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Preservation in microvascular endothelial function despite epicardial endothelial dysfunction in cardiac transplant recipients
The Journal of Heart and Lung Transplantation Volume 22, Number 1S less than 4 AR episodes (95.8). These preliminary results confirm the feasibility of assessing specific indirect allo-reactivity in heart transplanted pts by means of a PB sample and may suggest a possible role of allospecific IL10 producing cells in the regulation of graft acceptance. 281 BRAIN NATRIURETIC PEPTIDE PREDICTS REJECTION IN HEART TRANSPLANT RECIPIENTS INDEPENDENT OF PULMONARY CAPILLARY WEDGE PRESSURE A.H. Wu, K.D. Aaronson, D.B. Dyke, T.M. Koelling, Department of Internal Medicine, University of Michigan, Ann Arbor, MI Background: Serum brain natriuretic peptide (BNP) has been reported to be elevated in heart transplant recipients (HTR) with rejection. Whether elevations of BNP with rejection are due to concurrent elevation of pulmonary capillary wedge pressure (PCW) is not known. Methods: We analyzed serial BNP measurements in 40 HTR occurring beyond 60 days after transplantation, obtained during endomyocardial biopsy procedures performed as standard HTR care. To eliminate potential confounding from prior rejection episodes, we included only observations in which the previous biopsy grade was 0 or 1A (N ⫽ 206 observations). Normally distributed variables are expressed as mean ⫾ SD. Otherwise, variables are expressed as median (IQR). Non-parametric Kendall’s tau correlation coefficients were calculated between BNP level and biopsy grade (severity of grade 0 ⬍ 1A ⬍ 2 ⬍ 1B ⬍ 3A ⬍ vascular rejection) and hemodynamically significant rejection (HSR, biopsy grade ⱖ 2 and PCW ⬎ 20 mmHg). Multivariable logistic regression was performed to test the relationship between BNP and HSR while controlling for PCW. Results: The mean systolic blood pressure was 134 ⫾ 19 mm Hg, PCW 13 (11, 17) mm Hg, and cardiac index 2.8 ⫾ 0.7 L/min/m2. Median BNP was 154 (87, 284) pg/ml . BNP for grade 0 biopsies (N ⫽ 59) was 128 (70, 210) pg/ml; for grade 1A (N ⫽ 24) was 151 (99, 260) pg/ml; for grade 2 (N ⫽ 33) was 172 (85, 285) pg/ml; for grade 1B (N ⫽ 1) was 377 pg/ml; for grade 3A (N ⫽ 8) was 213 (109, 398) pg/ml; and for vascular rejection (N ⫽ 4) was 1020 (763,1300) pg/ml (ANOVA p ⫽ 0.001). BNP correlated significantly with both biopsy grade (R ⫽ 0.192, p ⫽ 0.005), HSR (R ⫽ 0.301, p ⬍ 0.001) and with PCW (R ⫽ 0.290, p ⬍ 0.001). After controlling for PCW, BNP was found to maintain a significant correlation with HSR (Beta 0.0046 ⫾ 0.0023, p ⫽ 0.03) Conclusion: BNP levels are elevated with increasing biopsy grade in HTR and these changes are independent of PCW. The use of BNP measurement at the time of endocardial biopsy may enhance the diagnosis of HSR. 282 CARDIAC ANGIOTENSIN II RECEPTORS PREDICT ALLOGRAFT VASCULOPATHY IN HEART TRANSPLANT RECIPIENTS M. Yousufuddin, R.C. Starling, E.M. Tuzcu, S. Haji, N.B. Ratliff, D.J. Cooke, A. Abdo, P.M. McCarthy, J.B. Young, M.H. Yamani, Kaufman Center for Heart Failure, Cleveland Clinic Foundation, Cleveland, OH Agiotensin II (Ang II) receptors type 1 (AT1R) and type 2 (AT2R) may be important determinants of accelerated cardiac allograft vasculopathy (CAV). Methods: We assessed mRNA expressions of AT1R and AT2R in endomyocaridal biopsies (EMBS) (quantitative RT-PCR by TaqMan system) and CAV as change in maximal intimal thickness (CMIT) and change in plaque volume (CPV) at worst sites at 1-yr after transplant (Tx) using IVUS in 41-recipients all were on immunosuppressives and
Abstracts
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25 were on ACE inhibitors (ACEI). Significant vasculopathy was defined as CMIT of ⬎0.3 mm at 1-yr. Results: overall mean average biopsy score (ABS) 1.28⫾0.52, baseline intimal thickness (BIT) 0.28⫾0.24 mm, CMIT 0.46⫾0.35, CPV 4.8⫾2.6 mm3, AT1R mRNA expression (relative to calibrator) 2.5⫾2.4 folds, AT2R 0.69⫾0.74. AT1R correlated with AT2R (r ⫽ 0.57, P ⫽ 0.0003) but neither with ABS. AT1R and AT2R, but not ABS were predictors of CMIT (AT1R: r ⫽ 0.64, R 2 0.41, P ⬍ 0.0001; AT2R: r ⫽ 0.63, R 2 0.40, P ⬍ 0.0001) and CPV (AT1R: r ⫽ 0.42,R 2 0.18, P ⫽ 0.006; AT2R: r ⫽ 0.40,R 2 0.16, P ⫽ 0.01) independent of age and ACEI status. 20patients had vasculopathy and 21did not with no differences in age, ACEI status, ABS and BIT. Patients with significant vasculopathy had a higher AT1R expression than those with no vasculopathy (3.3⫾2.8 vs 1.8⫾1.7 folds, P ⫽ 0.05). Conclusions: Cardiac Ang II receptors expressions predict indices of CAV supporting potentially important role of these receptors in disease progression.
283 PRESERVATION IN MICROVASCULAR ENDOTHELIAL FUNCTION DESPITE EPICARDIAL ENDOTHELIAL DYSFUNCTION IN CARDIAC TRANSPLANT RECIPIENTS S.S. Kushwaha, S. Higano, P. Chareonthaitawee, A. Lerman, Cardiovascular Diseases, Mayo Clinic, Rochester, MN Cardiac transplantation results in endothelial dysfunction of the large epicardial coronary arteries and this may predict the development of cardiac allograft vasculopathy (CAV). However, the relationship between epicardial endothelial function and microvascular endothelial function has not been clearly defined. In 10 cardiac transplant recipient with no evidence of CAV (2 -7 years post transplant), we undertook studies of coronary endothelial function using graded acetylcholine infusions at doses of 10-6, 10-5, and 10-4M, with measurements of myocardial blood flow velocity using an intracoronary Doppler wire. At the maximal dose of acetylcholine, all patients had evidence of epicardial endothelial dysfunction as evidenced by a vasoconstrictor or lack of response to the maximal dose of acetylcholine (10-4M). The mean vasoconstrictor response was -13.52 ⫾15.3 % (mean⫾SD) (range 0 to -38.1 %). By contrast, measurement of blood flow velocity, in response to acetylcholine infusion, showed an increase in blood flow in the majority of patients (7 of 10 patients) in whom there was an increase in blood flow of 119.4⫾75.1 % (range 44.0 to 227.8 %). In three patients there was a decrease in blood flow of -29.7⫾18.8 %. Coronary flow reserve (CFR) using intracoronary adenosine infusion demonstrated preservation of CFR in all patients with a mean value of 3.47⫾0.93. Measurement of myocardial blood flow and flow reserve using positron emission tomography in the same cohort of patients confirmed preservation of flow reserve in all regions of the myocardium yielding a mean value of 2.72⫾0.66. In conclusion, cardiac transplant recipients demonstrate epicardial endothelial dysfunction but microvascular endothelial function appears to be preserved in most patients. These findings suggest that epicardial
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The Journal of Heart and Lung Transplantation January 2003
CAV may precede the development of microvascular blood flow abnormalities in cardiac transplant recipients. 284 WHICH HEART TRANSPLANT RECIPIENTS ARE LIKELY TO SURVIVE MORE THAN 10 YEARS? J. Segovia, L. Alonso-Pulpo ´n, P. Ortiz, R. Peraira, E. Castedo, R. Burgos, A. Can ˜as, J. Jime´nez-Mazuecos, L. Silva, J. Ugarte, Cardiac Transplant Unit, Hospital Puerta de Hierro, Madrid, Spain Approximately half the heart transplant (HT) recipients are alive ten years after the operation. It would be of great help if we could know the variables that could predict such favourable outcome, in order to optimize the allocation of the limited number of donor hearts. For this purpose, we compared more than 115 variables of 2 cohorts of patients transplanted before 1992: Group A (n ⫽ 95) included patients who survived more than 10 years after HT, and group B (n ⫽ 73) included recipients who died between 6 months and 10 years of follow-up. Table 1 includes the variables that showed significant differences between groups in the univariate comparison. A multivariate logistic regression analysis was performed in order to identify independent predictors of long survival after HT. Results are shown in table 2. Conclusions: A combination of both recipient, donor and procedural variables influence long-term outcome after HT. Ideal candidates with a high probability of long survival after HT are young (less than 55 years old) recipients suffering from dilated cardiomyopathy who undergo HT on an elective basis, with a donor who is less than 40 years old and an ischemic time below 4 hours. Recipient’s age (years) Dilated Cardiomyopathy before HT Ischemic Cardiopathy before HT Emergency HT Donor’s age (years) Ischemic time ⬎ 240 min Odds Ratio Dilated Cardiomyopathy Donor age ⬎ 40 Ischemic time ⬎ 240 min
0.3 11.7 2.7
Group A
Group B
p
41 ⫾ 14 52% 29% 11% 23 ⫾ 7 36%
48 ⫾ 13 30% 41% 22% 26 ⫾ 11 64%
⬍0.001 0.03 0.02 0.03 0.02 0.02
Confidence interval 95% 0.18–0.73 2.4–57.6 11–6.8
p value

Standard error
0.005 0.002 0.023
⫺0.99 2.4 1.03
0.35 0.81 0.45
285 COMPARISON OF SURVIVAL BY ALLOCATION TO MEDICAL THERAPY, SURGERY OR HEART TRANSPLANTATION FOR ISCHAEMIC ADVANCED HEART FAILURE E. Lim,1 Z. Ali,1 A. Ali,1 R. Motalleb-Zadeh,1 C. Jackson,2 S.L. Ong,1 J. Halstead,1 L. Sharples,2 J. Parameshwar,1 J. Wallwork,1 S.R. Large,1 1 Transplant Unit, Papworth Hospital, Cambridge, United Kingdom; 2 Biostatistics Unit, Medical Research Council, Cambridge, United Kingdom Advances in medical and surgical therapy have improved the poor prognosis of heart failure. To ascertain survival by treatment allocation, we examined the outcome of patients who received medical therapy, high risk conventional surgery or transplantation after transplant assessment. Methods: Patients were excluded if primary aetiology was not ischaemic, and grouped according to treatment allocation at initial assessment. Analysis was performed by intention to treat, and actuarial survival calculated from the time of assessment using Kaplan Meier and
Cox Regression, with patients stratified using the Heart Failure Survival Score (HFSS). Results: From 1993 till 2001, 755 underwent transplant assessment with 348 (46.1%) identified with ischaemic origin. Variables required for calculation of the HFSS were available in 273 (78.4%), and 20 patients (7.3%) were lost to follow up. Of the remaining 253 patients, 89 (35.2%) were allocated to medical therapy, 32 (12.6%) to surgery and 132 (52.2%) to transplantation. The median follow up was 2.4 years (IQR 1.0 to 4.5). Actuarial survival was 74.1% for medicine, 94.5% for surgery and 82.9% for transplant (p ⫽ 0.09). Risk adjusted survival on HFSS categories revealed the relative risk (95% CL) of death compared to medical therapy was 0.86 (0.46 to 1.61) for surgery and 0.52 (0.34 to 0.81) for transplantation. In the low risk category, relative risks for death were 1.87 (0.63 to 5.60) for surgery and 1.97 (0.79 to 4.96) for transplant. Conclusions: Despite survival bias against transplantation with intention to treat, coronary surgery and transplantation improved prognosis of medium and high risk patients. In the low risk group, mortality was higher, but it did not reach statistical significance. Improvement in quality of life is an important measure not reflected by allocation on HFSS risk alone.
286 THERAPY OF ERECTILE DYSFUNCTION BY SILDENAFIL (VIAGRA) IN PATIENTS AFTER ORTHOTOPIC HEART TRANSPLANTATION K.W. Deyerling, G. Tenderich, U. Schulz, K. Minami, R. Koerfer, Department of Thoracic and Cardiovascular Surgery, Heart Center North Rhine-Westphalia, Bad Oeynhausen, NRW, Germany Objective: Quality of life after heart transplantation (HTX) is rapidly increasing after a short period of recovery. This is often accompanied by the wish of resumption of sexual activities. From October 1989 to May 2002 we detected 55 out of 1011 male HTX-pts. signalizing erection problems. A high estimated number of unreported cases has to be taken into account. Results: For 2 consecutive years we prospectively observed 27 pts. (39-71 y.; mean 59.8 y.) who underwent regular therapy with Sildenafil. 14 pts. (51.9%) suffered from dilative cardiomyopathy as HTX-diagnosis, 12 pts. (44.4%) from CAD and 3 pts (11.1%) from valvular heart disease. Risk factors or concomittant diseases were chronic renal insufficiency in 15 pts (55.6%), hyperlipidemia in 9 pts (33.3%), vascular occlusive disease in 8 pts (29.6%), hypertension in 8 pts. (29.6%) and diabetes in 7 pts. (25.9%). 9 pts (33.3%) had a history of smoking before HTX but stopped smoking afterwards. Therapy was started with single doses of 25 mg and increased up to 100 mg where necessary. Effect was detected after 20-60 minutes after taking. 5 pts. (18.5%) could not achieve any effect and terminated therapy. In 4 pts. (14.8%) a medication was no longer necessary after 2-5 months of therapy. 18 pts. (66.7%) continued therapy up to 2 years. Detected side effects were problems of colour detection and dysopsia in 10 pts. (37%), swelling of nasal mucosa (4 pts./14.8%), indisposition (4 pts./14.8%). 3 pts. (11.1%) suffered from gastrointestinal complaints, in 4 cases (14.8%) an initial flush-syndrome was observed. 6 pts. (22.2%) had no side effects. No severe cardiovascular events occurred, but 5 pts. (18.5%) had a complaint of slight and reversible dizzyness. Conclusion: The use of Sildenafil (Viagra) in cases of erectile dysfunction is effective and save even in patients after heart transplantation with a satisfying dose-dependent efficacy. The observed side effects are tolerated well without severe and irreversible effects.
Abstracts
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25 were on ACE inhibitors (ACEI). Significant vasculopathy was defined as CMIT of ⬎0.3 mm at 1-yr. Results: overall mean average biopsy score (ABS) 1.28⫾0.52, baseline intimal thickness (BIT) 0.28⫾0.24 mm, CMIT 0.46⫾0.35, CPV 4.8⫾2.6 mm3, AT1R mRNA expression (relative to calibrator) 2.5⫾2.4 folds, AT2R 0.69⫾0.74. AT1R correlated with AT2R (r ⫽ 0.57, P ⫽ 0.0003) but neither with ABS. AT1R and AT2R, but not ABS were predictors of CMIT (AT1R: r ⫽ 0.64, R 2 0.41, P ⬍ 0.0001; AT2R: r ⫽ 0.63, R 2 0.40, P ⬍ 0.0001) and CPV (AT1R: r ⫽ 0.42,R 2 0.18, P ⫽ 0.006; AT2R: r ⫽ 0.40,R 2 0.16, P ⫽ 0.01) independent of age and ACEI status. 20patients had vasculopathy and 21did not with no differences in age, ACEI status, ABS and BIT. Patients with significant vasculopathy had a higher AT1R expression than those with no vasculopathy (3.3⫾2.8 vs 1.8⫾1.7 folds, P ⫽ 0.05). Conclusions: Cardiac Ang II receptors expressions predict indices of CAV supporting potentially important role of these receptors in disease progression.
283 PRESERVATION IN MICROVASCULAR ENDOTHELIAL FUNCTION DESPITE EPICARDIAL ENDOTHELIAL DYSFUNCTION IN CARDIAC TRANSPLANT RECIPIENTS S.S. Kushwaha, S. Higano, P. Chareonthaitawee, A. Lerman, Cardiovascular Diseases, Mayo Clinic, Rochester, MN Cardiac transplantation results in endothelial dysfunction of the large epicardial coronary arteries and this may predict the development of cardiac allograft vasculopathy (CAV). However, the relationship between epicardial endothelial function and microvascular endothelial function has not been clearly defined. In 10 cardiac transplant recipient with no evidence of CAV (2 -7 years post transplant), we undertook studies of coronary endothelial function using graded acetylcholine infusions at doses of 10-6, 10-5, and 10-4M, with measurements of myocardial blood flow velocity using an intracoronary Doppler wire. At the maximal dose of acetylcholine, all patients had evidence of epicardial endothelial dysfunction as evidenced by a vasoconstrictor or lack of response to the maximal dose of acetylcholine (10-4M). The mean vasoconstrictor response was -13.52 ⫾15.3 % (mean⫾SD) (range 0 to -38.1 %). By contrast, measurement of blood flow velocity, in response to acetylcholine infusion, showed an increase in blood flow in the majority of patients (7 of 10 patients) in whom there was an increase in blood flow of 119.4⫾75.1 % (range 44.0 to 227.8 %). In three patients there was a decrease in blood flow of -29.7⫾18.8 %. Coronary flow reserve (CFR) using intracoronary adenosine infusion demonstrated preservation of CFR in all patients with a mean value of 3.47⫾0.93. Measurement of myocardial blood flow and flow reserve using positron emission tomography in the same cohort of patients confirmed preservation of flow reserve in all regions of the myocardium yielding a mean value of 2.72⫾0.66. In conclusion, cardiac transplant recipients demonstrate epicardial endothelial dysfunction but microvascular endothelial function appears to be preserved in most patients. These findings suggest that epicardial
S166
Abstracts
The Journal of Heart and Lung Transplantation January 2003
CAV may precede the development of microvascular blood flow abnormalities in cardiac transplant recipients. 284 WHICH HEART TRANSPLANT RECIPIENTS ARE LIKELY TO SURVIVE MORE THAN 10 YEARS? J. Segovia, L. Alonso-Pulpo ´n, P. Ortiz, R. Peraira, E. Castedo, R. Burgos, A. Can ˜as, J. Jime´nez-Mazuecos, L. Silva, J. Ugarte, Cardiac Transplant Unit, Hospital Puerta de Hierro, Madrid, Spain Approximately half the heart transplant (HT) recipients are alive ten years after the operation. It would be of great help if we could know the variables that could predict such favourable outcome, in order to optimize the allocation of the limited number of donor hearts. For this purpose, we compared more than 115 variables of 2 cohorts of patients transplanted before 1992: Group A (n ⫽ 95) included patients who survived more than 10 years after HT, and group B (n ⫽ 73) included recipients who died between 6 months and 10 years of follow-up. Table 1 includes the variables that showed significant differences between groups in the univariate comparison. A multivariate logistic regression analysis was performed in order to identify independent predictors of long survival after HT. Results are shown in table 2. Conclusions: A combination of both recipient, donor and procedural variables influence long-term outcome after HT. Ideal candidates with a high probability of long survival after HT are young (less than 55 years old) recipients suffering from dilated cardiomyopathy who undergo HT on an elective basis, with a donor who is less than 40 years old and an ischemic time below 4 hours. Recipient’s age (years) Dilated Cardiomyopathy before HT Ischemic Cardiopathy before HT Emergency HT Donor’s age (years) Ischemic time ⬎ 240 min Odds Ratio Dilated Cardiomyopathy Donor age ⬎ 40 Ischemic time ⬎ 240 min
0.3 11.7 2.7
Group A
Group B
p
41 ⫾ 14 52% 29% 11% 23 ⫾ 7 36%
48 ⫾ 13 30% 41% 22% 26 ⫾ 11 64%
⬍0.001 0.03 0.02 0.03 0.02 0.02
Confidence interval 95% 0.18–0.73 2.4–57.6 11–6.8
p value

Standard error
0.005 0.002 0.023
⫺0.99 2.4 1.03
0.35 0.81 0.45
285 COMPARISON OF SURVIVAL BY ALLOCATION TO MEDICAL THERAPY, SURGERY OR HEART TRANSPLANTATION FOR ISCHAEMIC ADVANCED HEART FAILURE E. Lim,1 Z. Ali,1 A. Ali,1 R. Motalleb-Zadeh,1 C. Jackson,2 S.L. Ong,1 J. Halstead,1 L. Sharples,2 J. Parameshwar,1 J. Wallwork,1 S.R. Large,1 1 Transplant Unit, Papworth Hospital, Cambridge, United Kingdom; 2 Biostatistics Unit, Medical Research Council, Cambridge, United Kingdom Advances in medical and surgical therapy have improved the poor prognosis of heart failure. To ascertain survival by treatment allocation, we examined the outcome of patients who received medical therapy, high risk conventional surgery or transplantation after transplant assessment. Methods: Patients were excluded if primary aetiology was not ischaemic, and grouped according to treatment allocation at initial assessment. Analysis was performed by intention to treat, and actuarial survival calculated from the time of assessment using Kaplan Meier and
Cox Regression, with patients stratified using the Heart Failure Survival Score (HFSS). Results: From 1993 till 2001, 755 underwent transplant assessment with 348 (46.1%) identified with ischaemic origin. Variables required for calculation of the HFSS were available in 273 (78.4%), and 20 patients (7.3%) were lost to follow up. Of the remaining 253 patients, 89 (35.2%) were allocated to medical therapy, 32 (12.6%) to surgery and 132 (52.2%) to transplantation. The median follow up was 2.4 years (IQR 1.0 to 4.5). Actuarial survival was 74.1% for medicine, 94.5% for surgery and 82.9% for transplant (p ⫽ 0.09). Risk adjusted survival on HFSS categories revealed the relative risk (95% CL) of death compared to medical therapy was 0.86 (0.46 to 1.61) for surgery and 0.52 (0.34 to 0.81) for transplantation. In the low risk category, relative risks for death were 1.87 (0.63 to 5.60) for surgery and 1.97 (0.79 to 4.96) for transplant. Conclusions: Despite survival bias against transplantation with intention to treat, coronary surgery and transplantation improved prognosis of medium and high risk patients. In the low risk group, mortality was higher, but it did not reach statistical significance. Improvement in quality of life is an important measure not reflected by allocation on HFSS risk alone.
286 THERAPY OF ERECTILE DYSFUNCTION BY SILDENAFIL (VIAGRA) IN PATIENTS AFTER ORTHOTOPIC HEART TRANSPLANTATION K.W. Deyerling, G. Tenderich, U. Schulz, K. Minami, R. Koerfer, Department of Thoracic and Cardiovascular Surgery, Heart Center North Rhine-Westphalia, Bad Oeynhausen, NRW, Germany Objective: Quality of life after heart transplantation (HTX) is rapidly increasing after a short period of recovery. This is often accompanied by the wish of resumption of sexual activities. From October 1989 to May 2002 we detected 55 out of 1011 male HTX-pts. signalizing erection problems. A high estimated number of unreported cases has to be taken into account. Results: For 2 consecutive years we prospectively observed 27 pts. (39-71 y.; mean 59.8 y.) who underwent regular therapy with Sildenafil. 14 pts. (51.9%) suffered from dilative cardiomyopathy as HTX-diagnosis, 12 pts. (44.4%) from CAD and 3 pts (11.1%) from valvular heart disease. Risk factors or concomittant diseases were chronic renal insufficiency in 15 pts (55.6%), hyperlipidemia in 9 pts (33.3%), vascular occlusive disease in 8 pts (29.6%), hypertension in 8 pts. (29.6%) and diabetes in 7 pts. (25.9%). 9 pts (33.3%) had a history of smoking before HTX but stopped smoking afterwards. Therapy was started with single doses of 25 mg and increased up to 100 mg where necessary. Effect was detected after 20-60 minutes after taking. 5 pts. (18.5%) could not achieve any effect and terminated therapy. In 4 pts. (14.8%) a medication was no longer necessary after 2-5 months of therapy. 18 pts. (66.7%) continued therapy up to 2 years. Detected side effects were problems of colour detection and dysopsia in 10 pts. (37%), swelling of nasal mucosa (4 pts./14.8%), indisposition (4 pts./14.8%). 3 pts. (11.1%) suffered from gastrointestinal complaints, in 4 cases (14.8%) an initial flush-syndrome was observed. 6 pts. (22.2%) had no side effects. No severe cardiovascular events occurred, but 5 pts. (18.5%) had a complaint of slight and reversible dizzyness. Conclusion: The use of Sildenafil (Viagra) in cases of erectile dysfunction is effective and save even in patients after heart transplantation with a satisfying dose-dependent efficacy. The observed side effects are tolerated well without severe and irreversible effects.