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Utility of C2 Monitoring in Prediction of Diastolic Dysfunction in Renal Transplant Recipients
Utility of C2 Monitoring in Prediction of Diastolic Dysfunction in Renal Transplant Recipients A. Kirkpantur, R. Yilmaz, G. Abali, M. Arici, B. Altun, T. Aki, I. Erkan, M. Bakkaloglu, U. Yasavul, and C. Turgan ABSTRACT Background. A number of experimental studies have suggested that cyclosporine (CsA) toxicity induces cardiac modifications which may cause diastolic dysfunction over the course of time. Doppler echocardiography with tissue Doppler imaging (TDI) could consistently detect diastolic dysfunction. The purpose of this study was to assess diastolic dysfunction using C2 monitoring of CsA exposure in stable renal transplant patients. Patients and Methods. Seventy-eight kidney recipients including 42 men and 36 women of overall mean age of 52 ⫾ 9 years were obtained in 47 living and in 31 cases from cadaveric donations over 12 or more months after transplantation using cases from CsA, mycophenolate mofetil, and steroid. C2 levels were measured by an enzyme multi-immune assay technique. The patients underwent conventional and Doppler echocardiography with TDI. Results. The patients were divided into 2 groups according to C2 levels less than 500 g/L (group 1, n ⫽ 40) versus greater than 500 g/L (group 2, n ⫽ 38). The demographic parameters, serum creatinine and lipid levels, systolic and diastolic blood pressures, number and type of antihypertensive medications, and conventional echocardiographic parameters did not differ significantly between the groups. However, group 1 patients showed significantly higher isovolumic relaxation time (109 ⫾ 27 vs 86 ⫾ 14 ms), early diastolic deceleration time (189 ⫾ 52 vs 137 ⫾ 59 ms), and lower values of E velocity (56 ⫾ 32 vs 92 ⫾ 27 cm/s) and E/A ratios (0.81 ⫾ 0.23 vs 1.15 ⫾ 0.46) than group 2. TDI studies revealed significantly lower E=/A= (0.76 ⫾ 0.25 vs 1.09 ⫾ 0.32, P ⬍ .05) in group 1 versus group 2. Conclusion. The data suggested that the higher C2 levels may induce diastolic dysfunction in the hearts of kidney recipients without impairment of contractile performance.
T
HE INTRODUCTION OF cyclosporine (CsA) in clinical practice has been a great advance for the efficacy of immunosuppression in solid organ transplantation. However, CsA is a critical dose immunosuppressant drug with a narrow therapeutic window and considerable clinical consequences like hypertension, nephrotoxicity, and increased frequency of cardiac myocyte hypertrophy and interstitial fibrosis. CsA concentration monitoring by 2-hour postdosing levels (C2) may lead to a more precise control of CsA exposure. C2 monitoring has been shown to have a close correlation with clinical outcomes in renal transplantation.1,2 The aim of this study was to assess the utility of C2 levels as a practical monitoring tool to predict the presence of diastolic dysfunction as detected by Doppler echocardiography with tissue Doppler imaging (TDI). © 2008 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 40, 171–173 (2008)
PATIENTS AND METHODS Patients and Laboratory Tests Seventy-eight renal transplant recipients including 42 men and 36 women of overall mean age of 52 ⫾ 9 years were involved in this study. Forty-seven organs were obtained from living and 31 from cadaveric donors. The patients had to be at least 12 months after the procedure on stable immunosuppressive therapy with CsA From the Department of Internal Medicine, Nephrology Unit (A.K., R.Y., M.A., B.A., U.Y., C.T.) and the Departments of Cardiology (G.A.) and Urology (T.A., I.E., M.B.), Hacettepe University Faculty of Medicine, Ankara, Turkey. Address reprint requests to Dr Alper Kirkpantur, 74, Sokak No. 3/13 Bahcelievler, Cankaya, Ankara, Turkey. E-mail: [email protected] 0041-1345/08/$–see front matter doi:10.1016/j.transproceed.2007.11.031 171
172
KIRKPANTUR, YILMAZ, ABALI ET AL
(Neoral, Novartis Pharma, Basel, Switzerland), mycophenolate mofetil, and steroid. Each patient underwent a complete blood count and biochemical analysis of blood urea nitrogen, creatinine, uric acid, glucose, sodium, potassium, calcium, phosphorus, alanine aminotransferase, aspartate aminotransferase, serum lipid profile including total cholesterol, triglycerides, high-density and lowdensity lipoprotein-cholesterol. C2 levels were measured by an enzyme multi-immune assay technique (EMIT) every 2 months yielding 24 measurements for each patient. The CsA dose was adjusted to target a C2 level of less than 800 g/L.3 All participants were questioned about their cardiovascular disease history and risk factors. In addition, electrocardiography was performed to exclude cardiac disease. There were no smokers and no documented previous cardiovascular events among the study population.
Echocardiography
Statistical Analysis The data were expressed as mean values ⫾ SD. P ⫽ .05 was used to determine statistical significance for all analyses. Patients diTable 1. Demographic, Clinical, and Serum Biochemical Parameters
Age (y) Gender (male/female) Mean time on dialysis before transplantation (months) BMI (kg/m2) Hb (g/dL) Creatinine (mg/dL) Glucose (mg/dL) LDL-C (mg/dL) HDL-C (mg/dL) Triglycerides (mg/dL) Systolic BP (mm Hg) Diastolic BP (mm Hg) ACE inhibitor (%) ARB (%) CCB (%) Beta-blocker (%)
Serum creatinine (mg/dL) Baseline At 3 months At 6 months At 12 months C2 (g/L) Baseline At 3 months At 6 months At 12 months
Group 1 (n ⫽ 40)
Group 2 (n ⫽ 38)
1.29 ⫾ 0.20 1.36 ⫾ 0.19 1.33 ⫾ 0.40 1.31 ⫾ 0.30
1.35 ⫾ 0.11 1.36 ⫾ 0.30 1.40 ⫾ 0.19 1.37 ⫾ 0.20
.56 .99 .27 .44
495 ⫾ 102 392 ⫾ 110 570 ⫾ 91 501 ⫾ 85
707 ⫾ 88 711 ⫾ 100 625 ⫾ 87 825 ⫾ 96
⬍.05 ⬍.05 ⬍.05 ⬍.05
P
C2, cyclosporine concentration monitoring by 2-hour postdosing levels.
Echocardiography was performed using conventional and Doppler echocardiography with TDI (Vingmed, United States). The left ventricular (LV) end-systolic and end-diastolic diameters and the thicknesses of the LV posterior wall and LV septum were measured from the long axis in the parasternal plane according to guidelines of the American Society of Echocardiography.4 On Doppler echocardiography, we studied the transmitral peak early diastolic velocity (E), transmitral peak atrial contraction velocity (A), the proportion of these 2 variables (E/A), the deceleration time of the early diastolic wave (E Dec), and the isovolumic relaxation time (IVRT). Myocardial tissue velocities were measured in early diastole (E=) and with atrial contraction (A=) at the lateral corner of the mitral annulus via TDI. The study protocol was approved by the Ethics Committee; the patients gave written informed consent before enrollment.
Parameter
Table 2. Serum Creatinine and C2 Levels During the Study Period
Group 1 (n ⫽ 40)
Group 2 (n ⫽ 38)
54 ⫾ 10 22/18 47 ⫾ 9
49 ⫾ 9 20/18 50 ⫾ 10
.23 .87 .37
23.4 ⫾ 3.1 12.5 ⫾ 1.4 1.31 ⫾ 0.3 84 ⫾ 9 109 ⫾ 11 48 ⫾ 5 167 ⫾ 21 132 ⫾ 10 77 ⫾ 6 38 14 19 11
22.7 ⫾ 3.4 12.2 ⫾ 1.3 1.37 ⫾ 0.2 79 ⫾ 8 106 ⫾ 14 45 ⫾ 7 159 ⫾ 16 127 ⫾ 11 71 ⫾ 6 34 15 21 9
.46 .92 .44 .57 .76 .64 .55 .72 .28 .50 .78 .35 .63
vided into 2 groups according to the median C2 level were evaluated for differences by chi-square analysis for categoric variables and the independent sample Student t test for continuous variables. All statistical analyses were performed using the SPSS 11.0 for Windows (SPSS Inc, Chicago, Ill, United States).
RESULTS
The patients were divided into 2 groups according to C2 levels less than 500 g/L (group 1, n ⫽ 40) versus greater than 500 g/L (group 2, n ⫽ 38). The demographic parameters, serum creatinine and lipid levels, systolic and diastolic blood pressures, as well as number and type of antihypertensive medications did not differ significantly between the groups (Table 1). In addition, renal function did not significantly correlate with C2 measurements during the follow-up (Table 2). LV ejection fraction was normal in both groups. LV end-diastolic volume, fractional shortening, thicknesses of the posterior wall and the interventricular septum did not differ significantly between the groups (Table 3). On Doppler echocardiography, A velocities were similar
P
BMI, body mass index; Hb, hemoglobin; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; BP, blood pressure; ACE, angiotensin converting enzyme; ARB, angiotensin II receptor antagonist; CCB, calcium channel blocker.
Table 3. Comparison of Conventional, Doppler Echocardiographic, and Tissue Doppler Imaging Findings Between Groups 1 and 2 (Mean Values ⴞ SD) Parameter
Group 1 (n ⫽ 40)
Group 2 (n ⫽ 38)
P
EDD (mm) FS (%) Sthd (mm) EF (%) E (cm/s) A (cm/s) E/A E Dec (ms) IVRT (ms) E=/A=
4.2 ⫾ 0.5 36.59 1.00 ⫾ 0.10 65.30 ⫾ 5.8 56 ⫾ 32 75 ⫾ 29 0.81 ⫾ 0.23 189 ⫾ 52 109 ⫾ 27 0.76 ⫾ 0.25
4.4 ⫾ 0.6 35.78 1.02 ⫾ 0.11 62.92 ⫾ 6.1 92 ⫾ 27 83 ⫾ 31 1.15 ⫾ 0.46 137 ⫾ 59 86 ⫾ 14 1.09 ⫾ 0.32
.87 .62 .55 .77 ⬍.05 .47 ⬍.05 ⬍.05 ⬍.05 ⬍.05
EDD, end-diastolic diameter of left ventricle; FS, fractional shortening; Sthd, interventricular septal thickness diastole; EF, ejection fraction; E, conventional Doppler early diastolic inflow; A, conventional Doppler late atrial inflow; E/A, ratio of early diastolic inflow to late atrial inflow; E Dec, early diastolic deceleration time; IVRT, isovolumic left ventricular relaxation time; E’/A’, ratio of early to late diastolic myocardial tissue velocities.
C2 MONITORING PREDICTS DIASTOLIC DYSFUNCTION
between groups. However, group 1 patients showed significantly greater IVRT (109 ⫾ 27 vs 86 ⫾ 14 ms) and early diastolic deceleration time (189 ⫾ 52 vs 137 ⫾ 59 ms) with lower values of E velocity (56 ⫾ 32 vs 92 ⫾ 27 cm/s) and E/A ratios (0.81 ⫾ 0.23 vs. 1.15 ⫾ 0.46) than group 2 (Table 3). In group 1 versus group 2 TDI studies revealed significantly lower E=/A=: 0.76 ⫾ 0.25 vs. 1.09 ⫾ 0.32 (P ⬍ .05; Table 3). DISCUSSION
The purpose of this study was to evaluate the association of C2 levels with indices of LV function among stable renal transplant recipients. This study demonstrated that a target C2 level correlated with LV diastolic dysfunction despite no cardiac symptoms. C2 levels greater than 500 g/L were significantly associated with LV diastolic dysfunction by Doppler echocardiographic indices. The predictive value of C2 levels for LV diastolic dysfunction may be explained by the hypothesis that patients with higher C2 levels represent overexposure to CsA. The overexposure may contribute to adverse effects in the myocardial fiber network which can be detected by changes in myocardial velocities on Doppler echocardiography with TDI. CsA has revolutionized solid organ transplantation; it remains one of the most important drugs against acute rejection. However, the drug itself has been related to cardiotoxicity in both experimental models and in patients.5– 8 CsA can decrease cytochrome c oxidase expression and increase reactive oxygen species (ROS) production in the myocardium.9 Moreover, CsA can also lead to up-regulation of matrix metalloproteinase-2 (MMP2) and down-regulation of their endogenous inhibitors (TIMP2) as mediated by ROS production.9 The inappropriate activation of MMPs and/or an imbalance between MMP actions and those of their inhibitors due to an ROS increase have all been implicated in cardiac remodeling.10 Experimental data have revealed increased MMP2 activity and myocardial extracellular matrix disorganization with the disappearance of a normal network among the fibers after CsA treatment.5 Furthermore, MMP2 up-regulation with inhibition of endogenous antioxidant systems has been shown in the dysregulation of the myocardial extracellular matrix in various cardiomyopathies.11 Indirect effects of CsA may influence collagen accumulation in the extracellular cardiac matrix in vivo. CsA is known to induce hypertension, and uncontrolled hyperten-
173
sion has been shown to produce disproportionate collagen accumulation and myocardial interstitial fibrosis in experimental animals12 with subsequent development of LV dysfunction and congestive heart failure.13 However, the systolic and diastolic blood pressures as well as the number and type of antihypertensive medications did not differ significantly between the groups. In conclusion, the present study showed an advantage of C2 monitoring among the population treated with a regimen including CsA. This study suggested that a target level of C2 lower than 500 g/L was associated with preserved graft function with a lower prevalance of diastolic dysfunction among stable renal transplant recipients at 12 or more months. Further clinical and pathological studies are needed to confirm these findings. REFERENCES 1. Pescovitz MD, Barbeito R, Simulect US01 Study Group: Two-hour post-dose cyclosporine level is a better predictor than trough level of acute rejection of renal allografts. Clin Transpl 16:378, 2002 2. Levy G, Thervet E, Lake J, et al: Patient management by Neoral C2 monitoring: an international consensus. Transplantation 73:S12, 2002 3. Keown PA: New concepts in cyclosporine monitoring. Curr Opin Nephrol Hypertens 11:619, 2002 4. Sahn DJ, De Maria A, Kisslo J, et al: Recommendations regarding quantitation in M-mode echocardiographic measurements. Circulation 58:1072, 1978 5. Bianchi R, Rodella L, Rezzani R: Cyclosporine A upregulates expression of matrix matalloproteinase 2 and vascular endothelial growth factor in rat heart. Int Immunopharmacol 3:427, 2003 6. Rezzani R, Rodella L, Dessy C, et al: Changes in Hsp90 expression determine the effects of cyclosporine A on the NO pathway in rat myocardium. FEBS Lett 552:125, 2003 7. Laczkovics A, Havel M, Teufelsbauer H, et al: Cyclosporin-A induced heart failure after orthotopic heart transplantation. J Thorac Cardiovasc Surg 35:83, 1987 8. Siostrzonek P, Teufelsbauer H, Kreiner G, et al: Relief of diastolic cardiac dysfunction after cyclosporine withdrawal in a cardiac transplant recipient. Eur Heart J 14:859, 1993 9. Rezzani R, Giugno L, Buffoli B, et al: The protective effect of caffeic acid phenethyl ester against cyclosporine A-induced cardiotoxicity in rats. Toxicology 212:155, 2005 10. Spinale FG: Matrix metalloproteinases: regulation and dysregulation in the failing heart. Circ Res 90:520, 2002 11. Siwik DA, Pagano PJ, Colucci WS: Oxidative stress regulates collagen synthesis and matrix metalloproteinase activity in cardiac fibroblasts. Am J Physiol Cell Physiol 280:C35, 2001 12. Weber KT: Cardiac interstitium in health and disease: the fibrillar collagen network. J Am Coll Cardiol 13:1637, 1989 13. Capasso JM, Palackal T, Olivetti G, et al: Left ventricular failure induced by long-term hypertension in rats. Circ Res 66: 1400, 1990
T
HE INTRODUCTION OF cyclosporine (CsA) in clinical practice has been a great advance for the efficacy of immunosuppression in solid organ transplantation. However, CsA is a critical dose immunosuppressant drug with a narrow therapeutic window and considerable clinical consequences like hypertension, nephrotoxicity, and increased frequency of cardiac myocyte hypertrophy and interstitial fibrosis. CsA concentration monitoring by 2-hour postdosing levels (C2) may lead to a more precise control of CsA exposure. C2 monitoring has been shown to have a close correlation with clinical outcomes in renal transplantation.1,2 The aim of this study was to assess the utility of C2 levels as a practical monitoring tool to predict the presence of diastolic dysfunction as detected by Doppler echocardiography with tissue Doppler imaging (TDI). © 2008 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 40, 171–173 (2008)
PATIENTS AND METHODS Patients and Laboratory Tests Seventy-eight renal transplant recipients including 42 men and 36 women of overall mean age of 52 ⫾ 9 years were involved in this study. Forty-seven organs were obtained from living and 31 from cadaveric donors. The patients had to be at least 12 months after the procedure on stable immunosuppressive therapy with CsA From the Department of Internal Medicine, Nephrology Unit (A.K., R.Y., M.A., B.A., U.Y., C.T.) and the Departments of Cardiology (G.A.) and Urology (T.A., I.E., M.B.), Hacettepe University Faculty of Medicine, Ankara, Turkey. Address reprint requests to Dr Alper Kirkpantur, 74, Sokak No. 3/13 Bahcelievler, Cankaya, Ankara, Turkey. E-mail: [email protected] 0041-1345/08/$–see front matter doi:10.1016/j.transproceed.2007.11.031 171
172
KIRKPANTUR, YILMAZ, ABALI ET AL
(Neoral, Novartis Pharma, Basel, Switzerland), mycophenolate mofetil, and steroid. Each patient underwent a complete blood count and biochemical analysis of blood urea nitrogen, creatinine, uric acid, glucose, sodium, potassium, calcium, phosphorus, alanine aminotransferase, aspartate aminotransferase, serum lipid profile including total cholesterol, triglycerides, high-density and lowdensity lipoprotein-cholesterol. C2 levels were measured by an enzyme multi-immune assay technique (EMIT) every 2 months yielding 24 measurements for each patient. The CsA dose was adjusted to target a C2 level of less than 800 g/L.3 All participants were questioned about their cardiovascular disease history and risk factors. In addition, electrocardiography was performed to exclude cardiac disease. There were no smokers and no documented previous cardiovascular events among the study population.
Echocardiography
Statistical Analysis The data were expressed as mean values ⫾ SD. P ⫽ .05 was used to determine statistical significance for all analyses. Patients diTable 1. Demographic, Clinical, and Serum Biochemical Parameters
Age (y) Gender (male/female) Mean time on dialysis before transplantation (months) BMI (kg/m2) Hb (g/dL) Creatinine (mg/dL) Glucose (mg/dL) LDL-C (mg/dL) HDL-C (mg/dL) Triglycerides (mg/dL) Systolic BP (mm Hg) Diastolic BP (mm Hg) ACE inhibitor (%) ARB (%) CCB (%) Beta-blocker (%)
Serum creatinine (mg/dL) Baseline At 3 months At 6 months At 12 months C2 (g/L) Baseline At 3 months At 6 months At 12 months
Group 1 (n ⫽ 40)
Group 2 (n ⫽ 38)
1.29 ⫾ 0.20 1.36 ⫾ 0.19 1.33 ⫾ 0.40 1.31 ⫾ 0.30
1.35 ⫾ 0.11 1.36 ⫾ 0.30 1.40 ⫾ 0.19 1.37 ⫾ 0.20
.56 .99 .27 .44
495 ⫾ 102 392 ⫾ 110 570 ⫾ 91 501 ⫾ 85
707 ⫾ 88 711 ⫾ 100 625 ⫾ 87 825 ⫾ 96
⬍.05 ⬍.05 ⬍.05 ⬍.05
P
C2, cyclosporine concentration monitoring by 2-hour postdosing levels.
Echocardiography was performed using conventional and Doppler echocardiography with TDI (Vingmed, United States). The left ventricular (LV) end-systolic and end-diastolic diameters and the thicknesses of the LV posterior wall and LV septum were measured from the long axis in the parasternal plane according to guidelines of the American Society of Echocardiography.4 On Doppler echocardiography, we studied the transmitral peak early diastolic velocity (E), transmitral peak atrial contraction velocity (A), the proportion of these 2 variables (E/A), the deceleration time of the early diastolic wave (E Dec), and the isovolumic relaxation time (IVRT). Myocardial tissue velocities were measured in early diastole (E=) and with atrial contraction (A=) at the lateral corner of the mitral annulus via TDI. The study protocol was approved by the Ethics Committee; the patients gave written informed consent before enrollment.
Parameter
Table 2. Serum Creatinine and C2 Levels During the Study Period
Group 1 (n ⫽ 40)
Group 2 (n ⫽ 38)
54 ⫾ 10 22/18 47 ⫾ 9
49 ⫾ 9 20/18 50 ⫾ 10
.23 .87 .37
23.4 ⫾ 3.1 12.5 ⫾ 1.4 1.31 ⫾ 0.3 84 ⫾ 9 109 ⫾ 11 48 ⫾ 5 167 ⫾ 21 132 ⫾ 10 77 ⫾ 6 38 14 19 11
22.7 ⫾ 3.4 12.2 ⫾ 1.3 1.37 ⫾ 0.2 79 ⫾ 8 106 ⫾ 14 45 ⫾ 7 159 ⫾ 16 127 ⫾ 11 71 ⫾ 6 34 15 21 9
.46 .92 .44 .57 .76 .64 .55 .72 .28 .50 .78 .35 .63
vided into 2 groups according to the median C2 level were evaluated for differences by chi-square analysis for categoric variables and the independent sample Student t test for continuous variables. All statistical analyses were performed using the SPSS 11.0 for Windows (SPSS Inc, Chicago, Ill, United States).
RESULTS
The patients were divided into 2 groups according to C2 levels less than 500 g/L (group 1, n ⫽ 40) versus greater than 500 g/L (group 2, n ⫽ 38). The demographic parameters, serum creatinine and lipid levels, systolic and diastolic blood pressures, as well as number and type of antihypertensive medications did not differ significantly between the groups (Table 1). In addition, renal function did not significantly correlate with C2 measurements during the follow-up (Table 2). LV ejection fraction was normal in both groups. LV end-diastolic volume, fractional shortening, thicknesses of the posterior wall and the interventricular septum did not differ significantly between the groups (Table 3). On Doppler echocardiography, A velocities were similar
P
BMI, body mass index; Hb, hemoglobin; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; BP, blood pressure; ACE, angiotensin converting enzyme; ARB, angiotensin II receptor antagonist; CCB, calcium channel blocker.
Table 3. Comparison of Conventional, Doppler Echocardiographic, and Tissue Doppler Imaging Findings Between Groups 1 and 2 (Mean Values ⴞ SD) Parameter
Group 1 (n ⫽ 40)
Group 2 (n ⫽ 38)
P
EDD (mm) FS (%) Sthd (mm) EF (%) E (cm/s) A (cm/s) E/A E Dec (ms) IVRT (ms) E=/A=
4.2 ⫾ 0.5 36.59 1.00 ⫾ 0.10 65.30 ⫾ 5.8 56 ⫾ 32 75 ⫾ 29 0.81 ⫾ 0.23 189 ⫾ 52 109 ⫾ 27 0.76 ⫾ 0.25
4.4 ⫾ 0.6 35.78 1.02 ⫾ 0.11 62.92 ⫾ 6.1 92 ⫾ 27 83 ⫾ 31 1.15 ⫾ 0.46 137 ⫾ 59 86 ⫾ 14 1.09 ⫾ 0.32
.87 .62 .55 .77 ⬍.05 .47 ⬍.05 ⬍.05 ⬍.05 ⬍.05
EDD, end-diastolic diameter of left ventricle; FS, fractional shortening; Sthd, interventricular septal thickness diastole; EF, ejection fraction; E, conventional Doppler early diastolic inflow; A, conventional Doppler late atrial inflow; E/A, ratio of early diastolic inflow to late atrial inflow; E Dec, early diastolic deceleration time; IVRT, isovolumic left ventricular relaxation time; E’/A’, ratio of early to late diastolic myocardial tissue velocities.
C2 MONITORING PREDICTS DIASTOLIC DYSFUNCTION
between groups. However, group 1 patients showed significantly greater IVRT (109 ⫾ 27 vs 86 ⫾ 14 ms) and early diastolic deceleration time (189 ⫾ 52 vs 137 ⫾ 59 ms) with lower values of E velocity (56 ⫾ 32 vs 92 ⫾ 27 cm/s) and E/A ratios (0.81 ⫾ 0.23 vs. 1.15 ⫾ 0.46) than group 2 (Table 3). In group 1 versus group 2 TDI studies revealed significantly lower E=/A=: 0.76 ⫾ 0.25 vs. 1.09 ⫾ 0.32 (P ⬍ .05; Table 3). DISCUSSION
The purpose of this study was to evaluate the association of C2 levels with indices of LV function among stable renal transplant recipients. This study demonstrated that a target C2 level correlated with LV diastolic dysfunction despite no cardiac symptoms. C2 levels greater than 500 g/L were significantly associated with LV diastolic dysfunction by Doppler echocardiographic indices. The predictive value of C2 levels for LV diastolic dysfunction may be explained by the hypothesis that patients with higher C2 levels represent overexposure to CsA. The overexposure may contribute to adverse effects in the myocardial fiber network which can be detected by changes in myocardial velocities on Doppler echocardiography with TDI. CsA has revolutionized solid organ transplantation; it remains one of the most important drugs against acute rejection. However, the drug itself has been related to cardiotoxicity in both experimental models and in patients.5– 8 CsA can decrease cytochrome c oxidase expression and increase reactive oxygen species (ROS) production in the myocardium.9 Moreover, CsA can also lead to up-regulation of matrix metalloproteinase-2 (MMP2) and down-regulation of their endogenous inhibitors (TIMP2) as mediated by ROS production.9 The inappropriate activation of MMPs and/or an imbalance between MMP actions and those of their inhibitors due to an ROS increase have all been implicated in cardiac remodeling.10 Experimental data have revealed increased MMP2 activity and myocardial extracellular matrix disorganization with the disappearance of a normal network among the fibers after CsA treatment.5 Furthermore, MMP2 up-regulation with inhibition of endogenous antioxidant systems has been shown in the dysregulation of the myocardial extracellular matrix in various cardiomyopathies.11 Indirect effects of CsA may influence collagen accumulation in the extracellular cardiac matrix in vivo. CsA is known to induce hypertension, and uncontrolled hyperten-
173
sion has been shown to produce disproportionate collagen accumulation and myocardial interstitial fibrosis in experimental animals12 with subsequent development of LV dysfunction and congestive heart failure.13 However, the systolic and diastolic blood pressures as well as the number and type of antihypertensive medications did not differ significantly between the groups. In conclusion, the present study showed an advantage of C2 monitoring among the population treated with a regimen including CsA. This study suggested that a target level of C2 lower than 500 g/L was associated with preserved graft function with a lower prevalance of diastolic dysfunction among stable renal transplant recipients at 12 or more months. Further clinical and pathological studies are needed to confirm these findings. REFERENCES 1. Pescovitz MD, Barbeito R, Simulect US01 Study Group: Two-hour post-dose cyclosporine level is a better predictor than trough level of acute rejection of renal allografts. Clin Transpl 16:378, 2002 2. Levy G, Thervet E, Lake J, et al: Patient management by Neoral C2 monitoring: an international consensus. Transplantation 73:S12, 2002 3. Keown PA: New concepts in cyclosporine monitoring. Curr Opin Nephrol Hypertens 11:619, 2002 4. Sahn DJ, De Maria A, Kisslo J, et al: Recommendations regarding quantitation in M-mode echocardiographic measurements. Circulation 58:1072, 1978 5. Bianchi R, Rodella L, Rezzani R: Cyclosporine A upregulates expression of matrix matalloproteinase 2 and vascular endothelial growth factor in rat heart. Int Immunopharmacol 3:427, 2003 6. Rezzani R, Rodella L, Dessy C, et al: Changes in Hsp90 expression determine the effects of cyclosporine A on the NO pathway in rat myocardium. FEBS Lett 552:125, 2003 7. Laczkovics A, Havel M, Teufelsbauer H, et al: Cyclosporin-A induced heart failure after orthotopic heart transplantation. J Thorac Cardiovasc Surg 35:83, 1987 8. Siostrzonek P, Teufelsbauer H, Kreiner G, et al: Relief of diastolic cardiac dysfunction after cyclosporine withdrawal in a cardiac transplant recipient. Eur Heart J 14:859, 1993 9. Rezzani R, Giugno L, Buffoli B, et al: The protective effect of caffeic acid phenethyl ester against cyclosporine A-induced cardiotoxicity in rats. Toxicology 212:155, 2005 10. Spinale FG: Matrix metalloproteinases: regulation and dysregulation in the failing heart. Circ Res 90:520, 2002 11. Siwik DA, Pagano PJ, Colucci WS: Oxidative stress regulates collagen synthesis and matrix metalloproteinase activity in cardiac fibroblasts. Am J Physiol Cell Physiol 280:C35, 2001 12. Weber KT: Cardiac interstitium in health and disease: the fibrillar collagen network. J Am Coll Cardiol 13:1637, 1989 13. Capasso JM, Palackal T, Olivetti G, et al: Left ventricular failure induced by long-term hypertension in rats. Circ Res 66: 1400, 1990