Association between Prior Cytomegalovirus Infection and the Risk of Restenosis after Coronary Atherectomy
Yi Fu Zhou, M.D., Martin B. Leon, M.D., Myron A. Waclawiw, Ph.D., Jeffery J. Popma, M.D., Zu Xi Yu, M.D., Toren Finkel, M.D., Ph.D., and Stephen E. Epstein, M.D.
Background Restenosis occurs commonly after coronary angioplastyand atherectomy, but the causes of restenosis are poorly understood.Recently, it has been found that cytomegalovirus (CMV) DNA ispresent in restenotic lesions from atherectomy specimens. Thisand other evidence suggest that CMV may have a role in the processof restenosis.
Methods We prospectively studied 75 consecutive patients undergoingdirectional coronary atherectomy for symptomatic coronary arterydisease. Before atherectomy was performed, we measured bloodlevels of anti-CMV IgG antibodies to determine whether previousexposure to CMV increased the risk of restenosis, as determinedby coronary angiography performed six months after atherectomy.
Results After atherectomy, the mean (±SD) minimal luminaldiameter of the target vessel was greater in the 49 patientswho were seropositive for CMV than in the 26 patients who wereseronegative (3.18±0.51 mm vs. 2.89±0.45 mm, P= 0.01). After six months, however, the seropositive patientshad a greater reduction in the luminal diameter (1.24±0.83mm vs. 0.68±0.69 mm, P = 0.003), resulting in a significantlyhigher rate of restenosis in the seropositive patients (43 percentvs. 8 percent, P = 0.002). In a multivariable logistic-regressionmodel, CMV seropositivity and the CMV titer were independentlypredictive of restenosis (odds ratios, 12.9 and 8.1, respectively).There was no evidence of acute infection, since the titer ofanti-CMV IgG antibodies did not increase over time and testsfor anti-CMV IgM antibodies were negative in all patients.
Conclusions Prior infection with CMV is a strong independentrisk factor for restenosis after coronary atherectomy. If confirmed,these findings may help identify patients at risk for restenosis.
Neointimal hyperplasia and arterial remodeling cause restenosisin 20 to 50 percent of patients who have undergone coronaryangioplasty.1,2 Although the mechanisms are unknown, previousfindings have raised the possibility that cytomegalovirus (CMV)contributes to the development of restenosis in some patients.3In approximately one third of patients with restenosis, thelesions contain CMV DNA sequences. Smooth-muscle cells grownfrom such lesions express IE84, one of the virus's immediateearly proteins, and IE84 binds to and inhibits the p53 tumor-suppressorgene product. These effects may enhance the proliferation ofsmooth-muscle cells or inhibit apoptosis, either of which maycontribute to restenosis.3
CMV infection in immunocompetent adults is common4 and usuallyasymptomatic.5,6 Like other herpesviruses, CMV persists indefinitelyin certain host cells.7,8 Under certain circumstances (suchas immunosuppression due to the acquired immunodeficiency syndrome9or treatment after organ transplantation10), the virus can bereactivated and cause serious disease. In these situations,viral replication contributes to the disease process. However,there is evidence that CMV can also contribute to the diseaseprocess during an abortive infection,11 which is characterizedby viral-gene expression limited to immediate early gene productswithout viral replication. CMV immediate early gene products,for example, are known to affect the expression of many humancellular genes involved in inflammation and immunologic responses,12and as previously documented, CMV is present in smooth-musclecells from restenotic lesions and can express immediate earlygene products, which inhibit the p53 function.3 We thereforehypothesized that latent CMV may be reactivated locally in responseto vascular injury in a subgroup of patients undergoing coronaryangioplasty. By inhibiting the capacity of p53 either to blockthe progression of the cell cycle or to initiate apoptosis,as well as by other mechanisms, the virus may enhance the accumulationof smooth-muscle cells and thereby facilitate the developmentof restenosis. We conducted a prospective investigation to testthis hypothesis.
Methods
The patients in our study were part of the Optimal AtherectomyRestenosis Study (OARS), which was designed to determine thefrequency of restenosis after directional coronary atherectomy.A follow-up angiographic evaluation was performed approximatelysix months after the surgery. Our patients were from WashingtonHospital Center, Washington, D.C., which was one of four centersparticipating in OARS and which recruited 100 of its 211 patients.Of these 100 patients, 75 were enrolled in our study; 7 patientswere not enrolled because of an initial procedural complicationor a protocol violation, and 18 patients did not undergo follow-upangiography.
Before and six months after surgery, blood samples were collectedfor assays of anti-CMV IgG and IgM antibodies. The assays wereperformed without knowledge of the angiographic findings.
A patient was considered to have diabetes if he or she was takinginsulin or oral hypoglycemic agents or had previously receivedsuch treatment and was currently using dietary modificationto control the condition. A patient was considered to have hypertensionif he or she had received the diagnosis or was being treatedwith antihypertensive medications or dietary modification. Apatient was considered to have hypercholesterolemia if he orshe had a serum cholesterol value higher than 240 mg per deciliter(6.2 mmol per liter) at the time of angioplasty or was receivingcholesterol-lowering treatment.
Directional Atherectomy
Optimal directional coronary atherectomy consists of local plaqueresection followed by circumferential plaque resection withthe use of larger devices or higher balloon pressures and usuallyconcludes with adjunctive low-pressure balloon dilation. Ultrasonographicguidance is used to optimize the results. Of the 75 patientsin the study, 65 (87 percent) had adjunctive percutaneous transluminalcoronary angioplasty, resulting in a mean additional 10 percentreduction in the degree of stenosis. Stents were placed in twopatients (3 percent) after the atherectomy, because of severelumen-compromising dissections.
Angiographic Analysis
Cineangiograms were forwarded to the central angiographic laboratoryand were evaluated without knowledge of whether the patientswere seropositive or seronegative for anti-CMV antibodies. Base-line,postsurgical, and follow-up (six-month) cineangiograms wereanalyzed with an automated edge-detection algorithm (CardiovascularMeasurement System, Medis Medical Imaging Systems, Nuenen, theNetherlands). The minimal luminal diameter, interpolated referencediameter, and percentage of stenosis before and after atherectomyand at six months were measured from two projections; the averageof these two values is reported. An early gain in the diameterof the target vessel was defined as the minimal luminal diameterimmediately after surgery minus the minimal luminal diameterbefore surgery. A late loss in the luminal diameter was definedas the minimal luminal diameter immediately after surgery minusthe minimal luminal diameter at six months. The loss index wasdefined as the late loss divided by the early gain, expressedas a percentage. Restenosis was defined as more than 50 percentstenosis at follow-up in a vessel with less than 50 percentstenosis immediately after atherectomy.
Assays for CMV Antibodies
Tests for anti-CMV IgG antibodies were performed with an enzyme-linkedimmunosorbent assay (ELISA) kit (Cytomegelisa II, BioWhittaker,Walkersville, Md.), according to the manufacturer's directions.Antibody titers were determined on the basis of a standard curve.The threshold value was determined prospectively: an ELISA valueof less than 0.25 unit was considered a negative result, anda value of 0.25 unit or higher was considered a positive result,indicating prior exposure to CMV.
Tests for anti-CMV IgM antibodies were performed with an enzyme-linkedantibody-capture assay kit (CMV CAP-M, BioWhittaker), accordingto the manufacturer's directions. An index value of less than0.9 was interpreted as a negative result, and a value of morethan 1.1 was interpreted as a positive result; values between0.9 and 1.1 were considered equivocal results.
Statistical Analysis
Statistical analyses of frequency counts were performed withthe use of the chi-square test or Fisher's exact test for smallsamples, and means were compared with the two-sample t-test.All tests were two-sided. The odds ratio was used as a measureof the risk of restenosis in patients with a given risk factoras compared with those without the risk factor. Modeling ofthe dichotomous variable of restenosis at six months was performedwith the logistic-regression model. Factors affecting the lossindex were identified by linear regression. The covariates consideredwere seropositive CMV status, higher CMV titer, diabetes, hypercholesterolemia,hypertension, location of the stenosis in the left anteriordescending coronary artery, small reference vessel (<3 mmin diameter), a recent history of smoking, male sex, older age,and unstable angina as the indication for atherectomy. All covariateswere examined as predictors of restenosis and the loss indexin univariate analyses, as a group in one multivariate model,and in a stepwise multivariable model. Values are reported asmeans ±SD.
Results
Characteristics of the Patients
The 75 patients ranged in age from 35 to 78 years (mean, 58);there were 58 men and 17 women (Table 1). Our patients weresimilar to the total OARS cohort with respect to age, sex, andthe proportion of patients with single- or double-vessel disease(Table 1), suggesting that the subgroup was representative ofthe patients undergoing directional coronary atherectomy inthe larger study.
Table 1. Characteristics of the Total Cohort in the Optimal Atherectomy Restenosis Study (OARS) and the Subgroup of Patients in the Present Study.
Forty-nine of the 75 patients (65 percent) had positive testsfor anti-CMV IgG antibodies at the time of enrollment in thestudy, indicating prior exposure to CMV — a prevalenceof seropositivity similar to that reported in several epidemiologicstudies involving subjects of a similar age.12 Of the 18 patientsexcluded from the study because an angiogram was not obtainedat six months, 11 (61 percent) were seropositive for CMV, whichis similar to the prevalence among the 75 patients includedin the study. Restenosis developed in 23 of the 75 patients(31 percent).
The prevalence of several potential risk factors for restenosisdid not differ according to the CMV status of the patients.The one exception was hypertension, which was present in 59percent of the seropositive patients but in only 31 percentof the seronegative patients (P = 0.02). Additional analysesshowed, however, that the presence of hypertension was unrelatedto restenosis (P = 0.18).
Correlation between CMV Seropositivity and Restenosis
Of the 49 patients with prior exposure to CMV, 21 (43 percent)had restenosis at six months, as compared with only 2 of the26 patients (8 percent) without prior exposure to the virus(P = 0.002) (Figure 1). When the percentage of stenosis of thetarget vessel at follow-up was analyzed as a continuous variable,CMV infection was associated with more severe stenosis (P =0.01) (Table 2 and Figure 1). The minimal luminal diameter andpercentage of stenosis at base line, immediately after directionalcoronary atherectomy, and at six months are shown in Table 2.Figure 2 shows the distribution of stenotic target vessels accordingto the minimal luminal diameter at each of the three pointsin time. At base line, the reference diameter of the vesseland the minimal luminal diameter of the stenotic segment tendedto be larger in the seropositive patients than in the seronegativepatients, but there was no significant difference in the percentageof stenosis. Immediately after the procedure, the seropositivegroup had a slightly larger minimal luminal diameter (P = 0.01),but the mean gain was similar. At six months, however, the seropositivegroup had a much greater loss of luminal diameter (P = 0.003)and, most important, an 89 percent higher loss index than theseronegative group (P<0.001) (Table 2 and Figure 3).
Figure 1. Influence of Prior Cytomegalovirus (CMV) Infection on the Distribution of Stenosis in 85 Target Vessels in 75 Patients, as Determined by Angiography Six Months after Directional Coronary Atherectomy.
The patients were divided into two groups on the basis of whether they were seropositive or seronegative for anti-CMV IgG antibodies at base line. A seropositive status was defined prospectively as an assay value of 0.25 unit or higher. At six months, vessels in the seropositive patients had a higher percentage of stenosis than vessels in the seronegative patients (P = 0.01). The inset shows the incidence of restenosis (>50 percent narrowing of the vessel diameter), which was also higher in the seropositive patients (P = 0.002).
Figure 3. Distribution of the Loss Index at Six Months.
The loss index was calculated as the late loss (the minimal luminal diameter immediately after atherectomy minus the minimal luminal diameter at six months) divided by the early gain (the minimal luminal diameter immediately after atherectomy minus the minimal luminal diameter before atherectomy), expressed as a percentage. The seropositive patients had a higher loss index than the seronegative patients (P<0.001).
Influence of CMV Seropositivity and Other Risk Factors on Restenosis
Univariate analyses (Table 3) showed that CMV seropositivitywas the only statistically significant predictor of restenosis(odds ratio, 9.0; P = 0.002). An analysis of the associationbetween the mean IgG antibody titer and restenosis confirmedthe finding (mean titer, 0.66±0.30 unit among the patientswith restenosis and 0.44±0.35 unit among those withoutrestenosis; P = 0.01). There were no other statistically significantpredictors of restenosis. The relation of CMV seropositivityand the CMV titer with the risk of restenosis did not changein the multivariate logistic-regression models (odds ratio forrestenosis associated with a positive CMV status as comparedwith a negative status, 12.9; 95 percent confidence interval,2.3 to 71.1; P = 0.003; odds ratio associated with a higherCMV titer as compared with a lower titer, 8.1; 95 percent confidenceinterval, 1.5 to 43.2; P = 0.01).
Table 3. Univariate Association between Restenosis and Potential Risk Factors.
Influence of CMV Seropositivity and Other Risk Factors on the Loss Index
Simple linear regression models showed that both the continuousvariable for the CMV status (the CMV titer) and the dichotomousvariable for the CMV status (an ELISA value >0.25 unit indicatingseropositivity and a lower value indicating seronegativity)were strong predictors of the loss index (P = 0.01 and P = 0.002,respectively).
The full multiple regression model for the loss index showedthat the CMV status, analyzed as either a continuous or a dichotomousvariable, was a persistent and independent predictor of restenosis,over and above the effects of all other covariates in the model(P = 0.03 and P = 0.01, respectively). Table 4 shows the resultsof the full model with the CMV titer. The results of multivariateanalyses of the other risk factors did not differ appreciablyfrom the results of the univariate analyses. A stepwise approachto model selection also identified the continuous and dichotomousvariables for the CMV status as the only significant predictorsof the loss index. Although the relation between the CMV titerand restenosis was significant (P = 0.01), the CMV titer accountedfor only 7 percent of the variation in the loss index at sixmonths (r2 = 0.07). To put this in perspective, taken as a whole,all the risk factors we analyzed explained only 11.5 percentof the total variation in the loss index.
Table 4. Association between Potential Risk Factors and the Loss Index.
To determine whether the effect of exposure to CMV differedin subgroups of patients defined according to the other variablesanalyzed in the study, we tested a two-factor interaction ofeach variable with CMV exposure. None of the interactions weresignificant.
Evidence against the Presence of Acute Infection and Systemic Viremia
Anti-CMV IgM antibodies, which are usually present only earlyafter the acute infection, were not detected in any of the patientsat base line. At approximately six months (when follow-up angioplastywas performed), a second assay of anti-CMV IgG antibodies showedno significant change in the titer (Figure 4). Most important,no patient who was initially seropositive for anti-CMV IgG antibodieshad a significant increase in the titer (to more than two timesthe initial value), and titers fell to the seronegative rangein only four initially seropositive patients (all of whom hadrestenosis). In addition, none of the initially seronegativepatients became seropositive.
Figure 4. Titer of Anti-CMV IgG Antibodies at Base Line and at Six Months.
A titer of 0.25 unit or higher (i.e., a value above the broken line) was considered to indicate seropositivity.
Seropositivity for Hepatitis A Virus
To determine whether the correlation between CMV seropositivityand restenosis merely reflected a generalized susceptibilityto viral infection or an increased but nonspecific immune response,we determined whether there was a correlation between preexistingantibodies to hepatitis A virus and restenosis (the frequencyof seropositivity for hepatitis A virus is approximately thesame as that for CMV). Forty-one percent of the 75 patientswere seropositive for hepatitis A virus. However, no significantassociation was found between seropositivity and restenosis.The rate of restenosis was 35.7 percent among the patients whowere seropositive for hepatitis A virus and 37.5 percent amongthose who were seronegative.
Discussion
The present study provides prospective evidence that prior exposureto CMV, as indicated by the presence of anti-CMV IgG antibodiesat the time of coronary atherectomy, is a strong independentrisk factor for restenosis. The importance of this risk factoris reflected by the odds ratio for restenosis, which was ninetimes higher among the patients who had previously been exposedto CMV than among those who had not been exposed to the virus.None of the other variables tested were associated with a significantlyincreased risk of restenosis — findings that are generallyconsistent with the results of other studies.13,14,15,16,17,18
In our primary analysis, we considered the end point of restenosisas a dichotomous variable (i.e., restenosis vs. no restenosis).However, when the degree of stenosis was considered as a continuousvariable, the patients who were seropositive for CMV had a higherpercentage of stenosis than the seronegative patients. Consideredas a continuous variable, the minimal luminal diameter immediatelyafter directional coronary atherectomy was larger in the seropositivepatients than in the seronegative patients. However, the seropositivepatients had a markedly greater loss of luminal diameter anda higher loss index at six months, resulting in a tendency towarda smaller minimal luminal diameter and a higher incidence ofrestenosis.
Given that the processes leading to restenosis are complex andundoubtedly multifactorial, it is all the more compelling thatone factor — exposure to CMV — conveyed such a highrisk. The diagnosis of restenosis in this study was based onangiographic evaluation rather than clinical assessment, whichis known to be highly inaccurate in predicting restenosis. Confidencein the results also derives from the fact that this study wasprospective in design, that the angiograms were evaluated withoutknowledge of the patients' CMV status, and that the tests foranti-CMV antibodies were performed without knowledge of theangiographic results.
The association between the development of restenosis and priorexposure to CMV was based on assays of anti-CMV IgG antibodiesperformed at the time of the atherectomy. Antibody levels didnot increase during the ensuing six months. This finding, inconjunction with the fact that anti-CMV IgM antibodies werenot detected, suggests that acute CMV infection with systemicviremia did not occur. We cannot rule out the possibility thatacute viremia developed shortly after the atherectomy, withantibody levels returning to base-line values by six months.Our results, however, are most compatible with the idea thateither the virus produced an abortive infection (i.e., the expressionof viral genes was limited to immediate early gene products)or viral replication occurred locally in the absence of systemicviremia.
CMV is a complex virus — it has a large genome with over200 open reading frames. Thus, it undoubtedly possesses manyviral proteins that may influence neointimal accumulation. Inaddition to the effects of IE84, which binds to and inactivatesp53, the infection of smooth-muscle cells with CMV leads tothe expression and secretion of growth factors,19,20 and CMVinfection has been shown to activate NF-B, a transcription factorinvolved in stimulating a broad range of genes, including thosethat have roles in inflammatory and immune responses.21 Thevirus also increases the adhesion of leukocytes and plateletsto endothelial cells by inducing cellular expression of adhesionmolecules22,23,24,25 and causes changes that are procoagulant.26,27,28Furthermore, CMV increases the activity of the scavenger receptor,and IE72, another immediate early gene product, increases theexpression of the scavenger-receptor gene.29 The increased accumulationof oxidized low-density lipoprotein cholesterol in lesionalsmooth-muscle cells may contribute to an atherogenic processsuch as restenosis. Finally, it has recently been shown thatIE72 and IE84 inhibit apoptosis, which may increase neointimalaccumulation.30
Unexpectedly, we also found a strong association between exposureto CMV and hypertension. Because this association was not aprospectively defined end point, additional studies are neededto validate the potentially important link between CMV infectionand hypertension. It is possible that the relation between CMVinfection and restenosis observed in the present investigationis due to the particular type of angioplasty used — atherectomy— and that different results would have been observedwith other types, such as balloon angioplasty. Separate studiesof other types of angioplasty will be needed to settle thisissue.
It is possible that CMV seropositivity, instead of reflectinga causal role of CMV infection in the development of restenosis,is just a marker of another process that causes restenosis.Although a causal relation has not yet been definitively demonstrated,our previous studies showed that CMV DNA is present in restenoticlesions in humans,3 a CMV gene product inhibits the transcriptionalactivity of p53 in human coronary-artery smooth-muscle cells,3and acute CMV infection increases neointimal formation in ratswith balloon injuries.31 Taken together with the results presentedhere, these findings support the idea that CMV infection playsa part in restenosis.
The results of the present investigation, if confirmed by additionallarge studies, demonstrate that CMV provides a means of stratifyingpatients according to the risk of restenosis. Thus, the knowledge(based on the results of a simple, standard blood test) thata given patient has less than a 10 percent chance of restenosis(i.e., is seronegative for CMV) or more than a 40 percent chance(i.e., is seropositive for CMV), when considered together withthe patient's specific clinical profile, may influence the clinician'sjudgment of whether that patient will benefit from atherectomyor should instead undergo coronary-artery bypass surgery. Andif future studies establish a causal role of CMV infection inthe development of restenosis, it may be possible to preventrestenosis by using specific antiviral strategies.
We are indebted to Drs. Kenneth M. Kent, Lowell F. Satler, AugustoD. Pichard, and the rest of the OARS investigators, who madethis study possible; to Dr. E.S. Huang for his invaluable adviceon the immunovirologic aspects of CMV; to Regina A. Deible,R.N., Theresa A. Bucher, R.N., and Linda Leon, B.S., for theirhelp in obtaining blood samples; to Richard Maters and his associatesfor performing the hepatitis A antibody test; and to D. Kochfor expert preparation of the manuscript.
Source Information
From the Cardiology Branch, National Heart, Lung, and Blood Institute, Bethesda, Md. (Y.F.Z., M.A.W., Z.X.Y., T.F., S.E.E.), and the Washington Hospital Center, Washington, D.C. (M.B.L., J.J.P.).
Address reprint requests to Dr. Epstein at the Cardiology Branch, National Heart, Lung, and Blood Institute, Bldg. 10, Rm. 7B15, 10 Center Dr., MSC 1650, Bethesda, MD 20892-1650.
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B, a transcription factor involved in stimulating a broad range of genes, including those that have roles in inflammatory and immune responses.21 The virus also increases the adhesion of leukocytes and platelets to endothelial cells by inducing cellular expression of adhesion molecules22,23,24,25 and causes changes that are procoagulant.26,27,28 Furthermore, CMV increases the activity of the scavenger receptor, and IE72, another immediate early gene product, increases the expression of the scavenger-receptor gene.29 The increased accumulation of oxidized low-density lipoprotein cholesterol in lesional smooth-muscle cells may contribute to an atherogenic process such as restenosis. Finally, it has recently been shown that IE72 and IE84 inhibit apoptosis, which may increase neointimal accumulation.30 
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