Myth: Cholesterol Causes Stroke
September 20, 2007
(This article is a summary of an article that will appear in the Fall issue of the magazine, Wise Traditions.)
Stroke is the third leading cause of death in the United States1 and the single greatest cause of disability in most developed countries.2 The American Heart Association states that high cholesterol levels contribute to stroke and lists this disease as the second most important reason for avoiding cholesterol-rich foods such as butter, egg yolks and organ meats.3
Does cholesterol really cause stroke — is this a myth or a reality?
Different Strokes
Through the early 1990s neither epidemiological studies4 nor controlled trials of cholesterol-lowering drugs5 were able to generate any evidence for an association between cholesterol levels and the risk of stroke.
In fact, a 1995 report in which researchers pooled together the results of 45 prospective cohort studies involving over 450,000 people found that the risk of stroke slightly declined with increasing cholesterol levels — though the effect was so small that it could easily have been due to chance.4
It would soon become evident, however, that the failure to find any association between cholesterol and stroke resulted from the failure to differentiate between the two major categories of stroke: hemorrhagic and ischemic. Hemorrhagic stroke occurs when a blood vessel ruptures, whereas ischemic stroke occurs when a blockage closes off the flow of blood within the vessel.2
Studies that have differentiated between these two forms have shown that cholesterol is associated with a decreased risk of hemorrhagic stroke — less common but more deadly — and an increased risk of ischemic stroke.
Finding the Correlations
The Honolulu Heart Study enrolled 8,000 Japanese American men between 1965 and 1968, measured their cholesterol levels, and followed them for fifteen years. In 1980, the researchers running the study published a six-year follow-up report in which serum cholesterol had no association with ischemic stroke; as cholesterol levels increased, however, the risk of hemorrhagic stroke declined.6 In 1994, the fifteen-year follow-up report showed that high cholesterol (over 213 milligrams per deciliter or mg/dL) was indeed associated with an increased risk of ischemic stroke. Those with cholesterol levels under 213 had a 2.5 chance of ischemic stroke over 10 years while those with cholesterol levels over 240 had a 3.2 chance of ischemic stroke over the same length of time.7
The Multiple Risk Factor Intervention Trial (MR FIT) confirmed these findings in over 350,000 men. Those with cholesterol levels under 160 had three times the risk of hemorrhagic stroke as those with higher levels, while those with levels over 200 had a higher risk of ischemic stroke than those with lower levels. Between 200 and 240, the risk increased only 20 percent, but levels over 280 were associated with 2.5-fold increase in risk.8
The Eastern Stroke and Coronary Heart Disease Collaborative Research Group confirmed the findings in eastern Asian countries as well. The group pooled the results of 18 prospective studies conducted in China and Japan involving nearly 125,000 people. For every 23-point drop in serum cholesterol, the risk of ischemic stroke decreased by 23 percent and the risk of hemorrhagic stroke increased by 27 percent.9
Shifting the Balance: Ischemic vs. Hemorrhagic Stroke
Thus, it began to become clear that as cholesterol levels go up, the risk of ischemic stroke goes up and the risk of hemorrhagic stroke goes down. Some authors have suggested that because over 90 percent of strokes in the US are ischemic, our best bet to avoid stroke is to eat a low-fat, low-cholesterol diet so we can reduce our risk of the most common form.10
The data indicate, however, that our ratio of ischemic to hemorrhagic strokes is so high only because our cholesterol levels are so high. In Japanese American men living Hawaii, whose cholesterol levels are between those of Japanese living in Japan and mainland Americans, hemorrhagic stroke constitutes 25 percent of all strokes.6 In China and Japan, where serum cholesterol levels correspond to the bottom two thirds of the range of western levels, hemorrhagic stroke constitutes 42 percent of all strokes.9
Victims of hemorrhagic stroke suffer greater neurological deficits, are more likely to be institutionalized, and are four times more likely to die within thirty days than victims of ischemic strokes. A recent comparison of the two types showed that only 7 percent of ischemic stroke victims died within this period of time, whereas fully 28 percent of hemorrhagic stroke victims died.11
So a cholesterol-lowering diet should merely shift our risk from a less deadly to a more deadly form of stroke. Yet there is an even larger flaw in the reasoning. Conventional wisdom would have us believe that if high cholesterol is associated with ischemic stroke, so is a diet high in animal fat. But the conventional wisdom is wrong.
Eat Your Cholesterol: Animal Fat Intake Associated With a Decreased Risk of Ischemic Stroke
In the Honolulu Heart Study, the risk of ischemic stroke decreased as the intake of total and saturated fat went up.12 Among stroke fatality victims who also had heart disease, there was no relationship between any dietary factors and the amount of atherosclerosis in the blood vessels supplying the brain. Among the others, atherosclerosis of the large arteries was associated with a decreased intake of animal protein and total fat and an increased intake of carbohydrate; atherosclerosis of the small arteries was associated with a decreased intake of fish.13
The Framingham Heart Study followed 800 men over the course of 19 years and found a decreased risk of ischemic stroke associated with an increased intake of total, monounsaturated and saturated fat.14
Studies since this time have occasionally shown no relationship between the intake of animal fat and the risk of ischemic stroke, but most have continued to show a decreased risk of this disease associated with an increased intake of animal fat and fish.15
Does High Cholesterol Cause Ischemic Stroke?
It is a fundamental principle of science that correlation does not prove causation. Thus, the correlation of high cholesterol with the risk of ischemic stroke does not prove that the high level of cholesterol causes the increased risk. If, however, interventions that specifically increase or decrease cholesterol levels without affecting other variables are able to increase or decrease the risk of ischemic stroke, this would represent powerful evidence for causation. Is this the case?
Cholesterol-Lowering Drugs and the Risk of Stroke
Early trials with cholesterol-lowering drugs were less than promising. A 1993 report pooled together the results of 13 trials conducted between 1966 and 1992 involving over 45,000 men. Cholesterol lowering had no association with the risk of stroke. It tended to decrease the risk of fatal stroke and increase the risk of nonfatal stroke, but the magnitudes of these differences were only strong enough to be distinguished from the effects of chance in trials using the drug clofibrate. Treatment with this drug more than doubled the risk of fatal stroke. The only trial that distinguished between the risk of ischemic and hemorrhagic stroke used a similar drug called gemfibrozil; treatment with this drug increased the risk of fatal hemorrhagic stroke by a factor of five.5
The results of later trials with statins were more impressive. A 2004 report that pooled together the results of 120 lipid-lowering trials, including 24 using statins, showed that treatment with statins lowered the risk of stroke by 18 percent, due almost entirely to a decrease in ischemic stroke.16 The reduction in LDL correlates to the reduction in atherosclerosis of the carotid artery — a main artery supplying the brain — and to the reduction in the risk of stroke.17
Statins, Rho, and Nitric Oxide
Although some would argue that the old cholesterol-lowering drugs were less effective than statins simply because they were less effective at reducing cholesterol, the fact is that statins do a lot more than lower cholesterol, and their efficacy against ischemic stroke cannot by any means be construed as evidence that high cholesterol causes ischemic stroke — even when this efficacy correlates with the degree of total or LDL cholesterol reduction.
Statins decrease the activation of Rho through the same mechanism through which they decrease cholesterol levels. Their ability to decrease the activation of Rho correlates with their ability to decrease cholesterol levels. As explained in the this article, Rho activation suppresses the levels of nitric oxide made by the blood vessel wall, which increases the risk of atherosclerosis.
By inhibiting the activation of Rho,18 statins greatly increase the amount of nitric oxide made by the blood vessel lining.19, 20 This results in a great reduction in the magnitude of stroke and its residual neurological effects in laboratory animals.21 There is also further evidence that statins protect against stroke by increasing the body's ability to dissolve blood clots independently of both nitric oxide and cholesterol.22
Is Cholesterol Irrelevant?
It would be a mistake to assume that, because statins clearly have protective effects against stroke that do not involve cholesterol, cholesterol itself must be entirely irrelevant. Most likely, the level of LDL is a loose indicator of the level of oxidized LDL.
When the phospholipids and proteins at the surface of an LDL particle oxidize, that LDL particle can accumulate in atherosclerotic plaque23 and depress the production of nitric oxide.20 Likewise, a high level of sugar in the blood can damage this LDL by a process called "glycation," which also makes it accumulate in atherosclerotic plaque24 and depress the production of nitric oxide.25
Selective filtering of LDL from the blood of patients with very high cholesterol — most of which is oxidized — appears to improve nitric oxide production and blood flow.26 Unfortunately, researchers have only tested the effect of this treatment on these parameters in small, uncontrolled trials.
It appears — though this can't be proven beyond a shadow of a doubt — very likely that oxidized and glycated LDL contributes to the disease process that lies behind ischemic stroke. How important these factors are compared to the myriad others that affect the process of inflammation and oxidative damage, however, we cannot quantify.
Whether and how low cholesterol causes the increased risk of hemorrhagic stroke with which it is associated is still an open question. Animal experiments have shown that diets high in animal fat and cholesterol reduce the incidence of stroke in rats with high blood pressure.14 In humans, the association of low cholesterol with hemorrhagic stroke primarily exists among those with diastolic blood pressure above 90 millimeters mercury (mm Hg).8 It is possible, then, that cholesterol protects against hemorrhage by strengthening and stabilizing the blood vessel walls, especially when they need extra strength to withstand the constant onslaught of high blood pressure.
What's for Dinner?
If we look at the science objectively, it appears that both high and low cholesterol levels will increase the risk of stroke. In the MR FIT trial, stroke mortality was lowest between 180 and 200, increased somewhat below 180 and above 240, and was the highest below 160 and above 300.8 So it makes sense to use exercise, and proper control of chronic infections (which increase both cholesterol levels and Rho activation) to maintain moderate cholesterol levels. In all likelihood, however, the association between high cholesterol and ischemic stroke is, if causal, due primarily not to LDL itself but to oxidized and glycated LDL — so maintaining good antioxidant status should take the lead role.
As discussed above, ischemic stroke and atherosclerosis of the blood vessels that lead to the brain appear to be associated with a low intake of animal protein and fat, a low intake of fish, and a high intake of carbohydrate. In the Diet and Reinfarction Trial (DART), subjects who reduced their total fat intake from 35 percent of calories to 32 percent of calories and doubled their polyunsaturated-to-saturated fat ratio from 0.4 to 0.8 doubled their risk of dying of stroke.27
The research tells us that, with respect to stroke, animal foods are our friends, and refined carbohydrates and vegetable oils are our enemies.
Is cholesterol involved in stroke? Yes. Does it cause stroke? Low and high cholesterol may both play contributory roles, but do not have the final word. Should we avoid eggs, butter and organ meats in order to lower our risk of stroke? Absolutely not — that is the myth that has no grounding in scientific reality.
References
1. Heron MP, Smith BL. Deaths: leading causes for 2003. Natl Vital Stat Rep. 2007;55(10):1-92.
2. Collins C. Pathophysiology and classification of stroke. Nurs Stand. 2007;21(28):35-39.
3. American Heart Association. How Can I Lower High Cholesterol? http://www.americanheart.org/downloadable/heart/110288182952015%20LwrHighChol.pdf. Published 2004. Accessed August 18, 2007.
4. Prospective Studies Collaboration. Cholesterol, diastolic blood pressure, and stroke: 13,000 strokes in 450,000 people in 45 prospective cohorts. Lancet 1995;346:1647-53.
5. Atkins D, Psaty BM, Koepsell TD, Longstreth WT, Larson EB. Cholesterol Reduction and the Risk for Stroke in Men. A Meta-Analysis of Randomized, Controlled Trials. Ann Intern Med. 1993;119(2):136-45.
6. Kagan A, Popper JS, Rhoads GG. Factors related to stroke incidence in Hawaii Japanese men. The Honolulu Heart Study. Stroke. 1980;11:14-21.
7. Benfante R, Yano K, Hwang L-J, Curb JD, Kagan A, Ross W. Elevated Serum Cholesterol Is a Risk Factor for Both Coronary Heart Disease and Thromboembolic Stroke in Hawaiian Japanese Men. Implications of Shared Risk. Stroke. 1994;25:814-820.
8. Iso H, Jacobs Jr. DR, Wentworth D, Neaton JD, Cohen JD for the MRFIT Research Group. Serum cholesterol levels and six-year mortality from stroke in 350,977 men screened for the multiple risk factor intervention trial. New Engl J Med. 1989;320:904-10.
9. Eastern Stroke and Coronary Heart Disease Collaborative Research Group. Blood pressure, cholesterol, and stroke in eastern Asia. Lancet. 1998;352:1801-07.
10. Fuhrman J. Eat to Live: The Revolutionary Formula for Fast and Sustained Weight Loss. New York, NY: Little, Brown and Company. 2003; pp. 132-133.
11. Barber M, Roditi G, Stott DJ, Langhorne P. Poor outcome in primary intracerebral haemorrhage: results of a matched comparison. Postgrad Med J. 2004;80:89-92.
12. Kagain A, Popper JS, Rhoads GG, Yano K. Dietary and other risk factors for stroke in Hawaiian Japanese men. Stroke. 1985;16:390-396.
13. Reed DM, Resch JA, Hayashi T, MacLean C, Yano K. A prospective study of cerebral artery atherosclerosis. Stroke. 1988;19:820-825.
14. Gillman MW, Cupples A, Millen BE, Ellison RC, Wolf PA. Inverse Association of Dietary Fat With Development of Ischemic Stroke in Men. JAMA. 1997;278:2145-2150.
15. He K, Xu Y, Van Horn L. The Puzzle of Dietary Fat Intake and Risk of Ischemic Stroke. A Brief Review of Epidemiologic Data. J Am Diet Assoc. 2007;107:287-295.
16. Briel M, Studer M, Glass TR, Bucher HC. Effects of Statins on Stroke Prevention in Patients with and without Coronary Heart Disease: A Meta-analysis of Randomized Controlled Trials. Am J Med. 2004;117:596-606.
17. Amarenco P, Labreuche J, Lavallee, Touboul P-J. Statins in Stroke Prevention and Carotid Atherosclerosis: Systematic Review and Up-to-Date Meta-Analysis. Stroke. 2004;35:2902-2909.
18. Laufs U, Liao JK. Post-transcriptional Regulation of Endothelial Nitric Oxide Synthase mRNA Stability by Rho GTPase. J Biol Chem. 1998;273(37):24266-24271.
19. Laufs U, Fata VL, Liao JK. Inhibition of 3-Hydroxy-3-methylglutaryl (HMG)-CoA Reductase Blocks Hypoxia-mediated Down-regulation of endothelial Nitric Oxide Synthase. J Biol Chem. 1997;272(50):31725-31729.
20. Laufs U, Fata VL, Plutzky J, Liao JK. Upregulation of Endothelial Nitric Oxide Synthase by HMG CoA Reductase Inhibitors. Circulation. 1998;97:1129-1135.
21. Endres M, Laufs U, Huang Z, Nakamura T, Huang P, Moskowitz MA, Liao JK. Stroke protection by 3-hhydroxy-3-methylglutaryl (HMG) CoA reductase inhibitors mediated by endothelial nitric oxide synthase. Proc Natl Acad Sci USA. 1998;95:8880-8885.
22. Asahi M, Hunag Z, Thomas S, Yoshimura S, Sumii T, Mori T. Protective effects of statins involving both eNOS and tPA in focal cerebral ischemia. J Cereb Blood Flow Metab. 2005;25(6):722-9.
23. Prescott MF, Muller KR< Flammer R, Feige U. The effect of LDL and modified LDL on macrophage secretion products. Agents Actions Suppl. 1994;16:163-170.
24. Rashid I, van Reyk DM, Davies MJ. Carnosine and its constituents inhibit glycation of low-density lipoproteins that promotes foam cell formation in vitro. FEBS Letters. 2007;581:1067-1070.
25. Ji Y, Diao J, Han Y, Huang Y, Bai H, Chen Q, Leming F, Ferro A. Pyridoxine prevents dysfunction of endothelial cell nitric oxide production in response to low-density lipoprotein. Atherosclerosis. 2006;188:84-94.
26. Tamai O, Matsuoka H, Itabe H, Wada Y, Kohno K, Imaizumi T. Single LDL Apheresis Improves Endothelium-Dependent Vasodilation in Hypercholesterolemic Humans. Circulation. 1997;95:76-82.
27. Ness AR, Hughes J, Elwood PC, Whitley E, Smith GD, Burr ML. The long-term effect of dietary advice in men with coronary disease: follow-up of the Diet and Reinfarction trial (DART). Eur J Clin Nutr. 2002;56:512-518.