Increased Coronary Heart Disease Risk by Dietary Recommendations That Were Made Based on the Cholesterol Hypothesis

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A large-scale Multiple Risk Factor Intervention Trial (MRFIT) failed to prove the effectiveness of lipid nutrition based on the Cholesterol Hypothesis

Data taken from Multiple Risk Factor Intervention Trial Research Group [1982] JAMA 248:1465-1477.

Control 83.6 value mm Hg cT

240.3 mg/dl

19.3/ 40.4/ 1,000 1,000 persons persons

Subgroup with hypertension and ECG anomaly

17.7/ 39.7/ 1,000 1,000 persons persons

Subjects were male (35-57 years old) with high risk for CHD. Special intervention consisted of stepped-care treatment for hypertension, counseling for cigarette smoking, and dietary advice for lowering TC shown in table 2 . Follow-up was for 7 years on average.

Conclusions and Discussion: Three possible explanations for these findings are considered: (1) the overall intervention program, under these circumstances, does not affect CHD mortality; (2) the intervention used does affect CHD mortality, but the benefit was not observed in this trial of 7years' average duration, with lower-than-expected mortality and with considerable risk factor change in the UC (usual care) group, and (3) measures to reduce cigarette smoking and to lower blood cholesterol levels may have reduced CHD mortality within subgroups of the SI (special intervention) cohort, with a possibly unfavorable response to antihypertensive drug therapy in certain but not all hypertensive subjects. This last possibility was considered most likely, needs further investigation, and lends support to some preventive measures while requiring reassessment of others.

Our comments: Nutritional recommendations that were made based on the Cholesterol Hypothesis were found to be essentially ineffective in lowering TC and mortalities from CHD and all causes. In a subgroup with anomaly in ECG (electrocardiogram) and hypertension, the CHD and all-cause mortality rates were greater in the intervention group than in the control group. Hypotensive drugs were suspected as a cause for increased CHD events in this subgroup. However, CHD events among drug-treated patients were only 12% higher than average, which appears to be too small to account for the observed overall increase in CHD and all-cause mortalities following the multiple interventions. Perhaps imbalanced intakes of «6 and «3 played a role in the greater death rates, because analysis of dietary intakes (chap. 6) showed that CHD mortality in the 'usual care' group was negatively correlated with quintiles of dietary «3 FAs (fig. 61), and analysis of serum phospholipid FAs confirmed that a 1 SD higher «6 DGLA was associated with a 40% higher risk of CHD and a 1 SD higher «3 DPA or DHA accompanied a 33% lower CHD risk [Simon et al., 1995].

Fig. 10

Helsinki Businessmen Study proved that lipid nutrition based on the Cholesterol Hypothesis is even risky -Study I

Reproduced from Strandberg et al. [1991], with kind permission from American Medical Association. Copyright©, American Medical Association. All rights reserved.

Dietary intervention to raise P/S ratio was found to increase CHD 40 -|-----

Dietary intervention to raise P/S ratio was found to increase CHD 40 -|-----

Follow-up (years)

Follow-up (years)

Those with high risk factors were divided into two groups; hypotensive and hypolipidemic drugs were used in the intervention group for the first 5 years and lifestyle intervention was continued for 15 years. The intervention included energy restriction, reduction of the intake of saturated fat, cholesterol, alcohol and sugar, and increase in the intake of P (mainly as soft margarine), fish, chicken, veal and vegetables. Increasing exercise was also advised and these advices were repeated.

Outcome: CHD and all-cause mortality were higher in the intervention group.

Conclusion: The program reduced the incidence of stroke, but tended to increase that of coronary disease. In view of the small number of events, however, the significance of this observation remains uncertain. Results of Strandberg et al. [1991]: Multiple logistic regression analysis of treatments in the intervention group did not explain the 15-year excess cardiac mortality.

Our comments: For the first 5 years, hypotensive and hypolipidemic drugs were used but the amount of drug users at year 10 was similarly low in the two groups (<30%), and the difference in CHD mortality between the two groups increased after 10 years, supporting the interpretation that the increased CHD mortality is due mainly to the dietary recommendations made throughout the 15 years. All-cause mortality was also significantly higher in the intervention group (1.4-fold).

Miettinen et al. [1972] reported earlier that CHD mortality decreased by raising the P/S ratio. However, that design was a 6-year crossover study, and its conclusion is contradicted by figure 10 where the difference in CHD mortalities became greater after 10 years of intervention while TC varied little.

Further follow-up (28 years) supported the conclusion of Study I but the summary was ambiguous - Helsinki Businessmen Study II

Data taken from Strandberg et al. [1995].

Table 4

Risk Factor Group

Low risk Control Intervention Excluded Refused n = 593 n = 610 n = 612 n = 563 n = 867

Systolic Blood Pressure, mm Hg 130 135 135 144 136

Smokers, % 24.8 43.1 44.5 45.7 46.9 Mortality/1,000

Violent Death 25.3 1.6 26.1 21.3 18.5

All-cause 79.3 106.6 155.2 259.3 179.9

Beside the two groups (control and intervention groups) listed in figure 10, three groups (low risk, excluded and refused groups) were added for analysis, and the follow-up period was extended.

Conclusion: The traditional risk factors (smoking, blood pressure and cholesterol) are significantly associated with the 28-year mortality.

Our Comments: By following up a period of 28 years, the authors reached the conclusion described above. However, the added groups differ significantly in the baseline data including the known risk factors of CHD as shown in this table, hence precise comparison is possible only between the control and intervention groups, the results of which supported the original conclusion (fig. 10).

It should be noted that increased LA intake (in the form of soft margarine in this intervention) was shown in these Helsinki Businessmen Study I and II to be associated with increased CHD and all-cause mortalities while suppressing the LA (arachidonic acid) cascade has been shown to be beneficial for the prevention of CHD (fig. 67; chap. 6). We are concerned that ethical problems can be raised for continuing the same intervention for 28 years despite the lack of observed benefit after the initial 15 years of follow-up (fig. 10).

Table 5

Low-fat, low-cholesterol diet in secondary prevention of CHD - An Australian Secondary Prevention Study

Data taken from Woodhill et al. [1978].

Low-fat, low-cholesterol diet in secondary prevention of CHD - An Australian Secondary Prevention Study


P/S ratio of


TC, mg/dl

TG, mg/dl















0.5 0.5

486 508





100 100

After 5 years

0.8 1.7b

342 248b





84 76a

1 Survival data were calculated from the survival curves shown as a figure in the original paper. a p <0.001; b p <0.001.

1 Survival data were calculated from the survival curves shown as a figure in the original paper. a p <0.001; b p <0.001.

Four hundred and eight men with CHD participated in a trial of secondary prevention for 2-7 years in Australia. The group (F) with elevated P/S ratio of ingested FAs (p < 0.001), decreased cholesterol intake (p < 0.001) and lowered plasma TC levels (p < 0.01) exhibited a significantly smaller survival rate (p < 0.01) at 5 years of the trial.

Conclusion: Multivariate analysis showed that none ofthe dietaryfactors were significantly related to survival. Prognosis was determined largely by the extent of coronary and myocardial disease as judged by the usual clinical parameters. Recreational physical activity had a strongfavorable influence on survival when all other factors were kept constant.

Our comment: Despite the conclusion drawn by the authors, we interpret the data to indicate that the intervention based on the 'Cholesterol Hypothesis' brought about unfavorable effects on CHD patients.

Dietary advice was revealed to be the most serious risk factor for CHD in Japan.

An area-matched control study in relation to the Japan Lipid Intervention Trial (J-LIT)

Data taken from Yoshiike and Tanaka [2001].

Dietary advice (yes vs. no) Age (+10 years) Blood pressure (+10 mm Hg) Hypotensive drugs (yes vs. no) TC value (+10 mg/dl) HDL-cholesterol (+10 mg/dl) Gender (F vs. M)

Dietary advice (yes vs. no) Age (+10 years) Blood pressure (+10 mm Hg) Hypotensive drugs (yes vs. no) TC value (+10 mg/dl) HDL-cholesterol (+10 mg/dl) Gender (F vs. M)

p values








Hazard ratio

p values








Hazard ratio

This is a kind of control study to the J-LIT in which the effects of a low dose of simvastatin were evaluated (fig. 42). Subjects with TC values of 220299 mg/dl (n = 4,918, 35-70 years of age) and under 'usual care' were followed for 6 years. The incidence of MI and sudden cardiac death was 36 for 29,025 persons-year. Changes in TC value were -10.9 mg/dl for those without hypolipidemic drugs and -17.9 mg/dl for those who started taking hypolipidemic drugs.

Conclusions: Dietary advice was strongly associated with high risk of CHD, but possible confounding factors must be considered (translated).

Our comments: Currently, in the medical field in Japan, dietary advice is based on both the Cholesterol Hypothesis and the effectiveness of seafood «3 FAs (Ministry of Health, Labor and Welfare Japan, and Japan Medical Society). That is, increasing the intake of P (LA in vegetable oils) and seafood «3 FAs while decreasing the intake of saturated fats and cholesterol is recommended. However, LA («6) and other «6 FAs compete with «3 FAs at many enzymatic steps (chap. 7, section 2). Therefore, advising increased intake of both «6 and «3 FAs at the same time is not reasonable. We suggest that increased intake of LA may be a major cause for the observed increase in CHD incidence in the group with dietary advice. Higher intakes of LA accompanied higher rates of CHD (fig. 9-11; tables 4, 5), whereas decreasing LA intake was effective for the secondary prevention of CHD events (fig. 67). Similarly, the nutritional changes according to the Cholesterol Hypothesis were associated with increased CHD as seen in the Israeli Paradox [Yam et al., 1996], the Indian Paradox [Pella et al., 2003], and the Okinawa, Japan, story [Okuyama et al., 1996].


Cholesterol metabolism in our body is regulated in a complex manner, and the consequences of short-term and long-term dietary manipulations differ. Needless to say, dietary recommendations for the prevention of chronic diseases must be based on the results from long-term interventions or habitual nutrition (>several years). The difference, if any, in hypocholesterolemic activities of equal calorie amounts of animal fats and high-LA vegetable oils is very small in the long term. Because much TC is carried on LDL, TC values and LDL-C values are highly positively correlated, and either measure is associated with CHD in similar ways. The dietary recommendations based on the so-called Cholesterol Hypothesis actually increased CHD risk as noted in the MRFIT Study (subgroup), Helsinki Businessmen Study, Australian Study and Japanese J-LIT Area-Matched Control Study. Other studies also point out the increased CHD mortality by raised P/S ratio of foods (Israeli Paradox, Indian Paradox, Okinawan observation).

Chapter 2

Association of High Total Cholesterol with Coronary Heart Disease Mortality Differs among Subject Populations - Familial Hypercholesterolemia as a Key Concept

The association of TC with CHD (relative risk for the highest to lowest TC) differs among subject populations and among age groups. The mortality ratios range from more or less 5 (MRFIT Study, Tarui Report in Japan) to a nonsignificant level as in general populations in Japan and aged populations in the Western countries. The association is strong in younger generations (30-40 years of age) but very weak in aged groups (MRFIT Study, Framingham Heart Study). In some Japanese studies, the proportions of familial hypercholesterolemia (FH) were estimated or there were descriptions suggesting the presence of more than average proportion of FH (~0.2%). When subjects with high risks for CHD (e.g. high TC values) were selected, the subject populations are likely to include more than average proportions of FH.

So far, non-FH subjects with high TC values have been assumed to have pathological properties analogous to those of FH. However, there appear to be a number of differences in lipid metabolism in peripheral tissues (blood vessels) between FH and hypercholesterolemic non-FH cases. In this chapter, we put emphasis on the proportion of FH in the subject populations to interpret apparent discrepancies (variability) in relative risks of high TC in CHD mortality.


Characteristics of Familial Hypercholesterolemia

Table a

Table a

Characteristics of familial hypercholesterolemia

• Characterized by Brown & Goldstein as those with abnormal LDL receptor functions

• High TC and high LDL/HDL ratios even from young ages

• CHD events are higher by >10-fold even in heterozygote (Mabuchi et al., 1986)

• Lifespan is shorter by roughly 20% in heterozygote and 60% in homozygote

• Frequency is roughly 0.2% in the Western countries and in Japan (Fouchier et al., 2001)

• Relatively resistant to statin inhibition of cholesterol synthesis

• Up-regulation and inadequate feedback suppression of cholesterol synthesis

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