Reply to D Lanzmann-Petithory et al

University of Groningen Department of General Practice Bloemsingel 1 9713 BZ Groningen Netherlands E-mail: w.bemelmans{at}med.rug.nl

Dear Sir:

We appreciate the comments of Lanzmann-Petithory et al on our MARGARIN (Mediterranean Alpha-linolenic enRiched Groningen dietARy INtervention) study regarding the effects of -linolenic acid (ALA) on the primary prevention of ischemic heart disease (1). We would like to respond to several of the issues raised. First, as pointed out in our article, the intent of the MARGARIN study was not to investigate the effects of ALA on morbidity or mortality. The power of our study was not sufficient, and, because of budgetary and logistic reasons, it was not possible to include 600 persons, as Lanzmann-Petithory et al suggest we should have. Actually, at the time our study was designed, we considered that 600 persons would not be sufficient because event rates are much lower in a primary prevention trial than in a secondary prevention trial such as the Lyon Diet Heart Study (2). Furthermore, Lanzmann-Petithory et al state that our results regarding coronary events were beneficial (which indeed is intriguing in itself), but they ignored our observation that the overall mortality rate seemed to be less favorable in the ALA group than in the linoleic acid (LA) group (3 deaths compared with 1 death).

The goal of the MARGARIN study was to investigate the long-term effects of ALA on cardiovascular disease risk factors in a population at high risk of ischemic heart disease (1). We found that ALA had less favorable effects on serum lipids than did LA: not only a lower HDL-cholesterol concentration but a higher (by 0.24 mmol/L) serum triacylglycerol concentration. In contrast, the effect on plasma fibrinogen was beneficial, which may indicate a positive effect on thrombolytic processes. In addition, we also found a lower concentration of C-reactive protein among ALA users (WJE Bemelmans, J Broer, AJ Smit, and EJM Feskens, unpublished observations, 2002). This suggests another explanation for the lower plasma fibrinogen concentration, namely an inhibitory effect of ALA on inflammatory processes or a proinflammatory effect of LA, as was shown in several experimental models (3). Hence, our conclusion was that the long-term effects on primary prevention seem to be similar because the positive effects on plasma fibrinogen (and C-reactive protein) may be counteracted by the negative effects on HDL cholesterol and serum triacylglycerol. We respectfully disagree with Lanzmann-Petithory et al that this conclusion would be misleading because it refers to the estimated risk of developing ischemic heart disease. A similar effect of ALA and LA was also seen on other measures of ischemic heart disease risk in our study group. We recently reported an association of changes in saturated fat intake with changes in intima-media thickness and soluble intercellular adhesion molecule 1 (4) but found no difference between the effects of ALA and LA in this respect.

Regarding the cardioprotective effects of ALA, we would like to add the following. Certainly, other mechanisms besides the serum lipid profile play a role in the potentially protective effect of ALA. Therefore, according to the study protocol, the outcome measures of the MARGARIN study initially included the response of platelets to aggregation. Unfortunately, we could not use the results of these analyses because of laboratory difficulties. Evidence in the literature regarding the effects of ALA on thrombolytic processes is not conclusive (5, 6); the same is true for the effects of ALA on the prevention of cardiac arrhythmia in animal studies (7).

Furthermore, results from large observational studies are conflicting (8). Finally, in the Lyon Diet Heart Study, other changes in the diet were not completely controlled for and could partially explain the protective effects of the diet in the intervention group. Hence, in our opinion, more research is needed to obtain insight on the protective effects of ALA because the evidence is not conclusive. The contribution of the MARGARIN study is the finding that it seems to be safe to increase ALA intakes (up to 6 times the usual intake) long term in persons at high risk of ischemic heart disease. However, it cannot be concluded from our study that ALA intake should be increased.

REFERENCES

1. Bemelmans WJE, Broer J, Feskens EJM, et al. Effects of an increased intake of -linolenic acid and group nutritional education on cardiovascular risk factors: the Mediterranean Alpha-linolenic Enriched Groningen Dietary Intervention (MARGARIN) study. Am J Clin Nutr 2002;75:221–7.
2. De Lorgeril M, Renaud S, Mamelle N, et al. Mediterranean alpha-linolenic acid-rich diet in secondary prevention of coronary heart disease. Lancet 1994;343:1454–9.
3. Young VM, Toborek M, Yang F, et al. Effect of linoleic acid on endothelial cell inflammatory mediators. Metabolism 1998;47:566–72.
4. Bemelmans WJE, Lefrandt JD, Feskens EJM, et al. Change in saturated fat intake is associated with progression of carotid and femoral intima-media thickness, and with levels of soluble intercellular adhesion molecule-1. Atherosclerosis 2002;163:113–20.
5. Li D, Sinclair A, Wilson A, et al. Effect of dietary -linolenic acid on thrombotic risk factors in vegetarian men. Am J Clin Nutr 1999;69:872–82.
6. Wensing AG, Mensink RP, Hornstra G. Effects of dietary n-3 polyunsaturated fatty acids from plant and marine origin on platelet aggregation in healthy elderly subjects. Br J Nutr 1999;82:183–91.
7. Schimke I, Haberland A, Wirth M, et al. Influence of long-term supplementation with alpha-linolenic acid on myocardial lipid peroxidation and antioxidative capacity in spontaneously hypertensive rats. Prostaglandins Leukot Essent Fatty Acids 1997;57:545–50.
8. Oomen CM, Ocké MC, Feskens EJM, et al. -Linolenic acid intake is not beneficially associated with 10-year risk of coronary artery disease incidence: the Zutphen Elderly Study. Am J Clin Nutr 2001;74:457–63.