microvascular disease—the cinderella of uraemic heart disease

Nephrol Dial Transplant (2000) 15: 1493–1503Nephrology

DialysisTransplantationTony Raine Memorial Lecture

Microvascular disease—the Cinderella of uraemic heart disease*

Kerstin Amann1 and Eberhard Ritz2

1Department of Pathology, University of Erlangen-Nurnberg and 2Department of Internal Medicine, University ofHeidelberg, Germany

On October 14, 1995, Professor A. Raine (St the late Professor Raine, i.e. the interrelation of kidneyand blood pressure.Bartholomew’s Hospital, London) died at the young age

of 46 years. He was a fascinating man who combined arigorous scientific approach with clinical acumen. Heexcelled in the fields of hypertension research and Abstract It has been known for a long time thatnephrological research. He was an inspiring investigator atherosclerosis, particularly plaques in the epicardiacwhose untimely death is mourned by many colleagues in coronary conduit arteries, are more frequent in patientsEuropean nephrology. with chronic renal failure than in non-uraemic patients.

NDT commemorates the outstanding contributions of It has been only recently, however, that modificationour former subject editor in the field of hypertension by of post-stenotic remodelling of cardiac arteries as wella contribution bearing on the major research topic of as abnormalities of the arterioles and the capillaries in

the myocardium of uraemic animals and uraemicpatients have been recognized and analysed. Theselesions can be dissociated from changes in bloodpressure and may be an important cause contributingto reduced ischaemia tolerance and cardiac malfunc-tion (pump failure, arrhythmia) thus predisposing tocardiac death. Recent insights into angiogenesis, par-ticularly adaptive angiogenesis in response to hypoxia,may potentially provide novel approaches to the under-standing and management of cardiac microangiopathyin renal failure.

Keywords: uraemia; uraemic cardiomyopathy; coronaryheart disease; heart capillaries; myocardial infarction

Epidemiology of cardiac disease in renal failure

Ever since the seminal report of Lindner et al. [1] ahigh rate of myocardial infarction and excessive cardiacmortality have repeatedly been documented in uraemicpatients. The epidemiological magnitude of the prob-lem has been clearly pointed out by the late TonyRaine [2] who found that the cardiac death rate waselevated by a factor of approximately 15–20 relativeto the rates in the respective background population.It is well known that only 20–30% of cardiac deathsin renal patients are due to myocardial infarction [3].Professor Antony Raine 21.7.49–14.10.95.The prevalence of coronary atheroma in uraemic

Correspondence and offprint requests to: K. Amann, Department of patients is approximately 30% by autopsy [4] andPathology, Krankenhausstrasse 8–10, D-91054 Erlangen, Germany. coronary angiography studies [5]. Not only is the* After the first Tony Raine memorial lecture on the occassion of

prevalence high, but also the case fatality rate ofthe Annual Meeting of the European Renal Association(ERA/EDTA) Madrid, Spain 5–8 September 1999. myocardial infarction. Recently, Herzog et al. [6 ] noted

© 2000 European Renal Association–European Dialysis and Transplant Association

K. Amann and E. Ritz1494

excess mortality in uraemic patients having had a [4,14] and this is confirmed by angiographic studies[5,15–17]. Studies of Ibels et al. [18], had documentedmyocardial infarct; the 1 year mortality was 55.4% and

62.3% in uraemic patients with and without diabetes, thickening of the intima and calcification of the mediaof renal and iliac arteries as well as increased calciumrespectively, compared to about 10–15% in non-

uraemic patients. This study goes beyond the well- content of the aorta of uraemic patients.known notion that uraemia is associated with more In a recent study we analysed the coronaries of 27frequent and more severe atherosclerosis and shows patients with end-stage renal disease and of controlsthat, in addition, the adaptation to coronary perfusion with non-renal disease matched for age and sex [19].deficits is inappropriate. We therefore posit that apart As shown in Figure 1 the intima thickness tended tofrom coronary factors, non-coronary factors may play be higher (158±38 mm vs 142±31 mm) in renal patientsan important role in the genesis of cardiac complica- but this difference was not significant. In contrast, thetions in the renal patient. media thickness of coronary arteries was significantly

It is well known that in patients with angiograph- higher (187±53 mm vs 135±29 mm in controls).ically documented coronary artery stenosis vascular Although plaque area was comparable in renal patientsreactivity in non-stenotic segments of the coronary and controls, the residual lumen ( lumen area) wascirculation is abnormal as well. Thus Depre et al. [7] significantly lower in patients with end-stage renalfound that the coronary perfusion reserve was diffusely disease. In addition, heavily calcified plaques (type VIIreduced in the hearts of patients with angiographically according to Stary, ref. 20) were significantly moreconfirmed, circumscribed coronary artery stenosis and frequent in uraemic patients, i.e. (18/27 vs 5/27 ina number of studies documented reduced coronary controls). The latter observation is of considerablereserve in patients with the so-called syndrome X, i.e. interest in view of the recent observation of Blockpatients with angina pectoris but patent coronary et al. [21] that in dialysed patients hyperphosphataemiaarteries [8]. is a significant predictor of death, and in a more recent

Non-coronary factors comprise both functional, e.g. analysis specifically a predictor of cardiac death [22].abnormal vasodilatation, and structural abnormalities It appears therefore that hyperphosphataemia is ain the macro- and microvasculature, respectively. These novel uraemia specific coronary risk factor. It has notinclude increased extravascular resistance resulting definitely been established whether the action of phos-from left ventricular hypertrophy and interstitial fib- phate is mediated via parathyroid hormone (PTH) orrosis as well as abnormal structure of the microcircul- not [23]. However these autopsy data are in goodation (arterioles, capillaries). agreement with previous findings in dialysed patients

The work of the late Tony Raine showed that, in in whom rapidly progressive coronary calcification wasaddition, cardiac metabolism is abnormal in uraemia. noted using fast electron CT [24]. It is of interest thatIt is characterized by increased ATP breakdown under even in non-renal patients serum phosphate is correl-hypoxic conditions, but increased diastolic cytosolic ated to coronary calcification [25]. The pronouncedcalcium concentrations [9]. It is well known that during tendency of plaques to undergo calcification may alsohypoxia as well as under ex-hypoxic conditions the explain the extremely poor outcome of percutaneousheart changes the metabolic substrate from fatty acids coronary arterial dilatation (PTCA) in uraemicto glucose [10,11]. In this context it is of interest patients, the 1 year reocclusion rate being 70% inthat expression of the glucose transporter (Glut 4) uraemic patients compared to 20% in the non-uraemicis reduced in the heart of rats with experimental population [26,27]. These results may improve in theuraemia [12]. future with stenting and modern antiplatelet therapy,

It is obvious from the above that cardiac disease in however.the renal patient is multifactorial in origin. In the To the extent that this can be analysed in heavilyfollowing we shall focus only on one specific aspect, calcified plaques, it is of interest that we noted infiltra-i.e. the structure of epicardial and myocardial vessels. tion with, and activation of, macrophages in plaquesThese findings help to better understand the following (see Figure 2). This is in line with the notion proposedconditions by the late Russel Ross [28] that atherosclerosis is an

inflammatory process. This may be related to the$ angina pectoris of the renal patients in the absenceresults of recent prospective studies in dialysis patientsof coronary artery stenosis [13]indicating that serum fibrinogen and CRP concentra-$ insufficient adaptation of the heart to regionaltions are powerful predictors of cardiac death [29–31].ischaemia, e.g. after myocardial infarction (unpub-

Whether this process is initiated by or amplified bylished experimental observations)factors specific for uraemia [32] e.g. advanced oxida-$ increased susceptibility of the heart to hypoxiation products, advanced glycation products, activatedpredisposing to arrhythmia and structural damagecomplement components, etc. requires further studies.of cardiomyocytes

There is consensus [28] that a lesion of the endothel-ial cell is the central event in atherogenesis. It is

Atherosclerotic lesions of the coronary arteries therefore of interest that endothelial cell dependentvasodilatation of coronary arteries in response tointracoronary injection of acetylcholine, which is pre-Morphological studies have clearly documented a high

prevalence of coronary atheroma in uraemic patients sumably mediated via nitric oxide (NO), is abnormal

Microvascular disease—the Cinderella of uraemic heart disease 1495

Fig. 1. Intima and media thickness in patients with renal failure and non renal control patients matched for age and sex.

Fig. 3. Mechanisms of vessel formation by vasculogenesis andangiogenesis.

Furthermore, both experimental [38,39] and clinicalstudies [40] suggest that synthesis and release ofFig. 2. Accumulation of CD 68 positive macrophages in an athero-

sclerotic plaque of a coronary artery of an uraemic patient. endothelin-1, another endothelial cell autacoid, is alsoImmunohistochemistry, magnification: ×500. abnormal in uraemia. Recent studies in this laboratory

[41] suggest that under low flow conditions intimal

Table 1. Wall thickening of intramyocardial arteries independent of blood pressure reduction [after 46 ]

Wall thickness Wall-to-lumen ratio(mm) (mm)

Untreated sham operated controls (n=10) 1.71±0.27 0.056±0.011Treated sham operated controls1 (n=9) 1.61±0.13 0.052±0.006Untreated subtotally nephrectomized rats (n=8) 2.33±0.35* 0.077±0.011*Treated subtotally nephrectomized rats1 (n=5) 2.15±0.19* 0.066±0.007*Analysis of variance P<0.001 P<0.001

*P<0.05 vs sham operated control groups.1Antihypertensive treatment with dihydralazine and furosemide.

in dialysis patients [33]. Recent studies suggest that proliferation is strikingly elevated in arteries of sub-totally nephrectomized rats. This finding is of interestin uraemia there is generalized impairment of

NO-mediated vasodilatation [34] and diminished because it is compatible with the notion that behindtight coronary stenoses low blood flow triggers over-whole body NO production [35] possibly because of

circulating inhibitors of NO synthase [36,37]. shooting intimal proliferation (as suggested by our


Fig. 4. Myocardial capillarisation in a subtotally nephrectomized rat (B) and a sham operated control rat (A). Please note the markedlower number of capillary profiles in the myocardium of the subtotally nephrectomized rat (B). Semithin sections, magnification: ×1250.


Table 2. Myocardial capillarisation in different experimental models At postmortem our qualitative observations showedof myocardial hypertrophy (after 55) marked thickening of arterioles in the heart of uraemic

patients compared to controls. Such thickening wasLength density of more pronounced than in patients with essential hyper-cardiac capillaries tension. Studies in subtotally nephrectomized rats con-(mm/mm3)

firmed thickening of the arterioles and this was notexplained by the elevation of blood pressure, since wall

Sham operated control rats 3329±199thickening persisted in subtotally nephrectomizedSubtotally nephrectomized rats 2485±265*animals the blood pressure of which had been normal-Normotensive Wistar Kyoto control rats 3900±440

Spontaneously hypertensive rats (SHR) 3800±270 ized by antihypertensive agents (Table 1) [46 ]. WhilstIC-2K rats with renovascular hypertension 3155±312 in SHR rats arteriolar thickening is the results of

hypertrophy and polyploidy of vascular smooth muscle*P<0.05 vs sham operated controls. cells, wall thickening of myocardial arterioles in subto-

tally nephrectomized animals is the result of prolifera-tion and hypertrophy [47,48]. Some indication of thepathogenesis of arteriolar wall thickening is providedby interventional studies. In SHR rats arteriolar thick-ening is prevented or reversed by administration ofcalcium channel blockers. In contrast, calcium channelblockers were ineffective in subtotally nephrectomizedanimals but two manoeuvres, i.e. administration ofACE-inhibitors and endothelin receptor blockers,largely prevented arteriolar thickening [49,50]. Theseobservations argue for an aetiological role of therenin–angiotensin and the endothelial systems.

The functional consequences of arteriolar thickeningFig. 5. Stimulation of angiogenesis.have not been well investigated. In patients with coron-ary stenosis [51] it could be shown that baselineTable 3. Vasculogenesis/angiogenesiscoronary perfusion is not affected except by extremelytight stenoses. In contrast perfusion reserve, i.e. perfu-Positive regulatorssion after the maximal vasodilatation with Persantin,VEGFwas strikingly reduced. It is plausible, but currentlybFGF

TGF-b/CTGF unproven, that arteriolar wall thickening interferesangiogenins/angiopoietins with the coronary reserve. This could explain the

Negative regulatorsoccurrence of angina pectoris in classical syndrome Xangiostatin (plasminogen)[43] and in renal patients with angina pectoris despiteendostatin (collagen XVIII )

vasostatin (calreticulin) no coronary stenosis [16 ].On repeated occasions it has been stated that the

coronary reserve is reduced in renal failure. It is ofown uncontrolled qualitative autopsy observations in interest that Melin [52] noted that progressive reduc-uraemic patients). In the experimental study this prolif- tion of coronary reserve is also found in elderly indi-eration was abrogated by endothelin receptor blockers viduals—in line with the concept proposed by us [53]specific for the subtype receptor A. These findings and others [54,55] that uraemia is a state of acceler-suggest that a ‘secondary stenosis’ so-to-speak is cre- ated ageing.ated behind tight coronary stenoses. This may also berelated to the excessive intimal proliferation at the site

Capillary abnormalitiesof the venous anastomosis of a malfunctioning PTFEgraft [42].

In tissues undergoing hypertrophy, new capillariesform through sprouting, branching and acquisition of

Arteriolar abnormalities pericytes [Figure 3]. Capillary density in the hearts ofSHR rats is only slightly diminished compared toWistar Kyoto control rats [44]. In contrast, in theThickening and remodelling of myocardial arterioles

is a known feature of essential hypertension [43] and heart of subtotally nephrectomized rats we noted astriking and significant diminution of capillary lengthits close animal model the spontaneously hypertensive

rat (SHR) [44]. Patients with the syndrome X [8] have density (Figure 4, Table 2) [56 ]. Capillary length den-sity is conceptually the length of all capillaries addedangina pectoris upon exercise but no coronary stenosis

on coronary angiography. In endomyocardial biopsies one to the other contained within one unit volume ofcardiac tissue. As shown in Table 2 a similar reductionof such patients one finds thickening of arterioles [43]

and this is reversible after administration of ACE- of capillary length density is not seen in SHR ratsand rats with renovascular hypertension (1C-2K).inhibitors [45].


Fig. 6. Increased expression of VEGF mRNA (A, by non radioactive in situ hybridization) and protein (B, by immunohistochemistry)expression in intramyocardial arteriolar smooth muscle cells of subtotally nephrectomized rats. (Non-radioactive in situ hybridization wascourtesy of Prof. Dr H.-J. Grone, DKFZ, Heidelberg). Magnifications: ×450.

Recently, these experimental data could be extended lary growth does not keep pace with cardiomyocytegrowth. As shown in detail elsewhere [56 ] this mustby showing that capillary length density was also

reduced in the left ventricle of dialysed patients com- by necessity increase the oxygen diffusion distance, i.e.from the centre of the capillary to the centre of thepared to patients with essential hypertension and to

control individuals [57]. These findings imply that cardiomyocyte by up to 25% according to ourcalculations (Figure 4).when cardiomyocytes hypertrophy in uraemia, capil-


Fig. 7. Increased endothelin-1 mRNA expression in the heart of a subtotally nephrectomized animal (B) compared to the normal situationin a sham operated control animal (A). Magnification: ×180.


It is evident that under conditions of hypoxia or provide an outlook and to review some concepts whichischaemia an increase of the critical oxygen diffusion have recently emerged concerning vasculogenesis anddistance will expose the cardiomyocyte to the risk of angiogenesis [68–70].hypoxic damage. Hypoxia is sensed by hypoxia sensing Development of new vessels occurs in response tomolecules (HIF=hypoxia inducible factor). Whether stimuli such as hypoxia and increased wall stressthis is abnormal in uraemia is currently under (Figure 5) [71–73]. After a brief summary of recentinvestigation. findings in this field we shall provide working hypo-

Again, capillary length density is affected by inter- theses to explain the abnormalities in uraemia. Suchventions, particularly central blockade of the central hypotheses are susceptible to experimental testing.sympathetic system [49] and administration of As schematically shown in Figure 3, in the embryoendothelin type A receptor blockers [58]. It is known so-called vasculogenesis is caused by differentiation ofthat erythropoietin (Epo) is an angiogenic factor. pluripotential haemangioblasts into angioblasts andConceivably low Epo concentrations in uraemic subsequently endothelial cells. The latter recruit auxili-animals might contribute to undercapillarization, but ary cells, i.e. pericytes in the capillaries and smooththis hypothesis could not be confirmed in our recent muscle cells in the arteries. They then form matureexperimental study [59]. The question can be raised vessels after appropriate sprouting, branching andwhether diminished capillarization is specific for the differentiation. In the grown organism new vesselheart or a generalized characteristic of renal failure. formation, so-called angiogenesis, is believed to origin-We examined parenchymal organs, i.e. liver and pan- ate only from pre-existing vessels, although recentlycreas as well as muscle tissue of subtotally nephrectom- circulating endothelial cell precursors analogous toized rats. There was no evidence of diminished haemangioblasts have also been identified [74]. Ascapillarization in any of these organs, capillary density summarized in Table 3 the delicate process of angiogen-was thoroughly quantitated in skeletal muscle and esis reflects the balance between positive and negativefound to be unchanged [60]. This negative observation regulators. Negative regulators, i.e. inhibitors of angi-does not completely exclude a generalized defect, since ogenesis, are currently hotly investigated because ofthese organs had not been subjected to the stimulus of the perspective to interfere with tumour growth byhypertrophy. Diminished capillary density has also preventing new vessel formation and so-to-speak starv-been noted, however, in the skin of dialysed patients. ing the tumour by underperfusion. These negativeThis finding is difficult to interpret, however, in view regulators, so called angiostatins, originate from highof many confounding factors [61]. molecular weight precursors such as plasminogen,

What is the potential functional relevance of the collagen XVIII, and calreticulin [75–78]. The angio-capillary abnormality in the heart? Recent findings statins are substances with relatively low molecularshow that abnormal capillarization in VEGF164 and weight. Whether they cumulate in renal failure andVEGF188 knockout mice causes functional ischaemic thus impair angiogenesis is currently undercardiomyopathy [62]. As stated by Isner et al. in an investigation.accompanying editorial [63] ‘congestive heart failure Angiogenesis must be triggered by stimuli as schem-may be the result of myocardial ischemia despite atically shown in Figure 5. Known stimuli include thethe absence of extramural artery obstruction …. peptides endothelin-1 and angiotensin II as well as theAngiographically occult intramural coronary vas- hypoxia sensing factor HIF-1. They upregulate theculature may constitute the locus of the disease as well vascular endothelial growth factor (VEGF), whichas (hopefully) the cure’. This statement also underlines exists in several isoforms. It is therefore of interest thatthe potential functional relevance of the microcircula- our immunohistochemical study [79] showed increasedtory abnormality in renal failure. expression of VEGF in intramyocardial arteriolar

The recognition that formation of new vessels, i.e. smooth muscle cells (Figure 6). This finding does notangiogenesis, is a potential target for therapeutic inter- reflect non-specific uptake of circulating VEGF, sincevention has recently led to at least partially successful increased VEGF mRNA could be documented as well.attempts at transfecting VEGF in the heart [64,65] The finding of increased expression of this factorand peripheral muscle [66,67] of non-uraemic animals stimulating vascular growth on the mRNA and proteinor patients with coronary and peripheral arterial dis- level is surprising in view of diminished capillarogen-ease, respectively. This led to transient improvement esis. Whether this indicates some type of VEGF resist-of tissue perfusion. Against this background, the micro- ance at the receptor or postreceptor level is currentlycirculatory abnormalities that we identified are more

under investigation.than innocent academic findings and may provide aAnother known regulator of cardiac capillary neo-perspective for therapeutic intervention in the distant

formation, particularly in response to increased wallfuture.stress, is basic fibroblast growth factor (bFGF) [80].Our own observations in bFGF knockout mice show

Potential pathomechanisms causing faulty impaired capillarization, possibly implying that embry-angiogenesis onic capillarogenesis may be bFGF dependent as well,

and not only capillarogenesis in response to increaseddemand as thought so far [81].The above results document abnormal vascular remod-

elling in renal failure. In the following we wish to Angiotensin II and endothelin-1 are known pro-


14. European Transplantation and Dialysis Association. Report onmoters of neovascularisation. This has been shownManagement of Renal Failure in Europe, XXIV, 1993. Nephrolboth in culture systems and by in vivo studies [82–85].Dial Transplant 1995; 10 [Suppl 5]: 12In this context it is again of interest that our own 15. Ansari A, Kaupke CJ, Vaziri ND, Miller R, Barbari A. Cardiac

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microvascular disease—the cinderella of uraemic heart disease

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