Hyperlipidemia and atherosclerosis

Author

Ross R, Harker L Reference

Science 1976; 193: 1094-1100 Abstract

Chronic hyperlipidemia initiates and maintains lesions by endothelial cell desquamation and lipid accumulation.

Summary

In this paper, Ross and Harker describe the effect of hyperlipidemia on the growth of vascular lesions, with and without mechanical injury, in primates. The article begins with an overview of the response to injury hypothesis to explain atherosclerosis development. According to this hypothesis (in 1976), everyone is susceptible to various forms of endothelial injury including mechanical, chemical, immunological and toxic sources. If the injury is a single event, the lesions would be reversible but continuous exposure to a toxic stimulus would lead to lesion progression which may be irreversible. Upon disruption of endothelial integrity, the vascular smooth muscle cells would be exposed to elements from the plasma that would stimulate proliferation. At the time of this paper, the principle mitogen present in blood serum responsible for the stimulation of smooth muscle cell growth was thought to be platelet-derived. In studies examining the effect of hyper-lipidemia on vascular lesion formation, a group of monkeys were fed a hypercholesterolaemic diet and followed for up to 18 months after aorto-iliac balloon injury. At 6 weeks to 3 months following arterial injury, hypercholesterolaemic monkeys displayed thickened intima filled with lipid-laden cells which were presumptively identified as vascular smooth muscle cells. The number of cells comprising the intima in a control group of normolipidemic monkeys following injury was similar but the amorphous lipid inclusions were lacking. Long-term follow-up revealed that the lesions in the hyperlipidemic group had progressed while those in the normolipidemic group had regressed. Thus, hyperlipidemia promoted intimal growth after injury. Critical observations were then made in the non-injured iliac artery. By 10 months following initiation of hyperlipidemia, there were no differences between the injured and non-injured iliac arteries. Both arteries (injured and non-injured) contained 10-15 layers of lipid-laden smooth muscle cells surrounded by extracellular lipid and large quantities of newly formed connective tissue matrix. To search for evidence that hyperlipidemia was causing endothelial injury, Ross examined endothelial integrity in the hyper-lipidemic animals using special staining techniques. In all of the hyperlipidemic animals, there was focal loss of endothelial cells accounting for approximately 5% of the aorto-iliac endothelial surface. In some areas, the longitudinal shape of the endothelial cells had changed to a polyhedral or round configuration, indicating abnormal endothelial regeneration.

Since platelet-derived factors were believed to be critical to the growth of vascular lesions following endothelial injury, measures of platelet activity were performed. Ross and Harker found that platelet survival was reduced from 8 days to 5.8 days in animals that were hyperlipidemic for more than 6 months. To determine whether the reduced platelet survival was due to increased platelet consumption at exposed endothelial surfaces or secondary to a direct effect of hyper-lipidemia, labelled platelets were transfused from a normolipidemic animal into a hyperlipidemic

Response Injury Hypothesis

Figure 1 In the response to injury hypothesis, two different cyclic events may occur. The outer or regression cycle may represen t common single occurrences in all individuals in which endothelial injury leads to desquamation., platelet adherence, aggregation, and release, followed by intimal smooth muscle proliferation and connective tissue formation. If the injury is a single event, the lesions may go on to heal and regression occurs. The inner or progression cycle demonstrates the possible consequences of repeated or chronic endothelial injury as may occur in chronic hyperlipidemia. In this instance, lipid, deposition as well as continued smooth muscle proliferation may occur after recurrent sequences of proliferation and regression, and these may lead to complicated, lesions that calcify. Such lesions could go on to produce clinical sequelae, such as thrombosis and infarction.

Figure 1 In the response to injury hypothesis, two different cyclic events may occur. The outer or regression cycle may represen t common single occurrences in all individuals in which endothelial injury leads to desquamation., platelet adherence, aggregation, and release, followed by intimal smooth muscle proliferation and connective tissue formation. If the injury is a single event, the lesions may go on to heal and regression occurs. The inner or progression cycle demonstrates the possible consequences of repeated or chronic endothelial injury as may occur in chronic hyperlipidemia. In this instance, lipid, deposition as well as continued smooth muscle proliferation may occur after recurrent sequences of proliferation and regression, and these may lead to complicated, lesions that calcify. Such lesions could go on to produce clinical sequelae, such as thrombosis and infarction.

animal and from a hyperlipidemic animal to a normolipidemic animal. Platelets from the hyper-lipidemic animals survived normally in the normolipidemic animals while survival of platelets from the normolipidemic animals was reduced in the hyperlipidemic animals. The authors concluded that reduced platelet survival was due to increased platelet consumption on exposed sub-endothelium and they went on to demonstrate a correlation between the amount of endothe-lium removed and platelet survival.

Citation Count 543

Key message

Hyperlipidemia is sufficient to cause endothelial injury, initiation, and growth of atherosclerotic plaques. This study also demonstrated the effect of the hyperlipidemic environment on the progression of vascular lesions following mechanical injury.

Strengths

In a primate model, the authors clearly demonstrated a critical direct role for a hypercholestero-laemic diet in the initiation and progression of atherosclerosis. The implications of these studies were that understanding and targeting factors involved in lipid metabolism could lead to therapeutic breakthroughs.

Weaknesses

The hypothesis that platelets or platelet products were essential to growth of the atherosclerotic plaque was not adequately tested. Thus the role of platelets in atherosclerotic lesion growth, based on in vitro vascular smooth muscle cell culture experiments and the transfusion experiments, was probably overemphasized.

Title 3

The role of the monocyte in atherogenesis:

I. Transition of blood-borne monocytes into foam cells in fatty lesions

II. Migration of foam cells from atherosclerotic lesions

Author

Gerrity RG Reference

Am J Pathol 1981; 103: 181-190, 191-199 Abstract

Paper I:

In a previous publication the author and his co-workers demonstrated that atherosclerotic lesion development in the aorta of hypercholesterolemic pigs was preceded by intimal penetration of blood-borne mononuclear cells, and that medial smooth muscle cells were not involved in the formation of early fatty lesions in this model. The current study shows that aortic arch lesions do not progress beyond the fatty cell lesion stage for up to 30 weeks of a moderate cholesterol/lard diet, although they become more extensive in area. Mononuclear cells were found adherent to the endothelium, in endothelial junctions, and in the intima during this period, and were ultrastructurally identified as monocytes by the presence of peroxidase-positive granules (peroxisomes) in their cytoplasm. In addition, lesion areas with nonspecific esterase activity correlated well with Sudan IV staining. Intimal monocytes and altered intimal monocytes with an enlarged cytoplasm and containing a few lipid droplets were both shown to be phagocytic by their uptake of ferritin, which had penetrated the intima after intravenous injection. Circulating monocytes and those adherent to the endothelial surface did not contain ferritin in these animals. The results indicate that blood mononuclear cells associated with lesion formation in this model are, in fact, monocytes, which subsequently undergo transformation into macrophage foam cells in fatty streak lesions. The absence of medial cell involvement indicates that mono-cytes are the major foam cell precursor in these lesions.

Paper II:

A defined role in the atherogenic sequence is proposed for the circulating monocyte. The author has been able to demonstrate a "monocyte clearance system" in which large numbers of circulating monocytes invade the intima of lesion-prone areas in arteries, become phagocytic, and accumulate lipid. A fatty cell lesion results. Once lipid-laden, foam cells migrate back into the bloodstream by crossing the arterial endothelium. The ratio of penetrating monocytes to emerging foam cells decreases as fatty cell lesions develop until a one-to-one ratio is achieved in late fatty cell lesions, which do not progress further. Advanced fibroatherosclerotic plaques in the same animals do not show the same characteristics and have smooth muscle cell involvement. It would appear that advancement of the lesion is at least partially a result of failure of the mono-cyte clearance system to remove sufficient lipid. The invasion of monocytes and endothelial damage caused by foam cell clearance may, in late fatty lesions, contribute to plaque evolution by introducing growth factors from macrophages and platelets and allowing greater lipid influx. Elucidation of this system was facilitated by the examination of vessels from diet initiation onwards and by the observation of late nonprogressing fatty cell lesions. It is possible that this

Monocytes Nucleus

Figure 1 (a) TEM of monocyte (M) trapped in junction of endothelium (E) from arch area of 12-week pig. Main body and nucleus of cell are in the lumen (Lu), with cellular extensions (arrows) spread below endothelium (uranyl acetate, lead citrate, X 12,400). (b) Monocyte (M) beneath endothelium (E) in a 15-week arch lesion from a pig injected with ferritin 15 min before death. Ferritin can be seen in phagocytotic vacuoles (arrows), one of which is open to the intimal space. Inset shows ferritin in vacuole in squared area (unstained, X 15,500; inset, X 61,000). (c) SEM of monocyte (M) adherent to endothelium (E). Cytoplasmic extensions from monocyte can be seen to indent endothelial plasma membrane (arrows); (d) TEM of "hypertrophied" monocyte (HM) beneath endothelium (E) in 30-week abdominal lesion.. Peroxidase-positive granules (arrows) can be seen in the cytoplasm (uranly acetate, lead citrate; peroxidase-reacted, X 12,500).

Figure 1 (a) TEM of monocyte (M) trapped in junction of endothelium (E) from arch area of 12-week pig. Main body and nucleus of cell are in the lumen (Lu), with cellular extensions (arrows) spread below endothelium (uranyl acetate, lead citrate, X 12,400). (b) Monocyte (M) beneath endothelium (E) in a 15-week arch lesion from a pig injected with ferritin 15 min before death. Ferritin can be seen in phagocytotic vacuoles (arrows), one of which is open to the intimal space. Inset shows ferritin in vacuole in squared area (unstained, X 15,500; inset, X 61,000). (c) SEM of monocyte (M) adherent to endothelium (E). Cytoplasmic extensions from monocyte can be seen to indent endothelial plasma membrane (arrows); (d) TEM of "hypertrophied" monocyte (HM) beneath endothelium (E) in 30-week abdominal lesion.. Peroxidase-positive granules (arrows) can be seen in the cytoplasm (uranly acetate, lead citrate; peroxidase-reacted, X 12,500).

system exists in other models but has been overlooked by a predilection for the study of advanced lesions that prevails in the literature.

Summary

In this paper, parts I and II, Ross Gerrity described the progression of atherosclerotic lesions in a hypercholesterolaemic pig model. At the time of these studies the predominant cell type in growing atherosclerotic plaques was controversial with much emphasis placed on the vascular smooth muscle cell. Although other authors had described monocytes in atherosclerotic lesions, this paper carefully studies the progression of atheroma at different time points and characterizes the lesion composition. Yorkshire pigs were fed a normal chow or high-fat chow and sacrificed at 6, 12, 15 and 30 weeks after the initiation of diet. At 15 weeks following high-fat chow, "lesions were always of a foam cell nature, confined to the intima, with no evidence of medial cell involvement in the intima or engorgement of smooth muscle cells with lipid". Monocytes were identified using various histo-logical criteria. At 30 weeks following high-fat diet, fibrous lesions were described as fibrous caps overlying necrotic lipid cores. Gerrity hypothesized, based on this and earlier studies from his group, that blood-derived monocytes adhere to the endothelium, which is not necessarily associated with endothelial damage, and then penetrate into the intima. He also demonstrated that intimal monocytes are phagocytic at a time that lipid droplets appear in their cytoplasm. Thus, early lesions of atherosclerosis consist of monocyte foam cells that actively accumulate lipid and may be a source of a growth factor. The author also suggests a role of the monocyte in lesion lipid efflux.

Citation Count Paper I: 1132, Paper II: 354

Key message

Blood-derived monocytes are the predominant cell type in early atherosclerotic lesions. This is a fundamental underpinning to our current understanding of atherosclerosis as an inflammatory disease.

Strengths

A detailed histological examination with elegant electron micrographs of lesions at various stages of development using a hypercholesterolaemic pig model.

Weaknesses

Primarily observational, descriptive data.

Title 4

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Responses

  • Ronja
    How does hyperlipidemia affect the endothelium?
    6 years ago
  • SCUDAMOR
    What is platelet consumption?
    5 years ago

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