09. CARDIOVASCULAR 1/1/04 00:53 Página 34 NEFROLOGÍA. Vol. XXIV. Número Extraordinario (IV). 2004 III. PATOLOGÍA CARDIOVASCULAR EN LA INSUFICIENCIA RENAL Cardiovascular disease in chronic renal failure. Risk factors and prevention D. Henriquez, R. Dikow and E. Ritz Department Internal Medicine. Ruperto Carola University Heidelberg. Germany. EPIDEMIOLOGY After B. Scribner had introduced maintenance hemodialysis the naïve view had prevailed in many quarters that if one eliminated uremic toxins by hemodialysis, life expectancy would eventually appro- ximate that seen in the general population. This naïve view was thoroughly dispelled when Lindner1 reported 13 years later that more than 40% of the patients dialysed in Seattle had died, mostly from cardiovascular causes. As shown in figure 1, Raine subsequently documented that the risk of a dialysed 80 United Kingdom 80 Italy 60 per 1,000 patient years per 1,000 patient years 60 40 40 20 20 0 35-44 45-54 55-64 65-74 0 35-44 Age (years) 45-54 55-64 65-74 Fig. 1.--Comparison of death from ischaemic heart disease in the corresponding background population (grey columns) and in male dialyzed patients (black columns) in a country with high (UK) and low (Italy) cardiovascular mortality 2. Correspondence: Dr. Daniel Henriquez Dr. Ralf Dikow Professor Dr. Dr. h.c. mult. Eberhard Ritz Department Internal Medicine Bergheimer Str. 58 D - 69115 Heidelberg E-mail: Prof.E.Ritz@t-online.de 34 09. CARDIOVASCULAR 1/1/04 00:53 Página 35 CARDIOVASCULAR DISEASE IN CHRONIC RENAL FAILURE. RISK FACTORS AND PREVENTION patients to die from ischemic heart disease was higher by a factor of 15-20 compared to the background population 2 and this has recently been amply confirmed by Foley et al 2. CAUSES OF CARDIOVASCULAR DEATH brosis (see below) play an important role. Furthermore, congestive heart failure, which carries a particularly poor prognosis 4 is very frequent in renal failure and is not fully explained by ischemic heart disease. UNDERLYING PATHOPHYSIOLOGY In the past it had been assumed that ischemic events completely accounted for excess mortality. While ischemic heart disease is certainly extremely prevalent, the most frequent cause of death is sudden death, however 3, as shown in table 1. Whilst ischemic heart disease is an important cause of sudden death, it is most likely that other factors, particularly sympathetic overactivity and cardiac fi- Table I. Adjusted cause specific death rates 19992001 Deaths per 100 pat. years Acute MI Cardiac arrest Cardiomyopathy Cardiac arrhythmia Heart valve disease Cerebrovascular Total After reference3. (%) 19.9 51.9 8.4 11.2 1.4 12.3 236 ppm (8.4%) (21.9%) (3.6%) (4.7%) (0.6%) (4.7%) (100%) As postulated by Lindner 1, atherogenesis is undoubtedly accelerated in renal failure and, according to animal experiments, is seen in the very earliest stages of renal dysfunction, and even after uninephrectomy 5. We have also postulated 6, however, that ischemic heart disease is so devastating in the renal patient because in addition the ischemia tolerance of the heart is reduced. We attribute this to several factors, including (i) left ventricular hypertrophy and the associated increase in oxygen demand, (ii) microvessel disease characterized by abnormalities of the vascular bed distal to the coronary conduit arteries, on the level of both arterioles and capillaries 6 as well as (iii) decreased hypoxia tolerance secondary to abnormal cardiac metabolism leading to instability of high energy nucleotides 7 and hyporesponsiveness to insulin 8. Figure 2 shows that insulin-mediated glucose uptake is significantly decreased in the Langendorf heart preparation of uremic rats compared to controls 8. The presence of ischemia intolerance is well illustrated by the 10-6 mol/g/h 100 80 60 40 20 Controls NS Fig. 2.--Insulin dependent glucose uptake in the isolated perfused Langendorf heart of uremic rats 8. 35 09. CARDIOVASCULAR 1/1/04 00:53 Página 36 D. HENRIQUEZ y cols. observation that coronary ligation causes larger zones of total necrosis in the heart of uremic as compared to control rats 9. We wish to draw attention also to two further pathomechanisms which have been appreciated relatively late. Congestive heart failure carryies an excessively poor prognosis and may to a large extent be explained by cardiomyocyte drop-out presumably the result of cardiomyocyte apoptosis or necrosis. Amann found that the number of cardiomyocytes per left ventricle was reduced after subtotal nephrectomy and this defect was abrogated by the administration of ACE inhibitors 10. Furthermore, it has been recognized that presumably through activation of intrarenal baroreceptors or chemoreceptors sympathetic activity is strongly stimulated in patients with endstage renal disease 11, 12. Klein et al.13 could show that this abnormality was demonstrable in hypertensive patients with renal disease, even when glomerular filtration rate was not yet reduced. Not only is the sympathetic activity increased, but the response to sympathetic activation may be abnormal for two reasons. Autonomic polyneuropathy causes patchy cardiac denervation with presumed denervation suprasensitivity to catecholamines, thus aggravating the risk of arrhythmia. Second, the natural antagonist to catecholamines, nitric oxide (NO) is decreased because of inhibition of NO synthase by the circulating inhibitor ADMA and because of scavenging of NO as a result of interaction with reactive oxygen species. The high frequency of arrhythmia and sudden death in renal patients may to a large extent be explained by increased availability of, and reaction to, catecholamines. RELATION OF RENAL DYSFUNCTION TO CARDIOVASCULAR RISK It has only recently been recognized that even minor renal dysfunction strongly increases the risk of cardiovascular death 14. After the initial observation in the Framingham study this has been well documented in the general population by Henry 15, in patients with hypertension by Ruilope 16, and in patients at high cardiovascular risk by Mann 17. Henry et al. found that when GFR was lower by 5 ml/min. 1.732 the relative risk of cardiovascular death was higher by 26%15. If renal patients have an ischemic cardiac event in hospital mortality and post discharge mortality are dramatically increased 18 and the same is true after coronary intervention 19, 20. 36 PREVENTION Unfortunately there is no controlled prospective information on the effect of intervention. Nevertheless, based on observational studies and a priori reasoning, clinical common sense would suggest that the interventions listed in table 2 are sensible. Blood pressure lowering The initial fear that aggressive blood lowering would increase the risk of cardiac death as the result of a J-curve phenomenon was not confirmed in the MDRD trial. In a study on type 2 diabetic patients (ABCD trial) it had been shown that blood pressure lowering within the range of normotensive values significantly decreased stroke and tended to lower cardiovascular events 21. RAS blockade It is very likely that pharmacological blockade of the renin angiotensin system causes further blood pressure independent reduction of the cardiovascular risk 22. The recent studies with angiotensin receptor blockers, i.e. the IDNT study 23 and the RENAAL studies 24 point to a tendency of lower cardiovascular events although both studies were not powered to prove this point. Since ACE inhibitors have a beneficial effect on left ventricular hypertrophy, a known predictor of high cardiovascular risk, and reduce cardiac fibrosis as well as cardiomyocyte drop-out in experimental studies, routine RAS blockade does make sense. A recent retrospective study on dialysed patients even reported less cardiovascular events in dialysed patients on ACE inhibitors although this study certainly requires confirmation 25. Table II. Cardiovascular prevention in renal patients · · · · · · · · · · · Lowering of blood pressure Blockade of RAS â-blockade Statins EPO Aspirin Folate Vitamin E ? Vitamin C ? Control of phosphatemia,calcemia, PTH Avoidance of malnutrition 09. CARDIOVASCULAR 1/1/04 00:53 Página 37 CARDIOVASCULAR DISEASE IN CHRONIC RENAL FAILURE. RISK FACTORS AND PREVENTION Betablockade We postulated years ago 26 that uremic patients, particularly diabetic patients, should routinely receive betablockers. This was based on the observation that in a prospective study on dialysed type 2 diabetic patients only 4% of individuals dying of cardiac causes had received betablockers whilst 12% of those surviving had been on betablockers. The recent DOPPS study also shows significantly lower mortality in dialysed patients receiving betablockers for hypertension or ischemic heart disease. Improved survival or an improved ejection fraction has recently been demonstrated in dialysed patients who were treated with Carvedilol compared to patients receiving placebo 27. Because of the above considerations betablockers are indicated even if there is no overt cardiac disease. This postulate is based on the consideration that these patients have both sympathetic overactivity and increased sympathetic reponsiveness. The argument holds even if patients are on ACE inhibitors, since, at least in non-renal patients the recent Capricon Study 28 documented that betablockers provided additional benefit even when patients had been on ACE inhibitors. Aspirin There is no controlled evidence whether aspirin is equally effective in renal patients as it is in non-renal individuals, but there are good a priori reasons for routine administration. Folate ­ Whether elevated Homocystein concentrations are causally linked to cardiovascular death is uncertain, but since folate is both cheap and safe (at least if latent B12 deficiency is excluded) its use is certainly legitimate. Antioxidants Vitamin E is an interesting issue. Although all large studies in non-renal patients showed no benefit 36, a beneficial effect on cardiovascular events although not on cardiovascular death, was reported in a small study on renal patients 37 and an impressive beneficial effect of vitamin E administration on abnormal cardiovascular structure was documented in uremic animals 38. Plausible reasons why vitamin E might be more effective in uremia could be very high oxidative stress and possibly also accumulation of biologically active vitamin E metabolites. Malnutrition Although malnutrition is not a conventional risk factor it has recently been shown to be a powerful risk predictor in dialysed patients and for this reason avoidance of malnutrition should be a matter of high priority 39. Lipid lowering agents Because of the pathogenetic importance of dyslipidemia routine administration of statins appears to be clearly indicated, particularly since in 3 recent controlled prospective studies the sub-group of patients with impaired renal function was shown to derive benefit from administration of statins, i.e. in the ALERT 29 ASCOT 30 and CARE 31 studies. A retrospective analysis also showed an approximately 10% lower event rate in dialysis patients receiving statins 32. The issue is currently under examination in the 4D study 33. REFERENCES 1. Lindner A, Charra B, Sherrard DJ, Scribner BH: Accelerated atherosclerosis in prolonged maintenance hemodialysis. N Engl J Med 290: 697-701, 1974. 2. Raine AE, Margreiter R, Brunner FP, Ehrich JH, Geerlings W, Landais P, Loirat C, Mallick NP, Selwood NH, Tufveson G y cols.: Report on management of renal failure in Europe, XXII, 1991. Nephrol Dial Transplant 7 (Supl. 2): 7-35, 1992. 3. USRDS: Annual Report. 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