low blood total cholesterol and mortality: causality, consequence and confounders

EDITORIALS

Low Blood Total Cholesterol and Mortality: Causality, Consequence and Confounders

Barry Lewis, MD, PhD, and Matti J. Tikkanen, MD, PhD

I n the prevention of cardiovascular disease, 2 of its 3 classic risk factors are coming under increasingly ef- fective control: in many countries cigarette use is de-

clining, while hypertension is being detected and treated with growing success. Risk conferred by high plasma total cholesterol levels has received less vigorous attention; at least in most European countries, con- sumption of dietary fat has changed but little, and the proportion of adults who have had a cholesterol measurement is often low. Is this conservative approach to cholesterol justified,’ or is it a major reason for the on- going high mortality from coronary artery disease (CAD) in many parts of the world? In the U.S.A., CAD deaths decreased by 6.3% in one recent year, and total mortality by 2.3%2; CAD mortality has halved in the U.S.A. and Australia in the past 25 years, and in Eu- rope only Finland has approached this success.3 Inci- dence has fallen as well as mortal@+‘; hence these trends represent a striking achievement by preventive medicine.

The grounds for conservatism toward treating hypercholesterolemia have varied in the past 20 years. Initial doubts about its causal role in CAD became untenable as trials of cholesterol lowering showed reduction in CAD incidence5-7 and arrest of coronary atherosclerosis progression.8,9 It was later argued that the reduction in CAD was unacceptably small since trials suggested that many patients would need to be treated for each CAD event that was prevented. Although this “prevention paradox” is true of all preventive measures it has not been canvassed as an argument against antismoking policies or immunizations. In clinical practice treatment of hyperlipidemia is predicted on risk of CADlO rather than on lipid levels (as in trials); this minimizes unnec- essary treatment. A subsequent debate centered on cost/ benefit calculations based on lipid-lowering trials, some of which showed the cost of prolonging life to be high.” Other estimates based on selective treatment of persons at high risk have shown cost-effectiveness to be compa- rable to other accepted preventive procedures.12 Current concern about cholesterol lowering has shifted to the possibility that it may increase the risk of noncardiovascular death.‘,13>14 In this article we review evidence from epidemiology, clinical trials, and cell biolo- gy relevant to this potentially serious issue.

From the University of London, London, United Kingdom; and the First Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland. Manuscript received April 16, 1993; revised manuscript received and accepted July 9, 1993.

Address for reprints: Matti J. Tikkanen, MD, PhD, First Depart- ment of Medicine, Helsinki University Central Hospital, Haartmanin- katu 4, 00290 Helsinki, Finland.

TOTAL MORTALITY EpidemiologIy: Many factors influence longevity in

different countries. Nevertheless, there is a consistent association in population comparisons between low intakes of fat or of saturated fat (which correlate with low mean serum cholesterol15) and greater expectation of life.16,17 In 1 study low mean serum cholesterol levels were associated with low total mortality rates,15 but in another this relation was present in women but not in men.@ The recent downward trend in cholesterol levels in the U.S.A.19 has been accompanied by decreasing all- cause mortality.17

Two longitudinal epidemiologic studies, unique in their 30-year duration, have shown low cholesterol levels (~4.7 mmol/liter [182 mg/dl]) to be followed by the lowest mortality.2o,21 The effect appears most pro- nounced when cholesterol is measured in early adult life. In shorter, although larger studies, however, a J-shaped relation is seen; in one, all-cause mortality increased when serum cholesterol levels were ~3.62 mmolfliter (140 mg/dl); above this level all-cause mortality increased with increasing cholesterol levels.22 Levels ~3.62 mmol/liter (140 mg/dl) are rare in Western populations. In 1 study, mortality excess at the lowest cholesterol levels was small, nonsignificant, and occurred only in men with levels ~3.34 mmol/liter (130 mg/dl)23; in another it was significant in women but not in men, at levels ~4.7 mmol/liter (182 mg/d1).24 In Shanghai, where the low average serum cholesterol would be expected to amplify any association between low levels and all- cause mortality, no relation was found.25

A recent overview of 19 studies, published by the U.S. National Heart, Lung, and Blood Institute (NHLBI)26 shows a U-shaped relation between all-cause mortality and blood cholesterol in men: death rates increased to a similar extent above and below the range of 4.1 to 5.2 mmol/liter (160 to 201 mg/dl). In women mortality appeared greatest at levels ~4.1 mmol/liter (160 mgldl), decreasing nonsignificantly with higher levels. To lessen the known effects of undiagnosed disease in lowering cholesterol levels, deaths in years 1 to 5 were excluded. Nevertheless, the time course of cholesterol lowering in chronic disease is unknown and is cer- tainly prolonged.27,28

The inconsistencies among longitudinal studies, and between these and population comparisons, remain unexplained, as do the sex differences. The assumption that longitudinal data reflect relations between lifelong cholesterol levels and mortality may not be justified; before death from colon cancer, serum cholesterol decreases progressively over a lo-year period.27 One ten- able interpretation is that the association between low

80 THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 73 JANUARY 1,1994

plasma cholesterol and at least some common fatal diseases reflects a decrease in cholesterol levels caused by chronic disease over an extended period.

Clinical trials: When CAD is a common cause of death, a reduction in fatal CAD should decrease total mortality. This is the case in trials of lipid lowering in patients with preexisting CAD. Meta-analysis of all 8 qualifying secondary prevention trials shows reductions both in CAD and total mortality29,30; the same trends are evident in an additional trial characterized by profound cholesterol lowering. 31 In primary preven tion trials, up- ward as well as downward trends in total mortality have been reported, suggesting a possible untoward effect of cholesterol lowering on noncardiac disease rates. One overview has shown an excess of borderline statistical significance in noncardiac deaths in the treatment group; however, this was unrelated to the extent and duration of cholesterol lowering. 32 Another meta-analysis of 19 trials indicated a trend toward greater total mortality in the treatment groups in trials in which cholesterol reduction was small, but a trend toward lower total mortality in trials in which cholesterol was substantially reduced.33 If cholesterol lowering caused an increase in total mortality, the opposite trend would be expected: a dose-response relation would be predicted, with highest rates in the treatment groups of trials in which cholesterol reduction was largest. The statistical power of all published randomized trials of cholesterol lowering, even combined, may be insufficient to detect an effect on total mortality.34 No published trial has approached the estimated size needed to detect an effect on total mortality given the modest reductions achieved in cholesterol levels.3s

Four further trials have used multiple risk factor intervention. In 3, there was no excess of noncardiovascular deaths.36-38 In the fourth, there was no significant change in total mortality during the trial, whereas increased mortality during the post-trial follow-up was statistically associated with antihypertensive therapy.39-n

In any trial it is unclear whether an adverse trend is mediated by the decrease in cholesterol or by a direct effect of the intervention. Known fatal side effects of current lipid-lowering drugs are very rare,42 but serious consequences of drug interactions are recognized.42 Such consequences are possible in closed trials and could well occur in a post-trial follow-up. Some obsolete drugs are more hazardous, e.g., D-thyroxine and high-dosage es- trogen43,44; inclusion of trials of these agents in meta- analyses biases toward an unfavorable outcome.45

A wide range of causes of death contributes to the excess total mortality that has been associated with low plasma total cholesterol. The lirst to receive attention was cancer - lung cancer predominantly.z6~46 Numerous noncardiovascular, non-cancer causes of death are over- represented, particularly respiratory and digestive diseases and trauma. The nonspecificity of these associations between low cholesterol and mortality is unusual for etiologic relations.

CANCER Epidemiology: Some 50 longitudinal studies have

been reviewed for evidence of a relation between low

plasma total cholesterol and cancerr7; an association was present in about one half of these studies. It is note- worthy that cholesterol levels are particularly low in those who are to die within 1 year of measurement.46,47 Although the relation does not disappear after longer time intervals, it becomes progressively weaker.46,47 This was interpreted to indicate that cancer preceded and led to a decrease in plasma total cholesterol, an effect that was most marked when clinical presentation and death were imminent.22,46,47 When this preclinical cancer effect was taken into account, only 15 of 51 longitudinal studies showed a persisting association between low cholesterol and death from cancer.47 In the NHLBI overview, a modest excess of lung cancer deaths occurred in men, but not significantly in women, with cholesterol levels ~4.1 mmol/Iiter (160 mg/dl),26 and was apparent in non-smokers as well as smokers; however, in the largest single study (n = >350,0) excess risk of lung cancer was conlined to smokers with low cholesterol levels.22

In an overview of 35 studies a moderate excess of cancer was found among those with lowest serum cholesterol, but as this was absent in studies involving populations of high socioeconomic levels, social class appears to be a signilicant confounder.48

In the Shanghai study, despite low mean cholesterol levels, the relation between serum cholesterol and cancer was direct, with lowest mortality in those with low cholesterol levels.25 Only hepatoma was overrepresent- ed in the lowest quartile of cholesterol, the association probably reflecting the known effect of chronic hepatitis in decreasing serum cholesterol.49 Other longitudinal studies have shown a direct relation50 or no associa- tion24,51 between cholesterol levels and cancer rates. Population comparisons, too, have mostly shown a direct relation between fat and cholesterol intakes and deaths from lung, breast, colon and prostate cancer.52

Clinical trials: Selective meta-analyses of subgroups of trials have given varying results. In the meta-analysis of 8 secondary prevention trials, the cancer incidence was lower (nonsignificantly) in treatment group~.~~ Con- versely, a meta-analysis of 6 primary prevention trials reported a 43% higher cancer incidence in the treatment grou~.~~ Cancer incidence was unaffected in a trial of partial ileal bypass in which cholesterol levels decreased by as much as 23%,31 and in 2 primary prevention trials using drugs.5,6 In the World Health Organization clofibrate trial,54 there was an excess of cancer, chiefly rectal, in the treated group. In a further clofibrate trial there was no difference in cancer rates.55 It may be con- cluded that the clinical trial data, like the epidemiology, yields no persuasive evidence of a causal relation between low cholesterol levels and cancer.

SUICIDE, VIOLENT DEATH, AND OTHER NONCARDIOVASCULAR, NON-CANCER MORTALITY

Epidemiology: In the NHLBI overview,26 6% of deaths were due to trauma, and 5 and 4% were due, re- spectively, to nonmalignant respiratory and digestive diseases. For each, mortality was greatest in subjects with serum cholesterol ~4.1 mmol/liter (160 mg/dl). For trau-

EDITORIALS 81

ma deaths this trend was significant only in men and it was nonsignificantly graded, i.e., rates did not vary in the upper part of the cholesterol distribution. This overview was conEned to deaths occurring 5 years or more after entry. In a further study an excess of suicidal injury deaths was reported in men in the lowest quartile of serum cholesterol, but not in wome@; unlike the NHLBI Endings, the inverse relation was confined to the Erst 6 years of follow-up but was absent in years 7 to 20.

In 2 further studies there was no consistent relation between serum cholesterol and violent death?2,57 In the Shanghai study,25 an apparent excess of not-medical deaths in the lowest cholesterol quartile became nonsignificant after adjustment for confounding variables.

In understanding the relation between low plasma total cholesterol and noncardiovascular, non-cancer deaths, the possible role of confounding is critical. In a recent IS-year study on 18,000 men,23 noncardiovascular, non-cancer deaths showed a graded, inverse relation to plasma total cholesterol. When adjustment was made for confounders, however, the cholesterol-mortality relation was attenuated and became statistically nonsignificant. Characteristics that were associated both with lower plasma total cholesterol and higher mortality were lower employment grade, being unmarried, unexplained weight loss, respiratory symptoms, low forced expirato- ry volume in 1 second, and low body mass index. Once these confounders were taken into account there was little evidence of an association between cholesterol and non-cancer noncardiovascular disease. That employment status is a confounder is further illustrated by the absence of inverse relations between cholesterol and mortality in employed men5*; those who died of CAD, cancer, or other causes (chiefly accidents) had higher mean cholesterol levels than those who survived. In the 30-year study already referred toF1 the association between cholesterol level and noncardiovascular deaths may be estimated from the reported data to be a direct one.

In another longitudinal study, a depression score was significantly higher in men aged 280 years, with cholesterol levels ~4.1 mmol/liter (160 mg/dl), than in those with higher levels.59 Some causes of confounding such as bereavement (likely to be operative in this age group) could have contributed to the association. In a recent trial designed to detect changes in emotional state, patients adhering to a cholesterol-lowering diet displayed reduced depression and hostility scores60

Clinical trials: In 2 recent trials there was an excess of deaths from violence and suicide in those receiving different lipid-lowering drugs.5,6 In a trial of partial ileal bypass, however, despite marked reduction in serum cholesterol, there was no such excess3$ there was a small and nonsigniEcant excess of deaths from these causes in a meta-analysis of secondary prevention trials.30 Depending on criteria for eligibility, 22 or as many as 32 primary and secondary prevention trials have been reported. In meta-analyses of 6 or 8 of the primary prevention trials, the treatment groups were found to have an excess of trauma deaths14,53; in a meta-analysis of 26

trials, no such effect of treatment was detected,34 and no deEnite adverse effect of treatment was identified in a further unpublished meta-analysis of 22 trials (Pet0 R, Collins R, personal communication, 1993). Among all the trials there was no single trial showing a significant excess of trauma deaths, nor was there a significant excess of these deaths in the treatment groups when all trials were combined.34 Four comments may be presented on these trials and meta-analyses:

1. Some lipid-lowering drugs have become obsolete because of toxicity; inclusion of several trials of D-thyroxine or high-dose estrogen in meta-analyses45 renders the conclusions uninformative in relation to current therapy of hyperlipidemia. Exclusion of the World Health Organization cloEbrate trial from me&analyses largely removes the excess of noncardiovascular deaths; this drug, too, is used very little today.

2. Although the intention-to-treat principle is necessary in assessing treatment effects on CAD incidence, there is evidence that it can result in a serious overesti- mate of the effect of treatment on other clinical events.61 In CAD prevention trials, protocols seldom lay down di- agnostic criteria for fatal events other than CAD. De- pendence on death certificates for estimating noncardiovascular death rates may therefore be unreliable. The apparent causes of nonmedical deaths have been reexam- ined in the 2 major trials in which an excess was reported in the treated subjects, on the basis of intention- to-treat.61 Both in the Lipid Research Clinics and Helsinki trials, this independent audit revealed features in most case records that render a causal interpretation untenable. Nonadherence to treatment for long periods before death, and failure of serum cholesterol to decrease, were common; some accidental deaths seemed unavoidable, and other deaths were in passive victims of homicide. In the LRC trial, 3 of 4 treated subjects who committed suicide had psychiatric histories ante- dating the trial. This audit provides no evidence that cholesterol lowering, or the drugs used, cause increased nonmedical deaths.

3. Neither meta-analysis in which lipid lowering was linked with increased nonmedical deaths provided evidence that the excess of deaths was greatest in the trials in which the largest reductions in cholesterol occurred.14,53

4. Improper inclusion of trials in a me&analysis in- fluences the generalizability of its findings, especially if only a minority of all trials is included. Among 8 trials selected for inclusion in 1 meta-analysis that suggested an increase in injury deaths,14 2 had durations of about 1 year; 1 was a nonrandomized trial on mental hospital in-patients, and 2 were designed to identify drug side effects. Two included data from a post-trial follow-up during which many participants abandoned their original as- signment to treatment or placebo.

Evidence of an association between low cholesterol levels and nonmedical deaths is inconsistent both among epidemiologic studies and clinical trials. Problems of interpretation include confounding, misclassification of causes of death, and improper selection of trials for meta-analysis.


STROKE A study of 350,000 men has revealed a complex re-

lation between cerebral hemorrhage and low serum cholesterol? Mortality from nonhemorrhagic stroke increased over a threefold range with increasing serum cholesterol, in a graded manner. In the initial report,62 intracranial hemorrhage was unrelated to serum cholesterol only in men; but in men with diastolic pressure >90 mm Hg, those with serum cholesterol ~4.1 mmol/liter (160 mg/dl) had a marked excess of intracranial hemorrhage. The association was not graded. The association with elevated blood pressure appears to attenuate after longer follow-up. 22 Because serum cholesterol and blood pressure were correlated, low cholesterol coincided rel- atively infrequently with hypertension; intracranial hemorrhage caused ~2% of cardiovascular deaths, a rate of 2.36/10,000 men. A far greater number of cardiovascular deaths were due to CAD (60.5/10,000) plus nonhemorrhagic stroke (2.62/10,000). A possible role of cholesterol levels of ~4.1 mmol/liter (160 mg/dl) in increasing the risk of cerebral hemorrhage in hypertensive men cannot be discounted, but a far greater number of cardiovascular events is associated with high rather than low cholesterol levels.

BIOLOGICAL PLAUSIBILITY The evidence that cholesterol lowering causes major

hazards would gain credibility if mechanisms were identified that could explain low cholesterol-mortality associations in causal terms. The excess total mortality associated with low plasma total cholesterol or cholesterol lowering in some studies is due to a heterogeneous range of causes of death, a nonspecificity that is atypical of etiologic relations. It follows either that the low cholesterol levels are not the cause of the associated fatalities, or that some unusual unifying mechanism must exist to mediate wide-ranging effects of low plasma total cholesterol. The mechanism would have to account for some or all of the following: increased incidence of cancer, respiratory diseases, digestive diseases, suicide, homicide, and road traflic accidents.

A graded or dose-response relation, expected in causal associations, has not been shown for total or cause-specific mortality rates in lipid-lowering trials, or for the epidemiologic association between low cholesterol and suicide. A causal sequence has not been clearly established: associations between low serum total cholesterol and cancer seems best explained on the basis that decreasing cholesterol levels follow and are caused by malignancy.27,28,46 Consistency, also expected of causal associations, is lacking, e.g., between longitudinal studies and population comparisons. The clinical pic- ture in familial hypolipidemias has no features in common with the disorders associated epidemiologically and in trials with low serum cholesterol.63

Biological mechanisms. I. Low cholesterol as a cause of disease: Cholesterol is a component of cell membranes, in which its content varies within narrow limits and is one determinant of an important property, the fluidity, of the membrane. Fluidity intluences such functions as activity of cell membrane receptors, ion

transport and immune function. Cell cholesterol is de- rived from endogenous synthesis and from uptake of cholesterol-rich lipoproteins from tissue fluid, and ulti- mately from plasma. In theory, therefore, plasma total cholesterol level may inlluence the availability of cholesterol to cells. Anthropologic evidence of the diet of early humans suggests that plasma total cholesterol was low and implies that human cells adapted to such an envi- ronment. Plasma total cholesterol levels in human neo- nates, about 2 mmol/liter (77 mg/dl), are compatible with growth and rapid cell division, and mean levels <3 mmol/liter (116 mg/dl) are normal in healthy Chinese adults.25

Sensitive homeostatic mechanisms regulate cell cholesterol content by controlling the rates of cholesterol synthesis, of low-density lipoprotein (LDL) uptake through LDL receptors,@ and of cholesterol efflux.65 The contributions made by synthesis and by LDL uptake to cell cholesterol have been quantified in laboratory animals.66,67 In tissues other than the spleen, endogenous synthesis is the major source; in the brain it appears to be the sole source of the small amount of cholesterol turned over because there is no measurable LDL uptake.66Jj7 The latter finding is important in view of the suggestion that low plasma total cholesterol may, by depleting brain cholesterol, lead to neurotransmitter depletion and increased risk of suicide.(j8

In the face of these homeostatic mechanisms, it seems unlikely that cells would be depleted of cholesterol at plasma total cholesterol levels associated with increased noncardiovascular mortality in epidemiologic studies. This reasoning is in keeping with observations on mononuclear cells from normal subjects69; fluidity and free cholesterol content were identical in cells from those with plasma LDL cholesterol in the lowest and highest quintile. Fluidity and cholesterol content of fi- broblasts too were unchanged by incubation in LDL concentrations as low as 0.1 mmol/liter (3.9 mddl), cor- responding to plasma total cholesterol of about 3 to 3.5 mmol/liter (116 to 135.5 mg/d1).69 Such lindings lend no support to the hypothesis that low plasma total cholesterol, by compromising cell membrane fluidity, predis- poses to noncardiovascular disease; this suggestion, first made 14 years ago, has received no support from the current, extensive understanding of cholesterol home- ostasis. Also, there are no plausible mechanisms for an increased risk of .disparate disorders as a result of altered membrane fluidity.

A report of impaired function in natural killer cells incubated with lovastatin in vitro has prompted the suggestion that cancer mortality may be increased through impaired immunosurveillance70; but when natural killer cells from lovastatin-treated patients were studied ex vivo no abnormality in function was found.71

Last, it has been speculated that the effects of lowered cholesterol levels may differ from those of innate- ly low levels.14 This would imply that cells become dependent on the high cholesterol levels of Western populations, although such levels are recent in evolu- tionary terms. During the duration of clinical trials a large number of generations of cells would arise in most

EDITORIALS 83

tissues in the course of cell turnover. For later generations to be affected by a decrease from formerly high cholesterol levels, some unidentified “cholesterol mem- ory” would need to be hypothesized.

Biological mechanisms. II. Low cholesterol as consequence of disease: Several known bases exist for low cholesterol levels to be the consequence of disease. One is weight loss, well recognized to lower plasma lipids. Underlying illness or depression, through weight loss or anorexia, may therefore mediate an association between low plasma total cholesterol and increased mortality, as observed for respiratory deaths.23

Another mechanism is the effect of tumor necrosis factor and other cytokines in lowering plasma total cholesterol in laboratory animals.72,73 Increased cytokine production is a feature not only of malignant disease but also of inflammation.73 Furthermore, acute leukemic cells express high LDL receptor activity, which by en- hancing LDL clearance from plasma lowers cholesterol levels.74 At least in part, therefore, the association between low cholesterol and increased mortality could be due to a decrease in plasma total cholesterol resulting from preclinical or unrecorded illness.

CONCLUSION, While fuller understanding of the relations between

lipid metabolism and noncardiovascular disease is high- ly desirable, much of the low cholesterol-mortality association may reflect the status of low plasma total cholesterol as a marker of serious disease. The often-repeated suggestion that cholesterol lowering can predispose to a wide range of fatal disorders, through depletion of cell cholesterol, is unsupported by evidence and does not take into account the sensitive homeostatic mechanisms that regulate cellular cholesterol content. The absence of proof that low or lowered cholesterol levels are causally related to noncardiovascular mortality contrasts with substantial evidence that reduction of plasma total cholesterol decreases the incidence of CAD.5-7 Preven- tive action against CAD should take into account this balance of evidence. Possible risks should be kept under scrutiny as with all treatments, but existing evidence of adverse. effects is insufficient to justify foregoing the ben- efits of treating elevated plasma total cholesterol levels. The latter statement must be qualified, however, by the rule that the choice of treatment should be appropriate to the patient’s overall level of cardiovascular risk.‘O Vigorous lipid lowering is justified by a high level of risk, whether conferred by existing CAD (secondary prevention) or by multiple risk factors or familial hyperlipidemias in apparently healthy persons.

1. Oliver MF. Might treabnent of hypercholesterolaemia increase nor&xliac mortality? Lancet 1991;339:1529-1531. 2. National Center for Disease Statistics. Advance Report of Final Mortality Statis- tics, 1989. Hyattsville: US Department of Health and Human Services. Public Health Service, Center for Disease Control 1992;40(8) (Monthly vital statistic report, suppl). 3. Tuomilehto J, Puska P, Korhonen H, Mustaniemi H, Vatiainen E, Nissinen A, Kuulasmaa K, Niemensivu H, Salonen JT. Trends and determinants of ischaemic heart disease mortality in Finland: with special reference to a possible levelling off in the early 1980s. Int J Epidemiol 1989;18(suppl l):SlO%S117. 4. Pell S, Fayaweather WE. Trends in the incidence of myocardial infarction and in associated mortality and morbidity in a large employed population, 1957-1983. N Engl J Med 1984;312:1005-1011. 5. Lipid Research Clinics Program. The Lipid Research Clinics primary Prwen-

tion Trial results. I. Reduction in incidence of coronary heat disease. JAMA 1984; 251:351-374. 6. Fxick MH, Elo 0, Haapa K, Heinonen OP, Heinsahni P, He10 P, Huthmen JK, Kaitanietni P, Koskinen P, Manninen V, Mienp% H, Mtitinen M, M&it&i M, Nomla S, Pastemack A, Pikkarainen J, Rome M, Sjiiblom T, NiilP EA. Helsin- ki Heart Study: primary prevention trial with gemfibrozil in middle-aged men with dyslipidemia. N Engl .I Med 1982317: 1237-1245. 7. Stamler J. Review of primaq prevention trials of coronary heart disease. Acta Med Stand 1985;(supp1)701:10~128. 8. Brown BG, Albers JJ, Fisher LD, Schaefer SM, Lin J-T, Kaplan C, Zhao X-Q, Bisson BD, Fitzpatrick VF, Dodge HT. Regression of coronary artay disease as a result of aggressive lipid lowering in men with high levels of apolipoprotein B. N Engl J Med 1990;323:128%1298. 9. Watts GF, Lewis B, Brunt JNH, Lewis ES, Coltart DJ, Smith LDR, Mann JI, Swan AV. Effects on coronary artery disease of lipid lowering diet, or diet plus cholestymmine, in the St. Thomas’ Hospital Atherosclerosis Regression Study (STARS). Lancet 1992339563-569. 10. Study Group. Prevention of coronary heart disease. Scientific background and new clinical guidelines of the European Atherosclerosis Society. Nutr Metab Car- diovasc Dis 1992;2:113-154. 11. Oster G, Epstein AM. Cost-effectiveness of antihyperlipemic therapy in the prevention of coronary heart disease. The case of cholestyramine. JAMA 1987;258: 2381-2387. 12. Reckless JPD. Cost-effectiveness of clinical care for hyperlipidaemia. In: Lewis B, Assmann G, eds. The social and economic contexts of coronaq prevention. Lon- don: Current Medical Literature, 1990:94-108. 13. Hulley SB, Walsh JMB, Newman TB. Health policy on blood cholesterol. Time to change directions. Circulation 1992;86:102&1029. 14. Smith GD, Pekkanen J. Should there be a moratorium on the use of cholesterol lowering drugs? BMJ 1992;304:431433. 15. Keys A, ed. Seven Countries. Cambridge Mass: Harvard University Press, 1980. 16. Stan&r J. Population studies. In: Levy R, Rifkind B, Dennis B, Ernst N, eds. Nutrition, lipids and coronsuy heart disease: a global view. New York: Raven Press, 1979.

17. Havlii RJ, Feinleib M, eds. Proceedings of the Conference on the Decline in Coronary Heart Disease. Mortality, 1979. @HEW publication no. (NM) 79.1610). 16. Keil U, Kuulasmaa K. World Health Organization: MONICA Project. lnt J Epidemiol 1989;18:(suppl l)S4f%S55. 19. Burke GL, Spr&a JM, Folsom AR, Hahn LP, Luepker RV, Blackbum H. Trends in serum cholesterol levels from 1980 to 1984. The Minnesota Heart Sur- vey. N Engl J Med 1991;324z941-946. 20. Anderson KM, Castelli WP, Levy D. Cholesterol and mortality: 30 years of follow-up from the Framingham Study. JAMA 1987;257:217&2180. 21. Klag MJ, Ford DE, Mead LA, He J, Whelton PK, Liang K-Y, Levine DM. Serum cholesterol in young men and subsequent cardiovascular disease. N Engl J Med 1993;328:313-318. 22. Neaton JD, Blackburn H, Jacobs D, Kuller L, Lee D-J, Shetwin R, Shii J, Stan&r J, Wenthworth D, Multiple Risk Factor Intervention Research Group. Sawn cholesterol and mortality: findings for men screened in the Multiple Risk Factor In- te~ention Trial. Arch Intern Med 1992;152:1490-1500. 23. Smith GD, Shipley MJ, Marmot MG, Rose G. Plasma cholesterol concentration and mortality. The Whitehall Study. JAMA 1992;267:7&76. 24. Salonen JT. Risk of cancer and death in relation ‘to serum cholesterol. Am J Epidemiol 1982;116:622-630. 26. Chen Z, Peto R, Collins R, MacMahon S, Lu J, Li W. Serum cholesterol concentration and coronary heart diseases in population with low cholesterol concentration. BMJ 1991;303:276-282, 26. Jacobs D, Blackbum H, Higgins M, Reed D, Iso H, McMillan G, Neaton J, Nelson J, Potter J, Rifkind B, Rossouw J, Shekelle R, Yusuf S, for Participants in the Conference on Low Cholesterol-Mortality Associations. Report of the Confer- ence on Low Blood Cholesterol: mortality associations. Circulation 1992;86: 10461060. 27. Winawer SJ, Flehinger BJ, Buchalter J, Herbert E, Shike M. Declining serum cholesterol prior to diagnosis of colon cancer. A time-trend, case-control study. JAMA 1990;263:2083-2085. 26. Kritchevslq SB, Wilcosky TC, Morris DL, Truong KN, Tyroler HA. Changes in plasma lipid and lipoprotein cholesterol and weight prior to the diagnosis of cancer. Cancer Res 1991;51:3198-3203. 29. Rossouw JE, Lewis B, Rifkind BM. The value of lowering cholesterol after myocardial infarction. N Engl J Med 1990;323:1112-1119. 30. Rossouw JE, Lewis B, Rifkind BM. Deaths from injury, violence, and suicide in secondary prevention trials of cholesterol lowering (letter). N Engl J Med 1992;325: 1813. 31. Buchwald H, Vaxo RL, Matts JP, Long JM, Fitch LL, Campbell GS, Pearce MB, Yellin AE, Edmiston WA, Smink RD, Sawin HS, Campos CT, Hansen BJ, Tuna N, Kamegis JN, Sanmarco ME, Amplatz K, Castan&.-Zunica WR, Hunter DW, Bisset JK, Weber FJ, Stevenson JW, Leon AS, Chalmers TC, and the POSCH Group. Effect of partial ileal bypass surgery on mortality and morbidity from coronary heart disease in patients with hypercholesterolemia. Report of the Program on the Surgical Control of the Hyperlipidemias (POSCH). N Engl J Med 1990;323: 94&955. 32. Yusuf S, Wittes J, Friedman L. Overview of results of randomized clinical trials in heart disease. II. Unstable angina, heart failure, primaq prevention with as- pirin, and risk factor modification. JAMA 1988;260:225%2263. 33. Holme 1. An analysis of randomized trials evaluating the effect of cholesterol


reduction on total mortality and coronary heart disease incidence. Circulation 1990; 82:1916-1924. 34. MacMahon S. Lowering cholesterol: effects on trauma death, cancer death and total mortality. Aust NZ J Med 1992;22:58&582. 35. Holme I. Relation of coronary heat disease incidence and total mortality to plasma cholesterol reduction in random&d trials: use of meta-analysis. Br Hear-r J 1993;69(suppl):S42-S47. 36. WHO European Collaborative Group. European Collaborative Trial of Mul- tifactorial Prevention of Coronary Heart Disease. Final report on the 6-year results. Lancet 1986;1:869%372. 37. Hjenman I, Velve Bye K, Holme I; Leren P. Effect of diet and smoking intervention on the incidence of coronary heart disease. Lance? 1981;2: 1303-13 10. 36. Multiple Risk Factor Intervention Trial Research Group. Coronary heat disease death, nonfatal acute myocardial infarction and other clinical outcomes in the Multiple Risk Factor. Intervention Trial. Am .I Car&l 1986;58:1-13. 36. Strandberg TE, Salomaa VV, Naukkarinen VA, Vanhanen HT, Sama SJ, Miet- tinen TA. Long-term mortality after 5.year multifactorial primaty prevention of cardiovascular diseases in middle-aged men. JAMA 1991;266: 1225-1229. 40. Miettinen TA, Huthmen JK, Naukkainen VA, Strandberg T, Mattila S, Kum- lin T, Sama S. Multifactorial primary prevention of cardiovascular disease in middle-aged men. JAMA 1985;254:2097-2102. 41. Strandberg TE, Salomaa V, Vanhanen H, Naukkarinen V, Sama S, Miettinen TA. Long-tam effects of probucol and beta-blocker treatment in a primary prevention trial of coronary heart disease (abstr). Em Heart J 1989;10:217. 42. Tikkanen MJ. Practical drug therapy for common hyperlipidaemias. Baillieres Chin Endocrinol Metab 1990;4:719-742. 43. Coronary Drug Project Research Group. The CDP: finding leading to discon- tinuation of the 2.5 mg/day estrogen group. JAMA 1973;226:652657. 44. Coronary Drug Project Research Group. The CDP: findings leading to further modifications of its protocol with respect to dextmthyroxine. JAMA 1972;220: 9961008. 45. Ravnskov U. Cholesterol lowering trials in coronary heart disease: frequency of citation and outcome. BMJ 1992;305:15-19. 46. International Collaborative Group. Circulating cholesterol level and risk of death from cancer in men aged 40 to 69 years. JAMA 1982;248:2853-2859. 47. Epstein FH. The effect of coronary heart disease prevention on the prevention of noncardiovascular diseases. In: Descovich GC, Gaddi A, Magri GL, Lenzi S, eds. Atherosclerosis and Cardiovascular Disease. Boston: Kleuver Academic Pub- lishers, 1990:7-14. 46. Law MR, Thompson SG. Serum cholesterol and cancer. Conclusions from an analysis of data from all the prospective studies. Cancer Causes Contml 1991;2: 253-261. 49. MacIntyre N, Owen JS. Plasma lipids and lipoproteins in liver disease. In: Cohen RD, Lewis B, Alberti KGMM, Denman AM, eds. Metabolic and Molecu- lar Basis of Acquired Disease. vol. 2. London: B&l&e-Tiixlall, 1990:1176-l 192. 60. Tamberg SA, Holm L-E, Carstensen JM. Eklund GA. Risks of cancer of the colon and rectum in’ relation to semm cholesterol and b&-lipoprotein. N Engl J Med 1986;315:1629-1633. 51. Hiatt RA, Fireman BH. Serum cholesterol and the incidence of cancer in a large cohort. J Chron Dis 1986;39;861-870. 52. Epstein FH. Low serum cholesterol, cancer and other non-cardiovascular disorders. Ather-osclerosis 199294: l-12. 53. Muldoon MF, Manuck SB, Matthews KA. Lowering cholesterol concentrations and mortality: a qualitative review of primary prevention trials. BMJ 1990;301

309-314. 54. Committee of Principal Investigators. A cooperative trial in the primary prevention of ischaemic heart disease using clofibrate. Br Heart J 1978;40:1069-1118. 55. Coronary Drug Project Research Group. Clolibmte and niacin in coronary heart disease. JAMA 1975;231:36@381. 56. Lindbag G, R&m L, Gullberg B, Eklund GA. Low serum cholesterol concentration and short term mortalitv from iniuries in men and women. BA4J 1992305: 277-279. 57. Pekkanen J, Nissinen A, Punsar S, Karwnen MJ. Serum cholesterol and risk of accidental or violent death in a 25.year follow-up: the Finnish cohorts of the Seven Countries Study. Arch Intern Med 1989;149:1589-1591. 66. Persson B, Johansson BW. The Kockum Study: 22.yea follow-up. Acta Med Stand 1984;216:485493. 59. Morgan RE, Paliikas LA, Barrett-Connor EL, Wingard DL. Plasma cholesterol and depressive symptoms in older men. Lancet 1993;341:75-79. 60. Weidner G, Connor SL, Hollis JF, Connor WE. Improvements in hostility and depression in relation to dietary change and cholesterol lowering. Ann Intern Med 1992;117:82&823.

61. Wysowski DK, Gross TP. Deaths due to accidents and violence in two recent trials of cholesterol-lowering drugs. Arch Inter-n Med 1990; 150:2169-2172. 62. Iso H, Jacobs DR Jr, Wentworth D, Neaton JD, Cohen JD. Serum cholesterol levels and six-year mortality from stroke in 350,977 men screened for the Mul- tiple Risk Factbr Intervention Trial. N En@ J Med 1989;320:90&910. 63. M&y MJ, Kane JP. Hypolipidemia. Med Clin North Am 1982;66:469484. 64. Goldstein JL, Brown MS. The low density lipoprotein pathway and its relation to atherosclerosis. Annu Rev Biochem 1977;46:897-939. 65. Oram JF. Effects of high density lipoprotein subfractions on cholesterol home- ostasis in human tibroblasts and arterial smooth muscle cells. Arteriosclerosis 1983;3:420-132.

66. Dietschy JM. Regulation of cholesterol metabolism in man and in other species. Klin Wochenschr 1984;62:338-345. 67. Spady DK. Bilheimer DW, Dietschy JM. Rates of receptor-dependent and independent low density lipoprotein uptake in the hamster. Proc Nat1 Acad Sci US A 1983;80:349%3503.

66. Engelberg H. Low serum cholesterol and suicide. Lancet 1992;339:727-729. 69. Marenah CB, Lewis B, Hassall D, La Ville A, Co&se C, Mitchell WD, Bmck- do&r KR, Slavin B, Miller NE, Turner PR, Heduan E. Hypocholesterblaemia and non-canliovascular disease: metabolic studies on subjects with low plasma cholesterol concentrations. BMJ 1983;286:1603-1606. 70. Cutts AL, Bankhurst AD. Suppression of lymphoid cell function in vitro by inhibition of 3.hydroxy-3.methylglutaryl coenzyme A reductase by lovastatin. Int J Immunopha~-mcol 1989;8:863-869. 71. McPherson R, Tsoukas CM, Baines MG, Vost A, Pmss HF. Effects of lovastatin on natural killer cell function and other immunological parameters in man (abstr). Xl International Symposium on Drugs Affecting Lipid Metabolism, Flor- ence, 1992. Lorenzini Foundation Symposium 19922227. 72. Ettinger WH. Miller LD, Albers JJ, Smith TK, Parks JS. Lipopolysaccharide and tumor necrosis factor cause fall in plasma concentration of lecithin-cholesterol acyltransferase in cynomolgus monkeys. J Lipid Res 1990;31:109~1107. 73. Beutler B. A pro-inflammatory mediator with potential relevance in aging. J Am Gwiatr Sot 1990;38: 1027-1036. 74. Vitols S, BjGrkholm M, Gahrton G, Peterson C. Hypocholesterolaemia in malignancy due to elevated low-density-lipoprotein receptor activity in hunour cells: evidence from studies in patients with leukaemia. Lancer 1985;2:1150-1154.

Relief of Rheumatic Mitral Stenosis - When and How?

M. Rafique Essop, MBBCh, MRCP, FCP

Mitral stenosis is not only one of the most distressing forms of cardiac disease, but in its severe forms it resists all treatment by medicine. On looking at the contracted mitral ortfice in a severe case of this disease the wish unconsciously arises that one could divide the constriction as easily during ltfe as one can after death. The risk which such an opera- tion would entail naturally makes one shrinkfuom it.

Sir Lauder Bmnton, 1902l

From the Division of Cardiology, Baragwanath Hospital and University of the Witwatersrand, Johannesburg, South Africa. Manuscript received June 8,1993; revised manuscript received and accepted July 6, 1993.

Address for reprints: M. Rafique Essop, MBBCh, MRCP, FCP, Di- vision of Cardiology, Baragwanath Hospital, PO Bertsham 2013, Jo- hannesburg, South Africa.

T iming of surgery in patients with mitral regurgita- tion may be difficult; too early incurs the unnec- essary risks of surgery and possibly a prosthetic

valve, and too late may result in irreversible left ventric- ular dysfunction.2 These constraints have not applied to patients with mitral stenosis in whom conventional practice is to await the development of symptoms before considering surgery3 This teaching, however, is based on experience when pharmacologic options were limit- ed and surgery was the only alternative when intervention was necessary. But we have come a long way since Brunton’s’ challenge in 1902. With advances in medical therapy4 and surgical techniques, and more recently the advent of percutaneous balloon mitral valvotomy,5 several issues are of concern. Is mitral stenosis in the

EDITORIALS 85

low blood total cholesterol and mortality: causality, consequence and confounders

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