Microvascular disease—the Cinderella of uraemic heart disease

On October 14, 1995, Professor A. Raine (St Bartholomew's Hospital, London) died at the young age of 46 years. He was a fascinating man who combined a rigorous scientific approach with clinical acumen. He excelled in the fields of hypertension research and nephrological research. He was an inspiring investigator whose untimely death is mourned by many colleagues in European nephrology. NDT commemorates the outstanding contributions of our former subject editor in the field of hypertension by a contribution bearing on the major research topic of the late Professor Raine, i.e. the interrelation of kidney and blood pressure. Professor Antony Raine 21.7.49–14.10.95.

Kerstin Amann1, and Eberhard Ritz2

1 Department of Pathology, University of Erlangen-Nürnberg and 2 Department of Internal Medicine, University of Heidelberg, Germany

Abstract

It has been known for a long time that atherosclerosis, particularly plaques in the epicardiac coronary conduit arteries, are more frequent in patients with chronic renal failure than in non-uraemic patients. It has been only recently, however, that modification of post-stenotic remodelling of cardiac arteries as well as abnormalities of the arterioles and the capillaries in the myocardium of uraemic animals and uraemic patients have been recognized and analysed. These lesions can be dissociated from changes in blood pressure and may be an important cause contributing to reduced ischaemia tolerance and cardiac malfunction (pump failure, arrhythmia) thus predisposing to cardiac death. Recent insights into angiogenesis, particularly adaptive angiogenesis in response to hypoxia, may potentially provide novel approaches to the understanding and management of cardiac microangiopathy in renal failure.

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

Epidemiology of cardiac disease in renal failure

Ever since the seminal report of Lindner et al. [1] a high rate of myocardial infarction and excessive cardiac mortality have repeatedly been documented in uraemic patients. The epidemiological magnitude of the problem has been clearly pointed out by the late Tony Raine [2] who found that the cardiac death rate was elevated by a factor of approximately 15–20 relative to the rates in the respective background population. It is well known that only 20–30% of cardiac deaths in renal patients are due to myocardial infarction [3]. The prevalence of coronary atheroma in uraemic patients is approximately 30% by autopsy [4] and coronary angiography studies [5]. Not only is the prevalence high, but also the case fatality rate of myocardial infarction. Recently, Herzog et al. [6] noted excess mortality in uraemic patients having had a myocardial infarct; the 1 year mortality was 55.4% and 62.3% in uraemic patients with and without diabetes, respectively, compared to about 10–15% in non-uraemic patients. This study goes beyond the well-known notion that uraemia is associated with more frequent and more severe atherosclerosis and shows that, in addition, the adaptation to coronary perfusion deficits is inappropriate. We therefore posit that apart from coronary factors, non-coronary factors may play an important role in the genesis of cardiac complications in the renal patient.

It is well known that in patients with angiographically documented coronary artery stenosis vascular reactivity in non-stenotic segments of the coronary circulation is abnormal as well. Thus Depre et al. [7] found that the coronary perfusion reserve was diffusely reduced in the hearts of patients with angiographically confirmed, circumscribed coronary artery stenosis and a number of studies documented reduced coronary reserve in patients with the so-called syndrome X, i.e. patients with angina pectoris but patent coronary arteries [8].

Non-coronary factors comprise both functional, e.g. abnormal vasodilatation, and structural abnormalities in the macro- and microvasculature, respectively. These include increased extravascular resistance resulting from left ventricular hypertrophy and interstitial fibrosis as well as abnormal structure of the microcirculation (arterioles, capillaries).

The work of the late Tony Raine showed that, in addition, cardiac metabolism is abnormal in uraemia. It is characterized by increased ATP breakdown under hypoxic conditions, but increased diastolic cytosolic calcium concentrations [9]. It is well known that during hypoxia as well as under ex-hypoxic conditions the heart changes the metabolic substrate from fatty acids to glucose [10,11]. In this context it is of interest that expression of the glucose transporter (Glut 4) is reduced in the heart of rats with experimental uraemia [12].

It is obvious from the above that cardiac disease in the renal patient is multifactorial in origin. In the following we shall focus only on one specific aspect, i.e. the structure of epicardial and myocardial vessels. These findings help to better understand the following conditions

Atherosclerotic lesions of the coronary arteries

Morphological studies have clearly documented a high prevalence of coronary atheroma in uraemic patients [4,14] and this is confirmed by angiographic studies [5,1517]. Studies of Ibels et al. [18], had documented thickening of the intima and calcification of the media of renal and iliac arteries as well as increased calcium content of the aorta of uraemic patients.

In a recent study we analysed the coronaries of 27 patients with end-stage renal disease and of controls with non-renal disease matched for age and sex [19]. As shown in Figure 1Go the intima thickness tended to be higher (158±38 µm vs 142±31 µm) in renal patients but this difference was not significant. In contrast, the media thickness of coronary arteries was significantly higher (187±53 µm vs 135±29 µm in controls). Although plaque area was comparable in renal patients and controls, the residual lumen (lumen area) was significantly lower in patients with end-stage renal disease. In addition, heavily calcified plaques (type VII according to Stary, ref. 20) were significantly more frequent in uraemic patients, i.e. (18/27 vs 5/27 in controls). The latter observation is of considerable interest in view of the recent observation of Block et al. [21] that in dialysed patients hyperphosphataemia is a significant predictor of death, and in a more recent analysis specifically a predictor of cardiac death [22]. It appears therefore that hyperphosphataemia is a novel uraemia specific coronary risk factor. It has not definitely been established whether the action of phosphate is mediated via parathyroid hormone (PTH) or not [23]. However these autopsy data are in good agreement with previous findings in dialysed patients in whom rapidly progressive coronary calcification was noted using fast electron CT [24]. It is of interest that even in non-renal patients serum phosphate is correlated to coronary calcification [25]. The pronounced tendency of plaques to undergo calcification may also explain the extremely poor outcome of percutaneous coronary arterial dilatation (PTCA) in uraemic patients, the 1 year reocclusion rate being 70% in uraemic patients compared to 20% in the non-uraemic population [26,27]. These results may improve in the future with stenting and modern antiplatelet therapy, however.



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

 
To the extent that this can be analysed in heavily calcified plaques, it is of interest that we noted infiltration with, and activation of, macrophages in plaques (see Figure 2Go). This is in line with the notion proposed by the late Russel Ross [28] that atherosclerosis is an inflammatory process. This may be related to the results of recent prospective studies in dialysis patients indicating that serum fibrinogen and CRP concentrations are powerful predictors of cardiac death [2931].



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Fig. 2. Accumulation of CD 68 positive macrophages in an atherosclerotic plaque of a coronary artery of an uraemic patient. Immunohistochemistry, magnification: x500.

 
Whether this process is initiated by or amplified by factors specific for uraemia [32] e.g. advanced oxidation products, advanced glycation products, activated complement components, etc. requires further studies.

There is consensus [28] that a lesion of the endothelial cell is the central event in atherogenesis. It is therefore of interest that endothelial cell dependent vasodilatation of coronary arteries in response to intracoronary injection of acetylcholine, which is presumably mediated via nitric oxide (NO), is abnormal in dialysis patients [33]. Recent studies suggest that in uraemia there is generalized impairment of NO-mediated vasodilatation [34] and diminished whole body NO production [35] possibly because of circulating inhibitors of NO synthase [36,37]. Furthermore, both experimental [38,39] and clinical studies [40] suggest that synthesis and release of endothelin-1, another endothelial cell autacoid, is also abnormal in uraemia. Recent studies in this laboratory [41] suggest that under low flow conditions intimal proliferation is strikingly elevated in arteries of subtotally nephrectomized rats. This finding is of interest because it is compatible with the notion that behind tight coronary stenoses low blood flow triggers overshooting intimal proliferation (as suggested by our own uncontrolled qualitative autopsy observations in uraemic patients). In the experimental study this proliferation was abrogated by endothelin receptor blockers specific for the subtype receptor A. These findings suggest that a ‘secondary stenosis’ so-to-speak is created behind tight coronary stenoses. This may also be related to the excessive intimal proliferation at the site of the venous anastomosis of a malfunctioning PTFE graft [42].

Arteriolar abnormalities

Thickening and remodelling of myocardial arterioles is a known feature of essential hypertension [43] and its close animal model the spontaneously hypertensive rat (SHR) [44]. Patients with the syndrome X [8] have angina pectoris upon exercise but no coronary stenosis on coronary angiography. In endomyocardial biopsies of such patients one finds thickening of arterioles [43] and this is reversible after administration of ACE-inhibitors [45].

At postmortem our qualitative observations showed marked thickening of arterioles in the heart of uraemic patients compared to controls. Such thickening was more pronounced than in patients with essential hypertension. Studies in subtotally nephrectomized rats confirmed thickening of the arterioles and this was not explained by the elevation of blood pressure, since wall thickening persisted in subtotally nephrectomized animals the blood pressure of which had been normalized by antihypertensive agents (Table 1Go) [46]. Whilst in SHR rats arteriolar thickening is the results of hypertrophy and polyploidy of vascular smooth muscle cells, wall thickening of myocardial arterioles in subtotally nephrectomized animals is the result of proliferation and hypertrophy [47,48]. Some indication of the pathogenesis of arteriolar wall thickening is provided by interventional studies. In SHR rats arteriolar thickening is prevented or reversed by administration of calcium channel blockers. In contrast, calcium channel blockers were ineffective in subtotally nephrectomized animals but two manoeuvres, i.e. administration of ACE-inhibitors and endothelin receptor blockers, largely prevented arteriolar thickening [49,50]. These observations argue for an aetiological role of the renin–angiotensin and the endothelial systems.


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

 
The functional consequences of arteriolar thickening have not been well investigated. In patients with coronary stenosis [51] it could be shown that baseline coronary perfusion is not affected except by extremely tight stenoses. In contrast perfusion reserve, i.e. perfusion after the maximal vasodilatation with Persantin, was strikingly reduced. It is plausible, but currently unproven, that arteriolar wall thickening interferes with the coronary reserve. This could explain the occurrence of angina pectoris in classical syndrome X [43] and in renal patients with angina pectoris despite no coronary stenosis [16].

On repeated occasions it has been stated that the coronary reserve is reduced in renal failure. It is of interest that Melin [52] noted that progressive reduction of coronary reserve is also found in elderly individuals—in line with the concept proposed by us [53] and others [54,55] that uraemia is a state of accelerated ageing.

Capillary abnormalities

In tissues undergoing hypertrophy, new capillaries form through sprouting, branching and acquisition of pericytes [Figure 3Go]. Capillary density in the hearts of SHR rats is only slightly diminished compared to Wistar Kyoto control rats [44]. In contrast, in the heart of subtotally nephrectomized rats we noted a striking and significant diminution of capillary length density (Figure 4Go, Table 2Go) [56]. Capillary length density is conceptually the length of all capillaries added one to the other contained within one unit volume of cardiac tissue. As shown in Table 2Go a similar reduction of capillary length density is not seen in SHR rats and rats with renovascular hypertension (1C-2K). Recently, these experimental data could be extended by showing that capillary length density was also reduced in the left ventricle of dialysed patients compared to patients with essential hypertension and to control individuals [57]. These findings imply that when cardiomyocytes hypertrophy in uraemia, capillary growth does not keep pace with cardiomyocyte growth. As shown in detail elsewhere [56] this must by necessity increase the oxygen diffusion distance, i.e. from the centre of the capillary to the centre of the cardiomyocyte by up to 25% according to our calculations (Figure 4Go).



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Fig. 3. Mechanisms of vessel formation by vasculogenesis and angiogenesis.

 


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Fig. 4. Myocardial capillarisation in a subtotally nephrectomized rat (B) and a sham operated control rat (A). Please note the marked lower number of capillary profiles in the myocardium of the subtotally nephrectomized rat (B). Semithin sections, magnification: x1250.

 

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Table 2. Myocardial capillarisation in different experimental models of myocardial hypertrophy (after 55)

 
It is evident that under conditions of hypoxia or ischaemia an increase of the critical oxygen diffusion distance will expose the cardiomyocyte to the risk of hypoxic damage. Hypoxia is sensed by hypoxia sensing molecules (HIF=hypoxia inducible factor). Whether this is abnormal in uraemia is currently under investigation.

Again, capillary length density is affected by interventions, particularly central blockade of the central sympathetic system [49] and administration of endothelin type A receptor blockers [58]. It is known that erythropoietin (Epo) is an angiogenic factor. Conceivably low Epo concentrations in uraemic animals might contribute to undercapillarization, but this hypothesis could not be confirmed in our recent experimental study [59]. The question can be raised whether diminished capillarization is specific for the heart or a generalized characteristic of renal failure. We examined parenchymal organs, i.e. liver and pancreas as well as muscle tissue of subtotally nephrectomized rats. There was no evidence of diminished capillarization in any of these organs, capillary density was thoroughly quantitated in skeletal muscle and found to be unchanged [60]. This negative observation does not completely exclude a generalized defect, since these organs had not been subjected to the stimulus of hypertrophy. Diminished capillary density has also been noted, however, in the skin of dialysed patients. This finding is difficult to interpret, however, in view of many confounding factors [61].

What is the potential functional relevance of the capillary abnormality in the heart? Recent findings show that abnormal capillarization in VEGF164 and VEGF188 knockout mice causes functional ischaemic cardiomyopathy [62]. As stated by Isner et al. in an accompanying editorial [63] ‘congestive heart failure may be the result of myocardial ischemia despite the absence of extramural artery obstruction.... Angiographically occult intramural coronary vasculature may constitute the locus of the disease as well as (hopefully) the cure’. This statement also underlines the potential functional relevance of the microcirculatory abnormality in renal failure.

The recognition that formation of new vessels, i.e. angiogenesis, is a potential target for therapeutic intervention has recently led to at least partially successful attempts at transfecting VEGF in the heart [64,65] and peripheral muscle [66,67] of non-uraemic animals or patients with coronary and peripheral arterial disease, respectively. This led to transient improvement of tissue perfusion. Against this background, the microcirculatory abnormalities that we identified are more than innocent academic findings and may provide a perspective for therapeutic intervention in the distant future.

Potential pathomechanisms causing faulty angiogenesis

The above results document abnormal vascular remodelling in renal failure. In the following we wish to provide an outlook and to review some concepts which have recently emerged concerning vasculogenesis and angiogenesis [6870].

Development of new vessels occurs in response to stimuli such as hypoxia and increased wall stress (Figure 5Go) [7173]. After a brief summary of recent findings in this field we shall provide working hypotheses to explain the abnormalities in uraemia. Such hypotheses are susceptible to experimental testing.



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Fig. 5. Stimulation of angiogenesis.

 
As schematically shown in Figure 3Go, in the embryo so-called vasculogenesis is caused by differentiation of pluripotential haemangioblasts into angioblasts and subsequently endothelial cells. The latter recruit auxiliary cells, i.e. pericytes in the capillaries and smooth muscle cells in the arteries. They then form mature vessels after appropriate sprouting, branching and differentiation. In the grown organism new vessel formation, so-called angiogenesis, is believed to originate only from pre-existing vessels, although recently circulating endothelial cell precursors analogous to haemangioblasts have also been identified [74]. As summarized in Table 3Go the delicate process of angiogenesis reflects the balance between positive and negative regulators. Negative regulators, i.e. inhibitors of angiogenesis, are currently hotly investigated because of the perspective to interfere with tumour growth by preventing new vessel formation and so-to-speak starving the tumour by underperfusion. These negative regulators, so called angiostatins, originate from high molecular weight precursors such as plasminogen, collagen XVIII, and calreticulin [7578]. The angiostatins are substances with relatively low molecular weight. Whether they cumulate in renal failure and thus impair angiogenesis is currently under investigation.


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Table 3. Vasculogenesis/angiogenesis

 
Angiogenesis must be triggered by stimuli as schematically shown in Figure 5Go. Known stimuli include the peptides endothelin-1 and angiotensin II as well as the hypoxia sensing factor HIF-1. They upregulate the vascular endothelial growth factor (VEGF), which exists in several isoforms. It is therefore of interest that our immunohistochemical study [79] showed increased expression of VEGF in intramyocardial arteriolar smooth muscle cells (Figure 6Go). This finding does not reflect non-specific uptake of circulating VEGF, since increased VEGF mRNA could be documented as well. The finding of increased expression of this factor stimulating vascular growth on the mRNA and protein level is surprising in view of diminished capillarogenesis. Whether this indicates some type of VEGF resistance at the receptor or postreceptor level is currently under investigation.



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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 was courtesy of Prof. Dr H.-J. Gröne, DKFZ, Heidelberg). Magnifications: x450.

 
Another known regulator of cardiac capillary neoformation, particularly in response to increased wall stress, is basic fibroblast growth factor (bFGF) [80]. Our own observations in bFGF knockout mice show impaired capillarization, possibly implying that embryonic capillarogenesis may be bFGF dependent as well, and not only capillarogenesis in response to increased demand as thought so far [81].

Angiotensin II and endothelin-1 are known promoters of neovascularisation. This has been shown both in culture systems and by in vivo studies [8285]. In this context it is again of interest that our own studies document increased local formation of renin/angiotensin II on the one hand and of endothelin-1 on the other hand in the heart of uraemic animals [58,86]. The latter is illustrated in Figure 7Go.



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Fig. 7. Increased endothelin-1 mRNA expression in the heart of a subtotally nephrectomized animal (B) compared to the normal situation in a sham operated control animal (A). Magnification: x180.

 
Nephrologists are aware that the current rates of survival on dialysis are completely unsatisfactory. The above findings on the microcirculation of the heart in uraemia are not definitive. At least they provide, however, novel approaches to the understanding and management of cardiac ischaemia in renal failure. It would be to our great satisfaction if such novel approaches would help to bring to reality the long standing wish of the late Professor Antony Raine that some day the cardiac prognosis of the renal patient can be substantially improved.

Acknowledgments

The skillful technical assistance of Z. Antoni, Dipl. Ing. H. Derks, K. Herbig, P. Rieger, H. Ziebart, M. Weckbach and Dipl. Biol. S. Wessels is greatfully acknowledged.

Notes

Correspondence and offprint requests to: K. Amann, Department of Pathology, Krankenhausstrasse 8–10, D-91054 Erlangen, Germany. Back

After the first Tony Raine memorial lecture on the occassion of the Annual Meeting of the European Renal Association (ERA/EDTA) Madrid, Spain 5–8 September 1999. Back

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