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371: First-Year Statin Resistant Hypercholesterolemia: A Cause for Concern in the Development of Cardiac Allograft Vasculopathy
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Abstracts
Methods and Materials: Routine echocardiographic studies, performed at 1 week, 1 and 5 years after HTx were analyzed in 104 heart recipients. The mean age of the cohort was 47⫾16 years and the period of follow up was 4.96 ⫾ 2.45 years. The total cohort was divided into three sub-groups based on determination of LV geometry at 1-week after transplantation: (1) NG - normal left ventricle geometry (relative wall thickness (RWT) ⬍0.42 and LVM ⬍ 225 for males and ⬍ 163 for females); (2) CR - concentric remodeling (RWT ⱖ0.42, LVM⬍ 225 for males and 163 for females); and (3) CH - concentric hypertrophy (RWT ⱖ0.42, LVM ⱖ225 for males and 163 for females). Results: Abnormal LV geometry was found as early as 1 week after HTx in 85% of patients (59% CR, 26% CH) with explosive mode of donor brain death being the most significant determinant for CH (OR - 2.9, CI - 0.4-3.18, p⫽0.01) by multivariable logistic regression. There was no significant difference in blood pressure control or cellular rejection score between the 3 groups. Patients with abnormal LV geometry at 1 week had significantly higher prevalence of graft vasculopathy by angiography at 5 years (0% in NG, 9% in CR and 30% in CH, p⫽0.0015). The prevalence of CH continued to increase to 30% at 1 year and 41% at 5 years after HTx primarily due to a progressive increase in RWT and LV mass in the NG group and increase in LV mass in the CR group. Patients with CH at 1 year had significantly higher mortality as compared to patients with normal LV geometry (RR-1.87, p ⫽0.03). Conclusions: Cardiac allograft remodeling occurs early and frequently after HTX, with explosive mode of donor brain death a significant factor. Subsequently, the presence of CH is associated with increased graft arteriosclerosis and mortality. 369 Prophylaxis vs. Pre-Emptive Strategies in Preventing Cytomegalovirus-Dependent Cardiac Allograft Vasculopathy L. Potena,1 A.C. Musuraca,1 F. Grigioni,1 P. Ortolani,1 G. Pastorelli,1 F. Angeli,1 M.G. Vetrugno,1 G. Magnani,1 F. Fallani,1 F. Coccolo,1 A. Russo,1 A. Branzi,1 1Institute of Cardiology, University of Bologna, Bologna, Italy Purpose: Although cytomegalovirus (CMV) infection is a recognized risk factor for cardiac allograft vasculopathy (CAV), it is still unknown which CMV-prevention strategy is more effective in delaying CAV development. Thus, we designed this observational study to compare the effect of pre-emptive vs. prophylaxis approach on intravascular ultrasound (IVUS)-detected CAV. Methods and Materials: Thirty-six consecutive patients receiving heart transplant (HT) between January 2004 and June 2006, induction with thymoglobuline and maintenance therapy with cyclosporine, mycophenolate mofetil and prednisone, underwent IVUS of the proximal 30 mm of left anterior descending artery at month 1 and month 12 after HT. Recipients transplanted before October 2005 were treated pre-emptively with intravenous ganciclovir only when pp65 antigenemia raised over 25-30 cells/105 neutrophils. Subsequently all recipients received prophylaxis with valganciclovir 450mg b.i.d. for 40 days (90 days if donor/recipient serological mismatch), starting within day 10 after HT. Major study outcome measures were changes in intimal volume and in maximal intimal thickness. Results: Twenty-one patients received pre-emptive and 15 prophylaxis approach. Baseline characteristics were similar between the two groups and no difference in lipid panel was noted during the follow-up. Median peak pp65 positive cells were higher in the pre-emptive than in the prophylaxis group(31 [5to54] vs. 9 [2to26] cells/105 neutrophyls; P⫽0.04). Intimal volume increased significantly by 21% (P⫽0.04) in the pre-emptive group but not in the prophylaxis group (⫹10% P⫽NS). Increase in maximal intimal thickness was significantly greater in the pre-emptive than in the prophylaxis group (0.30⫾0.22 vs. 0.15⫾0.16 mm, respectively, P⫽0.01).
The Journal of Heart and Lung Transplantation February 2008
Conclusions: As compared with patients treated with pre-emptive approach, those receiving anti-CMV prophylaxis with valganciclovir showed a significant reduction of CMV infection burden and of IVUS-detected CAV 1 year after HT. Randomized studies are needed to confirm these observations. 370 Kidney Transplantation in UK Cardiothoracic Transplant Recipients H.L. Thomas,1 D. Collett,1 N.R. Banner,2 1UK Transplant, Bristol, United Kingdom; 2Harefield Hospital, Harefield, United Kingdom; 3 On Behalf of the UK Transplant Cardiothoracic Advisory Group, Bristol, United Kingdom Purpose: Renal disease is a late complication of cardiothoracic transplantation. We investigated kidney transplantation after cardiothoracic transplantation in the UK. Methods and Materials: Data on 6,682 first adult cardiothoracic transplants in the UK, 1985 to 2006, were obtained from the National Transplant Database. Multi-organ, heterotopic, non-heartbeating and living donor transplants were excluded. Time to listing for kidney transplantation was estimated using the Kaplan-Meier method and compared for recipients of heart(H), lung(L) and heart/lung(HL) transplant (N⫽4295, 1640 and 747 respectively). For patients listed, waiting time to kidney transplant was compared with 4,730 renal patients listed for their second kidney transplant. Post-transplant patient and graft survival were also compared. Results: HL recipients were significantly younger than H or L recipients (median age 33, 50 and 50). Donor age, donor sex and recipient sex were also significantly different between the groups. Time to listing for kidney transplantation varied significantly by transplant type (log-rank test, p⬍0.0001). Ten years after cardiothoracic transplant, the estimated proportion of patients listed for kidney transplant was 3.6% H, 5.7% L and 12.7% HL. Waiting time to deceased donor kidney transplant was similar across cardiothoracic transplant types, and did not differ from the waiting time of patients awaiting second renal transplant (median waiting time 2.4y vs 3.3y, p⫽0.17). Kidney graft survival (death with functioning graft censored) was comparable regardless of the previous type of transplant (p⫽0.27), but patient survival was inferior for cardiothoracic transplant recipients (5y mortality 30% vs 16%, p⫽0.011). Conclusions: Within 10 years of cardiothoracic transplant, the estimated proportion of recipients listed for kidney transplant was 4.7%. Waiting time to kidney transplant was comparable to those awaiting a second renal transplant. Patient survival following kidney transplant was inferior, but kidney graft survival was similar. 371 First-Year Statin Resistant Hypercholesterolemia: A Cause for Concern in the Development of Cardiac Allograft Vasculopathy J.K. Patel,1 J.C. Kawano,1 M.M. Kittleson,1 U. Duong,1 M.A. Kawano,1 A. Ardehali,2 J.A. Kobashigawa,1 1Cardiology, David Geffen School of Medicine at UCLA, Los Angeles, CA; 2 Cardiothoracic Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA Purpose: Hypercholesterolemia is common after heart transplant. The use of statins to lower cholesterol levels has been suggested to have an immunomodulatory effect. In non-transplant patients, it has been demonstrated that the lower the total cholesterol (TC) level, the
The Journal of Heart and Lung Transplantation Volume 27, Number 2S
better the outcome. It has not been shown whether lower TC levels result in better outcome after heart transplant. Methods and Materials: Between 1994 and 2000 we reviewed 301 patients who survived ⬎1 year after heart transplant. TC levels were averaged in the first year (at 3, 6, 9, 12 months). The mean first year lipid level was correlated to 5 year outcome of survival, non-fatal major adverse cardiac events (nf-MACE), and the development of cardiac allograft vasculopathy (CAV), diagnosed by any stenosis ⱖ 30% on angiography. Mean first year TC levels were divided into four groups: group 1⫽TC ⱕ150 mg/dl, group 2⫽TC 151-200, group 3⫽TC 201-250, group 4⫽TC ⬎250. All patients were maintained on statin therapy and/or ezetimibe. Results: Patients in group 4 (highest TC level) had signficantly lower freedom from CAV compared to groups 1-3 (see figure, p⫽0.008). Group 1 (lowest TC level) did not appear to have greater freedom from CAV compared to groups 2 and 3 (see figure). Among all groups, there was comparable 5 year survival and nf-MACE. Multivariate analysis of risk factors showed TC ⬎250 to be an independent variable for poor outcome. Conclusions: Despite statin therapy, elevated mean first year total cholesterol level (⬎250 mg/dl) is associated with increased incidence of CAV. Further modalities to lower this statin resistant hypercholesterolemia may be needed. However, achieving lowest cholesterol levels may not provide added benefit.
Abstracts
S195
Methods and Materials: This abstracted work focuses on the analysis of gene expression data to initially identify biomarkers of chronic heart rejection. BiT’s chronic rejection cohort of heart transplants consists of 18 patients (26 to 70 years old; 2/3 being male; time post-transplant, range 1 to 13 years). Nine patients were diagnosed with chronic rejection based on quantitative analysis of angiograms and/or intravascular ultrasound and chart review. PAXgene whole blood RNA was extracted and processed using Affymetrix GeneChip U133 Plus 2.0 microarrays. The microarray data was normalized using the Robust Multichip Average (RMA) algorithm and pre-filtered to remove probesets with similar expression across all samples. After pre-filtering, 24,951 probesets were analyzed using the Local Pooled Error (LPE) statistical method to identify differentially expressed genes between stable and chronic rejection patients. LPE is a robust analysis method that removes the issue of outlying observations within each group of patients and addresses the problem of having small sample sizes. Results: Nine probesets were identified as differentially expressed (p-value⬍10-5, adjusted p-value⬍0.1). Four probesets were up-regulated in the chronic rejection patients and five were down-regulated. These probesets correspond to 8 genes; three are associated with immune response and antigen processing/presentation, and two are potentially implicated in tissue injury and remodeling. Conclusions: BiT identified potential biomarkers of chronic heart rejection which will be validated in an independent cohort of patients. Future work will combine gene expression data with clinical and proteomics data to enhance our ability to clearly discriminate between both patient groups. Acknowledgements: Genome Canada, Novartis, IBM, Genome British Columbia. 373 Potential Role of Circulating Progenitor Cells in Coronary Microvascular Dysfunction of Heart Transplant Patients with Normal Coronary Angiograms E. Osto,1 F. Tona,1 G. Fadini,2 I. Baesso,3 A.L.P. Caforio,1 C. Agostini,3 G. Tarantini,1 A. Avogaro,2 A. Angelini,4 G. Gerosa,5 S. Iliceto,1 1Cardiology, University of Padova, Padova, Italy; 2 Division of Metabolic Disease, University of Padova, Padova, Italy; 3Clinical Immunology, University of Padova, Padova, Italy; 4 Cardiovascular Pathology, University of Padova, Padova, Italy; 5 Cardiovascular Surgery, University of Padova, Padova, Italy
372 Genomic Biomarkers of Chronic Heart Allograft Rejection G. Cohen Freue,1 C. Imai,2 A. Ignaszewski,2 G.B.J. Mancini,2 Z. Hollander,3 J. Wilson-McManus,4 R. Balshaw,1 R. Ng,5 R. McMaster,6 P. Keown,2 B. McManus,4 1Statistics, University of British Columbia, Vancouver, BC, Canada; 2Medicine, University of British Columbia, Vancouver, BC, Canada; 3James Hogg iCAPTURE Centre for Cardiovascular and Pulmonary Research, St Pauls-University of British Columbia, Vancouver, BC, Canada; 4 Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada; 5Computer Science, University of British Columbia, Vancouver, BC, Canada; 6Medical Genetics, University of British Columbia, Vancouver, BC, Canada Purpose: The goal of the Biomarkers in Transplantation (BiT) project is to discover and validate an inexpensive, non-invasive and useful biomarker panel for rejection and therapeutic responses in acute and chronic heart, kidney and liver rejection.
Purpose: Peripheral blood progenitor cells (PCs) may play a role in the early stages of cardiac allograft vasculopathy (CAV). We assessed the relationship between PCs and coronary microvascular function in heart transplant (HT) patients (pts) with normal coronary angiograms. Methods and Materials: We studied 41 pts (36 M, aged 50 ⫾ 12 years) at 6 ⫾ 3 years from HT and 40 age and sex matched healthy subjects. Six subpopulations of PCs were determined by flow cytometry as follows: uncommitted (CD34⫹, CD133⫹, CD34⫹CD133⫹) and endothelial PCs (EPCs, CD34⫹KDR⫹, CD133⫹KDR⫹, CD34⫹CD133⫹KDR⫹). Coronary flow velocity in the LAD was detected at rest and during i.v. adenosine by transthoracic echocardiography. Coronary flow reserve (CFR) was the ratio of hyperemic diastolic mean velocity (DMV) to resting DMV. CFR ⬍2.5 was considered abnormal. CFR was measured in 10 pts (8 M, aged 50 ⫾ 12 years) and was abnormal in 3 (group A) and normal in 7 (group B). Results: EPCs were lower in pts than in controls (p⬍0.05). CD34⫹ cell count was higher in group A than in group B (583 ⫾ 100 vs 282 ⫾ 185 cells/10^6 cytometric events, p⫽0.01). CD34⫹ cell count was also inversely correlated with CFR as shown in the figure. At multivariable analysis, adjusted for time from HT, diabetes, hypertension and hypertrophy, CD34⫹ cell count was the only independent predictor of CFR (beta⫽-0.773, p⫽0.006).
Abstracts
Methods and Materials: Routine echocardiographic studies, performed at 1 week, 1 and 5 years after HTx were analyzed in 104 heart recipients. The mean age of the cohort was 47⫾16 years and the period of follow up was 4.96 ⫾ 2.45 years. The total cohort was divided into three sub-groups based on determination of LV geometry at 1-week after transplantation: (1) NG - normal left ventricle geometry (relative wall thickness (RWT) ⬍0.42 and LVM ⬍ 225 for males and ⬍ 163 for females); (2) CR - concentric remodeling (RWT ⱖ0.42, LVM⬍ 225 for males and 163 for females); and (3) CH - concentric hypertrophy (RWT ⱖ0.42, LVM ⱖ225 for males and 163 for females). Results: Abnormal LV geometry was found as early as 1 week after HTx in 85% of patients (59% CR, 26% CH) with explosive mode of donor brain death being the most significant determinant for CH (OR - 2.9, CI - 0.4-3.18, p⫽0.01) by multivariable logistic regression. There was no significant difference in blood pressure control or cellular rejection score between the 3 groups. Patients with abnormal LV geometry at 1 week had significantly higher prevalence of graft vasculopathy by angiography at 5 years (0% in NG, 9% in CR and 30% in CH, p⫽0.0015). The prevalence of CH continued to increase to 30% at 1 year and 41% at 5 years after HTx primarily due to a progressive increase in RWT and LV mass in the NG group and increase in LV mass in the CR group. Patients with CH at 1 year had significantly higher mortality as compared to patients with normal LV geometry (RR-1.87, p ⫽0.03). Conclusions: Cardiac allograft remodeling occurs early and frequently after HTX, with explosive mode of donor brain death a significant factor. Subsequently, the presence of CH is associated with increased graft arteriosclerosis and mortality. 369 Prophylaxis vs. Pre-Emptive Strategies in Preventing Cytomegalovirus-Dependent Cardiac Allograft Vasculopathy L. Potena,1 A.C. Musuraca,1 F. Grigioni,1 P. Ortolani,1 G. Pastorelli,1 F. Angeli,1 M.G. Vetrugno,1 G. Magnani,1 F. Fallani,1 F. Coccolo,1 A. Russo,1 A. Branzi,1 1Institute of Cardiology, University of Bologna, Bologna, Italy Purpose: Although cytomegalovirus (CMV) infection is a recognized risk factor for cardiac allograft vasculopathy (CAV), it is still unknown which CMV-prevention strategy is more effective in delaying CAV development. Thus, we designed this observational study to compare the effect of pre-emptive vs. prophylaxis approach on intravascular ultrasound (IVUS)-detected CAV. Methods and Materials: Thirty-six consecutive patients receiving heart transplant (HT) between January 2004 and June 2006, induction with thymoglobuline and maintenance therapy with cyclosporine, mycophenolate mofetil and prednisone, underwent IVUS of the proximal 30 mm of left anterior descending artery at month 1 and month 12 after HT. Recipients transplanted before October 2005 were treated pre-emptively with intravenous ganciclovir only when pp65 antigenemia raised over 25-30 cells/105 neutrophils. Subsequently all recipients received prophylaxis with valganciclovir 450mg b.i.d. for 40 days (90 days if donor/recipient serological mismatch), starting within day 10 after HT. Major study outcome measures were changes in intimal volume and in maximal intimal thickness. Results: Twenty-one patients received pre-emptive and 15 prophylaxis approach. Baseline characteristics were similar between the two groups and no difference in lipid panel was noted during the follow-up. Median peak pp65 positive cells were higher in the pre-emptive than in the prophylaxis group(31 [5to54] vs. 9 [2to26] cells/105 neutrophyls; P⫽0.04). Intimal volume increased significantly by 21% (P⫽0.04) in the pre-emptive group but not in the prophylaxis group (⫹10% P⫽NS). Increase in maximal intimal thickness was significantly greater in the pre-emptive than in the prophylaxis group (0.30⫾0.22 vs. 0.15⫾0.16 mm, respectively, P⫽0.01).
The Journal of Heart and Lung Transplantation February 2008
Conclusions: As compared with patients treated with pre-emptive approach, those receiving anti-CMV prophylaxis with valganciclovir showed a significant reduction of CMV infection burden and of IVUS-detected CAV 1 year after HT. Randomized studies are needed to confirm these observations. 370 Kidney Transplantation in UK Cardiothoracic Transplant Recipients H.L. Thomas,1 D. Collett,1 N.R. Banner,2 1UK Transplant, Bristol, United Kingdom; 2Harefield Hospital, Harefield, United Kingdom; 3 On Behalf of the UK Transplant Cardiothoracic Advisory Group, Bristol, United Kingdom Purpose: Renal disease is a late complication of cardiothoracic transplantation. We investigated kidney transplantation after cardiothoracic transplantation in the UK. Methods and Materials: Data on 6,682 first adult cardiothoracic transplants in the UK, 1985 to 2006, were obtained from the National Transplant Database. Multi-organ, heterotopic, non-heartbeating and living donor transplants were excluded. Time to listing for kidney transplantation was estimated using the Kaplan-Meier method and compared for recipients of heart(H), lung(L) and heart/lung(HL) transplant (N⫽4295, 1640 and 747 respectively). For patients listed, waiting time to kidney transplant was compared with 4,730 renal patients listed for their second kidney transplant. Post-transplant patient and graft survival were also compared. Results: HL recipients were significantly younger than H or L recipients (median age 33, 50 and 50). Donor age, donor sex and recipient sex were also significantly different between the groups. Time to listing for kidney transplantation varied significantly by transplant type (log-rank test, p⬍0.0001). Ten years after cardiothoracic transplant, the estimated proportion of patients listed for kidney transplant was 3.6% H, 5.7% L and 12.7% HL. Waiting time to deceased donor kidney transplant was similar across cardiothoracic transplant types, and did not differ from the waiting time of patients awaiting second renal transplant (median waiting time 2.4y vs 3.3y, p⫽0.17). Kidney graft survival (death with functioning graft censored) was comparable regardless of the previous type of transplant (p⫽0.27), but patient survival was inferior for cardiothoracic transplant recipients (5y mortality 30% vs 16%, p⫽0.011). Conclusions: Within 10 years of cardiothoracic transplant, the estimated proportion of recipients listed for kidney transplant was 4.7%. Waiting time to kidney transplant was comparable to those awaiting a second renal transplant. Patient survival following kidney transplant was inferior, but kidney graft survival was similar. 371 First-Year Statin Resistant Hypercholesterolemia: A Cause for Concern in the Development of Cardiac Allograft Vasculopathy J.K. Patel,1 J.C. Kawano,1 M.M. Kittleson,1 U. Duong,1 M.A. Kawano,1 A. Ardehali,2 J.A. Kobashigawa,1 1Cardiology, David Geffen School of Medicine at UCLA, Los Angeles, CA; 2 Cardiothoracic Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA Purpose: Hypercholesterolemia is common after heart transplant. The use of statins to lower cholesterol levels has been suggested to have an immunomodulatory effect. In non-transplant patients, it has been demonstrated that the lower the total cholesterol (TC) level, the
The Journal of Heart and Lung Transplantation Volume 27, Number 2S
better the outcome. It has not been shown whether lower TC levels result in better outcome after heart transplant. Methods and Materials: Between 1994 and 2000 we reviewed 301 patients who survived ⬎1 year after heart transplant. TC levels were averaged in the first year (at 3, 6, 9, 12 months). The mean first year lipid level was correlated to 5 year outcome of survival, non-fatal major adverse cardiac events (nf-MACE), and the development of cardiac allograft vasculopathy (CAV), diagnosed by any stenosis ⱖ 30% on angiography. Mean first year TC levels were divided into four groups: group 1⫽TC ⱕ150 mg/dl, group 2⫽TC 151-200, group 3⫽TC 201-250, group 4⫽TC ⬎250. All patients were maintained on statin therapy and/or ezetimibe. Results: Patients in group 4 (highest TC level) had signficantly lower freedom from CAV compared to groups 1-3 (see figure, p⫽0.008). Group 1 (lowest TC level) did not appear to have greater freedom from CAV compared to groups 2 and 3 (see figure). Among all groups, there was comparable 5 year survival and nf-MACE. Multivariate analysis of risk factors showed TC ⬎250 to be an independent variable for poor outcome. Conclusions: Despite statin therapy, elevated mean first year total cholesterol level (⬎250 mg/dl) is associated with increased incidence of CAV. Further modalities to lower this statin resistant hypercholesterolemia may be needed. However, achieving lowest cholesterol levels may not provide added benefit.
Abstracts
S195
Methods and Materials: This abstracted work focuses on the analysis of gene expression data to initially identify biomarkers of chronic heart rejection. BiT’s chronic rejection cohort of heart transplants consists of 18 patients (26 to 70 years old; 2/3 being male; time post-transplant, range 1 to 13 years). Nine patients were diagnosed with chronic rejection based on quantitative analysis of angiograms and/or intravascular ultrasound and chart review. PAXgene whole blood RNA was extracted and processed using Affymetrix GeneChip U133 Plus 2.0 microarrays. The microarray data was normalized using the Robust Multichip Average (RMA) algorithm and pre-filtered to remove probesets with similar expression across all samples. After pre-filtering, 24,951 probesets were analyzed using the Local Pooled Error (LPE) statistical method to identify differentially expressed genes between stable and chronic rejection patients. LPE is a robust analysis method that removes the issue of outlying observations within each group of patients and addresses the problem of having small sample sizes. Results: Nine probesets were identified as differentially expressed (p-value⬍10-5, adjusted p-value⬍0.1). Four probesets were up-regulated in the chronic rejection patients and five were down-regulated. These probesets correspond to 8 genes; three are associated with immune response and antigen processing/presentation, and two are potentially implicated in tissue injury and remodeling. Conclusions: BiT identified potential biomarkers of chronic heart rejection which will be validated in an independent cohort of patients. Future work will combine gene expression data with clinical and proteomics data to enhance our ability to clearly discriminate between both patient groups. Acknowledgements: Genome Canada, Novartis, IBM, Genome British Columbia. 373 Potential Role of Circulating Progenitor Cells in Coronary Microvascular Dysfunction of Heart Transplant Patients with Normal Coronary Angiograms E. Osto,1 F. Tona,1 G. Fadini,2 I. Baesso,3 A.L.P. Caforio,1 C. Agostini,3 G. Tarantini,1 A. Avogaro,2 A. Angelini,4 G. Gerosa,5 S. Iliceto,1 1Cardiology, University of Padova, Padova, Italy; 2 Division of Metabolic Disease, University of Padova, Padova, Italy; 3Clinical Immunology, University of Padova, Padova, Italy; 4 Cardiovascular Pathology, University of Padova, Padova, Italy; 5 Cardiovascular Surgery, University of Padova, Padova, Italy
372 Genomic Biomarkers of Chronic Heart Allograft Rejection G. Cohen Freue,1 C. Imai,2 A. Ignaszewski,2 G.B.J. Mancini,2 Z. Hollander,3 J. Wilson-McManus,4 R. Balshaw,1 R. Ng,5 R. McMaster,6 P. Keown,2 B. McManus,4 1Statistics, University of British Columbia, Vancouver, BC, Canada; 2Medicine, University of British Columbia, Vancouver, BC, Canada; 3James Hogg iCAPTURE Centre for Cardiovascular and Pulmonary Research, St Pauls-University of British Columbia, Vancouver, BC, Canada; 4 Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada; 5Computer Science, University of British Columbia, Vancouver, BC, Canada; 6Medical Genetics, University of British Columbia, Vancouver, BC, Canada Purpose: The goal of the Biomarkers in Transplantation (BiT) project is to discover and validate an inexpensive, non-invasive and useful biomarker panel for rejection and therapeutic responses in acute and chronic heart, kidney and liver rejection.
Purpose: Peripheral blood progenitor cells (PCs) may play a role in the early stages of cardiac allograft vasculopathy (CAV). We assessed the relationship between PCs and coronary microvascular function in heart transplant (HT) patients (pts) with normal coronary angiograms. Methods and Materials: We studied 41 pts (36 M, aged 50 ⫾ 12 years) at 6 ⫾ 3 years from HT and 40 age and sex matched healthy subjects. Six subpopulations of PCs were determined by flow cytometry as follows: uncommitted (CD34⫹, CD133⫹, CD34⫹CD133⫹) and endothelial PCs (EPCs, CD34⫹KDR⫹, CD133⫹KDR⫹, CD34⫹CD133⫹KDR⫹). Coronary flow velocity in the LAD was detected at rest and during i.v. adenosine by transthoracic echocardiography. Coronary flow reserve (CFR) was the ratio of hyperemic diastolic mean velocity (DMV) to resting DMV. CFR ⬍2.5 was considered abnormal. CFR was measured in 10 pts (8 M, aged 50 ⫾ 12 years) and was abnormal in 3 (group A) and normal in 7 (group B). Results: EPCs were lower in pts than in controls (p⬍0.05). CD34⫹ cell count was higher in group A than in group B (583 ⫾ 100 vs 282 ⫾ 185 cells/10^6 cytometric events, p⫽0.01). CD34⫹ cell count was also inversely correlated with CFR as shown in the figure. At multivariable analysis, adjusted for time from HT, diabetes, hypertension and hypertrophy, CD34⫹ cell count was the only independent predictor of CFR (beta⫽-0.773, p⫽0.006).