LETTER TO THE EDITOR
Heterogeneity of response to lipid-lowering therapy
Richard G. Bach, MDa
a Cardiac Intensive Care Unit, Washington University Medical Center, Box 8086, 660 South Euclid Avenue, St. Louis, Missouri 63110 USA
rbach{at}im.wustl.edu
I read with great interest the article by Penny et al. (1) on changes in endothelium-dependent vasomotor responses in mildly diseased coronary arteries after lipid-lowering therapy. In that report, the investigators studied angiographic responses to acetylcholine (Ach) along successive 3-mm coronary segments. On average there was a small improvement in vasoresponsiveness to Ach after lipid-lowering therapy. Changes in responsiveness correlated with a marker of oxidized low-density lipoprotein (LDL), but not with LDL or total cholesterol levels. As the title implies, the researchers concluded that, overall, lipid-lowering drug treatment reverses coronary endothelial dysfunction.
Although the reported observations generally support the broad concept that, on average, lipid lowering in hypercholesterolemic individuals with atherosclerotic disease can improve endothelial function, they also appear to suggest a potentially important additional and perhaps counterintuitive hypothesis: that the coronary vasomotor responses of some patients may actually react adversely to lipid-lowering therapy. Reiterating the original observations of El-Tamimi et al. (2), who showed adjacent segments in the same artery can show vasodilatory and vasoconstrictive responses, the investigators document an extraordinary heterogeneity in responses of individual coronary segments to Ach, both at baseline and after treatment. More remarkable, the changes in intraindividual coronary artery segment responses after therapy appear to occur in both directions, with a large number of segments showing a decline in vasodilation or vasoconstriction at follow-up. Though the majority of the "most constricted" segments at baseline demonstrated improved responses at follow-up, only 4 of the 29 patients showed arteries that lacked some segmental "deterioration" in function. Judging from Figure 3 in the Penny et al. (1) study, where individual segment response changes were plotted, it appears that 40% to 45% of patients showed a predominantly contrarian response, with more segments showing a decline in vasomotor responsiveness rather than "improvement." Whereas this may represent regression to the mean, the mechanism is unclear. Although the graphical expression of the data suggests moderation of responses at follow-up, it leaves some ambiguity with respect to the severity of the deteriorated segmental responses, and it seems possible that the magnitude of the heterogeneity may have been underestimated by the methods employed.
The benefits of lipid-lowering therapy for reducing clinical events in patients with hypercholesterolemia and coronary artery disease have been well established. The observations by Penny et al. (1), as well as the results of the Coronary Artery Reactivity After Treatment with Simvastatin (CARATS) trial (3), which failed to show significant improvement in endothelium-dependent coronary vasomotor and blood flow responses in patients treated for six months with simvistatin, highlight a degree of complexity and inter- and intraindividual variability of response to statin and/or lipid-lowering therapy that is currently poorly understood, and yet is one that raises important questions. Are these heterogeneous responses the result of random variability, or do the data imply that there is a subgroup of patients whose coronaries may respond poorly or even adversely to lipid-lowering therapy? Because the investigators have demonstrated a correlation between changes in responsiveness and levels of circulating oxidized LDL (which are not reliably reduced by statin therapy [4]), do the results imply that oxidized LDL levels may help identify those patients who are unlikely to show improvement in endothelial function with lipid-lowering therapy alone, and may need more aggressive additional treatment? Would the clinical benefit of statin therapy be greater if we could select likely patient/coronary "responders" from "nonresponders" or worse, "adverse responders"? Given that multiple mechanisms may be involved in the benefit of statin therapy, this interpretation might be overly simplistic. Nevertheless, the observations of Penny et al. (1) suggest variability in coronary responses to lipid-lowering therapy that may be clinically relevant and warrant further investigation.
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References
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1. Penny WF, Ben-Yehuda O, Kuroe K, et al. Improvement of coronary artery endothelial dysfunction with lipid-lowering therapy: heterogeneity of segmental response and correlation with plasma-oxidized low density lipoprotein. J Am Coll Cardiol. 2001;37:766–774[Abstract/Free Full Text]
2. El-Tamimi H, Mansour M, Wargovich TJ, et al. Constrictor and dilator responses to intracoronary acetylcholine in adjacent segments of the same coronary artery in patients with coronary artery disease: endothelial function revisited. Circulation. 1994;89:45–51[Abstract/Free Full Text]
3. Vita JA, Yeung AC, Winniford M, et al. Effect of cholesterol-lowering therapy on coronary endothelial vasomotor function in patients with coronary artery disease. Circulation. 2000;102:846–851[Abstract/Free Full Text]
4. Toshima S-T, Hasegawa A, Kurabayashi M, et al. Circulating oxidized low density lipoprotein levels: a biochemical risk marker for coronary heart disease. Arterioscler Thromb Vasc Biol. 2000;20:2243–2247[Abstract/Free Full Text]
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