3
Do Cardiovascular Risk Factors Influence Cardiac Allograft Vasculopathy? C.I. Chamorro, L. Almenar, L. Martı´nez-Dolz, E. Sánchez-Lacuesta, J. Martı´n-Pastor, F. Ten-Morro, R.M. Sánchez-Soriano, J. Agüero, V. Ortiz, J.A. Moro, and A. Salvador ABSTRACT Background. Cardiac allograft vasculopathy (CAV) is the leading cause of heart trans- plant failure after the first year. The etiological factors involved are currently a contro- versial matter. Intravascular ultrasound (IVUS) is considered the diagnostic procedure of choice. We assessed the relationship of cardiovascular risk factors with CAV. Materials. We analyzed prospectively 22 patients. We conducted a first study with coronary angiography and IVUS at 36 3 days and a second at 598 49 days. We performed an average of 5.6 clinical revisions per patient, assessing the effect of the classic cardiovascular risk factors, the cause of heart failure, and the age of the patient and donor. The statistics used were 2 , Fisher exact test, and Student t test. Results. CAV was found in 10 subjects (45.5%). Univariate analysis showed statistically significant differences in the assessment of the presence of diabetes and dyslipidemia posttransplantation, but not pretransplantation. Among the patients with CAV there was a higher percentage of diabetics (32.8% vs 12%, P .01). The patients with CAV also had higher levels of total cholesterol (211 40 mg/dL vs 195 35 mg/dL, P .02), triglycerides (172 108 mg/dL vs 136 66 mg/dL, P .03), low-density lipoprotein (133 35 mg/dL vs 117 30 mg/dL, P .01), and lower high-density lipoprotein levels (46 15 mg/dL vs 52 12 mg/dL, P .03). Conclusions. Only the diabetes and dyslipidemia present in the posttransplantation period were associated with CAV, which highlights the fact that it is a condition that both shares and has different features with atherosclerosis and probably requires a different diagnostic-therapeutic approach. C ARDIAC ALLOGRAFT VASCULOPATHY (CAV) is a rapidly progressing form of obliterating vascu- lopathy that affects diffusely the coronary tree in the arteries, capillaries, and veins of the heart transplant (HT) patient. 1,2 It is considered to be the leading cause of graft failure after the first year and affects 50% of the trans- planted population. 3 Its symptoms appear late as heart failure, ventricular arrhythmia, or sudden death, since it settles on denervated hearts, with no angina unless unusual organ reinnervation occurs. When the clinical diagnosis is obtained, the disease is already in an advanced stage and, at this point, the only valid therapeutic option is heart retrans- plantation. Intravascular ultrasound (IVUS) is considered to be the most sensitive and specific test for an early diagnosis, since it allows in vivo visualization of the arterial wall and detects intimal thickening and its differential characteristics with the atherosclerotic disease inherited from the donor. 4 Controversy exists regarding the related etiological fac- tors. Immunological and infectious theories have been postulated, and the classic cardiovascular risk factors and ischemic-reperfusion events have been implicated. In this study we analyzed the relationship between the cardiovas- cular risk factors present in the pre- and posttransplanta- tion periods. From the Cardiac Failure and Transplant Unit, La Fe University Hospital, Valencia, Spain. Address reprint requests to C.I. Chamorro Fernández, Hospital Universitario La Fe, Department of Cardiology, Avda. Campanar No. 21, 46009 Valencia, Spain. E-mail: [email protected] 0041-1345/06/$–see front matter © 2006 by Elsevier Inc. All rights reserved. doi:10.1016/j.transproceed.2006.08.034 360 Park Avenue South, New York, NY 10010-1710 2572 Transplantation Proceedings, 38, 2572–2574 (2006)

Do Cardiovascular Risk Factors Influence Cardiac Allograft Vasculopathy?

Embed Size (px)

Citation preview

Page 1: Do Cardiovascular Risk Factors Influence Cardiac Allograft Vasculopathy?

DA

CR

Clapfpfsootp

mi

0d

2

o Cardiovascular Risk Factors Influence Cardiacllograft Vasculopathy?

.I. Chamorro, L. Almenar, L. Martı́nez-Dolz, E. Sánchez-Lacuesta, J. Martı́n-Pastor, F. Ten-Morro,

.M. Sánchez-Soriano, J. Agüero, V. Ortiz, J.A. Moro, and A. Salvador

ABSTRACT

Background. Cardiac allograft vasculopathy (CAV) is the leading cause of heart trans-plant failure after the first year. The etiological factors involved are currently a contro-versial matter. Intravascular ultrasound (IVUS) is considered the diagnostic procedure ofchoice. We assessed the relationship of cardiovascular risk factors with CAV.Materials. We analyzed prospectively 22 patients. We conducted a first study withcoronary angiography and IVUS at 36 � 3 days and a second at 598 � 49 days. Weperformed an average of 5.6 clinical revisions per patient, assessing the effect of the classiccardiovascular risk factors, the cause of heart failure, and the age of the patient and donor.The statistics used were �2, Fisher exact test, and Student t test.Results. CAV was found in 10 subjects (45.5%). Univariate analysis showed statisticallysignificant differences in the assessment of the presence of diabetes and dyslipidemiaposttransplantation, but not pretransplantation. Among the patients with CAV there wasa higher percentage of diabetics (32.8% vs 12%, P � .01). The patients with CAV also hadhigher levels of total cholesterol (211 � 40 mg/dL vs 195 � 35 mg/dL, P � .02),triglycerides (172 � 108 mg/dL vs 136 � 66 mg/dL, P � .03), low-density lipoprotein(133 � 35 mg/dL vs 117 � 30 mg/dL, P � .01), and lower high-density lipoprotein levels(46 � 15 mg/dL vs 52 � 12 mg/dL, P � .03).Conclusions. Only the diabetes and dyslipidemia present in the posttransplantationperiod were associated with CAV, which highlights the fact that it is a condition that bothshares and has different features with atherosclerosis and probably requires a different

diagnostic-therapeutic approach.

itCtpisct

H

U

ARDIAC ALLOGRAFT VASCULOPATHY (CAV)is a rapidly progressing form of obliterating vascu-

opathy that affects diffusely the coronary tree in therteries, capillaries, and veins of the heart transplant (HT)atient.1,2 It is considered to be the leading cause of graftailure after the first year and affects 50% of the trans-lanted population.3 Its symptoms appear late as heartailure, ventricular arrhythmia, or sudden death, since itettles on denervated hearts, with no angina unless unusualrgan reinnervation occurs. When the clinical diagnosis isbtained, the disease is already in an advanced stage and, athis point, the only valid therapeutic option is heart retrans-lantation.Intravascular ultrasound (IVUS) is considered to be theost sensitive and specific test for an early diagnosis, since

t allows in vivo visualization of the arterial wall and detects N

041-1345/06/$–see front matteroi:10.1016/j.transproceed.2006.08.034

572

ntimal thickening and its differential characteristics withhe atherosclerotic disease inherited from the donor.4

ontroversy exists regarding the related etiological fac-ors. Immunological and infectious theories have beenostulated, and the classic cardiovascular risk factors and

schemic-reperfusion events have been implicated. In thistudy we analyzed the relationship between the cardiovas-ular risk factors present in the pre- and posttransplanta-ion periods.

From the Cardiac Failure and Transplant Unit, La Fe Universityospital, Valencia, Spain.Address reprint requests to C.I. Chamorro Fernández, Hospital

niversitario La Fe, Department of Cardiology, Avda. Campanar

o. 21, 46009 Valencia, Spain. E-mail: [email protected]

© 2006 by Elsevier Inc. All rights reserved.360 Park Avenue South, New York, NY 10010-1710

Transplantation Proceedings, 38, 2572–2574 (2006)

Page 2: Do Cardiovascular Risk Factors Influence Cardiac Allograft Vasculopathy?

M

BaswPppItepsa

paga5lfrp

cgKSias

R

OocfhfHts

D

Teeaeifitbtttg

cpdosmdsfiypm

tdsmahtpbrnsealddwpa

P

P

l

CARDIOVASCULAR RISK FACTORS 2573

ATERIALS AND METHODS

etween December 17, 2001, and December 15, 2004, we recruitedtotal of 22 patients who were studied prospectively. We included

ubjects who had undergone heart transplantation in our center,ho survived during the study period, and who gave their consent.atients transplanted in other centers, retransplantations, andediatric and cardiopulmonary transplantations were excluded. Allarticipants underwent a first study with coronary angiography andVUS at 36 � 3 days and a second control at 598 � 49 days afterransplantation. CAV was defined as the finding of intimal thick-ning at any time during the follow-up and in an area that wasreviously considered normal. The cutoff point established asignificant intimal thickening, predictive of cardiac events second-ry to CAV, was 0.5 mm or more.4

During the almost 600 days between the baseline and therogression study, the patients were admitted to the hospital onprogrammed basis and underwent clinical and electrocardio-

raphic examinations and right heart catheterization followed bybiopsy of the right ventricle. During this period an average of

.6 revisions were carried out per patient. Among the data col-ected, we focused on the presence of the classic cardiovascular riskactors during the posttransplantation and pretransplantation pe-iods, the cause leading to transplantation, and the ages of theatients and donors.Statistical analysis was done with �2 when we intended to

ompare qualitative variables and the Fisher exact test for smallroups. The analysis of all quantitative variables passed theolmogorov-Smirnov normality test, so they were compared by thetudent t test. The differences were considered statistically signif-

cant when the P value was .05 or lower. The qualitative variablesre expressed as percentages and the quantitative as means �tandard deviations.

ESULTS

f the 22 cases, CAV was shown in 10, giving a prevalencef 45.5%, similar to other studies.3 After analyzing theharacteristics of both groups (CAV or non-CAV), weound no differences in donor or recipient age, cause ofeart failure, body mass index, smoking, hypertension be-ore and after HT, and diabetes and dyslipidemia beforeT. However, we did find differences in the assessment of

he presence of diabetes and dyslipidemia after HT, ashown in Table 1.

ISCUSSION

he identification of factors that could predispose to themergence of graft vasculopathy is important, since it couldnhance our understanding of its pathophysiological mech-nisms and lead to preventive therapeutic approaches. IVUSnables detection of the lesions characteristic of CAV, includ-ng intimal thickening of circumferential growth, formed bybromuscular material; lack of calcium; and extension fromhe external elastic membrane to the internal elastic mem-rane, thereby including the media and not leading to disrup-ion of the intima. These characteristics allow for differen-iating CAV from the atherosclerotic disease inherited fromhe donor, which is defined by lesions of asymmetrical focal

rowth that invade the intima, causing disruptions, and that f

ontain calcium in their composition.5 However, these mor-hological differences do not allow us to establish a certainiagnosis since they are not always met and there are casesf mixed presentation. Unlike the reports from the firsttudies on CAV, where IVUS was not performed in the firstonths posttransplantation, we based the diagnosis on the

ifferent nature of the progression of both types of disease,ince CAV shows a fast progression, very infrequent in therst months of the transplant (becoming evident after the firstear of HT); while atherosclerosis from the donor is alreadyresent in the baseline study and hardly progresses in theedium-term follow-up.According to our experience, univariate analysis shows

he implication of dyslipidemia and diabetes mellitus in theevelopment of CAV. Multiple studies have shown theusceptibility of transplanted patients to suffer diabetesellitus, hypertriglyceridemia, and hypercholesterolemia6

fter the first year of the transplant. Furthermore, though itas been postulated that these disorders could be secondaryo the use of immunosuppressive therapy and to obesity, theathophysiological mechanisms causing them have not yeteen clearly described. Cyclosporine has been shown toeduce the activity of lipoprotein lipase and inhibit pred-isone clearance by interaction with the cytochrome P-450ystem. In addition, the diabetogenic and hyperlipidemicffects of glucocorticoids are well known. Insulin resistancelso enhances hypertriglyceridemia and low high-densityipoprotein levels. Experimental studies have shown thatiabetes and hypercholesterolemia can cause phenotypeisorders in the vascular smooth muscle cells, which thatould cause their proliferation and would increase theroduction of extracellular matrix characteristic of earlytherosclerosis lesions.

As in other studies, not all classic cardiovascular risk

Table 1. Results

CAV(n � 10)

Non-CAV(n � 12) P

re-HT variableBMI 28.14 25.41 .08Donor age (y) 30.44 33.50 .2Recipient age (y) 52.70 51.42 .16Ischemic heart disease (%) 31.8 18.2 .19Smoking (%) 40.9 31.8 .16Hypertension (%) 13.6 9.1 .62Dyslipidemia (%) 27.3 27.3 .69Diabetes (%) 13.6 9.1 .62

ost-HT variableHypertension (%) 14.4 16 .8Total cholesterol (mg/dL) 211 � 40 195 � 35 .02LDL (mg/dL) 133 � 35 117 � 30 .01HDL (mg/dL) 46 � 15 52 � 12 .05Triglycerides (mg/dL) 172 � 108 136 � 66 .03Diabetes (%) 32.8 12.3 �.01

CAV, cardiac allograft vasculopathy; BMI, body mass index; LDL, low-densityipoprotein; HDL, high-density lipoprotein.

actors are related to the disease,7 and, according to our

Page 3: Do Cardiovascular Risk Factors Influence Cardiac Allograft Vasculopathy?

eaftcttahopfwws

bpavpi

R

oM

c1

um

uoa

J

hC

aif

2574 CHAMORRO, ALMENAR, MARTÍNEZ-DOLZ ET AL

xperience, only dyslipidemia and de novo diabetes aressociated with vasculopathy, which is attributed to theact that the metabolic disorder per se is not enough forhe development of the disease; other factors shouldoexist for vascular involvement to occur. Evidence existshat statins, in addition to inhibiting cholesterol produc-ion, can decrease immunoglobulin G autoantibody levelsnd reduce the incidence of CAV.8 This reinforces theypothesis of the implication of dyslipidemia in the devel-pment of the vascular condition and presents a possiblereventive therapeutic option. Unlike other studies, weound no statistically significant difference, though thereas a trend, with regard to the relationship of vasculopathyith overweight, which could be attributed to the small

ample size.In conclusion, among all the factors analyzed, only dia-

etes and dyslipidemia present in the pretransplantationeriod were associated with CAV. Accordingly, prophylaxisnd treatment could help reduce the incidence of graftasculopathy and thus increase the survival of heart trans-lant patients. Nevertheless, prospective, randomized stud-

es must be designed to demonstrate this.pt

EFERENCES

1. Kobashigawa J: What is the optimal prophylaxis for treatmentf cardiac allograft vasculopathy? Curr Control Trials Cardiovasced 1:166, 20002. Labarrere CA: Relationship of fibrin deposition in microvas-

ulature to outcomes in cardiac transplantation. Curr Opin Cardiol4:133, 19993. Kapadia SR, Ziada KM, L’Allier PL, et al: Intravascular

ltrasound imaging after cardiac transplantation: advantage ofulti-vessel imaging. J Heart Lung Transplant 19:167, 20004. Tuzcu EM, Kapadia SR, Sachar R, et al: Intravascular

ltrasound evidence of angiographically silent progression in cor-nary atherosclerosis predicts long-term morbidity and mortalityfter cardiac transplantation. J Am Coll Cardiol 45:1538, 2005

5. Billingham ME: Histopathology of graft coronary disease.Heart Lung Transplant 11:S38, 19926. Lindenfeld J, Page RL 2nd, Zolty R, et al: Drug therapy in the

eart transplant recipient: Part III: common medical problems.irculation 111:113, 20057. Rickenbacher PR, Kemna MS, Pinto FJ, et al: Coronary

rtery intimal thickening in the transplanted heart. An in vivontracoronary untrasound study of immunologic and metabolic riskactors. Transplantation 61:46, 1996

8. Eisen HJ, Tuzcu EM, Dorent R, et al: Everolimus for the

revention of allograft rejection and vasculopathy in cardiac-ransplant recipients. N Engl J Med 349:847, 2003