Postgraduate Medical Journal (1985) 61, 773-778

Review Article

The effects of treatment on target organ damage inhypertensive disease

Jerome Lowenstein

Renal and Hypertension Section, NYU Medical Center, New York, NY 10016, USA.

Introduction

The mortality rate from malignant hypertension hasbeen dramatically reduced and the morbidity andmortality attributable to essential hypertension havebeen significantly decreased since the introduction ofpotent antihypertensive drugs (Mroczek et al., 1969;Gudbrandsson et al., 1970; Veterans AdministrationCooperative Group, 1970). While the efficacy ofantihypertensive treatment now seems quite wellestablished, it has become clear that not all of thetarget-organ effects ofhypertensive disease are equallywell prevented or reversed by therapy. This review willattempt to examine some of the responses of targetorgans to treatment in patients with hypertensivedisease.The major clinical features of malignant or

accelerated hypertension - hypertensive encephalop-thy, cerebral haemorrhage, and renal failure - can bestbe viewed as manifestation of a failure of autoregula-tion or 'autoregulatory breakthrough', i.e., the end-organ damage is a consequence of increased hydro-static pressure in the distal arteriolar and capillarybeds.

The cerebral circulation

The phenomenon of blood flow autoregulation hasbeen well studied in the cerebral circulation where ithas been shown that increased perfusion pressure isparalleled by an increase in vascular resistance and, asa consequence, both organ blood flow and microvas-cular pressures are maintained at near normal values(Strandgaard et al., 1974). Studies in experimentalanimals suggest that hypertensive encephalopathy isdue to a failure ofautoregulation at the very high levelsof arterial blood pressure which characterize malig-nant hypertension. Hypertensive encephalopathy is aclinical syndrome characterized by altered mental

state, severe headache, seizures, and focal neurologicaldeficits. Pathological examination of the brain revealscerebral oedema, petechial haemorrhage, and/or focalischaemic infarction. It was debated for many yearswhether the sequence ofevents leading to hypertensiveencephalopathy and cerebral haemorrhage was in-itiated by focal ischaemia - i.e., hypoperfusion (Meyeret al., 1960) - or by hyperperfusion (Farrer et al.,1976), i.e. autoregulatory breakdown. Byrom (1954)observed that the pial blood vessels of rats with renalartery clip hypertension and hypertensive ence-phalopathy exhibited alternating areas of constrictionand dilatation. He demonstrated in rats with braindysfunction that the dye, trypan blue, passed acrossthe blood brain barrier and stained the brain tissue.Geise (1964) subsequently demonstrated that thepenetration of a macromolecular tracer, colloidalcarbon, was localized to areas adjacent to the dilatedrather than the constricted segments of the cerebralvascular bed. This issue has been re-examined byTamaki et al. (1984), utilizing a strain of the Okamotospontaneous hypertensive rat (SHR), bred for suscep-tibility to the development of hypertensive ence-phalopathy and stroke - the stroke-prone SHR. Theseinvestigators examined the relationship between dis-ruption ofthe blood-brain barrier, assessed by leakageof Evan's blue tagged albumin, and regional cerebralblood flow, assessed by the accumulation of radioac-tive antipyrine (which passes freely across the blood-brain barrier), in stroke prone-SHR exhibitingneurological abnormalities. They found that localblood flow was increased in areas of the cerebralcortex in which the blood-brain barrier was disrupted(Evan's blue staining with little oedema). The symp-toms and minimal gross brain pathology suggest thatthis is a good experimental model for hypertensiveencephalopathy: the findings provide evidence thathyperperfusion is responsible for the pathologicalchanges and associated symptoms. In contrast, localcerebral blood flow was significantly reduced in areasin which disruption of the blood-brain barrier was

© The Fellowship of Postgraduate Medicine, 1985

J. Lowenstein, M.D.Received 26 February 1985.

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associated with marked focal oedema.They suggestedthat hyperperfusion with transudation of plasmaproteins and fluid into the substance ofthe brain mightbe the initiating events in regional cerebral ischaemiaand therefore responsible for stroke, both ischaemicand haemorrhagic, in these stroke prone SHR.A pathogenetic role for increased blood pressure

and 'autoregulatory breakthrough' in hypertensiveencephalopathy was further supported by the findingthat unilateral ablation of the cervical sympatheticganglion, denervating the blood vessels to one side ofthe brain, resulted in a striking preponderance of focalhaemorrhagic and ischaemic infarctions as well aspathological vascular changes in the denervatedhemisphere (Sadoshima et al., 1981). Morphometricstudy of the small cerebral vessels revealed a sig-nificant reduction in the wall-to-lumen ratio of vesselson the denervated side, i.e., less arteriolar hypertro-phy, suggesting a trophic role for the sympatheticnerves in mediating vessel hypertrophy in the hyper-tensive animal. Further, the localization of haemorr-hagic and ischaemic infarction in the denervatedhemisphere lends support to the concept thatarteriolar resistance plays an important role in protec-ting the microvasculature from the damaging effects ofincreased hydrostatic pressure. This experimental find-ing may provide an explanation for the clinicalobservation that hypertensive encephalopathy typical-ly occurs at lower levels of blood pressure in patientswith the sudden onset of severe hypertension, e.g.,eclampsia or glomerulonephritis, in which arteriolarhypertrophy may not yet have developed.

While the finding of regional cerebral hyperper-fusion provides a basis for the observed beneficialeffect of antihypertensive therapy in hypertensiveencephalopathy and cerebral haemorrhage in man, thefindings in the stroke-prone SHR also suggest amechanism which might account for the protectiveeffect of antihypertensive treatment on the develop-ment of ischaemic cerebral infarction in treatedpatients with benign essential hypertension. The vesselabnormalities responsible for cerebral infarction in theSHR are confined to arteries and arterioles of theorder of 50 to 200 microns in diameter. The path-ological changes in such vessels in hypertensives, welldescribed in a classic paper by Feigen & Prose (1959),are not atherosclerotic but rather are described aslypohyalinosis or hypertensive fibrinoid necrosis. Ithas been suggested that these vascular lesions might beresponsible for the small deep lacunar infarcts whichaccount for 20-50% of non-embolic strokes in hyper-tensives (Fisher, 1969). While atherosclerosis of largerintracranial vessels is increased in hypertensives andatherosclerosis of these larger arteries correlates withthe frequency of lacunar infarcts, localization of thelesions at autopsy or by computerized axial tomogra-phy suggest that smaller penetrating vessels are often

the site of occlusion. The finding that antihypertensivetherapy significantly reduces the incidence of bothhaemorrhagic and ischaemic cerebral infarcts (Reportof the Management Committee: The AustralianTherapeutic Trial in Mild Hypertension, 1980; Hyper-tension Detection and Followup ProgramCooperative Group, 1979) is more likely attributableto the prevention of hypertensive changes in smallvessels than to the prevention of cerebral atheros-clerosis.

The renal circulation

The pattern of renal vascular involvement in malig-nant hypertension has changed strikingly in the 25years since the introduction ofpotent antihypertensivedrugs. In the era before effective antihypertensivetherapy, the typical renal lesion seen in patients dyingof malignant hypertension was fibrinoid arteriolitis,characterized by the insudation of plasma proteinsand fibrin in the walls of preglomerular arterioles.With the advent of potent antihypertensive drugs, thecourse of the disease has been prolonged (Mroczek etal., 1969; Gudbrandsson et al., 1979) and the renallesion, seen in biopsy samples, nephrectomy ornecropsy material, is that ofmarked medial hypertro-phy and subintimal fibroplasia of arcuate and in-terlobular arteries associated with a variable degree ofglomerular sclerosis (Jones, 1974). A patho-physiological sequence similar to that which has beendescribed in the cerebral circulation, initiated byhyperfusion and autoregulatory failure, may be res-ponsible for these vascular changes and for the renalmanifestations in malignant hypertension -haematuria, proteinuria, and renal failure. Both thearteriolar and small arterial lesions may be the endresult of exposure of the intrarenal vasculature toincreased hydrostatic pressure (Helmchen et al., 1984).Intrarenal pressure has been found to be elevated insmall arteries, arterioles, and glomerular capillaries inseveral experimental models of hypertension. Koch etal. (1968) first observed a striking increase in in-trarenal pressure (peritubular capillary pressure) andglomerular hydrostatic pressure following acute eleva-tion of arterial pressure by carotid artery ligation inthe rat; pathological changes in the renal vasculaturewere not examined. Azar et al. (1974) observed thatintrarenal pressures were significantly increased in amodel of hypertension produced by salt loading, withor without uninephrectomy, in the Holtzman strain ofrat. Glomerular pressure was also elevated. Theyfound that single nephron blood flow and filtrationrate (SNGFR) were similarly increased. These ratsdeveloped extensive glomerulosclerosis and, as aresult, overall glomerular filtration rate (GFR) wasreduced despite increased single nephron blood flow,

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filtration pressure, and SNGFR, i.e., nephron hyper-perfusion.We observed a similar pattern of increased in-

trarenal pressure in patients with essential hyperten-sion (Lowenstein et al., 1970). In these studies,peritubular capillary pressure was estimated frommeasurements ofwedged renal vein pressure (WRVP)and, taken together with clearance measurements ofGFR and renal plasma flow, were used to estimateglomerular capillary pressure. Patients with moderatehypertension demonstrated significant elevations ofintrarenal and glomerular pressure. We attributed themaintenance of normal GFR, in the face of increasedglomerular pressure, to the associated increase inproximal tubular hydrostatic pressure with resultantunchanged net filtration pressure. It seems equallypossible that the total nephron number was reduced(by glomerulosclerosis) and that hyperfiltration inremaining nephrons offset the loss to maintain anormal overall filtration rate. There is increasingexperimental evidence that high glomerular pressureand blood flow may result in glomerular injury leadingto glomerular sclerosis (Hostetter et al., 1981). Eventhe vascular changes, seen as medial smooth musclehyperplasia and subintimal fibroplasia may reflect theeffects of pressure-mediated injury. In tissue culture,vascular smooth muscle hypertrophy can bestimulated by platelet derived growth factor (PDGF)-a polypeptide with structural homology to a recog-nized oncogene sequence - which binds to specificreceptors on smooth muscle cells and fibroblasts andinitiates DNA synthesis (Schwartz, 1984). It might bespeculated that PDGF gains access to muscle cells andsubintimal fibroblasts at sites of haemodynamicallymediated endothelial injury. While there is goodevidence that antihypertensive treatment appears toprevent or slow the rate ofprogression or renal failurein patients with malignant hypertension, particularlythose in whom therapy is begun before glomerularfiltration is significantly reduced, slowly progressiverenal failure is often observed despite adequate bloodpressure control. Experimental studies (Dworkin etal., 1984) suggest that glomerular hyperperfusion maypersist despite blood pressure reduction and might beresponsible for progressive renal injury. Furtherstudies and clinical correlation will be required todetermine whether the specific intrarenal haemodyn-amic effects of various classes of antihypertensiveagents differ and, if so, whether such differences arerelated to the progression of renal failure in treatedpatients with malignant hypertension.

Left ventricular hypertrophy

Left ventricular hypertrophy (LVH) is a well recog-nized consequence of sustained arterial hypertension.

While it might be expected that the occurrence andseverity of left ventricular hypertrophy would beclosely related to the magnitude and duration ofincreased arterial pressure, the degree of LVH,whether assessed by electrocardiographic (ECG)criteria or by direct measurement at necropsy,correlates poorly with mean arterial pressure (Tarazi& Levy, 1982). Echocardiography has made it possibleto examine the relationship of left ventricular mass toleft ventricular afterload. Afterload is the total forceagainst which the myocardium must contract duringthe ejection phase of systole. It follows that systolicblood pressure is probably more important than eitherdiastolic or mean arterial blood pressure as a deter-minant of hypertrophy. Abi-Samra et al. (1983) ex-amined the relationship between left ventricular wallmass, measured by M mode echocardiography andsystolic blood pressure, and found only a weakcorrelation. Although poorly understood, it appearsthat other factors such as the inotropic state, thedegree of adrenergic stimulation and perhaps theactivity ofthe renin-angiotensin system may be impor-tant determinants of the degree to which the myocar-dium hypertrophies in response to any given level ofblood pressure. Sen (1983) found that regression ofmyocardial hypertrophy, in the spontaneous hyper-tensive rat, followed treatment with either methyl-dopa, a combination of reserpine, hydralazine andthiazide, or captopril, but not treatment with thevasodilators, hydralazine or minoxidil, despite moreeffective blood pressure lowering with the latter drugs.She postulated that sympathetic inhibition by methyl-dopa or reserpine, as contrasted with reflex sympath-etic stimulation associated with hydralazine or minox-idil, might account for the disparate effects on theregression of myocardial hypertrophy. Lundin &Hallback-Norlander (1984) compared the effects ofmethyldopa, metoprolol, and the calcium channelantagonist, felopidine, on regression ofcardiovascularchanges in the SHR and concluded that the extent ofreduction in arterial pressure was the major determin-ant of the extent of reversal of structural changes.The application ofechocardiography to the study of

myocardial hypertrophy in hypertensive disease hasyielded several interesting and surprising findings.First, it has been noted that left ventricular hypertro-phy may be asymmetric rather than concentric inhypertensive disease. Hypertrophy has been found inyoung relatively mild hypertensives (Tarazi & Levy,1982). Hypertrophy has been observed to regressduring antihypertensive therapy in man. Wollam et al.(1983) made serial echocardiographic measurementsof left ventricular posterior wall thickness and septalthickness in a small series of hypertensive patienttreated for 18 months with either methyldopa, hydro-chlorothiazide, or a combination of these agents.Despite comparable blood pressure reduction with the

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three treatment protocols, regression of hypertrophywas not observed when the thiazide was given alone.The important implication ofthese early experimentaland clinical studies appears to be that left ventricularhypertrophy in hypertension is not a simple functionof the degree of blood pressure elevation and, as acorollary, that antihypertensive drugs might differ intheir capacity to prevent or to cause regression of leftventricular hypertrophy (Tarazi & Fouad, 1984).

Coronary heart disease

Finally, I would like to consider the effects of anti-hypertensive therapy on the develpment and course ofcoronary heart disease. Epidemiological studies havedemonstrated that hypertension is a major risk factorfor the development of coronary heart disease. Witheffective control of blood pressure in severe hyperten-sion, heart failure, hypertensive encephalopathy, andrenal failure have become less common and coronaryheart disease and stroke are emerging as the majorcardiovascular consequences of mild hypertension(defined as diastolic pressure between 90 and114mm Hg). Data from the Framingham study(Castelli, 1984) indicate that for adults with bloodpressure greater than 160/95 mm Hg the risk ofcoron-ary heart disease (CHD) is increased 2- 3-fold and thatof stroke 7-fold; for patients with BP 140-159/90-94mmHg, CHD risk is increased 1.5-fold andstroke 3-fold (Kannel, 1977).The Veterans Administration Cooperative study of

antihypertensive therapy (1970) found that in thestratum ofpatients with diastolic blood pressures from90- 114mm Hg the effects of lowering blood pressurewere limited to reduction in the frequency ofaccelerated hypertension, stroke and congestive heartfailure; the incidence ofmyocardial infarction was notreduced in the actively treated patients. It might beargued that, as the average age of the men in the studywas 51 y, coronary atherosclerosis was probablyalready well established at the time therapy was begun,and that it was therefore not surprising that theincidence ofmyocardial infarction was not reduced byantihypertensive therapy.The next major placebo-controlled study of the

effects of antihypertensive therapy was the US PublicHealth Service Hospitals Cooperative Study (Smith,1977). This 10 y trial in 389 men and women, averageage 44 y, with diastolic BP 90-114mm Hg, excludedpatients with either cardiomegaly or abnormal restingor exercise ECG. While all morbid events werereduced by almost 60% in the treated patients,protection was largely limited to the category of'hypertensive' complications (stroke, LVH, LV strain,and heart failure). The incidence ofmyocardial infarc-tion was not reduced in the treated group. Two

additional placebo controlled studies have addressedthis issue; the Australian Therapeutic Trial in MildHypertension studied 3400 hypertensive patients(1980) and the Oslo Study 785 men (Helgeland, 1980).Both trials confirmed the overall benefit of bloodpressure reduction but failed to find a significantreduction in the incidence of myocardial infarctionwith antihypertensive drug treatment.

Consideration of the possible reasons why anti-hypertensive therapy has failed to reduce the incidenceofmyocardial infarction raises several possibilities: (1)The possibility that atherosclerosis and hypertension'have a common cause but are not causally related'seems to ignore the many experimental studies whichdemonstrate a causal role for hypertension in thegenesis of atherosclerosis and fails to explain theincreased incidence of atherosclerosis in secondaryforms of hypertension. (2) The presence of coronaryatherosclerosis in young men was demonstrated Mnautopsy series in the Korean War (Enos et al., 1955)and attests to the early onset of this lesion. Thepossibility that this lesion was already present and thatits course could not be changed by antihypertensivetherapy cannot be rigorously excluded. (3) With thedevelopment of methods for ambulatory blood pres-sure monitoring, it has become clear that bloodpressure control in treated hypertensives does notapproximate the control of blood pressure over thecourse of 24 h in normotensive individuals. If athero-sclerosis is initiated by small areas of intimal injurywhich allow the access of growth factors andlipoproteins to subintimal smooth muscle cells, it maybe that the amplitude of blood pressure deviationsrather than the average or resting blood pressure maybe the critical variable in determining the developmentof atherosclerotic lesions. The importance ofhaemodynamic factors other than average bloodpressure is evident from the unique localization ofatherosclerotic plaques at specific sites (branch points,vessel ostia) in the arterial tree.

Finally, it has recently been recognized that many ofthe antihypertensive drugs affect serum lipoproteinconcentrations. It may be speculated that drug-in-duced alterations in lipoprotein and cholesterolmetabolism could offset the potentially beneficialeffects of blood pressure reduction. Diuretics, boththiazides and chlorthalidone, have been found toinduce an increase in low density lipoprotein choles-terol concentration (Goldman et al. 1980; Ballantyne& Ballantyne, 1983). Some investigators have reportedthat beta-adrenergic blocking drugs induce a decreasein the concentration of high density lipoproteincholesterol (Leren et al., 1980; Waal-Manning &Simpson, 1977). In contrast to the effects of beta-adrenergic antagonists the selective alpha-adrenergicantagonist, prazosin, has been reported to reducecholesterol and triglycerides and to cause a modest

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TARGET ORGAN DAMAGE IN HYPERTENSION 777

increase in the concentration of high densitylipoprotein cholesterol (Leren et al., 1980; Lowenstein& Neusby, 1984).The importance of serum cholesterol concentration

as a risk factor for the development of coronary heartdisease is well established. Low density lipoproteincholesterol concentration is positively correlated withcoronary risk and high density lipoprotein cholesterolis negatively correlated (Castelli, 1984). In light of theimportance of serum cholesterol concentration andlipoprotein fractions in the pathogenesis of coronaryartery disease, the finding that diuretic agents and

adrenergic blocking drugs alter serum lipid concentra-tions raises several important questions. (1) How longdo these serum lipid changes persist? Present datasuggests that they are still evident after at least 1 yearof treatment with diuretic (Goldman et al., 1980). Theduration of the changes induced by alpha- and beta-adrenergic antagonists is not known beyond about 2months. (2) Are the changes quantitatively sufficientto influence coronary risk? (3) Do these drug-inducedalterations in lipoprotein cholesterol-concentrationschange coronary risk? The answers to these importantquestions are not yet at hand.

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