Penny, William F.

Peterson, Kirk L.

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Heterogeneity of response to lipid-lowering therapy: Reply 

REFERENCES
1. Penny WF, Ben-Yehuda O, Kuroe K, et al. Improvement of coronary
artery endothelial dysfunction with lipid-lowering therapy: heterogene-
ity of segmental response and correlation with plasma-oxidized low
density lipoprotein. J Am Coll Cardiol 2001;37:766–74.
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.
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;102:846–51.
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;20:2243–7.
REPLY
We appreciate Dr. Bach’s interesting comments regarding our
study of the changes in coronary endothelial dysfunction occurring
after lipid lowering (1). We certainly agree that the segmental
heterogeneity of these changes in response to acetlycholine sug-
gests a level of complexity that has been previously underempha-
sized.
The reduction in clinical events in groups of patients on
lipid-lowering therapy is irrefutable. Our work confirms previous
reports that this therapy can also improve endothelial function in
a group of patients. However, as in all therapies, not all patients
respond equally, and the inclusion of all analyzable coronary
segments in our study expands on the original observation of
El-Tamimi et al. (2) that not all areas of the artery respond equally.
As pointed out in our current study (1) as well as in our earlier
work (3), it is difficult to separate true physiologic heterogeneity
from methodologic variablity inherent in all analytic techniques.
We reiterate that the phenomenon of regression to the mean may
well account for some of the findings of most constricted and most
dilated segmental responses being moderated on follow-up. How-
ever, the conclusion that some responses are actually adversely
affected by lipid reduction cannot be made by our study given the
lack of a comparative placebo group—a more abnormal response
might be expected at follow-up given the natural history of
atherosclerotic coronary disease, and some of these “worsened”
responses could have been an improvement over that seen in the
absence of lipid reduction.
We agree that the pattern of vasomotor response and the
correlation with oxidized low-density lipoprotein may possibly
reflect a given patient’s clinical response to lipid-lowering therapy.
This observation deserves further study.
William F. Penny, MD, FACC
Division of Cardiology
VA San Diego Healthcare System
University of California, San Diego
3350 La Jolla Village Drive
San Diego, California 92161
Kirk L. Peterson, MD, FACC
PII S0735-1097(01)01623-0
REFERENCES
1. Penny WF, Ben-Yehuda O, Kuroe K, et al. Improvement of coronary
artery endothelial dysfunction with lipid-lowering therapy: heterogene-
ity of segmental response and correlation with plasma-oxidized low
density lipoprotein. J Am Coll Cardiol 2001;37:766–74.
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.
3. Penny WF, Rockman H, Long J, et al. Heterogeneity of vasomotor
response to acetylcholine along the human coronary artery. J Am Coll
Cardiol 1995;25:1046–55.
Vascular Endothelial Growth Factor:
Angiogenesis, Atherogenesis or Both?
Vascular endothelial growth factor (VEGF), a specific mitogen for
endothelial cells, was initially regarded to be a remedy for impaired
reendothelialization of arteries in patients treated with balloon
angioplasty. Supplementation with VEGF was also expected to
induce the formation of blood vessels nourishing ischemic heart or
peripheral muscles.
Among the studies demonstrating the therapeutic efficiency of
VEGF were reports suggesting the opposite (1,2). It took, how-
ever, several years until stronger evidence was obtained. In recent
issues of JACC (1) and Nature Medicine (2) Celletti et al. (1,2) have
published data demonstrating that VEGF promotes atherogenesis.
They used two animal models: double knockout mice (apoE/
apoB100), in which spontaneous atherosclerosis was aggravated by
a single injection of a low dose of VEGF protein (2), and
cholesterol-fed rabbits, which when treated by VEGF developed
larger plaques (1,2). The investigators showed that VEGF in-
creased the total number of blood and plaque monocytes/
macrophages and enriched the pool of circulating CD34/flk1
progenitor cells that might enhance neoangiogenesis (1,2).
Those intriguing studies raise many questions. Particulary, it
remains to be established how those experimental data relate to the
results of the clinical trials with angiogenic growth factors, which
so far did not report any significant side effects. In our opinion the
results presented by Celletti et al. (1,2) force us also to reinvestigate
the role of VEGF using more basic approaches. One of the crucial
aims will be to understand the mechanisms governing VEGF
synthesis and angiogenic activity in normal and atherosclerotic
vessels.
We have recently demonstrated that nitric oxide (NO) enhanced
VEGF synthesis in vascular smooth muscle cells (VSMC) (3,4).
Nitric oxide synthesis is inhibited by modified low-density li-
poprotein (LDL), which is elevated in atherosclerosis (5). How-
ever, this does not result in attenuation of VEGF production. In
fact, lipid components of modified LDL enhanced VEGF expres-
sion in VSMC independently of their inhibitory effect on the
generation of NO by inducible nitric oxide synthase (iNOS) (5).
Those data, which are supported by others (6), show that
different factors can enhance VEGF in the vessel wall and initiate
or promote atherosclerosis. In fact, VEGF is strongly expressed in
the plaque (7,8). Thus, probably the inhibition, but not the
supplementation, of VEGF has to be regarded for the treatment of
atherosclerosis. Application of a strong antiangiogenic treatment
might not be a good option for patients with already impaired
blood supply and developing plaques. However, an interesting,
safer alternative might already exist. The statins, inhibitors of
2137JACC Vol. 38, No. 7, 2001 Letters to the Editor
December 2001:2131–8


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Heterogeneity of response to lipid-lowering therapy: Reply

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