Current Controversies in Managing End-Stage Renal Disease Patients
Effect of Lipid Modification on Progression of Coronary Calcification
Peter A. McCullough
Department of Medicine, Divisions of Cardiology, Nutrition, and Preventive Medicine, William Beaumont Hospital, Royal Oak, Michigan
Address correspondence to: Dr. Peter A. McCullough, Division of Nutrition and Preventive Medicine, William Beaumont Hospital, 4949 Coolidge, Royal Oak, MI 48073. Phone: 248-655-5765; Fax: 248-655-5714; E-mail: pmc975{at}yahoo.com
Coronary artery calcification (CAC) reflects the anatomic presenceof coronary atherosclerosis and the relative burden of coronaryartery disease (CAD). Higher levels of CAC are seen in the presenceof CAD risk factors, older age, and chronic kidney disease.The lipid profile (primarily low HDL cholesterol, elevated triglycerides,elevated LDL cholesterol, and elevated total cholesterol) areimportant factors in the calcification process. The annual progressionof CAC can be reduced from 25 to 30% to 0 to 6% with LDL cholesterolreduction caused by statins and possibly sevelamer. At treatedLDL cholesterol levels somewhere below 100 mg/dl, several sourcesof data suggest the anatomic burden of CAD, including CAC, regresses.Additional supportive studies indicate that carotid intimalmedial thickness and the volume of coronary atheroma also canbe reduced by LDL cholesterol reduction in concert with elevationof HDL cholesterol. This article reviews the data in supportof altering the natural history of CAC with lipid modification.
Atherosclerotic calcification begins as early as the seconddecade of life, just after fatty streak formation (1). Coronaryartery lesions of young adults have revealed small aggregatesof crystalline calcium within the lipid core of a plaque (1).Calcium phosphate (hydroxyapatite, Ca3[–PO4]2–xCa[OH]2),which contains 40% calcium by weight, precipitates in diseasedcoronary arteries by a mechanism similar to that found in osteogenesisand remodeling (2). Hydroxyapatite, the predominant crystallineform in calcium deposits, is formed primarily in vesicles thatpinch off from arterial wall cells, analogous to the way matrixvesicles pinch off from chondrocytes in developing bone (3,4).It has been postulated that vesicles, derived from apoptoticfoam and smooth muscle cell debris and contained within extracellularmatrix, may also serve as the sites of small calcium deposits.A very close spatial association between cholesterol depositsand hydroxyapatite also has been demonstrated (5). The exactmechanism and process of calcification within the arterial wallare not yet completely understood.
Coronary artery calcification (CAC) seems to occur exclusivelyin atherosclerotic arteries and is absent in normal vessel wall(6). Overall, recent findings lend credence to the idea thatatherosclerotic calcification is not merely passive adsorptionbut instead is an organized, regulated process similar to boneformation. Thus, the finding of calcification on human imagingstudies suggests the anatomic presence of atherosclerosis.
The presence of atherosclerosis is a necessary but not sufficientcondition to result in a coronary artery disease (CAD) event.Plaque rupture, exposure of the lipid-rich core to the bloodpool, thrombosis and vessel occlusion, and downstream embolizationof the platelet–thrombin complexes are believed to bethe sequence in which an acute coronary syndrome occurs. Hence,it makes sense that CAC (measured by noninvasive imaging methods)indicates that the substrate for an event is present; however,other risk factors for plaque rupture, including sheer stress,conventional cardiovascular risk factors, and inflammatory cytokines,all still contribute to the risk for a future CAD event (7–10).
Considerable interest exists in identifying and quantifyingCAC as a marker for CAD. In the general population, a high coronarycalcium score (>100) on electron beam computed tomography(EBCT) carries a relative risk for future CAD events of approximately10 compared with those with a score <100 (1,2) (Figure 1).Furthermore, it seems that a sufficiently high CAC score (>300)modifies the risk for future CAD events above that predictedby the conventional Framingham risk prediction (10). The absenceof detectable CAC is associated with a low future event rate;however, this rate is not zero. Approximately 5% of patientswith a CAC score of zero will incur a myocardial infarctionor cardiac death in the next 5 to 7 yr after EBCT (8,9). Thissuggests that atherosclerotic plaque can exist without a sufficientamount of calcification to be detected by EBCT. This plaque,although uncommon, is thought to be lipid laden and potentiallyprone to plaque rupture and thrombosis.
Figure 1. The attenuation of progression of coronary calcification that can be achieved with statin therapy. Electron beam tomography (EBT) 1 to 2 is untreated; EBT 2 to 3 is the annual change on statin therapy. (A) All 66 patients in this study. (B) Those whose achieved LDL cholesterol levels were <100 mg/dl. Reprinted from reference 15, with permission.
In a study of 6093 patients for whom CAC by EBCT, lipids, personalhealth history, and body morphology were recorded, the correlationbetween HDL cholesterol and CAC was three times that of LDLcholesterol (11,12). Patients with an HDL cholesterol level<40 mg/dl had significantly higher CAC scores, whereas increasesin HDL cholesterol were associated with a significant reductionin risk for the presence of any calcified plaque. Multivariatelogistic regression revealed that LDL cholesterol and HDL cholesterolwere independent predictors of CAC with the relative risk (RR)being 1.05 times higher for each 10-mg/dl increase in LDL cholesterol(P < 0.001). An LDL cholesterol >160 mg/dl had a 62% increasein odds for the presence of calcified plaque (12). CAC, onceidentified, seems to progress at a measurable, annual rate ofapproximately 30% in CAC volume on annual EBCT examinations(13). The progression of CAC has been linked to cigarette smoking,poor glycemic control in diabetes, and other conventional CADrisk factors (8,9,13) (Table 1). In patients with chronic kidneydisease (CKD), the annual rate of progression is the same; however,the absolute magnitude of increase in CAC volume is large giventhe high CAC scores at baseline in this population (14).
LDL Cholesterol Reduction
Several nonrandomized studies using treatment with 3-hydroxy-3-methylglutarylCoA (HMG-CoA) reductase inhibitors (statins) have demonstratedattenuation of progression in CAC associated with LDL cholesterolreduction (15,16). In a study of 66 patients who were followedduring a period without statin treatment and then during treatmentwith cerivastatin 0.3 mg/d orally, the median annualized relativechange was significantly higher in the untreated interval comparedwith the treated interval (25 versus 8.8%; P < 0.0001) (15).The annualized relative change of the CAC score in 32 patientswho achieved an LDL cholesterol level of <100 mg/dl decreasedfrom 27 to –3.4% (P < 0.0001; Figure 1). Callisteret al. (16) reported on 149 patients with CAD, 105 of whom weretaking statins, who underwent baseline and then follow-up EBCTstudies at 12 to 15 mo. As shown in Figure 2, patients who hadLDL cholesterol reductions <120 mg/dl on statins almost exclusivelypopulated the lower left quadrant, demonstrating regressionof CAC. There was a correlation (r = 0.50) between the reductionin LDL cholesterol and the change in CAC by EBCT with regressionin CAC beginning to occur on the line of best fit at an approximateLDL cholesterol level <100 mg/dl (Figure 3). Some patientsin these studies had had arrest or reversal in the calcificationprocess; however, the determinants beyond LDL cholesterol reductionof this reversal process are not completely understood (Figure 3)(16).
Figure 2. Scatterplot of the untreated and treated LDL cholesterol levels and the progression of coronary artery disease (CAD) at 12 to 15 mo by electron beam computed tomography (EBCT). , Patients who were not treated with statins (group 1); , treated patients with average LDL cholesterol levels of 120 mg/dl (group 2); •, treated patients with LDL cholesterol <120 mg/dl (group 3). Reprinted from reference 16, with permission.
Figure 3. Correlation between LDL cholesterol level (treated in 105 of 149 with statins) and rate of progression of coronary artery calcification (CAC) over 12 to 15 mo in patients with established CAD. Adapted from reference 16, with permission.
In an analogous study using the percentage change in coronaryatheroma volume, 502 assessable patients with CAD and considerableoverweight/obesity (body mass index 30.5 kg/m2) were randomlyassigned to pravastatin 40 mg versus atorvastatin 80 mg/d (17).Intravascular ultrasound examinations of the coronary tree wereperformed at baseline and at 18 mo. The LDL cholesterol valueswere lowered from 150.2 to 110.4 (25.2% reduction) and 150.2to 78.9 (46.3% reduction) mg/dl with 40 mg of pravastatin and80 mg of atorvastatin, respectively. This resulted in a slightoverall regression of coronary atheroma volume and, we infer,the overall burden of CAC if it had been measured (Figure 4).Thus, studies using EBCT and intravascular ultrasound suggestthat somewhere at or below an LDL cholesterol of 100 mg/dl ontreatment, CAD and CAC begin to regress.
Figure 4. Percentage of atheroma volume reduction over 18 mo when LDL cholesterol values were lowered from 150.2 to 110.4 (25.2% reduction) and 150.2 to 78.9 (46.3% reduction) mg/dl with 40 mg of pravastatin and 80 mg of atorvastatin, respectively. Data are from reference 17.
LDL Cholesterol Reduction in Patients with ESRD
Patients with ESRD that requires dialysis are the highest riskstates for incident and accelerated cardiovascular disease (18,19).Previous studies have shown that vascular calcification is enhancedin ESRD, and recent data using EBCT has shown a modest relationshipbetween calcium scores and calcium-phosphorus ion product (20).In contrast, when it has been evaluated, vascular calcificationhas been related consistently to the dyslipidemia of ESRD, includinga modestly elevated LDL cholesterol, depressed HDL cholesterol,and elevated triglycerides (TG) (14).
A variety of stimuli have been shown to induce or modulate phenotypictransformation of vascular smooth muscle cells to osteoblast-likecells with subsequent mineralization in vitro, including phosphorus,oxidized LDL cholesterol, calcitriol, parathyroid hormone (PTH),and parathyroid hormone–related peptide (21). As reviewedbelow, the clinical studies in ESRD suggest that the processis driven much more by the age, length of time on dialysis,and lipid status (22). A systematic review of the literatureconcerning CKD and ESRD (1982 to 2002, n = 2919) found 31 studiesthat were split on either finding or not finding significanceof serum calcium (Ca), serum phosphorus (PO4), calcium-phosphorusproduct (CPP), PTH, or treatments for calcium-phosphorus (Ca-PO4)balance including phosphate binders, calcium, and vitamin Danalogues, in relation to CAC (22). When taken into consideration,the lipid profiles (primarily HCL cholesterol, elevated TG,elevated LDL cholesterol, and elevated total cholesterol) werepredictive factors in four analyses. Most studies were too smallfor valid multivariate analyses, but five studies did use varioustechniques in an attempt to identify the independent predictors.When this was done, measures of Ca-PO4, in general, either droppedout of the model or markedly attenuated as predictive factors.
In the Treat to Goal trial by Chertow et al. (23), 200 patientswere randomly assigned to sevelamer versus calcium carbonate(in Europe) or calcium acetate (in the United States) and hadEBCT scans done at baseline and at 52 wk. Investigators werenot blinded to the measures of Ca-PO4 balance and were allowedto adjust phosphate binders and dialysate calcium or use vitaminD analogues. The baseline and final CPP values were 71 and 48(difference 23) and 69 and 49 (difference 20) for the sevelamerand calcium groups, respectively. However, there was a largedifference in the final LDL cholesterol levels between the sevelamerand the calcium groups, 65 versus 103 mg/dl, respectively (P< 0.0001). This is consistent with the known bile-acid sequestrantproperties of sevelamer. Accordingly, there was attenuationof progression of CAC with sevelamer with no differences inCPP or PTH, suggesting that the change in CAC was more relatedto lipid lowering as has been demonstrated in other studies(23).
Does attenuation of the progression of CAC in patients withESRD when the score is already at high levels reduce the chancesof a CAD event attributed to a calcified lesion? This will bedifficult to answer because the therapies (statins and sevelamer)that reduce attenuation of progression do so by primarily reducingLDL cholesterol and likely stabilizing less severe plaques elsewherein the coronary bed.
HDL Cholesterol Elevation
Two recent studies have evaluated measures of atheroscleroticplaque burden in patients with CAD with a specific attempt toraise HDL cholesterol. The Randomized Trial of a Strategy forIncreasing High-Density Lipoprotein Cholesterol Levels: Effectson Progression of Coronary Heart Disease and Clinical Events(AFREGS) was performed in 143 military retirees with low HDLcholesterol levels (<40 mg/dl) and known stable CAD (24).None had diabetes or kidney disease. All had LDL cholesterollevels <160 mg/dl. Patients were randomly assigned to aggressiveHDL cholesterol–increasing therapy with gemfibrozil, niacin,and cholestyramine or matching placebos for 30 mo. Drug doseswere adjusted regularly, and niacin and cholestyramine wereadded at month 3 and month 6, respectively. Compared with thosewho were taking placebos, patients who were treated with lipid-modifyingagents had a 26% decrease in LDL cholesterol level, 50% decreasein TG, and 36% increase in HDL cholesterol level. Coronary lesionsregressed slightly (1.35 versus –0.81% stenosis; P = 0.04)by quantitative coronary angiography with drug therapy and progressedwithout drug therapy. As expected, patients who were randomlyassigned to drug therapy had fewer total cardiovascular events.
The Arterial Biology for the Investigation of the TreatmentEffects of Reducing Cholesterol (ARBITER-2) trial randomly assigned149 patients with known CAD on a statin with LDL cholesterol< 130 mg/dl and HDL cholesterol < 45 mg/dl to extended-releaseniacin 1000 mg/d versus placebo (25). Niacin elevated the HDLcholesterol from 39 to 47 mg/dl (21% increase). This resultedin a significant attenuation in the rate of progression of carotidintimal medial thickness over 12 mo (Figure 5). There was noregression reported in this surrogate measure of coronary atherosclerosis.
Figure 5. Change in carotid intimal medial thickness (CIMT) in 149 patients who were known to have CAD and were randomly assigned to HDL cholesterol elevation with extended release (ER) niacin versus placebo. All patients were treated with statins at baseline. Data are from reference 23.
There are no trials of targeted HDL cholesterol elevation inpatients with CKD or ESRD. However, given that low HDL cholesterol(<45 mg/dl) is a very common finding in these patients, itis conceivable that like reduction in LDL cholesterol, elevationin HDL cholesterol may be related to attenuation of the progressionof atherosclerosis and CAC.
In conclusion, CAC is a common observation in CKD and ESRD andis mainly related to age, duration on dialysis, and possiblydyslipidemia. Whereas high levels of CAC almost certainly representsignificant CAD in patients with ESRD, the attenuation of progressionof CAC and its relation, if any, to CAD event reduction areunknown. The annual progression of CAC can be reduced from 25to 30% to 0 to 6% with LDL cholesterol reduction caused by statinsand possibly sevelamer. At treated LDL cholesterol levels somewherebelow 100 mg/dl, several sources of data suggest that the anatomicburden of CAD, including CAC, regresses. Additional supportivestudies indicate that carotid intimal medial thickness and thevolume of coronary atheroma can also be reduced by LDL cholesterolreduction in concert with elevation of HDL cholesterol.
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Abstract
Introduction
, Patients who were not treated with statins (group 1); 
, treated patients with average LDL cholesterol levels of 
120 mg/dl (group 2); •, treated patients with LDL cholesterol <120 mg/dl (group 3). Reprinted from reference 
