(Hypertension. 1995;26:509-513.)
© 1995 American Heart Association, Inc.
Articles |
Sick Vessel Syndrome
Recovery of Atherosclerotic and Hypertensive Vessels
From the Departments of Internal Medicine, Pharmacology, and Pathology, Cardiovascular Center and Center on Aging, College of Medicine and Veterans Administration Medical Center, Iowa City.
Correspondence to Donald D. Heistad, MD, Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, IA 52242.
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Abstract |
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 Top Abstract IntroductionSick Vessel Syndrome in...Sick Vessel Syndrome in...Recovery of Atherosclerotic...Recovery of Hypertensive VesselsReferences |
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Abstract This review describes vascular changes in atherosclerotic and hypertensive vessels as well as effects of treatment. Changes in vascular structure in both atherosclerosis and hypertension are characterized by thickening of the vessel wall and vascular "remodeling." Remodeling tends to preserve the size of the lumen in atherosclerotic vessels and results in a smaller lumen in hypertensive vessels. Changes in vascular function are characterized by preservation of smooth muscle relaxation, with the exception of activity of ATP-sensitive potassium channels, and dysfunction of endothelium. Regression of atherosclerosis, by treatment of hyperlipidemia, results in quite rapid removal of lipid from the vessel wall but with inconsistent improvement in maximal vasodilator capacity. In contrast, endothelial function improves during regression of atherosclerosis, and hyperresponsiveness to serotonin subsides rapidly. Effective treatment of hypertension produces regression of vascular hypertrophy, and some approaches (especially angiotensin-converting enzyme inhibitors) are effective in correcting vascular remodeling. Endothelium-dependent relaxation generally improves during antihypertensive treatment. Reduction in pulse pressure may be more important than reduction in mean arterial pressure in reversing the structural and functional abnormalities of hypertensive vessels.
Key Words: vascular remodeling • hypertension • endothelium • atherosclerosis • vascular hypertrophy
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Introduction |
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TopAbstractIntroductionSick Vessel Syndrome in...Sick Vessel Syndrome in...Recovery of Atherosclerotic...Recovery of Hypertensive VesselsReferences |
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Changes in structure and function in atherosclerotic and hypertensive vessels seem to have a distinctive pattern, which we have described as the "sick vessel syndrome."1 In relation to vascular structure, there is thickening of the vessel wall in both atherosclerosis and hypertension, and there is also vascular remodeling (Fig 1). In relation to vascular function, smooth muscle seems to be relatively normal in relation to mechanisms of relaxation, but there is endothelial dysfunction in both atherosclerotic and hypertensive vessels.
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One should consider whether it is appropriate to describe the vascular changes in atherosclerosis and hypertension as a syndrome. Certainly there are fundamental differences in the vascular changes during atherosclerosis and hypertension: the stimuli for the vascular changes differ, mechanisms that account for the vascular changes differ, and the structural appearances are very different. Yet, despite these fundamental differences, some basic aspects of vascular changes are surprisingly similar. The major characteristics of the syndrome in both atherosclerosis and hypertension are disparate changes in structure versus function and responses of vascular muscle versus endothelium. Structural changes (remodeling) are protective, and functional changes are maladaptive. Although vascular muscle function is generally normal, in relation to relaxation, endothelial function is very abnormal. Thus, although the responses of vessels to atherosclerosis and hypertension differ distinctly, we have chosen to emphasize the similarities of the structural and functional changes as a sick vessel syndrome.
In this review we will consider several aspects of the sick vessel syndrome, including possible mechanisms, implications of the vascular changes, and effects of treatment. Lipid lowering appears to reverse some but not all of the vascular changes of atherosclerosis. Effective reduction of blood pressure in hypertensive experimental animals also appears to reverse many of the abnormalities of the sick vessel syndrome.
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Sick Vessel Syndrome in Atherosclerosis |
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TopAbstractIntroductionSick Vessel Syndrome in...Sick Vessel Syndrome in...Recovery of Atherosclerotic...Recovery of Hypertensive VesselsReferences |
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In atherosclerotic arteries, cells proliferate in the intima media, resulting in thickening of the vessel wall. One would expect encroachment on the vascular lumen as the vessel thickens, but there is outward displacement or growth of the vessel wall, which has been called remodeling.2 3 4 Remodeling is characteristic of early and moderately severe atherosclerosis. In advanced disease, segmental or diffuse narrowing of the vessel may develop, probably from another superimposed process.
In relation to smooth muscle function, relaxation of vascular muscle that is mediated by increases in cGMP (for example, during administration of nitrovasodilators) or by increases in cAMP usually is relatively normal in atherosclerotic arteries in both experimental animals and humans.5 There seems to be some impairment of ATP-sensitive potassium channel activity in smooth muscle of atherosclerotic arteries.6
In contrast to relative preservation of vascular muscle function in atherosclerotic arteries, there is pronounced impairment of endothelium-dependent relaxation.5 6 7 8 9 Endothelium of atherosclerotic arteries is not denuded and may even make normal or increased amounts of nitric oxide.10 Impairment of endothelium-dependent relaxation in atherosclerotic arteries probably relates in part to increased destruction of nitric oxide, perhaps by release of oxygen radicals from leukocytes in the arterial wall.11 Endothelial function is impaired in the microcirculation as well as in large arteries of atherosclerotic animals and humans.12 The finding is very clear but nevertheless surprising because atherosclerotic lesions are confined to large arteries.
One consequence of endothelial dysfunction in atherosclerotic arteries may be a susceptibility to vasospasm, which is a common clinical problem in patients with atherosclerosis. Another consequence of endothelial dysfunction, which may be of greater importance, is the predisposition of atherosclerotic arteries to adherence of platelets and leukocytes to the endothelium, and perhaps also a predisposition to vascular thrombosis.
A hallmark of atherosclerotic arterial dysfunction is the susceptibility to vasospasm produced by serotonin. There is a relatively modest, nonspecific increase in responsiveness of atherosclerotic arteries to several vasoconstrictor stimuli.13 14 Responses to serotonin, however, are enormously potentiated in both atherosclerotic monkeys13 15 and humans.16 Several mechanisms may contribute to the augmented responses to serotonin, including membrane abnormalities (such as alteration in expression of subtypes of serotonin receptors,17 abnormalities of protein kinase C, and perhaps calcium mobilization, endothelial dysfunction, and other mechanisms).
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Sick Vessel Syndrome in Hypertension |
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TopAbstractIntroductionSick Vessel Syndrome in...Sick Vessel Syndrome in...Recovery of Atherosclerotic...Recovery of Hypertensive VesselsReferences |
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Structural changes in hypertensive blood vessels result in thickening of the vessel wall and encroachment on the vascular lumen. Hypertrophy generally occurs in hypertensive vessels and contributes to both thickening of the vessel wall and reduction in lumen size.18 In addition, blood vessels undergo remodeling during hypertension.19 We have characterized structural remodeling in hypertension as a reduction in external diameter (which is not the result of vascular hypertrophy) that is not accounted for by changes in vascular tone or compliance. Thus, vessels in many regions are smaller in hypertensive than normotensive animals and humans.20 21 22
Different mechanisms may account for the two structural changes (hypertrophy and remodeling) in vessels during hypertension. Sympathetic nerves contribute to the development of cerebral vascular hypertrophy,23 24 but we are not aware of evidence that neural factors contribute to remodeling. In addition, pulse pressure appears to play a critical role in the development of vascular hypertrophy,25 but pulse pressure does not seem to be important in vascular remodeling.
Genetic factors may be more important in the development of vascular remodeling than of vascular hypertrophy in hypertension. Vascular hypertrophy can be induced in nongenetic models of hypertension, including renal hypertension26 and coarctation of the aorta. Vascular remodeling, at least in cerebral blood vessels, occurs in genetic models of hypertension (stroke-prone spontaneously hypertensive rats [SHRSP]19 ; Dahl rats, G.L.B., unpublished observations, 1995) but not in nongenetic models, including renal hypertension26 or after long-term inhibition of nitric oxide synthase (G.L.B., unpublished observations, 1995). Thus, current evidence suggests that vascular remodeling but perhaps not vascular hypertrophy is determined by genetic factors.
In relation to vascular muscle function, similar to the findings in atherosclerotic arteries, relaxation of smooth muscle from hypertensive vessels appears to be relatively normal during activation of adenylate cyclase and guanylate cyclase.27 28 In contrast, responses to activation of ATP-sensitive K+ channels are impaired in cerebral vessels in SHRSP.28 Because ATP-sensitive K+ channels appear to be important mediators of relaxation during several important stimuli, including hypoxia29 and hypotension,30 impairment of the activity of these channels in hypertension may have important physiological consequences. We should point out that in contrast to impairment of the ATP-sensitive K+ channels in hypertension, activity of the calcium-activated K+ channel appears to be increased in chronic hypertension.31
In several vascular beds, endothelial function is impaired in experimental animals and patients with hypertension. A recent study failed to demonstrate linkage of the gene for endothelial nitric oxide synthase with essential hypertension in humans,32 although localization of the gene for inducible nitric oxide synthase may suggest linkage to hypertension.33 Impairment of endothelium-dependent relaxation in hypertension appears to be related primarily to release of an endothelium-derived contracting factor.34 In several vascular beds the endothelium-derived contracting factor appears to be a prostanoid, because indomethacin improves endothelium-dependent relaxation.34 35
Increases in pulse pressure reduce endothelium-dependent relaxation in vivo36 and in vitro, in part from generation of oxygen radicals.37 Increases in pulse pressure apparently contribute to impairment of endothelium-dependent relaxation in SHRSP.25 It is not clear whether this effect is related to decreases in nitric oxide or increases in endothelium-derived contracting factor in hypertension. We speculate, however, that impairment of endothelium-dependent relaxation in hypertension may be related in large part to increases in pulse pressure rather than increases in mean arterial pressure.
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Recovery of Atherosclerotic Arteries |
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TopAbstractIntroductionSick Vessel Syndrome in...Sick Vessel Syndrome in...Recovery of Atherosclerotic...Recovery of Hypertensive VesselsReferences |
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It has been known for many years that lipid can be depleted from atherosclerotic vessels in hypercholesterolemic atherosclerotic monkeys when cholesterol intake is reduced.38 39 Recent evidence suggests that the amount of lipid in atherosclerotic arteries can be greatly reduced within a few months.40
In relation to structural changes, several studies of regression of atherosclerosis in primates suggest that even though the arterial lumen is not reduced in atherosclerotic arteries,2 3 4 the arterial lumen is even larger after regression of lesions.41 Thus, further remodeling, or outward displacement of the arterial wall, occurs with regression of atherosclerotic lesions.
The standard hemodynamic approach for examining the consequences of structural changes in blood vessels is to determine maximal vasodilator capacity or minimum vascular resistance. Regression of atherosclerosis improves minimum resistance in the cerebral circulation but fails to increase minimum vascular resistance in the limb or coronary vascular bed.41 Thus, even though lipid is reabsorbed from blood vessels during regression of atherosclerosis and the lumen of large arteries tends to increase, irreversible changes in resistance vessels limit improvement in maximal vasodilator capacity.
As described above, relaxation of vascular muscle is relatively normal in atherosclerotic vessels, except for impairment of ATP-sensitive K+ channel activity. The abnormality of ATP-sensitive K+ channels apparently does not improve during regression of atherosclerosis.6 Of interest is the finding that activity, or the role, of the Ca2+-activated K+ channel may be increased during hypercholesterolemia.42
Most of the other abnormalities of vascular function in atherosclerotic arteries improve after regression of atherosclerosis. Endothelium-dependent relaxation to acetylcholine in vitro6 43 and responses to ADP in vivo44 improve after regression of atherosclerosis in monkeys. Perhaps the improvement in endothelial function is related to loss of inflammatory cells from atherosclerotic lesions during regression.45 If generation of oxygen radicals, including peroxynitrite,46 from leukocytes in atherosclerotic lesions inactivates nitric oxide, loss of these inflammatory cells may lead to improvement in endothelial function. Vasodilator responses to acetylcholine in coronary arteries of hypercholesterolemic humans improve markedly after only 6 months of lipid-lowering therapy.47
Hyperresponsiveness to serotonin is abolished by regression of atherosclerosis in several vascular beds.48 49 Hyperresponsiveness to serotonin subsides surprisingly rapidly, usually within several months of reversal of hypercholesterolemia.40 Abnormal constrictor responses to serotonin appear to subside more rapidly in small distal vessels than in larger proximal vessels (Fig 2). We suggest that evaluation of vascular reactivity is more sensitive than measurement of baseline arterial diameter for evaluation of atherosclerosis and regression of atherosclerosis (Fig 3).
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ADP and serotonin are vasoactive factors that are released in highest concentration when platelets aggregate. If platelets contribute to vasospasm,50 correction of the abnormality in the responses to ADP and serotonin implies that susceptibility to vasospasm may subside after regression of atherosclerosis. This hypothesis is supported by preliminary data that indicate that abnormal vasoconstrictor responses to platelet activation by infusion of collagen in atherosclerotic monkeys are corrected after regression of atherosclerosis.51
Leukocytes, as well as platelets, may contribute to vasomotor abnormalities of atherosclerotic arteries.52 Abnormal vasoconstrictor responses during activation of leukocytes improve after regression of atherosclerosis in parallel with loss of inflammatory cells from the atherosclerotic lesions.45 On the basis of improvement in endothelial function and correction of abnormal responses to activation of platelets and leukocytes, we are optimistic that susceptibility to vasospasm may subside during regression of atherosclerosis.
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Recovery of Hypertensive Vessels |
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TopAbstractIntroductionSick Vessel Syndrome in...Sick Vessel Syndrome in...Recovery of Atherosclerotic...Recovery of Hypertensive VesselsReferences |
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Several approaches have been used to examine the effects of treatment of hypertension on structural changes in blood vessels. Treatment of spontaneously hypertensive rats and SHRSP with either angiotensin-converting enzyme (ACE) inhibitors or hydralazine produces reductions in arterial pressure and complete or partial regression of vascular hypertrophy.53 54 In general, ACE inhibitors appear to be more effective than hydralazine in reducing vascular hypertrophy. The greater efficacy of the ACE inhibitors may be related to more effective reduction in arterial pressure or perhaps to inhibition of the renin-angiotensin system.
Another experimental approach is to produce a local reduction in pressure by ligation of upstream vessels. We have used this approach to examine structural changes in cerebral vessels in SHRSP.55 Ligation of the carotid artery produces a reduction in arterial pressure with marked improvement in vascular hypertrophy in SHRSP.
We and others have suggested that reduction in pulse pressure may be more important than reduction in mean arterial pressure in producing regression of vascular hypertrophy. Carotid ligation in SHRSP normalized pulse pressure but not mean pressure and was very effective in producing regression of cerebral arteriolar hypertrophy.55 There was a strong correlation between vascular hypertrophy and pulse pressure. In mesenteric arteries there is a strong correlation between pulse pressure and wall-to-lumen ratio during treatment with a variety of antihypertensive agents.56 Furthermore, increases in pulse pressure without an increase in mean arterial pressure produce vascular hypertrophy.57 These findings taken together suggest the importance of pulse pressure in the induction of vascular hypertrophy and reduction of vascular hypertrophy during treatment of hypertension.
Long-term treatment of hypertension with ACE inhibitors appears to prevent vascular remodeling.54 The effectiveness of ACE inhibitors in preventing remodeling may be related to their efficacy in the treatment of hypertension, or perhaps there is an additional effect from inhibition of the renin-angiotensin system.
Regarding vascular muscle function, because responses to stimuli that produce an increase in cAMP and cGMP in smooth muscle are not impaired in chronic hypertension, one would not anticipate improvement with antihypertensive treatment. Nevertheless, we have observed that cerebral vasodilatation in response to adenosine and nitroglycerin, which act through increases in cAMP and cGMP in vascular smooth muscle, is enhanced by administration of ACE inhibitors in SHRSP.58 Effects of the ACE inhibitors did not appear to be related to effects on blood pressure. Although the results were clear-cut, the mechanism by which ACE inhibitors may improve relaxation in vascular muscle of SHRSP is unclear.
Antihypertensive treatment improves endothelium-dependent relaxation in a variety of experimental models of hypertension. Treatment with an ACE inhibitor may be more effective than treatment with hydralazine in improving endothelium-dependent relaxation.59 Local reduction of arterial pressure by clipping of the proximal large artery also improves endothelial function in distal vessels.36 The relative importance of mean pressure, pulse pressure, and other factors in the improvement of endothelium-dependent relaxation during antihypertensive treatment is not entirely clear.
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Acknowledgments |
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Original studies described in this article were supported by National Institutes of Health grants NS-24621, AG-10269, HL-16066, HL-14388, HL-22149, and HL-38901 and by research funds from the Veterans Administration and American Heart Association. We thank Arlinda LaRose for typing the manuscript.
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Footnotes |
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1 Dr Armstrong died July 11, 1995.
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References |
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TopAbstractIntroductionSick Vessel Syndrome in...Sick Vessel Syndrome in...Recovery of Atherosclerotic...Recovery of Hypertensive VesselsReferences |
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