medicine and Hospital Physics, Royal Free Hospital, London W.C.1
Calcium absorption and bone disease have been investigated in twelve patients with primary biliary cirrhosis before and after treatment with intramuscular vitamin D. Calcium absorption measured by whole-body retention of calcium-47 after oral calcium-47 as chloride in water correlated well with estimation of absorption by plasma-levels of calcium-47. Before treatment, calcium absorption was subnormal in four patients. Impairment correlated well with the intensity of jaundice and less well with the fæcal-fat excretion. Absorption of aqueous calcium-47 chloride was normal when measured either between 1 and 3 months or after 12 months of vitamin-D treatment. Crush fractures of vertebræ were present in four patients, but none of the twelve had radiological signs of osteomalacia. Bone-biopsy specimens showed osteomalacia in only one of the twelve patients but seven excreted an abnormally low percentage of infused calcium and may have had early osteomalacia. After 1-3 months of treatment with vitamin D, calcium-infusion tests remained abnormal, but after 12 months were restored to normal in each of five patients on whom they were done. In spite of
Summary
*
Present address: University Clinic of Therapeutics, Alexandria Hospital, Athens, Greece. † Present address: Dunn Laboratories, Department of Medicine, St. Bartholomew’s Hospital, London E.C.1.
DR. OLIVER AND OTHERS:
REFERENCES—Continued
Forssman, O., Hansson, G., Jensen, C. C. (1952) Acta med. scand. 142, 441. Gazes, P. C., Richardson, J. A., Woods, E. F. (1959) Circulation, 19, 657. Gordon, R. S., Cherkes, A. (1956) J. clin. Invest. 35, 206. (1958) Proc. Soc. exp. Biol. Med. 102, 527. Havel, R. J., Goldfien, A. (1959) J. Lipid Res. 1, 102. Klein, A. J., Palmer, L. A. (1963) Am. J. Cardiol. 11, 332. Kurien, V. A., Greenwood, T. W., Oliver, M. F. (1967) Br. Heart J. 29, —
—
628.
Oliver, M. F. (1966) Lancet, ii, 122. Lawrie, D. M., Greenwood, T. W., Goddard, M. D., Harvey, A. C., Donald, K. W., Julian, D. G., Oliver, M. F. (1967) ibid. ii, 109. Logan, R. W., Murdoch, W. R. (1966) ibid. ii, 521. MacKenzie, G. J., Taylor, S. H., Flenley, D. C., MacDonald, A. H., Staunton, H. P., Donald, K. W. (1964) ibid. ii, 825. Mosinger, F. (1965) J. Lipid Res. 6, 157. Oliver, I. T. (1955) Biochem. J. 61, 116. Oliver, M. F., Julian, D. G., Donald, K. W. (1967) Am. J. Cardiol. 20, 465 Raab, W. (1966a) Prevention of Ischemic Heart Disease. Springfield, —
Illinois.
(1966b) Am. Heart. J. 72, 538. Reitman, S., Frankel, S. (1957) Am. J. clin. Path. 28, 56. Rose, G. A., Blackburn, H. A. (1966). Cardiovascular Population Studies. W.H.O., Geneva. Scheuer, J., Brachfield, N. (1966) Metabolism, 15, 945. Selye, H. (1961) The Pluricausal Cardiopathies. Springfield, Illinois. Shafrir, E., Steinberg, D. (1960) J. clin. Invest. 39, 310. Smith, A. F. (1967) Lancet, ii, 178. Trout, D. L., Estes, E. H., Friedberg, S. J. (1960) J. Lipid Res. 1, 199. Valori, C., Thomas, M., Shillingford, J. P. (1967) Lancet, i, 127. Wallace, A. G. (1968) in Acute Myocardial Infarction (edited by D. G. Julian and M. F. Oliver). Edinburgh (in the press). —
this, further bone fractures developed in three patients. Although vitamin-D therapy repairs the defective absorption of a soluble calcium salt, and prevents osteomalacia, it does not halt the progression of bone disease in
patients with primary biliary cirrhosis. Introduction
BoNE disease has been noted in patients with prolonged biliary obstruction and biliary cirrhosis (Atkinson, Nordin, and Sherlock 1956) but it is not clear whether the thinning is due to osteoporosis or to osteomalacia. Among the twenty-five patients studied by Atkinson, Nordin, and Sherlock (1956) seven had osteomalacia, three seemed to have osteoporosis alone, and two had both conditions. Bone thinning may also be noted in patients with other types of cirrhosis, osteoporosis being much more frequent than osteomalacia (Lichtwitz et al. 1959, Huguenin et al.
1960).
Osteoporosis and osteomalacia must be distinguished since the setiology and treatment are completely different. Osteomalacia is characterised biochemically by a low serum Ca x P product, by a raised serum-alkalinephosphatase, and histologically by wide osteoid seams. Osteoporosis, on the other hand, is a disease of unknown aetiology: there is no evident biochemical disorder, and histologically, the bone trabeculse are thinned. In practice, osteoporosis and osteomalacia often coexist, particularly in patients with malabsorption (Badenoch 1960, Deller et al. 1963). Although differential diagnosis depends ultimately on the bone histology even this can be confusing (Morgan et al. 1965). Bone disease might develop for several reasons in patients with hepatobiliary disorders. Bile salts are essential for the absorption of vitamin D (Schachter et al. 1964) and in obstructive jaundice lack of this vitamin would result in osteomalacia. In addition, bile-salt deficiency could allow insoluble calcium soaps of unabsorbed fatty acids to form in the small bowel lumen so making dietary calcium unavailable for absorption (Kehayoglou, Williams, Whimster, and Holdsworth 1968). Thirdly, bile salts may directly stimulate calcium absorption (Webling and Holdsworth 1965). Calcium absorption has been measured in a number of patients with liver disease. To reduce the number of variables, only one type of cholestasis, namely primary biliary cirrhosis, has been studied. For the same reason, calcium chloride was given in water and without any fat so that malabsorption could not be due solely to impaired fat absorption and to consequent formation of calcium soaps. In addition the degree and type of bone disease has been defined and correlated with the clinical severity of the hepatic disease and with the degree of impairment of calcium absorption. The effect of short and long-term vitamin-D therapy has also been investigated. Patients and Methods The twelve patients with primary biliary cirrhosis were all female (table i). Their ages ranged from 39 to 68 years and the duration of illness was from 9 months to 4 years. The diagnosis was made according to clinical criteria and liver histology, together with serological tests (Sherlock 1963, Walker, Doniach, Roitt, and Sherlock 1965). Pruritus was constant and in seven patients had preceded the jaundice. Serum-bilirubin levels were always elevated. No patient was in hepatic coma or precoma or had ascites. Five patients (nos. 1, 2, 4, 6, and 10) had xanthomas. Only 1 patient (case 1) complained of bone pain and tenderness. Patients 1-7 and patient 10 had lost weight. Initially, none of the patients
RELATION BETWEEN SERUM-FREE-FATTYACIDS AND ARRHYTHMIAS AND DEATH AFTER ACUTE MYOCARDIAL INFARCTION M.D.
M. F. OLIVER Edin., F.R.C.P.E., M.R.C.P.
PHYSICIAN, ROYAL INFIRMARY, EDINBURGH, AND SENIOR LECTURER IN MEDICINE, UNIVERSITY OF EDINBURGH
CONSULTANT
V. A. KURIEN Mysore, M.R.C.P.E.
M.B. Edin., B.Sc.
SENIOR HOUSE-OFFICER, ROYAL INFIRMARY,
EDINBURGH *
T. W. GREENWOOD M.A., M.B. Cantab. SENIOR
HOUSE-OFFICER, CORONARY CARE UNIT, INFIRMARY, EDINBURGH †
ROYAL
From the Departments of Cardiology and Clinical Chemistry, and the Coronary Care Unit, Royal Infirmary, Edinburgh 3
Serum-free-fatty-acid (F.F.A.) levels measured in 200 patients during the first fortyeight hours after an acute myocardial infarction have been related to the prevalence of arrhythmias detected by continuous monitoring of the electrocardiogram, to the clinical state of the patients, and to serum-enzyme and blood-glucose levels. Maximum elevation of serum F.F.A. occurred within four to eight hours in most patients after acute myocardial infarction. Those with a striking elevation (above 1200 µeq. per litre) had an increased prevalence of serious arrhythmias and disorders of conduction. Both early and late deaths were more frequent among these patients compared with those with less elevated levels. There was no correlation between serum-F.F.A. and the clinical state of the patients, except for cardiogenic shock; nor between serum-F.F.A. and serum-creatine-kinase or serum-aspartate-aminotransferase levels; nor between these serum-enzyme levels and the prevalence of arrhythmias. Serum-F.F.A. and bloodglucose levels did not show significant correlation, except in cardiogenic shock. It is concluded that measurement of serum-F.F.A. is a new and valuable early predictive index of the vulnerability of patients with acute myocardial infarction to serious arrhythmias. This relationship between serum-F.F.A. levels and arrhythmias could result from increased catecholamine activity, particularly that of noradrenaline, or it could be due directly to an increase in myocardial oxygen consumption caused by the utilisation of F.F.A. as the major energy substrate. Both mechanisms would intensify myocardial hypoxia in an already ischæmic heart. Summary
with very high serum-F.F.A. levels. Therefore, the present study was established in order to examine whether there is any relationship in patients with acute myocardial infarction between serum-F.F.A. levels and arrhythmias and death. Patients and Methods Selection of Patients The clinical material consisted of 200 patients admitted with acute myocardial infarction to the coronary care unit of the Royal Infirmary of Edinburgh. The electrocardiogram (E.C.G.) of each patient was monitored continuously by a SanbomVisomonitor ’ and on an oscilloscope from the time of admission for at least forty-eight hours, according to the policy of the coronary care unit (Lawrie, Greenwood, Goddard, Harvey, Donald, Julian, and Oliver 1967, Oliver et al. 1967). A permanent record could be made at any time and a strip was recorded automatically at least hourly and often half or quarter hourly. Male and female patients were accepted into the series on a consecutive basis providing they conformed to the following criteria:
(1) Age under seventy. (2) Onset of symptoms within the preceding twenty-four hours. (3) E.C.G. signs of myocardial infarction. The Minnesota code (Rose and Blackburn 1966) was used for classifying electrocardiograms and categories 1-1, 1-2, 1-3 with 4-1 or 5-1, and 7-1 were accepted. (4) Elevation of either serum-creatine-kinase (C.K.) or serumaspartate-aminotransferase (S.G.O.T.), or both. (5) No pre-existing diabetes mellitus. (6) No prior administration of heparin, catecholamines, steroids, antihypertensive drugs, or clofibrate (’ Atromid-S ’), all of which can influence serum-levels of F.F.A. (7) An arrhythmia was not known to have preceded the first venepuncture for serum-F.F.A. analysis. Patients with high-grade block on admission were included provided they had no preceding or associated tachycardia. (8) Serial serum-F.F.A. estimations were obtained according to the requirements described below.
Serum-F.F.A. Estimations Requirements.-One blood specimen had to be obtained within twenty-four hours of the onset of symptoms of acute myocardial infarction: this was usually not a fasting specimen unless the patient had been admitted during the night. A second blood specimen had to be obtained in the fasting state on the morning after admission. Usually three specimens were obtained from each patient and the first two were taken within twenty-four hours of the onset of symptoms. A patient from whom a single blood specimen was taken was accepted only if he had died before a second specimen could be obtained.
Introduction
SERUM-LEVELS of free-fatty-acids (F.F.A.) are elevated after acute myocardial infarction (Kurien and Oliver 1966). This rise is more than after a meal, whether predominantly fatty or carbohydrate in content, or after prolonged fasting. It is not due to the anxiety and stress of being admitted to hospital as an emergency, and is only partly related to pain. We suggested that it is most probably a consequence of mobilisation of F.F.A. from adipose tissue by noradrenaline (Kurien and Oliver 1966). During the course of this earlier work, a few patients who died after acute myocardial infarction had particularly high levels of serum-F.F.A., and we gained the impression that arrhythmias developed more frequently in patients *
Present appointment: physician, Holdsworth Memorial Hospital, Mysore, India. t Present appointment: medical registrar, Harold Wood Hospital, Harold Wood, Essex.
Fig. 1-Distribution of serum-F.F.A. levels in- 100 normal men (fasting) and 200 patients after acute myocardial infarction (maximum recorded levels).
711 with the criteria for normal and abnormal values, has been described by Smith (1967): a level of 80 I.U. per litre was taken as the limit separating myocardial infarction from coronary insufficiency. S.G.O.T. was measured by an autoanalyser adaptation of the method of Reitman and Frankel (1957); a value of 40 Reitman-Frankel units per litre was regarded as the upper limit of normal. Serum-triglycerides were estimated by the method of Carlson (1963) for determination of glyceride-glycerol. Results
Fig. 2-Serum-F.F.A.
response in 50
patients after acute myocardial
infarction.
In all patients three or more serial measurements were obtained: the first was usually not taken in the fasting state. The 95% confidence limits for the control population are shown in broken lines.
Method.-All blood-samples were centrifuged at 1000 g for fifteen minutes within one hour of withdrawal. A lipid extract was prepared without delay using the Trout modification of the Dole procedure (Dole 1956, Trout et al. 1960). Total F.F.A. were then measured from duplicate extracts using a modification (Kurien and Oliver 1966) of the colorimetric method of Mosinger (1965). The mean fasting level in 100 healthy male controls age between eighteen and sixty-two was 521 (±129) .eq. per litre giving an upper 95% confidence limit of 779 eq. per litre. No sex differences in serum-F.F.A. have been observed in our normal population. The controls were mostly members of the medical and laboratory staffs but included non-obese convalescent patients without vascular disease. The patients had normal blood-pressures and were mostly admitted for gastrointestinal diseases, mainly peptic ulceration. The distribution of serum-F.F.A. levels in these controls is shown in fig. 1. Method of expressing results.-Serum-F.F.A. levels reported here are maximum levels obtained; the only exception is the study of serial blood specimens during the first forty-eight hours (fig. 2). Usually the maximum rise after acute myocardial infarction was seen in the first specimen obtained. This observed maximum may be appreciably lower than the real maximum, but short of obtaining blood hourly from each patient, no closer approximation was possible. Other Laboratory Investigations Blood-glucose was measured on a Technicon Autoanalyser’ using a ferri-ferro-cyanide oxidation-reduction reaction. Serum-creatine-kinase was measured by a method based on that of Oliver (1955). The experience using serum-creatinekinase in the Royal Infirmary coronary care unit, together
Serum-F.F.A. Levels In fig. 1 the distribution of maximum observed serumF.F.A. levels from 200 patients with acute myocardial infarction is contrasted with the distribution of fasting serum-F.F.A. levels from 100 healthy male controls. The mean age of the patients (fifty-eight years) was higher than that of the controls (thirty-nine years); no age differences have been observed in our normal population. In fig. 2 the response after acute myocardial infarction is illustrated from serial changes in 50 patients from whom three or more blood specimens were obtained. Most of the specimens taken within the first twelve hours were not obtained in the fasting state since patients were admitted to the coronary care unit at all times during the day or night. Specimens obtained twenty-four or more hours after the onset of symptoms were taken after an overnight fast. The striking elevation of serumF.F.A. levels at six hours after the onset of symptoms compared with the levels at twenty-four hours and fortyeight hours is obvious, but the degree to which serumF.F.A. are elevated during the first six hours is less certain since it has not been possible to make sufficient observations so soon after the onset. For the presentation of results, serum-F.F.A. levels in the 200 patients with acute myocardial infarction have been grouped into four categories of approximately equal numerical size 500-799, 800-999, 1000-1199, and 1200 or more eq. per litre: the highest level recorded was 2186 (.Leq. per litre. The numbers, age, sex, and severity of response to myocardial infarction in each serumF.F.A. group are shown in table i. Unfortunately none of the existing systems for scoring severity take arrhythmias into account adequately, and, since we were primarily concerned with the development of arrhythmias in relation to initial serum-F.F.A. levels, we have restricted our grading of severity to the presence on admission of left ventricular failure (fourth-sound gallop and basal crepitations), congestive failure (jugular venous pressure raised 3 cm. or more), and shock (systolic blood-pressure of less than 90 mm. Hg with patients restless, confused, and sweating). No patient appears more than once in table I. The only significant correlation between severity and serum-F.F.A. was in shocked patients. It is important to emphasise that the presence of left ventricular failure or congestive failure is not significantly associated with or a reliable guide to high serum-F.F.A. levels.
TABLE I-MAXIMUM RECORDED SERUM-F.F.A. LEVELS AND SEVERITY OF MYOCARDIAL INFARCTION
712 TABLE II-MAXIMUM RECORDED SERUM-F.F.A. LEVELS AND ARRHYTHMIAS
TABLE III-MAXIMUM RECORDED SERUM-F.F.A. LEVELS AND DEATHS
Arrhythmias Table 11 shows how the incidence of the major arrhythmias which follow acute myocardial infarction varied with serum-F.F.A. The incidence of all arrhythmias is greater in patients with serum-F.F.A. above 1200 eq. per litre compared with those with lower levels. Two statistical analyses have been performed for each arrhythmia. One is a test of significance comparing the incidence of each arrhythmia in patients with serum-F.F.A. levels of 1200 p-eq. per litre or more with those in patients with lower levels, and the other is a test of homogeneity and shows a progressive increase in arrhythmias from the lowest through to the highest serum-F.F.A. group. The E.c.G.s of all patients were monitored continuously and displayed on oscilloscopes for at least forty-eight hours after admission; but continuous recording was not attempted, so the observed arrhythmias will be an under-
estimate of the time incidence. The term atrial arrhythmias is used to describe persistent or recurring arrhythmias and not just an occasional supraventricular premature beat. We have arbitrarily used v.p.B. to describe ventricular premature beats which occurred at a frequency of four in every ten seconds. In most instances, the knowledge of the arrhythmias was obtained from paper records of the E.C.G., although occasionally we had to rely on the written account of events seen on oscilloscopes. The descriptive terms of primary and complicating ventricular fibrillation (v.F.) or ventricular asystole (v.A.) have been used to describe cardiac arrest occurring unexpectedly in relatively well patients (primary) or in patients already ill from heartfailure or shock (complicating) (Oliver et al. 1967). Patients in terminal cardiac arrest or arrest induced by drugs or catheter electrodes have not been included in these cate-
gories.
TABLE IV-MAXIMUM RECORDED SERUM-CREATINE-KINASE LEVELS AND ARRHYTHMIAS
TABLE V-MAXIMUM RECORDED S.G.O.T. LEVELS AND ARRHYTHMIAS
713
Mortality Table in shows the relation between maximum serumlevel and mortality. Considering all deaths, whether in the coronary care unit or after transfer, significantly 1200 eq. more patients with very high serum-F.F.A. (> per litre) died compared with the rest. While the chief cause of death in the coronary care unit was cardiogenic shock, more deaths from cardiac arrest would have been expected outside an intensive monitoring unit. Thus, there were 18 additional patients with V.F. and 1 with asystole who survived during the period of study as a consequence of admission to the coronary care unit. The relation between high serum-F.F.A. levels and sudden death after transfer from the coronary care unit to general medical wards is also shown in table in. All these late deaths happened unexpectedly between the ninth and twenty-fourth days after admission. In 3 9 of the E.C.G. tracings showed ventricular fibrillation. 12 patients had been allowed out of bed, although only 3 were ambulant at the time of death. F.F.A.
Other
Findings
Neither serum-creatine-kinase nor s.G.o.T. were related to serum-F.F.A. Scatter diagrams were constructed; they showed no correlation. The incidence of arrhythmias is not related to serumcreatine-kinase (table iv ); and, except for high-grade block (P< 0-05), the same is true for s.G.o.T. levels (table v). The mortality-rate was significantly higher in patients with S.G.o.T. levels greater than 120 l.u., both in the coronarycare unit and after transfer (p < 0-005). Fig. 3 shows the serum-F.F.A. and the maximum observed blood-glucose levels (usually non-fasting) for 150 patients. No firm trend can be derived. Of 11
Fig.
3-A scatter diagram showing the relationship of maximum recorded blood-sugar and maximum recorded serum-F.F.A. in 150 patients. 8 patients with blood-sugar levels greater than 148 mg. per 100 ml. died in the coronary care unit and 7 of these deaths were due to
cardiogenic
shock.
deaths in the coronary care unit, 8 patients had bloodglucose levels above 140 mg. per 100 ml. and 7 of these 8 died from cardiogenic shock; this confirms the finding reported by MacKenzie et al. (1964) of hyperglycaemia in cardiogenic shock. Triglyceride levels were estimated on the first fasting serum specimen (see earlier) in most patients in this series. No correlation was evident between serum-triglyceride and serum-F.F.A. levels. We did not attempt to follow serum triglyceride levels serially in order to disclose a late change in relation to initial serum-F.F.A. levels. Discussion
Serious
arrhythmias and both early and late deaths were more common in cases of acute myocardial infarction where serum-F.F.A levels were notably raised. These observations amplify and support our preliminary results (Kurien, Greenwood, and Oliver 1967). Serum-F.F.A. levels and clinical state were not correlated, except for cardiogenic shock which was more common in patients with higher serum-F.F.A. levels; nor were serum-F.F.A levels and the size of the infarct, as estimated by enzyme levels. These findings suggest that measurement of serum-F.F.A. is a new and valuable early predictive index of vulnerability after acute myocardial infarction. We cannot explain the relationship between high serum-F.F.A. levels soon after infarction and late deaths. Most of these late deaths were sudden and unexpected and probably due to arrhythmias. If initially high levels of F.F.A. or of catecholamines sensitise the myocardium to further rises, anxiety, resumption of cigarette smoking and mobilisation may all be adverse influences since they can raise F.F.A. and catecholamines. Elsewhere (Kurien and Oliver 1966) we suggested that myocardial hypoxia and severe pain could be responsible for this rise in serum-F.F.A. by leading to release of noradrenaline from the myocardium and postganglionic sympathetic nerve-endings causing mobilisation of F.F.A. from adipose tissue. Carlson, Boberg, and Hogstedt (1965) have reviewed fully the factors influencing lipid mobilisation from adipose tissue. The speculation that hypoxia rather than myocardial infarction might be the explanation is strengthened by the lack of correlation between serum-F.F.A. levels and serum-creatine-kinase and S.G.o.T. The observation that the prevalence of serious arrhythmias correlated positively with the height of the serum-F.F.A. levels but not with serum-enzyme levels also suggests that it is not the extent of myocardial infarction but the metabolic disturbances resulting from hypoxia and sympathetic stimulation that may lead to serious arrhythmias and death. There are at least two mechanisms through which this relationship between serum-F.F.A. levels and arrhythmias and deaths can be explained. One is stimulation of the hypoxic and infarcted myocardium by increased circulating catecholamines. Another is an increase in myocardial oxygen requirements as a result of the utilisation of increased amounts of circulating F.F.A. as an energy substrate. Both of these explanations require examination. That there is an increase in urinary catecholamine excretion after tissue injury is not in doubt. In patients with severe burns, the degree of urinary excretion of catecholamines estimated by the ethylenediamine method (Birke et al. 1959) and of elevation of serum-F.F.A. (Birke et al. 1965) correlate well with the extent of tissue necrosis.
714
trihydroxyindole method, Wallace (1968) twenty-four-hour urinary excretion in 9 healthy people, in 9 patients with chest pain but no infarction, and in 26 patients for the first ten days after acute myocardial infarction. There was no difference in catecholamine excretion in the first two groups but nearly a fourfold increase during the first twenty-four hours in the myocardial infarct group; during the ten-day period
Using
the measured
catecholamine excretion remained elevated with a stepwise decrease each day. In patients whose myocardial infarction was uncomplicated, the increase in excretion was noradrenaline only. In patients with shock or heart block, the urinary levels of noradrenaline and adrenaline were both increased and there was a greater relative increase in adrenaline; the excretion of both catecholamines was highest in those with heart block. Noradrenaline and adrenaline were most strikingly elevated in those with the highest incidence of serious arrhythmias, but relative values are not given in these patients. This detailed study amplifies the earlier reports by Forssman et al. (1952), Gazes et al. (1959), who studied plasma levels, and Valori et al. (1967). Catecholamine increase after myocardial infarction could come from the myocardium, the postganglionic sympathetic nerve-endings, and the adrenal medulla. There is no evidence to apportion the importance of these three sources, although postganglionic nerve-endings are likely to contribute most to the catecholamine rise. Initially the first source may be the myocardium, which is rich in noradrenaline (a normal-sized heart probably contains between 400 and 600 fLg.). On the basis of the concentrations of intravenous noradrenaline required to raise serum-F.F.A., it can be calculated that depletion of 50% of this store would be sufficient to elevate circulating F.F.A. for about an hour. This depletion probably begins immediately after occlusion and is supplemented soon by catecholamine release from the sympathetic system. It is well known that catecholamines can induce disorders of rhythm after myocardial infarction and increase myocardial oxygen consumption and that prolonged sympathetic stimulation may be harmful to the myocardium (Raab 1966 a, b). Increased catecholamine levels could therefore aggravate the hypoxia of the infarcted myocardium predisposing to arrhythmias and failure. Sympathetic stimulation and catecholamines increase the susceptibility of the ventricles to disorganised behaviour and the likelihood of ectopic beats in the vulnerable period of the cardiac cycle (Daggett and Wallace 1966). Since increased sympathetic activity (Cardon and Gordon 1959) and catecholamines (Dole 1956, Gordon and Cherkes 1956, 1958, Havel and Goldfien 1959) cause mobilisation of F.F.A. from adipose tissue with elevation of circulating albumin-bound F.F.A., the correlation between arrhythmias and elevated serumF.F.A. levels observed in this study may merely be an indirect indication of increased circulating catecholamines. But another explanation of this correlation is that increase in the circulating F.F.A. could in itself lead to arrhythmias. Under normal conditions the myocardium can use up large amounts of F.F.A. as an energy source. Elevated F.F.A. concentrations have been shown, in the isolated perfused rat heart, to increase the oxygen consumption of the myocardium (Challoner and Steinberg 1966). This is independent of flow-rate suggesting a metabolic effect and is accompanied by an increase in extraction and oxidation of F.F.A. (Ballard et al. 1960,
Evans et al. 1963). In an adequately perfused heart with normal oxygen supply, this places no burden on the heart. In conditions of ischxmia, elevated plasma-F.F.A. levels may intensify myocardial hypoxia. This is particularly likely since the extraction of F.F.A. is already increased in myocardial ischasmia (Scheuer and Brachfield 1966). Lipids accumulate in the myocardium of dogs made ischxmic (Scheuer and Brachfield 1966) and after excessive F.F.A. mobilisation by noradrenaline (Carlson, Liljedahl, and Wirsen 1965), and this is probably due to stimulation of triglyceride synthesis as a result of increased F.F.A. levels and extraction. Whether increased catecholamines or F.F.A. or both are responsible for increasing myocardial oxygen requirements soon after acute infarction, the situation is probably aggravated further by an increase in adrenocortical steroids (Klein and Palmer 1963, Logan and Murdoch 1966, Bailey et al. 1967). It is interesting to note that the rise in plasma-hydrocortisone, which may be as much as in patients with Cushing’s syndrome, precedes that of serum-enzymes and is very similar in time to the rise in serum-F.F.A.-viz., within the first twelve hours (Logan and Murdoch 1966). Corticoids can " sensitise" the myocardium to the necrotising effects of catecholamines (Selye 1961), are necessary in dogs for the lipid-mobilising activity of catecholamines (Shafrir and Steinberg 1960), and cause potassium loss from the myocardium (Berger
1966). There are at least three possible therapeutic approaches elevation of serum-F.F.A. after acute myocardial infarction. One is to suppress the stimuli responsible by attempting to block noradrenaline release. Suppression of sympathetic stimuli, while achieved easily by3 or blocking drugs, may be clinically disastrous because it could deprive the myocardium of the inotropic and chronotropic effects indispensable after acute myocardial damage. Another is to block the release of F.F.A. from adipose tissue by nicotinic acid, but this might also tilt the balance hxmodynamically against survival by decreasing peripheral resistance. A third approach, and perhaps the most promising, is to present the hypoxic myocardium with a source of energy which will not increase oxygen requirements to the same degree, namely an adequate and continuous supply of glucose. We thank Mr. W. Lutz, senior lecturer in statistics, department of social medicine, for undertaking the statistical analysis; Prof. L. G. Whitby for advice and providing laboratory help; Mrs. Sandra Conrad, Miss Janice Yuill, and Mr. T. Healy for skilled technical assistance; and the medical and nursing staff of the coronary care unit. This research programme has been supported by a grant to
from the Scottish Hospital Endowments Research Trust. Requests for reprints should be addressed to M. F. 0., ment of Cardiology, Royal Infirmary, Edinburgh 3.
Depart-
REFERENCES
Bailey, R. R., Abernethy, M. H., Beaven, D. W. (1967) Lancet, i, 970. Ballard, F. B., Dandorth, W. H., Naegle, S., Bing, R. J. (1960) J. clin. Invest. 39, 717. Berger, H. (1966) in Electrolytes and Cardiovascular Diseases (edited by E. Bajusz); vol. II, p. 17. Basle. Birke, G., Carlson, L. A., Liljedahl, S-O. (1965) Acta med. scand. 178, 337. Liljedahl, S-O., Linderholm, H. (1959) Acta chir. scand. 114, 87. Cardon, P. V., Gordon, R. S. (1959) J. psychosom. Res. 4, 5. Carlson, L. A. (1963) J. Atheroscler. Res. 3, 334. Boberg, J., Hogstedt, B. (1965) in Adipose Tissue (edited by A. E. Renold and G. F. Cahill). Handbook of Physiology, section 5, p. 625. Liljedahl, S-O., Wirsen, C. (1965) Acta med. scand. 17, 81. Challoner, D. R., Steinberg, D. (1966) Am. J. Physiol. 210, 280. Daggett, W. H., Wallace, A. G. (1966) in Mechanisms and Therapy of Cardiac Arrhythmias (edited by L. S. Dreifus and W. Likoff); p. 64. —
—
—
New York.
Dole, V. P. (1956) J. clin. Invest. 35, 150. Evans, J. R., Opie, L. H., Shipp, J. C. (1963) Am. J. Physiol. 205, 766.
References continued
at
foot of next column
715
BONE DISEASE AND CALCIUM ABSORPTION IN PRIMARY BILIARY CIRRHOSIS With
Special Reference *
to
Vitamin-D
Therapy
M.D. Athens
C. D. HOLDSWORTH &dag er; M.D. Leeds, M.R.C.P.
RESEARCH FELLOW
LECTURER IN MEDICINE
A. K. KEHAYOGLOU
B.A. Cantab., M.Sc. Lond.
M. J. WHELTON M.B., B.Sc. N.U.I., M.R.C.P.,
ASSISTANT PHYSICIST
MEDICAL REGISTRAR
J. E. AGNEW
M.R.C.P.I.
SHEILA SHERLOCK M.D. Edin., F.R.C.P., F.R.C.P.E., F.A.C.P. (Hon.) From the
Department of Medicine and Hospital Physics, Royal Free Hospital, London W.C.1
Calcium absorption and bone disease have been investigated in twelve patients with primary biliary cirrhosis before and after treatment with intramuscular vitamin D. Calcium absorption measured by whole-body retention of calcium-47 after oral calcium-47 as chloride in water correlated well with estimation of absorption by plasma-levels of calcium-47. Before treatment, calcium absorption was subnormal in four patients. Impairment correlated well with the intensity of jaundice and less well with the fæcal-fat excretion. Absorption of aqueous calcium-47 chloride was normal when measured either between 1 and 3 months or after 12 months of vitamin-D treatment. Crush fractures of vertebræ were present in four patients, but none of the twelve had radiological signs of osteomalacia. Bone-biopsy specimens showed osteomalacia in only one of the twelve patients but seven excreted an abnormally low percentage of infused calcium and may have had early osteomalacia. After 1-3 months of treatment with vitamin D, calcium-infusion tests remained abnormal, but after 12 months were restored to normal in each of five patients on whom they were done. In spite of
Summary
*
Present address: University Clinic of Therapeutics, Alexandria Hospital, Athens, Greece. † Present address: Dunn Laboratories, Department of Medicine, St. Bartholomew’s Hospital, London E.C.1.
DR. OLIVER AND OTHERS:
REFERENCES—Continued
Forssman, O., Hansson, G., Jensen, C. C. (1952) Acta med. scand. 142, 441. Gazes, P. C., Richardson, J. A., Woods, E. F. (1959) Circulation, 19, 657. Gordon, R. S., Cherkes, A. (1956) J. clin. Invest. 35, 206. (1958) Proc. Soc. exp. Biol. Med. 102, 527. Havel, R. J., Goldfien, A. (1959) J. Lipid Res. 1, 102. Klein, A. J., Palmer, L. A. (1963) Am. J. Cardiol. 11, 332. Kurien, V. A., Greenwood, T. W., Oliver, M. F. (1967) Br. Heart J. 29, —
—
628.
Oliver, M. F. (1966) Lancet, ii, 122. Lawrie, D. M., Greenwood, T. W., Goddard, M. D., Harvey, A. C., Donald, K. W., Julian, D. G., Oliver, M. F. (1967) ibid. ii, 109. Logan, R. W., Murdoch, W. R. (1966) ibid. ii, 521. MacKenzie, G. J., Taylor, S. H., Flenley, D. C., MacDonald, A. H., Staunton, H. P., Donald, K. W. (1964) ibid. ii, 825. Mosinger, F. (1965) J. Lipid Res. 6, 157. Oliver, I. T. (1955) Biochem. J. 61, 116. Oliver, M. F., Julian, D. G., Donald, K. W. (1967) Am. J. Cardiol. 20, 465 Raab, W. (1966a) Prevention of Ischemic Heart Disease. Springfield, —
Illinois.
(1966b) Am. Heart. J. 72, 538. Reitman, S., Frankel, S. (1957) Am. J. clin. Path. 28, 56. Rose, G. A., Blackburn, H. A. (1966). Cardiovascular Population Studies. W.H.O., Geneva. Scheuer, J., Brachfield, N. (1966) Metabolism, 15, 945. Selye, H. (1961) The Pluricausal Cardiopathies. Springfield, Illinois. Shafrir, E., Steinberg, D. (1960) J. clin. Invest. 39, 310. Smith, A. F. (1967) Lancet, ii, 178. Trout, D. L., Estes, E. H., Friedberg, S. J. (1960) J. Lipid Res. 1, 199. Valori, C., Thomas, M., Shillingford, J. P. (1967) Lancet, i, 127. Wallace, A. G. (1968) in Acute Myocardial Infarction (edited by D. G. Julian and M. F. Oliver). Edinburgh (in the press). —
this, further bone fractures developed in three patients. Although vitamin-D therapy repairs the defective absorption of a soluble calcium salt, and prevents osteomalacia, it does not halt the progression of bone disease in
patients with primary biliary cirrhosis. Introduction
BoNE disease has been noted in patients with prolonged biliary obstruction and biliary cirrhosis (Atkinson, Nordin, and Sherlock 1956) but it is not clear whether the thinning is due to osteoporosis or to osteomalacia. Among the twenty-five patients studied by Atkinson, Nordin, and Sherlock (1956) seven had osteomalacia, three seemed to have osteoporosis alone, and two had both conditions. Bone thinning may also be noted in patients with other types of cirrhosis, osteoporosis being much more frequent than osteomalacia (Lichtwitz et al. 1959, Huguenin et al.
1960).
Osteoporosis and osteomalacia must be distinguished since the setiology and treatment are completely different. Osteomalacia is characterised biochemically by a low serum Ca x P product, by a raised serum-alkalinephosphatase, and histologically by wide osteoid seams. Osteoporosis, on the other hand, is a disease of unknown aetiology: there is no evident biochemical disorder, and histologically, the bone trabeculse are thinned. In practice, osteoporosis and osteomalacia often coexist, particularly in patients with malabsorption (Badenoch 1960, Deller et al. 1963). Although differential diagnosis depends ultimately on the bone histology even this can be confusing (Morgan et al. 1965). Bone disease might develop for several reasons in patients with hepatobiliary disorders. Bile salts are essential for the absorption of vitamin D (Schachter et al. 1964) and in obstructive jaundice lack of this vitamin would result in osteomalacia. In addition, bile-salt deficiency could allow insoluble calcium soaps of unabsorbed fatty acids to form in the small bowel lumen so making dietary calcium unavailable for absorption (Kehayoglou, Williams, Whimster, and Holdsworth 1968). Thirdly, bile salts may directly stimulate calcium absorption (Webling and Holdsworth 1965). Calcium absorption has been measured in a number of patients with liver disease. To reduce the number of variables, only one type of cholestasis, namely primary biliary cirrhosis, has been studied. For the same reason, calcium chloride was given in water and without any fat so that malabsorption could not be due solely to impaired fat absorption and to consequent formation of calcium soaps. In addition the degree and type of bone disease has been defined and correlated with the clinical severity of the hepatic disease and with the degree of impairment of calcium absorption. The effect of short and long-term vitamin-D therapy has also been investigated. Patients and Methods The twelve patients with primary biliary cirrhosis were all female (table i). Their ages ranged from 39 to 68 years and the duration of illness was from 9 months to 4 years. The diagnosis was made according to clinical criteria and liver histology, together with serological tests (Sherlock 1963, Walker, Doniach, Roitt, and Sherlock 1965). Pruritus was constant and in seven patients had preceded the jaundice. Serum-bilirubin levels were always elevated. No patient was in hepatic coma or precoma or had ascites. Five patients (nos. 1, 2, 4, 6, and 10) had xanthomas. Only 1 patient (case 1) complained of bone pain and tenderness. Patients 1-7 and patient 10 had lost weight. Initially, none of the patients