Correspondence

Cholesterol Lowering and Coronary Vasomotion

N Engl J Med 1995; 333:324-325August 3, 1995

Article

To the Editor:

Anderson et al. (Feb. 23 issue)1 suggest that the patients in their study obtained the most improvement in endothelium-dependent coronary vasomotion when treated with cholesterol-lowering therapy in combination with an antioxidant. The authors seem to be overinterpreting their findings.

It has previously been shown that dietary therapy has a favorable effect on endothelium-dependent vasorelaxation.2 It is disappointing that the compliance of the group that received dietary therapy alone was not monitored closely. It is unwise to dismiss an effect of diet without having the patients adhere to both the American Heart Association Step 1 and Step 2 diets, as proposed by the Adult Treatment Panel. Although the greatest improvement in vasomotion was evident in the group receiving both low-density lipoprotein (LDL)–lowering and antioxidant therapy as compared with dietary therapy alone, there were no significant differences in the groups with respect to symptoms of recurrent ischemia over the one-year period (35 percent and 27 percent, respectively). One could speculate that the lowering of high-density lipoprotein (HDL) cholesterol levels by probucol could have accounted for this finding.

Also, the authors do not justify their choice of the antioxidant probucol, given the recent disappointing findings of the Probucol Quantitative Regression Swedish Trial3 and the fact that probucol lowers HDL cholesterol levels and prolongs the QT interval, increasing the risk of arrhythmias. Other groups have clearly shown that antioxidants such as vitamin E might also promote endothelial-dependent vasorelaxation.4 To obtain the maximal benefit, it might be more beneficial to prescribe an antioxidant that does not have a deleterious effect on the plasma lipid profile or conducting system in combination with a cholesterol-lowering therapy.

I. Jialal, M.D.
University of Texas Southwestern Medical Center, Dallas, TX 75235-9072

4 References

1. 1

   Anderson TJ, Meredith IT, Yeung AC, Frei B, Selwyn AP, Ganz P. The effect of cholesterol-lowering and antioxidant therapy on endothelium-dependent coronary vasomotion. N Engl J Med 1995;332:488-493
   Full Text | Web of Science | Medline

2. 2

   Harrison DG, Armstrong ML, Freiman PC, Heistad DD. Restoration of endothelium-dependent relaxation by dietary treatment of atherosclerosis. J Clin Invest 1987;80:1808-1811
   CrossRef | Web of Science | Medline

3. 3

   Walldius G, Erikson U, Olsson AG, et al. The effect of probucol on femoral atherosclerosis: the Probucol Quantitative Regression Swedish Trial (PQRST). Am J Cardiol 1994;74:875-883
   CrossRef | Web of Science | Medline

4. 4

   Stewart-Lee AL, Forster LA, Nourooz-Zadeh J, Ferns GA, Anggard EE. Vitamin E protects against impairment of endothelium-mediated relaxations in cholesterol-fed rabbits. Arterioscler Thromb 1994;14:494-499
   CrossRef | Medline

Author/Editor Response

The authors reply:

To the Editor: Our study concluded that the combination of cholesterol-lowering and antioxidant therapy improved endothelium-dependent coronary vasomotion more than an American Heart Association Step 1 diet. Dr. Jialal suggests that aggressive dietary therapy may be an alternative to drug therapy.1 In the study by Harrison et al. that he cites in support of the concept that dietary therapy normalizes endothelial function, an animal model with cholesterol-induced atherosclerosis was used. Treated primates had cholesterol levels that were 80 to 90 percent less than those of untreated primates — reductions that cannot be obtained in humans. We chose a diet that could be followed by most patients with a high compliance rate. Although the data were not presented, compliance was excellent. There was no significant change in the cholesterol levels in our diet group, because most patients were following a prudent diet before the study. It is possible that coronary endothelial function may improve in the few patients who can follow an aggressive cholesterol-lowering diet that lowers total cholesterol to the same degree as drug therapy. This hypothesis has not been tested in humans. The method of cholesterol lowering may not be as important as the reduction in cholesterol itself.

The choice of the antioxidant was based on the best information available when the study began in 1991. At that time it had been shown that probucol could attenuate oxidative modification of LDL2 and was more potent than antioxidant vitamins in its ability to protect LDL against oxidation. Thus, we chose what we considered at the time to be the most potent antioxidant available. Recent evidence has demonstrated that vitamin antioxidants have a beneficial effect on endothelium-dependent vasomotion in animal models, although the clinical usefulness of these findings has yet to be determined.3

Todd Anderson, M.D.
Foothills Hospital, Calgary, AB T2N 2T9, Canada

Ian T. Meredith, M.B., B.S., Ph.D.
Peter Ganz, M.D.
Brigham and Women's Hospital, Boston, MA 02115

3 References

1. 1

   Ornish D, Brown SE, Scherwitz LW, et al. Can lifestyle changes reverse coronary heart disease? The Lifestyle Heart Trial. Lancet 1990;336:129-133
   CrossRef | Web of Science | Medline

2. 2

   Parthasarathy S, Young SG, Witztum JL, Pittman RC, Steinberg D. Probucol inhibits oxidative modification of low density lipoprotein. J Clin Invest 1986;77:641-644
   CrossRef | Web of Science | Medline

3. 3

   Keaney JF Jr, Gaziano JM, Xu A, et al. Dietary antioxidants preserve endothelium-dependent vessel relaxation in cholesterol-fed rabbits. Proc Natl Acad Sci U S A 1993;90:11880-11884
   CrossRef | Web of Science | Medline