Relation of hypertension to changes in the arteries

Relation

of Hypertension Robert

to Changes in the Arteries H. Heptinstall

H

which could be accentuated by hypertension.’ Studies on renal biopsiesof the wedgetype, taken at the sametime as operation for removal of the sympathetic chain for the relief of hypertension, revealed that hypertension could occur with1only minor grades of vascular changes.4-6This provided little support for the idea of small-vessel changecausinghypertension.

IGH BLOOD PRESSURE and changesin the walls of arteries and arterioles are intimately related. On the one hand, it is known that certain forms of arterial diseasecan lead to hypertension when they involve the renal circulation. For example, stenosisof the main renal artery by an arteriosclerotic plaque at its point of origin in the aorta, or the condition of fibromuscular dysplasia of the renal arteries, can initiate hypertension by interfering with the renal blood supply. Little will be said of this, and the article will be concerned mainly with the arterial changescaused by hypertension. Thesechangesvary dependingon the size of artery involved and, in the caseof certain lesions,on the degree of the hypertension. It should be observed that the term arteriosclerosis will be preferred to atherosclerosis. RELATION IN THE

Observations made on arteriolar necrosis, a change found in patients with malignant hypertension, suggestconclusively that this changeis a consequenceof hypertension. First, in the dog made hypertensive by the constriction of both renal arteries, such necroses are found only in vesselsexposed to high blood pressure, such as arterioles in the intestine.7 In rats with hypertensionproduced by constricting one renal artery, it is found that vascularnecrosesare present in the contralateral nonclipped kidney but not in the kidney whose vasculatureris-protected by- the clip ori’tlie main renal artery.8 Additionally, necroses are found most frequently in animalswith the highest levels of blood pressure,ga finding paralleled in man.6 Second, in both the laboratory animal and man, the number of vascular necrosescan he reduced if the high blood pressurecan be lowered by drug therapy. lo-r3 Third, observationsmadein pulmonary hypertension provide excellent evid.ence for the cause and effect relationship, necroses being found in hypertension in the pulmonary circuit resulting from Eisenmenger’scomplex, mitral stenosis,and emphysema,aswell asin the primary form.14-‘6 The mechanismby which necrosesare brought about appearsto be the inability o:Fthe arterial wall to withstand a distending force,‘7318 rather than an excessivecontraction of the wall, as wasthought to be the caseat one time.

OF SMALL-VESSEL CHANGES KIDNEY TO HYPERTENSION

Numerous studieshave been carried out in an attempt to study the relation of changesin the renal arteriolesand interlobular arteries to hypertension. In a study of kidneys obtained at autopsy from patients with and without hypertension, Moritz and Oldt’ came to the conclusion that arteriolar hyalinization was the counterpart of arteriosclerosis, becomingmore severeand widespreadwith advancing years. They felt that arteriolar hyalinization was more likely to be the cause, rather than the consequence,of hypertension. Bell2 and Smith,3 in similar studies, concluded that arteriolar hyalinization, or arteriolosclerosis,asit is sometimes called, was an aging phenomenon made worse by hypertension. They both considered that it was not a causeof hypertension. Intimal thickening of interlobular arteries, causedby an increasein the amount of elastica, was likewise consideredto be an aging change,independent of hypertension, but

A further feature of the kidney of malignant hypertension in man is the cellular, fine collagenous, and mutinous thickening of the intima of interlobular arteries, the so-calledendarteritis fibrosa. The relation of this to hypertension is far from clear at the moment. It has usually been accepted that this changeis the consequenceof hypertension, but the evidence for this is not overabundant. One of the reasons for caution in accepting this lesion as the consequenceof hyper-

From the Department of Pathology, the Johns Hopkins University School of Medicine, and the Johns Hopkins Hospital, Baltimore, Md. Supported by USPHS Research Grant HL 07835. Reprint requests should be addressed to Robert H. Heptinstall, M.D., Department of Pathology, the Johns Hopkins Hospital, Baltimore, Md. 21205. 0 1974 by Grune & Stratton, Inc. Progress

in Cardiovascular

Diseases,

Vol. XVII,

No. 1 (July/August),

1974

25

26

tension is its occurrence in such conditions as scleroderma, the syndrome of postpartum acute renal failure, and the hemolytic uremic syndrome. In these conditions, there may be no elevation of blood pressure, or the blood pressure may be normal initially only to rise rapidly over a very short period. The terminal rise in pressure in these diseases could well be caused by the endarteritis fibrosa producing ischemia and thus acting in a way similar to constriction of a main renal artery. If indeed a suitable mechanismcould be demonstrated for the production of the cellular, collagenous,and mutinous intimal thickening of interlobular arteries, then by analogy with such conditions as sclerodermaan explanation could be provided for the transition from the benign to the malignant phase of essential hypertension. By comparing these arterial changeswith similar ones found in the rejecting kidney,i’ the likelihood of intravascular coagulation with transformation to the cellular and mutinous intimal thickening should be considered. In the malignant phaseof essential hypertension, there is undoubted evidence for intravascular coagulation, and this is as follows. First, microangiopathic hemolytic anemia, with deformed red cells,hemolytic anemia,and reduced numbers of platelets, hasbeen describedon countless occasionsin clinical malignant hypertension. 20-24 The deformity of the red blood cells is regarded as being causedby the red cells traversing areasof fibrin on the lining of small arteries and arterioles. Second, small microthrombi are frequently seen in the lumen of afferent arterioles and smallerbranchesof interlobular arteries.These are seenalong with fibrin deposition in the wall of arterioles and small arteries, a change usually referred to as fibrinoid necrosis. Third, fibrin may also be seenin the depths of the cellular intimal thickening of interlobular arteries usingfluorescent antibody methods. How can thesevarious observations be synthesized?One explanation put forward by Linton et aL2’ suggeststhat, in patients with the benign phase of essentialhypertension, local damageto arterioles gives rise to the formation of microthrombi and to increased endothelial permeability that allows fibrin to passinto the wall. Lysis of red cells, damagedby contact with such vessels, then releasesthromboplastin, adenosine diphosphate, and conceivably inhibitors of fibrinolysis, which would enhance fibrin and platelet deposition at the site of arteriolar or arterial

ROBERT

H. HEPTINSTALL

damage.Organization of this fibrin then gives rise to the cellular and mutinous thickening of the interlobular arteries. The ensuingnarrowing of the lumen of the interlobular arteries would in turn accelerate the hypertensive process, causing the transition from the benign to the malignant phase of essentialhypertension. Much of what has been saidis speculativeand in need of further study. HYPERTENSION

AND

ARTERIOSCLEROSIS

P&nonary Circuit Arteriosclerosis doesnot occur in the pulmonary circulation with the frequency and severity that it doesin the major circuit. When it does,it takes the form of slightly raisedlipid plaqueson the endothelial surface of the pulmonary artery and its major branches.It is seenin pulmonary hypertension, an observation made over 50 yr agoby Turnbu11.25This association provides one of the best pieces of evidence for the potent effect of increasedblood pressure in the genesisof arteriosclerosis,for such lipid changesin the intima of pulmonary arteries are not seenwhen the pressure is normal. This evidence is all the more convincing in view of the occurrenoe of theselipid plaquesin the absenceof elevation of serumcholesterol. The plaques, made up of foamy lipid-containing cells, are seenwith such great regularity in patients with pulmonary hypertension that their presencein a patient without inordinate increasein serumlipids is virtually diagnostic of pulmonary hypertension. Thickening of the medial coat together with great hypertrophy of the wall of the right ventricle of the heart are changes accompanying the intimal lipid lesions. Changes consisting of medial hypertrophy, intimal thickening, etc., are seen in smaller branches, but these will not be discussed, since this section is confined to arteriosclerosisof the type with lipid changes.It should be observed in passingthat the changescausedin smallarteries by the impaction of multiple smallemboli can produce pulmonary hypertension.26 Coronary Arteries Coronary arteriosclerosis is of greater consequence in patients with hypertension than in those without it. The evidencefor this comesfrom three separate sources. First, there are various observations made at autopsy describing greater severity of the lesion asjudged either by visual means27-29

RELATION

OF HYPERTENSION

TO CHANGES

IN THE

27

ARTERIES

or by estimating the amount of lipid extractable from coronary arteries.30 Bell and Clawson, for example, found that coronary arteriosclerosis was not only more common but more intense in patients with hypertension than in those with a normal blood pressure. These features are seen in Table 1, which is modified from their paper. Using data from the International Atherosclerosis Project, Robertson and Strong2’ demonstrated that persons with hypertension had more coronary arteriosclerosis than those without hypertension regardless of sex, age, race, or geographic location. This was particularly true with regard to the raised fibrous lesion. Similar accentuation by hypertension was found in the aorta. An interesting study on a small group of patients was carried out by Evans.29 The subjects were psychotic patients whose blood pressures had been recorded for several years before death, and autopsy revealed a good correlation between severity of coronary artery disease and the level of the systolic blood pressure. Using chemical extractions, Paterson and his co-workers3’ determined the amount of lipid in the coronary arteries in each of 184 autopsies, and compared this with the presence or absence of hypertension. Significant relationships between hypertension and the severity of coronary artery disease as measured by chemical--extraction of lipids were found. Second, clinical observations reveal that there is a higher incidence of coronary artery disease among patients with hypertension than in those without it. This was brought out in the results of the Framingham study31 in which the incidence in subjects with hypertension was greater than in those with normal pressures. Similar good correlations between level of blood pressure and incidence of coronary heart disease have been recorded by others3’ This study revealed that the development of coronary artery disease correlated better with elevation of systolic blood pressure than with elevation of diastolic pressure. Third, data from insurance companies reveal that the chances of hypertensive males under 40 dying from coronary artery disease are 3.5 times as great as those with a normal pressure. In the case of men over 40, the chances are 2.3 times as great. Finally, a little-known study from this department34 has always seemed to me to provide incontrovertible evidence for the ability of hypertension to accentuate coronary arteriosclerosis. In a paper on cardiac lesions in hypertensive infants and children,

Table

1. Coronary and

Arteriosclerosis

Patients*

Percentage

Grade of Coronary Artery Disease (Left Artery)

None Slight

11.2

Severe

50.6 38.1

Thrombus

21.0 from

of

Hypertensives (152 Cases)

to moderate

*Modified

in Hypertensive

Nonhypertensive

Bell

and

Patients

in Each

Grade

Nonhypertunsives (146 Cases)

71.2 26.0 2.8 0

.-

Clawson.

the presence or absence of coronary arteriosclerosis was recorded at autopsy in a group of 52 children with the nephrotic syndrome. There was a common factor of elevation of the serum cholesterol, but when the blood pressure was considered it was found that 36 of the children had hypertension, whereas 1!6 did not have elevated pressures. Of the 36 children with hypertension, 11 had coronary arteriosclerosis, whereas of the 16 children with normal blood pressures, none had disease of the ccnonary arteries. This then is an experiment of nature in which the stage is set for the development of coronary arteriosclerosis at an early age by virtue of the raised levels of serum cholesterol. Those children who became hypertensive as a complication of the renal disease responsible for the nephrotic syndrome in turn developed more coronary artery disease than the children whose blood pressures did not rise. Arteries to the Brain Under the general heading of stroke, cerebral hemorrhage and infarction of the brain must be considered. Although the vascular pathology isdifferent for these two, there is good information to show an increased frequency of both in the hypertensive population. Cerebral hemorrhage is caused by rupture of small arteries of the brain and it is an old observation that this is one of the common modes of death in hypertension. The Framingham study3’ again provides convincing evidence for the deleterious effects of hypertension, the incidence of cerebral hemorrhage being almost three times as frequent among men who were hypertensive on admission to the study than among those with a normal pressure (Fig. 1). If one believes that the ruptures take place in Charcot-Bouchard aneurysms,36 an idea recently resurrected, 37 then the studies of Cole and Yates3’ assume great relevance. Briefly, using

28

I

ROBERT

*

NON - HEMORRHAGIC

HEMORRHAGIC 206

I

ABSENT

PRESENT

HYPERTENSION +I NON-HEMORRHAGIC

OOES

MOT INCLUDE

H. HEPTINSTALL

ABSENT

AT INITIAL

Fig. 1. Risk of cerebrovascular accident according to blood pressure at initial examination. Men aged 30-62 yr at entry to study. (By permission.35)

PRESENT

EXAM

CEREBRAL

EYBOLUS

the lipid content to be twice as great in patients with hypertension as in those with a normal blood pressure.30 The results of the Framingham study3’ show a convincing increase in what is referred to as atherothrombotic brain infarction (ABI) in patients with hypertension (Fig. 1). It is particularly revealing to consider the relative roles of levels of blood lipids and levels of blood pressure. Figure 2 shows that although elevated lipid levels are of great importance in determining the incidence of ABI in patients with normal blood pressure, these levels are of no great importance in patients with high blood pressure; that is, there is a considerable increase in incidence of ABI in the hypertensive

postmortem angiography, they demonstrated these aneurysms in 46 out of 100 autopsies on patients with hypertension, compared with seven out of 100 autopsies on, age- and, sex-matched patients with normal.blood pressuresIschemic episodes are related to occlusion of arteries to the brain, either within the skull or in the internal carotid or vertebral arteries outside the skull, Arteriosclerosis is the basic lesion, with a thrombotic episode often adding the finishing touches. Autopsy studies reveal a highly significant correlation between the severity of arteriosclerosis in the cerebral, carotid, and vertebral arteries, and the systolic blood pressure.29 Also, chemical analysis of cerebral vessels obtained at autopsy shows

St

CHOLESTEROL

t

204

20-400

PRE-BETA

~-LIPOPROTEIN IENDOQENOUS TFiIQLYCERIDE)

1 84

Fig. 2. Risk of atherothrombotic brain infarction after 14 yr according to blood lipid and blood pressure status. Nlen and women aged 30-62 yr at entry to study. (By permb sion.35 1

<260

i260

NORMOTENSIVE *Q

4260 $260 HYPERTENSIVE

4. 4th OUARTILE ~~~*230mqX, WOMEII?I59mqY

NOT P4 Q4)t MORHOTENSIVE

NOT 44 P4* HYPERTENSIVE

RELATION

OF HYPERTENSION

TO CHANGES

IN THE

ARTERIES

population regardless of the cholesterol or betalipoprotein levels in the serum. It should be noted, as the authors point out, that the exact mechanism of hypertension in the occurrence of strokes is not understood, and the notion that it accelerates atherogenesis is not conclusively proven. Of further interest is the mounting evidence for the beneficial effects of lowering the blood pressure in subjects with hypertension. The Veterans Administration Cooperative Study Group on Antihypertensive Agents jg has shown that the prevalence of strokes is considerably reduced in men with diastolic pressures of 90-I 14 mm Hg when antihypertensive agents are used. Also, a study by Marshal14’ has revealed that antihypertensive therapy significantly reducesthe frequency of further cerebrovascular accidents in men who have had a previousincident of presumednonembolic cerebral infarction. A similar reduction in frequency was found in women, although this did not reach the 0.05 significancelevel found in men. EXPERIMENTAL TENSION AND

STUDIES ON HYPERARTERIOSCLEROSIS

A brief word is in order on the effects of hypertension on experimentally induced arteriosclerosis. At the outset caution should be exercised, for,

29

certainly in the case of the rabbit, the model used for inducing arteriosclerosis is somewhat bizarre, involving inordinate increases in the level of serum cholesterol and the virtual saturation of certain organs with cholesterol. The type of arteriosclerosis induced by dietary means in the dog,41 rabbit,42 and rat43 is increased in intensity in animals with hypertension compared with those with a normal blood pressure. The mechanism by which this occurs is not known, but local vascular injury and increased transit of lipid across the endothelium are likely possibilities.

SUMMARY

Hypertension can damage small blood vessels, and this effect is best seenin the arterioles of the kidney, which undergo fibrinoid necrosis. It also has a potentiating effect on arteriosclerosisof the larger vesselssuch as the coronary, carotid, and vertebral arteries. The relation of hypertension to endarteritis fibrosa of the interlobular arteries of the kidney is not clear; while at one time ii: was felt that hypertension causedthis lesion, recently acquired information raisesthe possibility that the arterial changesresult from intravascular coagulation and may causeor acceleratethe hypertension.

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duction and resolution of hypertensive vascular lesions in the rabbit. Clin Sci 33:39,1967 11. McQueen EG, Hodge JV: Modification of secondary lesions in renal hypertensive rats by control of the blood pressure with reserpine. QJ Med 30:213,1961 12. Harrington M, K&aid-Smith P, Michael J: Results of treatment in malignant hypertension. A seven-year experience in 94 cases. Br Med J 2:969,1959 13. McCormack LJ, Beland JE, Schneckloth RE, let al: Effects of antihypertensive treatment on the evolution of the renal lesions in malignant nephrosclerosis. Am .I Path01 34:1011,1958 14. Old JW, Russell WO: Necrotizing pulmonary arteritis occurring with congenital heart disease (Eisenmenger complex): Report of case with necropsy. Am J Path01 26:789,1950 15. Spencer H: Pulmonary lesions in polyarteritis nodosa. Br J Tuberc 51:123,1957 16. Symmers WStC: Necrotizing pulmonary art.eriopathy associated with pulmonary hypertension. J Clin Path01 5:36,1952 17. Hill GS, Heptinstall RH: Steroid-induced hypertension in the rat. A microangiographic and histologic study on the pathogenesis of hypertensive vascular and glomerular lesions. Am J Path01 52:1,1968 18. Hill GS: Studies on the pathogenesis of hypertensive

30

vascular disease. Effect of high-pressure intraarterial injections in rats. Circ Res 27:657, 1970 19. Kincaid-Smith P: Histological diagnosis of rejection of renalhomografts in man. Lancet 2:849,1967 20. Brain MC, Dacie JV, Hourihane 0: Microangiopathic haemolytic anaemia: The possible role of vascular lesions in pathogenesis. Br J Haematol 8:374, 1962 21. Gavras H, Brown WCB, Brown JJ, et al: Microangiopathic hemolytic anemia and the development of the malignant phase of hypertension. Circ Res 28, 29 (Suppl II):ii-127, 1971 22. Linton AL, Gavras H, Gleadle RI, et al: Microangiopathic haemolytic anaemia and the pathogenesis of malignant hypertension. Lancet 1: 1277, 1969 23. Pardo V, Aburano A: Thrombotic microangiopathy and malignant hypertension. Am J Clin Path01 45:605, 1966 24. Sevitt LH, Evans DJ, Wrong OM: Acute oliguric renal failure due to accelerated (malignant) hypertension. Q J Med 40:127,1971 25. Turnbull HM: Alterations in arterial structure, and their relation to syphilis. Q J Med 8:201, 1915 26. Spencer H: Pathology of the Lung (ed 2). Elmsford, NY, Pergamon, 1968, p 655 27. Bell ET, Clawson BJ: Primary (essential) hypertension. A study of four hundred and twenty cases. Arch Path01 5:939, 1928 28. Robertson WB, Strong JP: Atherosclerosis in persons with hypertension and diabetes mellitus. Lab Invest 18:538, 1968 29. Evans PH: Relation of longstanding blood-pressure levels to atherosclerosis. Lancet 1:415, 1965 30. Paterson JC, Mills J, Lockwood CH; The role of hypertension in the progression of atherosclerosis. Can Med Assoc J 82:65, 1960 31. Kannel WB, Castelli WP, McNamara PM: The coronary profile: 1Zyear follow-up in the Framingham study. J Occup Med 9:611, 1967

ROBERT

H. HEPWNSTALL

32. Paul 0, Lepper MH, Phelan WH, et al: A longitwldinal study of coronary heart disease. Circulation 28: 20, 196.3 33. Gubner RC: Life expectancy of the younghqpertensive, in Brest AN, Moyer JH (eds): HypertersIum. Recent Advances. Philadelphia, Lea & Febiger, 1961, p 1% 34. Oppenheimer EH, Esterly JR: Cardiac lesions in hypertensive infants and children. Arch Pathol 84:318, 1967 35. Kannel WB, Wolf PA, Verter .I, et al: Epidemiologic assessment of the role of blood pressure in stroke. JAMA 214:301, 1970 36. Charcot JM, Bouchard C: Nouvelles recherches SUI la pathogenic de l’hemorrhagie cerebrale. Arch Physiol l:llO, 1868 37. Russell RWR: Observations on intracerebral aneurysms. Brain 86:425, 1963 38. Cole FM, Yates PO: The occurrence and significance of intracerebral micro-aneurysms. J Path01 Bacterial 93: 393,1967 39. Veterans Administration Cooperative Study Group on Antihypertensive Agents: Effects of treatment on morbidity in hypertension. II. Results in patients with diastolic blood pressure averaging 90 through 114 mm Hg. JAMA 213:1143,1970 40. Marshall J: A trial of long-term hypotensive therapy in cerebrovascular disease. Lancet 1: 10. 1964 41. Wakerlin GE, Moss WG, Kiely JP: Effect of experimental renal hypertension on experimental thiouracilcholesterol atherosclerosis in dogs. Circ Res 5:426, 1957 42. Bronte-Stewart B, Heptinstall RH: The relationship between experimental hypertension and choles&rolinduced atheroma in rabbits. 3 Pathol Bacterial 68:4Q7, 1954 43. Deming QB, Mosbach EH, Bevans M, et al: Blood pressure, cholesterol content of serum and tissues, and atherogenesis in the rat. The effect of variations in blood pressure on the cholesterol content of serum and tissues and on the development of atherosclerosis in rats on a high cholesterol diet. J Exp Med 107:581, 1958