Correspondence

Atherosclerosis — An Inflammatory Disease

N Engl J Med 1999; 340:1928-1929June 17, 1999

Article

To the Editor:

Several observations argue against Ross's hypothesis (Jan. 14 issue)1 that atherosclerosis is an inflammatory disease. Oxidized low-density lipoprotein (LDL) is widely distributed in the fetal aorta,2 but atherosclerotic plaques are not present until the third or fourth decade of life. This observation argues against a theory of atherogenesis based on in vitro data ascribing inflammatory activity to oxidized LDL. The presence of foamy macrophages in a fatty streak does not make the lesion inflammatory. The supposed entry of circulating monocytes into the developing fatty streak, which could be a basis for characterizing that lesion as “inflammatory,” is even in doubt. My colleagues and I have examined microscopically aortas from many young people, and we have never seen a monocyte that is adherent to the aortic endothelium.

None of the proatherogenic properties attributed to serum homocysteine, such as endothelial cytotoxicity and increased collagen synthesis, or to hypertension, such as elevated serum concentrations of angiotensin II or free radicals, explain the localization of atherosclerotic plaques. The abnormalities proposed as “proatherogenic” should also affect veins, in which atherosclerosis does not develop. Undoubtedly, decreased shear plays a part in determining the localization of atherosclerosis, as noted by Ross. But how do endothelial cytotoxicity, increased collagen production, high serum concentrations of angiotensin II, and free radicals interact with low shear to promote atherogenesis?

Gregory D. Sloop, M.D.
Louisiana State University School of Medicine, New Orleans, LA 70112

2 References

1. 1

   Ross R. Atherosclerosis -- an inflammatory disease. N Engl J Med 1999;340:115-126
   Full Text | Web of Science | Medline

2. 2

   Napoli C, D'Armiento FP, Mancini FP, et al. Fatty streak formation occurs in human fetal aortas and is greatly enhanced by maternal hypercholesterolemia. J Clin Invest 1997;100:2680-2690
   CrossRef | Web of Science | Medline

To the Editor:

Ross's review of atherosclerosis elegantly outlines its inflammatory aspects. However, we think that the importance of lipids and lipoproteins in the formation of arterial lesions is underplayed.

Is atherosclerosis fundamentally an inflammatory disease? There is considerable evidence that the root cause is the trapping and retention of cholesterol-rich, apolipoprotein B–rich lipoproteins within the arterial wall.1 Once trapped, these particles become enzymatically and oxidatively modified, they accumulate, and then they stimulate, among other responses, inflammation.

Even in the presence of other risk factors, atherosclerosis does not develop when serum cholesterol concentrations are below 80 mg per deciliter (2.1 mmol per liter), a concentration found in many animals. The arterial wall contains matrix and enzymes that retain and modify lipoproteins, thereby generating biologically active products that induce key components of the inflammatory response. Genetic, dietary, and other interventions that raise serum concentrations of atherogenic lipoproteins in animals provoke atherosclerosis. Conversely, there are no widely accepted models of atherosclerosis that arises from primary inflammatory derangements in the absence of hypercholesterolemia. Nonatherosclerotic arterial lesions can occur without arterial lipid deposition, but these are rare causes of acute vascular events and are easily distinguished from atherosclerosis. In animals with newly induced hypercholesterolemia, intramural lipoprotein retention and aggregation occur within hours in lesion-prone arterial sites,2 followed days later by endothelial expression of cell-adhesion molecules and finally by the inflammatory infiltrate. Interventions that remove arterial lipids in animals reduce the size of the lesion and correct endothelial dysfunction,3 and similar effects occur in humans treated aggressively with lipid-lowering drugs. Finally, animals expressing mutants of human apolipoprotein B engineered so that it no longer binds to arterial matrix have high serum LDL concentrations but few atherosclerotic lesions. Their LDL is no longer atherogenic, because it cannot be retained within the prelesional vessel wall.4

Kevin Jon Williams, M.D.
Thomas Jefferson University, Philadelphia, PA 19107

Ira Tabas, M.D., Ph.D.
Columbia University, New York, NY 10032

4 References

1. 1

   Williams KJ, Tabas I. The response-to-retention hypothesis of atherogenesis reinforced. Curr Opin Lipidol 1998;9:471-474
   CrossRef | Web of Science | Medline

2. 2

   Schwenke DC, Carew TE. Initiation of atherosclerotic lesions in cholesterol-fed rabbits. I. Focal increases in arterial LDL concentration precede development of fatty streak lesions. Arteriosclerosis 1989;9:895-907
   CrossRef | Medline

3. 3

   Scalia R, Rodrigueza WV, Mazany KD, Lefer AM, Williams KJ. Large unilamellar phospholipid vesicles (LUV) accelerate reverse lipid transport and normalize endothelial function in hyperlipidemic apo-E knock-out mice. Circulation 1998;98:Suppl I:I-732 abstract.
   

4. 4

   Boren J, Olin K, O'Brien KD, et al. Engineering non-atherogenic low density lipoproteins -- direct evidence for the “response-to-retention“ hypothesis of atherosclerosis. Circulation 1998;98:Suppl I:I-314 abstract.
   

To the Editor:

Twenty-three years ago, Ross and Glomset proposed that intimal proliferation of vascular smooth-muscle cells is fundamental to the development of atherosclerosis.1 Ross's review of atherosclerosis focuses more on inflammation than on the role of vascular smooth-muscle cells, but his commentary still favors a pathogenic role of these cells.

We now recognize the importance of vascular smooth-muscle cells in providing protection against plaque rupture.2 The fibrous cap is essential for the stability of the plaque, and as discussed by Ross, inflammatory cells produce proteolytic enzymes that erode it. Vascular smooth-muscle cells are responsible for the synthesis of the fibrous cap, and a dysfunction of these cells will favor instability of the plaque. The known biology of vascular smooth-muscle cells is entirely consistent with their role in plaque stability, since they change from a contractile to a synthetic (or repair) phenotype in response to injury and, in so doing, express genes that facilitate the repair and formation of the fibrous cap.

We agree with Ross that these cells are probably recruited and stimulated by activated macrophages, but we believe this is beneficial and, indeed, crucial to the stability of an evolving plaque. However, vascular smooth-muscle cells from advanced lesions are senescent and very susceptible to apoptosis.3-5 Thus, in advanced lesions the cells die readily and lack the capacity to regenerate in order to sustain the fibrous cap and contain the underlying inflammatory cells. In contrast, cells grown from restenotic lesions proliferate readily,4 suggesting that severe injury may lead to the recruitment of fresh vascular smooth-muscle cells into the intima, since plaque rupture rarely occurs at the site of previous angioplasty. Thus, the evidence suggests that the inflammation of atherosclerosis is balanced by a repair process mediated by vascular smooth-muscle cells, and a perturbation of this balance alters the stability of the plaque.

We agree with Ross's main theme that atherosclerosis is an inflammatory process, and we congratulate him on another important contribution to this field.

Peter L. Weissberg, M.D.
Martin R. Bennett, M.B., Ch.B., Ph.D.
University of Cambridge, Cambridge CB2 2QQ, United Kingdom

5 References

1. 1

   Ross R, Glomset JA. The pathogenesis of atherosclerosis. N Engl J Med 1976;295:369-377
   Full Text | Web of Science | Medline

2. 2

   Libby P. Molecular bases of the acute coronary syndromes. Circulation 1995;91:2844-2850
   Web of Science | Medline

3. 3

   Ross R, Wight TN, Strandness E, Thiele B. Human atherosclerosis. I. Cell constitution and characteristics of advanced lesions of the superficial femoral artery. Am J Pathol 1984;114:79-93
   Web of Science | Medline

4. 4

   Dartsch PC, Voisard R, Betz E. In vitro growth characteristics of human atherosclerotic plaque cells: comparison of cells from primary stenosing and restenosing lesions of peripheral and coronary arteries. Res Exp Med (Berl) 1990;190:77-87
   CrossRef | Medline

5. 5

   Bennett MR, Evan GI, Schwartz SM. Apoptosis of human vascular smooth muscle cells derived from normal vessels and coronary atherosclerotic plaques. J Clin Invest 1995;95:2266-2274
   CrossRef | Web of Science | Medline

Author/Editor Response

Dr. Ross replies:

To the Editor: Dr. Sloop suggests that several observations argue against the hypothesis that atherosclerosis is an inflammatory disease. However, he fails to note that in their earliest stages, the fatty streaks consist of collections of monocyte-derived macrophages (with or without lipid), together with varying numbers of T lymphocytes. By definition, such a collection of cells represents a form of chronic inflammation. Dr. Sloop also doubts that circulating monocytes enter developing fatty streaks. It is not surprising that in autopsies of young people one does not see monocytes adherent to the aortic endothelium, because this tissue is not perfusion-fixed and many changes take place before the tissue has been removed. In fact, the adherence of monocytes or T cells to the endothelium is probably an irregular phenomenon. The fact that monocytes and macrophages are present in each stage of the disease casts little doubt on the hypothesis that this is an inflammatory process. As progression to an advanced lesion occurs, it is accompanied by a fibroproliferative process, which is a characteristic response to long-standing inflammation. Angiotensin II, free radicals, and so forth could all easily participate in such a process.

Drs. Williams and Tabas suggest that atherosclerosis results from the accumulation of cholesterol-rich, apolipoprotein B–rich lipoproteins within the arterial wall and that, once trapped, these particles become modified and induce an inflammatory response. One of the earliest changes in the artery is the accumulation of extracellular lipid in various forms, such as lipoproteins and aggregated lipoproteins. In species other than humans and nonhuman primates, atherosclerosis does not develop when serum LDL cholesterol concentrations are below 80 mg per deciliter. Unfortunately, this fact does not help us understand what is happening in humans, in whom the lipoprotein profiles are so different. Furthermore, it is well known that patients with hypertension or those who smoke cigarettes but have normal serum lipid concentrations can have atherosclerotic lesions. However, I have no argument with the statement that when lipoproteins are retained by the matrix they can be modified and can induce the inflammatory response that we call atherogenesis.

The comments of Drs. Weissberg and Bennett are cogent as they relate to the role of smooth-muscle cells in forming the fibrous cap. The stability of the fibrous cap and inflammation, as well as senescence of smooth-muscle cells in advanced lesions, are critical to the prevention of cap rupture and sudden death.

Russell Ross, Ph.D.
University of Washington School of Medicine, Seattle, WA 98195-7470

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