Cholesterol and strokesBMJ 2000; 320 doi: https://doi.org/10.1136/bmj.320.7233.459 (Published 19 February 2000) Cite this as: BMJ 2000;320:459
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Professor Oliver's editorial (1) delineates the role of
hypercholesterolaemia and the place for statins in stroke prevention based
on currently available evidence. The absolute magnitude of morbidity and
mortality benefit is however likely to have been underestimated by
If parallels are to be drawn with coronary artery disease prevention then
the heterogeneous nature of stroke must be recognised and the plausible
impact of statins can only be expected in reducing non-embolic ischaemic
stroke or transient ischaemic attacks (TIAs).
Importantly, few patients with coronary artery disease in the three
secondary prevention statin trials had a prior history of stroke or TIA.
In LIPID, with over 9,000 patients, only 4% had a prior history of stroke
TIA respectively (3). The lower mean age of the populations in these
studies compared to that typically found in strokes has previously been
Though few patients over the age of 75yr were included in the above
studies, as the age specific incidence of stroke and mortality rises
sharply in this group, they may be ideal candidates for statin therapy
(4). Thus administration of statins to a relatively low risk population
for stroke who
were much more likely to suffer a cardiac death may explain the lack of
benefit in reducing overall stroke mortality in the meta-analyses.
Benefits may not be restricted to statins as suggested by the VA-HIT study
using Gemfibrozil were significant reductions in the secondary endpoints
and carotid endarterectomy were obtained (5).
With 140,000 strokes per annum in the UK and over 20,000 admissions for
TIAs, any measures to reduce the substantial physical, social and economic
burden consequent to a non-fatal disabling stroke are welcome. Targeting
lipid lowering therapy at high-risk older patients with a prior history of
non-embolic stroke or TIA is likely to confer significant benefits.
Clearly this has to occur in the context of other preventive therapies
rigorous blood pressure control, treatment of atrial fibrillation and
aspirin therapy. The results of long-term studies are awaited with
1. Oliver MF. Cholesterol and strokes. BMJ 2000;320:459-60
2. Hebert PR, Gaziano JM, Chan KS, Hennekens CH. Cholesterol lowering
with statin drugs, risk of stroke, and total mortality. An overview of
randomized trials. JAMA 1997;278:31321
3. The long-term intervention with pravastatin in Ischaemic Disease
(LIPID) Study Group. Prevention of cardiovascular events and death with
pravastatin in patients with coronary heart disease and a broad range of
initial cholesterol levels. N Engl J Med 1998;339:1349-1357
4. Khan KM, Talwar S. Statins for prevention of stroke in the
elderly. Br J Cardiol 1999 6:516-517
5. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention
Trial Study Group. Gemfibrozil for the secondary prevention of coronary
heart disease in men with low levels of high-density lipoprotein
Engl J Med 1999;341:410-8.
Dr. Khalid Khan
Specialist Registrar in Cardiology
Link 7Z, Royal Liverpool Hospital,
Competing interests: No competing interests
There is no doubt that hypercholesterolemia is associated with an
increased risk of atherosclerosis. Evidence increasingly supports the
concept that any plasma cholesterol above 160mg/dl may be regarded as
above an ideal level, and under the appropriate circumstances leads to
atherosclerosis. there is also increasing evidence to establish the role
of oxidised LDL in atherogenesis (1).
The oxidation hypothesis of athersclerosis states that the oxidative
modification of LDL (or other lipoproteins) is a quantitatively important
event (possibly even obligatory) in the pathogenesis of atherosclerotic
lesions. The important corollary is that inhibition of oxidation of LDL
should retard or inhibit atherosclerosis and consequently diseases, or
prevent clinical sequelae. The importance of oxidation was demonstrated by
the fact that a variety of antioxidants could inhibit the modification of
LDL in vitro and the antioxidant therapy of hypercholesterolemic animals
inhibited progression of atherosclerosis (2).
It has been suggested that the oxidation of LDL renders it
immunogenic and generates of a variety of oxidation-specific epitopes,
some of which could be unique to LDL, but many of which could be in common
with oxidation-specific epitopes generated on bacteria undergoing a
leucocyte-mediated attack on cells subjected to an increased oxidation
stress because of hypercholesterolemia, or cells undergoing apoptosis or
dying. These epitopes could in turn lead to the generation of many
different auto-antibodies, some of which would recognise common epitopes
and some which would recognise unique ones (1).
A commonly believed fallacy is that low cholesterol diets reduce the
risk of atherosclerosis. This statement is true only if the total amount
of fat consumed is reduced, not just the cholesterol content. Most
cholesterol is produced by the body and does not come from dietary
sources. The less the cholesterol consumed the more is that produced by
the body. Much of the cholesterol in deposits of atherosclerotic plaques
is produced within the body and is not derived from food cholesterol
directly. Some of it is produced within the plaque itself (3). In
controlled studies conducted at the Rockefeller University two-thirds of
the subjects tested for the effects of diet on cholesterol had only a
slight increase in blood cholesterol. Their bodies responded to the
challenge with an automatic cholesterol regulation process which tends to
keep blood levels constant.
Very little attention has been given to the quality of dietary fats
and oils. the emphasis has mistakenly been placed on the ratio of
saturated to polyunsaturated fatty acids, irrespective of lipid
peroxidation and cis- to trans-isomerisation. It is now known that
polyunsaturated fats are relatively more toxic. If dietary oils are
obtained from fresh, whole, unfractioned, unprocessed foods they will not
be peroxidised. Animal experiments have shown that if as little as 1% of
dietary cholesterol is consumed in its oxidised form, atherosclerosis may
Therefore it would be more accurate to correlate free radical
pathology and carotid atheroma formation than to correlate cholesterol
levels with stroke.
1. Witzum JL & Horkko S. The role of oxidised LDL in
atherogenesis: immunological responses and auto-phospholipid antibodies.
Ann. New York Acad. Sci. 1997; 811: 88-99
2. Steinberg DS et al. Beyond cholesterol: modification of low
density lipoprotein that increases its lipogenicity. N Eng J Med. 1989;
320 (14): 915-924
3. Cranton E. Bypassing the bypass. Hampton Roads Publishing Co.
Inc., 1997; 69-71; 215-217
4. Atherosclerosis and auto-oxidation of cholesterol. Editorial.
Lancet, 1980; ii: 964-65
5. Oliver MF. Cholesterol and stroke. BMJ 2000; 320: 459-460
Competing interests: No competing interests