Cardiovascular Calcifications in Uremic Patients: Clinical Impact on Cardiovascular Function
Gérard M. London
Nephrology Department, Société de Nephrologie, Centre Hospitalier F. H. Manhès–Service d’hémodialyse, Fleury-Mérogis, France
Correspondence to Dr. Gérard M. London, Centre Hospitalier F.H. Manhès, 8 Grande Rue, 91700 Fleury-Mérogis, France. Phone: 33 1 69 25 64 85; Fax: 33 1 69 25 65 25;
ABSTRACT. Cardiovascular disease is the leading cause of mortalityamong patients with ESRD (chronic kidney disease stage 5). Leftventricular hypertrophy and arterial diseases are the two principalrisk factors for cardiovascular mortality in hemodialysis patients.Epidemiologic studies show that damage to large conduit arteriescontributes to morbidity and mortality in patients with chronickidney disease. Atherosclerosis is primarily an intimal diseasecharacterized by the presence of plaques and occlusive lesions.Although atherosclerosis is the most frequent underlying causeof cardiovascular disease in patients with ESRD, it representsonly one form of structural response to metabolic and hemodynamicalterations that interfere with the process of aging. Arterialalterations in ESRD include nonocclusive arterial remodelingaccompanying the growing hemodynamic burden and humoral abnormalitiesthat are associated with chronic uremia. The consequences ofthese alterations are different from those attributed to atheroscleroticplaques and are characterized principally by hardening (stiffening)of arteries. Arteriosclerosis, characterized by stiffening ofthe aorta and large capacitative arteries, is a major determinantof left ventricular pressure overload and of abnormal coronaryperfusion. Atherosclerosis and arteriosclerosis are frequentlycomorbid and characterized by a high degree of both intimaland medial calcifications in patients with ESRD. The extentof calcifications and the degree of arterial stiffening areindependent predictors of mortality. Studies in patients withESRD have shown that attenuation of arterial stiffness can havea favorable effect, associated with regression of left ventricularhypertrophy, on survival. Calcium-free, metal-free phosphatebinders such as sevelamer can reduce calcification scores. E-mail:glondon@club-internet.fr
Cardiovascular disease is the leading cause of mortality amongpatients with end-stage renal disease (ESRD) (1). Arterial diseaseand left ventricular hypertrophy (LVH) (2) are two principalrisk factors driving the high rate of cardiovascular mortalityin hemodialysis patients. Although arterial disease is oftenthought of as being synonymous with coronary atherosclerosis,which is a well-known underlying cause of cardiovascular disease,arterial alterations are in fact more ubiquitous and, in addition,involve widespread vascular changes that contribute to stiffeningof arteries. The latter, referred to as "arteriosclerosis,"contributes to vascular remodeling and subsequent hemodynamicchanges that have clinical consequences of particular significancein the ESRD population. Atherosclerosis and arteriosclerosishave characteristic pathologic causes and consequences and arefrequently found associated with each other in patients withESRD.
In patients with ESRD, vascular changes typically develop earlyduring the course of renal insufficiency and progress in parallelwith declining kidney function. Vascular change or remodelingoccurs in response to the increasing hemodynamic burden andhumoral abnormalities (chronic uremia) caused by progressingkidney disease. Arterial disease associated with ESRD is characterizedby a high degree of intimal as well as medial calcification.Calcification has been shown to affect vascular elasticity (3)and mortality (4,5). The presence of calcification in patientswith ESRD has been associated with increased stiffness of largecapacity, elastic-type arteries like the aorta and the commoncarotid artery. In a Framingham Heart Study population, abdominalaortic calcification identified by lateral lumbar radiogramswas shown to be independently predictive of subsequent vascularmorbidity and mortality (5). Arterial calcification increaseswith age, fibrinogen level, and, of importance in the ESRD population,with the prescribed dose of calcium-based phosphate bindersand the duration of hemodialysis (3). It has been hypothesizedthat treatments that can reduce calcification should decreasecardiovascular morbidity and mortality. This article reviewsthe changes associated with arterial disease and calcificationamong dialysis patients and examines data showing benefits associatedwith treatments that alter the course of vascular calcificationand remodeling.
Atherosclerosis
Atherosclerosis refers to the now familiar process of plaqueformation or atheroma development. It may be described as aninflammatory response to oxidized LDL cholesterol. The processof atheroma formation begins with an accumulation of lipid-containingfoam cells (macrophages) in the vascular intima and evolvesinto successive structures that penetrate the vascular walland include lipids, smooth muscle cells, and collagen fibers(6). Calcification is an intrinsic part of the process and generallyinvolves the intima. Atherosclerotic lesions have a patchy distributionalong the length of the artery and cause local stenoses andocclusions. Because blood flow in the arterial system is dependenton the vessel caliber or cross-sectional area of the vessel,any decrease in diameter as a result of such stenosis can leadto impairments of conduit function and ischemia.
Arteriosclerosis
Arteriosclerosis refers to the hardening or stiffening of arteries(or arterioles). It is typically associated with aging and involvesthe entire arterial tree, although it principally affects theelastic arteries. Unlike atherosclerosis, arteriosclerosis involvesboth intimal and medial thickening. In ESRD, arteriosclerosiscan occur in the absence of significant atherosclerotic disease(7,8). Arteriosclerosis is associated with vascular hypertrophycharacterized by increased wall thickness, lumen enlargement,and increased length of arteries, collectively referred to asremodeling. As a consequence of remodeling, there is a dampeningof the "cushioning" effect of the arteries that results in adecreased ability of the arteries to smooth out the pulsatileflow occurring with intermittent ventricular ejection (9).
The efficiency of the cushioning function is determined by theviscoelastic properties of arterial walls. These propertiesare described in terms of compliance, distensibility, or stiffness.Under normal conditions, approximately 40% of the stroke volumeis directly forwarded to the peripheral circulation during systole,and the remaining stroke volume is stored in the large capacitativearteries, such as the aorta, that distend the arterial wallsto accommodate the additional volume and energy (9). Duringdiastole, the stored energy recoils the aorta, and the remainingblood flows into the peripheral circulation. Thus, the intermittentflow from the left ventricle is converted to smooth flow inthe peripheral vessels. When arterial distensibility decreases,as with increased calcification and remodeling, a greater proportionof the stroke volume is forwarded into the periphery duringsystole, increasing the amplitude of the arterial pulse waveand the magnitude of the systolic BP (SBP). Conversely, thediastolic BP (DBP) falls. The fall in DBP is greater with increasingstiffness of the large arteries. Because DBP is the moving forcefor coronary blood flow, a decrease in DBP results in compromisedcoronary perfusion. The speed with which the arterial pulsepressure wave (ventricular ejection pressure wave) moves awayfrom the heart is called the pulse-wave velocity (PWV). ThisPWV increases with arterial stiffening. Because the pressurewave can be reflected or returned at any point of structuralor geometric discontinuity, the stiffening of arteries may causean early return of reflected waves from the periphery towardthe aorta and left ventricle—which may now occur duringsystole rather than diastole—and further augment the amplitudeof the pulse wave and consequently the SBP in central arteriesand the left ventricle. Thus, overall BP and pulse pressureincrease and coronary flow decreases with increasing vascularstiffness. These hemodynamic changes, along with the metabolicchanges of uremia, can lead to increased LV afterload and LVH(10). Higher SBP and pulse pressure, lower DBP, and LVH havebeen identified as independent risk factors for morbidity andmortality in the general population (11,12).
Atherosclerosis and Arteriosclerosis in ESRD
Macrovascular disease involving atherosclerosis and arteriosclerosisdevelops rapidly in uremic patients (13) and is believed tobe responsible for the high incidence of ischemic heart disease,LVH, congestive heart disease, sudden death, and stroke in thesepatients (14). A significantly greater incidence of plaqueshas been reported in the common carotid artery of patients withESRD (15). A majority of these plaques have been shown to becalcified plaques as opposed to soft or mixed plaques (91.5%calcified versus 9% soft/mixed; P < 0.01) (15). In addition,common carotid artery (CCA) geometry in patients who have ESRDand are on hemodialysis indicates a significantly greater diameter(P < 0.001) and greater intima-media thickness (P < 0.001),consistent with arteriosclerotic remodeling (8). Systolic andpulse pressures are increased in ESRD (P < 0.001) (16). Anassessment of the elastic properties of the CCA indicated thatvessel wall distensibility was significantly reduced and end-diastolicdiameter was significantly increased in younger hemodialysispatients (36.3 ± 2 yr) compared with age-matched healthysubjects (17). No significant differences in vessel wall distensibilityor diameter was found in older (60.2 ± 2.3 yr) hemodialysispatients compared with age-matched healthy subjects (17). Inolder patients, the changes associated with "normal" aging maymask the changes caused by uremia.
The relationship between CCA geometry and cardiac hypertrophyhas also been investigated and found to be consistent with hemodynamicalterations of remodeling and the pathogenesis of LVH. Comparedwith control subjects, patients with ESRD have greater LV diameter(P < 0.01), greater wall thickness and mass (P < 0.001),increased CCA diameter (P < 0.001), greater CCA intima-mediathickness (P < 0.001), and an increased intima-media cross-sectionalarea (P < 0.001) (8). In uremic patients, arterial hypertrophyis associated with decreased CCA distensibility (P < 0.001)and compliance (P < 0.05), accelerated carotid-femoral pulsewave velocity (P < 0.001), and early return and increasedeffect of arterial wave reflections (P < 0.001), consistentwith the changes expected of less compliant or "stiff" bloodvessels. From a hemodynamic aspect, increased pulsatile pressurehas been noted in patients with ESRD compared with control subjects(P < 0.01). A decreased subendocardial viability index (P< 0.001) has also been noted in patients with ESRD and isreasonable considering the compromise in coronary perfusionthat would occur with decreased pressures. The CCA diameterwas correlated with the LV diameter (P < 0.01). Significantcorrelations have also been found between CCA wall thicknessor intima-media cross-sectional area and LV wall thickness and/orLV mass (P < 0.01) (8). In multivariate analysis, these relationshipswere independent of age, gender, BP, and body surface area.Thus, structural and functional alterations in large arteriescontribute to LVH; cardiac and vascular adaptations seem tooccur in parallel in ESRD.
Significance of Calcification in ESRD-Related Vascular Remodeling
It is clear that the structural changes in the vasculature ofpatients with ESRD have multiple functional and hemodynamiceffects. It also seems that calcification and loss of elasticityhave an impact on vascular changes. Vascular remodeling as measuredby geometric parameters has been shown independently to be proportionalto the calcification score in hemodialysis patients (3). Histologically,arteries from uremic patients have been reported to have fibrousor fibroelastic intimal thickening, calcification of the internalelastic lamella, medial ground substance and medial elasticfibers, and disruption and reduplication of the internal elasticlamella (18), indicating the predominance of arterial calcificationin uremia and providing histologic evidence for the loss ofelasticity in ESRD. Both degree of intimal thickness and arterialcalcium concentration were found to correlate with the durationof uremia in that study (18). Arterial calcium concentrationin the aorta was also found to correlate with age (18). Theauthors of this early study concluded that the arterial changesseen in uremic patients probably represent an acceleration ofthe normal arterial aging process. A more recent study has confirmedthat arterial calcification density increases with age, durationof hemodialysis, fibrinogen levels, and the dose of calcium-basedphosphate binders (3,19). The coronary artery calcificationscore as measured by electron beam computed tomography (EBT)has been shown to be directly proportional to the severity ofcoronary artery disease determined by single photon emissioncomputed tomography (Figure 1) (20). In multiple regressionanalyses, pulse pressure, smoking, phosphoremia, daily intakeof calcium, duration of hemodialysis, and presence of diabeteswere found to be independently related to coronary artery calcificationscores (21).
Figure 1. Prevalence of significant coronary artery disease by single photon emission computed tomography (SPECT) according to coronary artery calcium score by electron beam computed tomography. Reprinted with permission from He ZX, Hedrick TD, Pratt CM, Verani MS, Aquino V, Roberts R, Mahmarian JJ: Severity of coronary artery calcification by electron beam computed tomography predicts silent myocardial ischemia. Circulation 101: 244–251, 2000.
Clinical Impact of Calcification
Vascular calcification can occur as a "normal" consequence ofaging. In patients with ESRD, it is a manifestation of ectopiccalcification and is at least partially driven by the occurrenceof hyperphosphatemia among patients who are on dialysis (seethe article by Giachelli (22) in this supplement). Of clinicalrelevance, aortic calcification is a predictor of cardiovascularmortality (4), and vascular calcification, including the abdominalaorta, has been documented to be an independent predictor ofvascular morbidity and mortality (Figure 2) (23). The severityof calcification as measured by EBT can also predict silentmyocardial infarction (20). Even in asymptomatic patients, coronarycalcification is a strong predictor of cardiovascular morbidityand mortality (24). Thus, the hemodynamic and functional changesassociated with vascular calcification and remodeling have realand significant clinical impact that can affect morbidity andmortality among dialysis patients. Patients with intimal calcificationhave a worse prognosis (all-cause survival) than those withmedial calcification (21).
Figure 2. Increased mortality risk associated with arterial calcification. Reprinted with permission from Blacher J, Guérin AP, Pannier B, Marchais SJ, London GM: Arterial calcifications, arterial stiffness, and cardiovascular risk in ESRD. Hypertension 38: 938–942, 2001.
As discussed, DBP decreases and pulse pressure (PP) increaseswith increasing calcification (3). Both decreasing DBP (theprincipal moving force for coronary perfusion) (25) and increasingPP (26) are associated with poor survival in hemodialysis patients(24). However, high postdialysis DBP of 90 mmHg or greater hasalso been associated with increased cardiovascular mortality(27). Evidence suggests that there is also a "U" curve relationshipbetween postdialysis SBP and cardiovascular mortality in hemodialysispatients, with pressures of 180 mmHg or greater and <110mmHg being associated with increased mortality (27). The associationof increased mortality with lower SBP is most probably the resultof LV dysfunction and chronic heart failure, not of lower pressureas such. A direct correlation between calcification score andincreasing SBP and PP, and decreasing DBP has been noted amonghemodialysis patients, again confirming the contribution ofcalcification to unfavorable sequelae in patients with ESRD(3).
Clinical Impact of Aortic Stiffness
Aortic stiffness is measured by PWV. It is an independent predictorof all-cause mortality and cardiovascular mortality (28). Arterialstiffness results in higher SBP and lower DBP, causing increasedLV afterload and altering coronary perfusion (9,10). In hemodialysispatients, there is a correlation between increased aortic PWV(or stiffness) and increasing LV mass (29). The changes in arterialdistensibility and stiffness among hemodialysis patients aresignificantly different from control or nonhemodialysis subjects(30). Patients with LVH (>125 g/m2) have lower survival ratesthan those without LVH (<125 g/m2). Multiple regression analysisstudies show that heart rate, C-reactive protein, duration ofhemodialysis, and aortic calcification have an impact on aorticPWV (31). Of these, calcification is the most significant variable.
Attenuation or regression of LVH with treatment can have anindependent and favorable impact on all-cause mortality andcardiovascular mortality in patients with ESRD (32). Treatmentof hypertension and anemia has been shown to decrease LV massand have a positive impact on survival. This effect was persistentafter adjustment for age, gender, diabetes, history of cardiovasculardisease, and all nonspecific cardiovascular risk factors. Thehazard risk ratio associated with a 10% decrease in LV masswas 0.78 (95% confidence interval [CI], 0.63 to 0.92) for all-causemortality and 0.72 (95% CI, 0.51 to 0.90) for cardiovascularmortality (31). Similarly, treatment with angiotensin-convertingenzyme inhibitors (perindopril) (33) or calcium-channel blockers(nitrendipine) (10) has been shown in separate studies to increaseaortic distensibility and decrease LV mass, respectively, inpatients with ESRD. The calcium-channel blocker nifedipine hasalso been shown to prevent the progression of PWV in chronichemodialysis patients (34). In experimental rats with chronicrenal failure, the calcium-free, metal-free phosphate bindersevelamer was shown to prevent renal calcium deposition (35).Clinical data have shown that a 1 mg/dl increase in serum phosphatecan result in an increase in coronary artery calcification scoreequivalent to that occurring in 2.5 yr of dialysis (36). Inhemodialysis patients, EBT has consistently shown lower calciumscores in the aorta and coronary arteries of patients who aretreated with sevelamer when compared with those who are treatedwith calcium-based phosphate binders (37). Further studies areneeded in hemodialysis patients to confirm the benefits of calcium-free,metal-free phosphate binders in these patients. Overall, thesedata indicate that attenuation of hemodynamic problems associatedwith calcification-induced vascular remodeling can have positiveclinical benefits. These potential benefits should be consideredwhen designing a treatment plan for patients with ESRD.
Cardiovascular disease is the leading cause of mortality amongpatients with ESRD (1). The main causes for this high prevalenceare the widespread occurrence of arterial disease and LVH amonghemodialysis patients (2). Both atherosclerosis and arteriosclerosishave been shown to contribute to arterial disease in these patients.Whereas the former underlies ischemic heart disease, the latteris the driving force for vascular remodeling and hemodynamicchanges leading to LVH. Characteristically, vascular changein patients with ESRD is typified by calcification of both mediaand intima. The extent of calcification and degree of arterialstiffening are independent predictors of mortality. As discussedhere, calcification causes arterial stiffness and LVH. Attenuationof these parameters can have a favorable impact on LVH and survival.Attempts to lower calcification should have a beneficial effecton both cardiovascular and overall survival in hemodialysispatients. In this regard, the role of phosphate binders shouldbe explored further. Given the ability of sevelamer to inhibitor prevent progression of vascular calcification in ESRD, thepotential beneficial effects of sevelamer on cardiovascularfunction warrant further investigation.
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Abstract
Introduction
