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High Expression of Plasmocytoid Dendritic Cells in Peripheral Blood Lower the Risk of Acute Cellular Rejection in Heart Transplant Recipients
Abstracts S281 to investigate the relationship between acute heart allograft rejection (grade 1R) and MPA inter-dose AUC, trough level (c0) or mycophenolate mofetil (MMF) dose in cardiac transplants. Methods: Thirty two heart transplant patients (28 males and 4 females, median [min-max] age was 49[22-63] years) enrolled in the PIGREC study (first year post transplantation) participated in this substudy. Measurements of the MPA AUC and c0 were performed at 4 periods (day7-15, months 1, 3 and 12 post-transplantation). The associations between rejection and MPA exposure were investigated using time dependent Cox proportional hazards regression models. Results: Forty-six rejections 1R and 1 rejection 2R were observed in the 32 patients (ie, 105 event data).1R rejection was significantly associated with MPA AUC (per unit increase AUC: HR [95% CI] = 0.97 [0.95-0.99], p= 0.0145), but not with c0 (per unit increase: HR= 0.84[0.68-1.04, p= 0.115) or MMF dose (per unit increase: HR= 1.002[0.999-1.003], p= 0.0505). No association was found between rejection 2R and the 3 markers, probably due to a lack of power. An MPA AUC threshold was investigated using ROC curve analysis and although non significativity (p= 0.1122), the value associated with the best sensitivity/specificity ratio was 21 mgxh/L. The AUC was recoded accordingly and was significantly associated with 1R rejection (below vs. above threshold: HR= 2.87[1.42-5.82], p= 0.0033). Conclusion: These results are in accordance with those obtained in renal transplantation where MPA AUC has been found as the best marker for MMF monitoring. Using pharmacokinetic tools allowing estimation of the AUC in routine practice could improve the outcome of the heart transplant patients. 7( 71) A CNI-Free, Everolimus Based Regimen in De-Novo Heart Transplant Recipients Increases Albuminuria But Improves Glomerular Filtration Rate Compared With Conventional Immunosuppression F. Gustafsson ,1 A. Andreassen,2 S. Arora,2 B. Andersson,3 E. Gude,2 H. Eiskjær,4 G. Raadegran,5 G. Dellgren,6 L. Gullestad.2 1Department of Cardiology, Rigshospitalet, Copenhagen, Denmark; 2Department of Cardiology, Rikshospitalet, Oslo, Norway; 3Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden; 4Department of Cardiology, Skejby University Hospital, Aarhus, Denmark; 5Department of Cardiology, Skaane University Hospital, Lund, Sweden; 6Department of Cardiac Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden. Purpose: It is well known that albuminuria late after heart transplantation (HT) is associated with poor renal response to switching to a CNI lowered or free-, everolimus/sirolimus based- immunosuppressive regimen, but the significance of albuminuria associated with everolimus after early CNI withdrawal in de-novo HT is unknown. Methods: We tested if change in measured glomerular filtration rate (mGFR, measured by CrEDTA clearance) from time of HT to 12 months post transplant is associated with urine albumen/creatinine ratio (UCR) at 7 weeks or 12 months in a subgroup of patients included in the SCHEDULE trial. In the SCHEDULE trial de-novo HT patients were randomized to early (7-11 weeks post transplant) CNI withdrawal using everolimus (EVR) or conventional CNI based triple immunosuppression (CNI). All patients were treated with mycophenolate and steroids. In 7 patients in the EVR group a CNI had been reintroduced after 12 months. Non-parametric statistics were applied. Results: Of 115 included in the trial, UCR was available for 66 patients (median age 56 years, 76 % male, 32 EVR, 34 CNI). 18 % were transplanted from an LVAD and a history of hypertension or diabetes was present in 18 and 20 %, respectively. Median mGFR was 58 (48-74(25-75 %))ml/min/m2 at baseline. After 12 months median mGFR increased by 16.0 (5.5-31.0) ml/ min/m2 in the EVR group and decreased by -4.1 (-16.0- + 1.0) ml/min/m2) in the CNI group (P< 0.0001). Conversely UCR at 12 months was higher in the EVR group (4 (2-14) vs. 1 (1-3) mg/mmol, P= 0.002). There was no significant correlation between mGFR and log(UCR) at 12 months (P= 0.65) and log(UCR) 7 weeks post-transplant did not predict change in GFR during the first year after HT (P= 0.73). Excluding patients in the EVR group in whom CNI was reintroduced (crossover) did not change the results significantly. Conclusion: The effects of EVR with early CNI withdrawal after HT on albuminuria and renal function (GFR) are dissociated. When EVR is used in a CNI-free regimen early after HT, the clinical significance of an increase in albuminuria is uncertain, and should not necessarily lead to an alteration of the immunosuppressive strategy.
7( 72) Influence of Junctional-Adhesion-Molecules on Transendothelial Migration Under Hypothermic Conditions: What About the Rewarming During Reperfusion? N.V. Bogert , I. Werner, A. Moritz, A. Beiras-Fernandez. Department of Thoracic and Cardiovascular Surgery, University Hospital Frankfurt, Goethe University, Frankfurt am Main, Germany. Purpose: Patients during circulatory arrest in aortic surgery or organ transplantation are subjected to therapeutic hypothermia. The body is cooled down or organs are perfused with cold preservation solutions and rewarmed again to body temperature. Hypothermia evokes anti-inflammatory responses and rewarming leads to pro-inflammatory responses. The role of hypothermia and the rewarming process on transendothelial migration (t-m) of leukocytes is not clarified yet. We investigated the influence of hypothermia/rewarming on t-m and the influence of Junctional-adhesion-molecules A and B (JAM-A; JAM-B) on this process. Methods: PBMC and endothelial cells (EC) were used for analyzing t-m: 1) normothermic activation (act)+hypothermic t-m 2) hypothermic act+hypothermic t-m 3) hypothermic act+normothermic t-m. Expression of JAM-A/JAM-B was analyzed following hypothermic act+normothermic t-m. In every experimental group 4 treatment subassembly-groups were observed: A) ctr B) act-PBMC C) act-EC D) act-EC/act-PBMCs with 4 different temperature conditions: 37°C, 30°C, 18°C, 4°C. p< 0.05 was considered statistically significant. Results: Hypothermic/normothermic act following hypothermic t-m leads to a significant drop in t-m of non-act-PBMCs through act-EC with falling temperature. Act-PBMCs showed significant increased t-m through non-actEC with falling temperature. Act-EC and PBMCs showed a significant drop of t-m with falling temperature. Hypothermic act following normothermic t-m leads to a significant increase in t-m of non-act-PBMCs through act-EC with falling activation temperature. JAM-A expression correlates reciprocal with the results of t-m during rewarming. JAM-B expression shows only minimal changes. Conclusion: The in vitro re-enactment of clinical practice shows a significant influence of temperature on t-m. Our data show that migration of PBMCs through EC is not only modulated by cell-activation itself-the activation temperature and the rewarming processes are essential. The modifications in JAM-A, provide a potential mechanistic explanation for the observed changes during the rewarming process. EC protection prior to warm reperfusion should be considered in organ transplantation. 7( 73) High Expression of Plasmocytoid Dendritic Cells in Peripheral Blood Lower the Risk of Acute Cellular Rejection in Heart Transplant Recipients M.J. Barten ,1 M. Dieterlen,1 J. Garbade,1 S. Dhein,1 F.W. Mohr,1 H.B. Bittner.2 1Cardiac Surgery, University Leipzig, Heart Center, Leipzig, Germany; 2Department of Cardiothoracic Transplantation and Advanced Cardiac Surgery, Florida Hospital Orlando, Orlando, FL. Purpose: Over the last decade many studies evaluated the potential of certain biomarkers to predict acute cellular rejection (ACR) without finding their way in the clinical routine. Thus, in our study we monitored dendritic cells (DCs) in heart transplant recipients (HTxR) treated either with a tacrolimus (TAC) or cyclosporine A (CsA) -based immunosuppressive regimen in the context of ACR. Methods: Both groups consisted of 14 maintenance HTxR. At different study time points (0, 3 and 6 months after study start) peripheral blood from all HTxR was drawn to analyse for (1) blood CsA or TAC concentration (trough value) and (2) to analyse myeloid and plasmocytoid (m and p) DCs with FACS. Histological rejection grading was performed of endomyocardial biopsies. Results: TAC treated HTxR had significantly higher values of pDCs (CsAgroup 53.9± 13.0%, TAC-group 67.5±8.4%, p< 0.05) and significantly lower values of mDCs than CsA treated HTxR (CsA-group 57.9±19.0%, TACgroup 45.2±10.7%, p< 0.05). In general, HTxR with rejection grade of ≥ 2 ISHLT 1990 had significant (p< 0.05) lower values of pDCs (55.1±16.2%) compared to HTxR without rejection (63.6±10.5%). TAC treated HTxR had
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significantly less rejections compared to CsA treated HTxR (CsA-group 0.86±0.95%, TAC- group 0.2±0.4%, p< 0.05). Conclusion: Our results showed that HTxR with high pDCs have a lower risk of rejection and that TAC treated HTxR had higher pDCs valuescompared to CsA treated HTxR. Future studies are needed to confirm if monitoring pDCs and mDCs have the potential value as biomarkers to identify HTxR at risk to develop ACR. 7( 74) Usefulness of ECMO for Cardiac Transplanted Patients Suffering From Early Cardiac Dysfunction A. Defontaine , T. Le Poivre, M. Treilhaud, P. Bizouarn, S. Pattier, J. Roussel, O. Baron. CHU Nantes, Nantes, France. Purpose: Use of ExtraCorporeal Membrane Oxygenation (ECMO) as a circulatory support during early postoperative period of heart transplantation has increased for the last years adding a new mean to deal with early cardiac dysfunction. The objective was to study survival for heart-transplanted patients requiring ECMO compared to heart-transplanted patients within the same period. Methods: A retrospective review of heart-transplanted patients older than 18 in our centre was leaded. The main objective was to compare survival at one year for two groups of patients (receiving or not ECMO) in terms of mortality and dialysis. The influences of pretransplantation Pulmonary Hypertension (PH), prior Ventricular Assist Device (VAD) as well as the moment of ECMO setup were also analysed. Results: 83 consecutive transplanted patients were included between January 2009 and December 2012: 25 (30%) in the ECMO group and 58 (70%) in the NoECMO group. Populations were comparable in terms of receivers, donors, mismatch gender and graft ischemia duration. Survival at one year was not different between the two groups (19-76% patients in ECMO group, 50-86% in NoECMO group, p= 0.11) as well as the requirement of at least one session of dialysis (18-72% in ECMO group, 29-50% in NoECMO group, p= 0.06). Among patients suffering from pretransplantation PH (15-60% in ECMO group, 29-50% in NoECMO group), survival showed no difference (p= 0.33) whereas there was less dialysis in NoECMO group (p= 0.04). For those with prior VAD (7-28% in ECMO group, 17-29% in NoECMO group), survival was better in NoECMO group (p= 0.02) whereas there was no difference in terms of dialysis (p= 0.34). 15 (60%) ECMOs were set up in intraoperative period while 9 (36%, 1 NA-4%) were set up after transplantation and return in intensive care unit (> = Day0) with no difference in terms of survival regarding the moment of the ECMO setup (p= 0.35) but a reduce of dialysis when ECMO was setup in intraoperative period (p= 0.03). Conclusion: ECMO appears as a first choice hemodynamic support in early postoperative period for heart-transplanted patients suffering from graft dysfunction. Survival at one year is not different for patients requiring ECMO support compared to the other heart-transplanted patients. Moreover, should requirement to ECMO be considered, the trend may be to set it early in intraoperative period in order to reduce dialysis need. 7( 75) Association Between Steroids Withdrawal During the First Year After Heart Transplantation and Changes in Total Cholesterol and Its Fractions in a Two Year Follow-Up. RESTCO Study M.G. Crespo-Leiro ,1 M.J. Paniagua-Martín,1 M. Gómez-Bueno,2 J.L. Lambert-Rodríguez,3 J. Fernández-Yáñez,4 J.M. Arizón del Prado,5 F. González-Vilchez,6 T. Blasco-Peiró,7 L. de la Fuente Galán,8 V. Brossa-Loidi,9 L. Almenar Bonet,10 I. Garrido-Bravo,11 E. Lage-Galle,12 J. Muñiz-García,13 J. Delgado-Jiménez.14 1Heart Transplant Unit, Hospital Universitario A Coruña, La Coruña, Spain; 2Hospital Universitario Puerta de Hierro, Madrid, Spain; 3Hospital Universitario Central de Asturias, Asturias, Spain; 4Hospital General Universitario Gregorio Marañón, Madrid, Spain; 5Hospital Universitario Reina Sofía, Córdoba, Spain; 6Hospital Universitario Marqués de Valdecilla, Santander, Spain; 7Hospital Universitario Miguel Servet, Zaragoza, Spain; 8Hospital Clínico Universitario de Valladolid, Valladolid, Spain; 9Hospital Santa Creu i Sant Pau, Barcelona, Spain; 10Hospital Universitari i Politècnic La Fe, Valencia, Spain; 11Hospital Universitario Virgen de la Arrixaca, Murcia, Spain; 12Hospital Universitario Virgen del Rocio, Sevilla, Spain; 13Instituto Universitario de Ciencias de la Salud.
Universidad de A Coruña, La Coruña, Spain; 14Hospital Universitario 12 de Octubre, Madrid, Spain. Purpose: There is still debate on whether steroids withdrawal is the best option in the immunosuppression of heart transplant patients. While we know the frequency of this practice in Spain, little is known on the magnitude of the potential beneficial effect in different clinical variables (i.e. lipids) really achieved for the extra rejection risk assumed associated with steroids withdrawal. To study the association between steroids withdrawal during the first year after heart transplantation (HT) and changes in serum total cholesterol and its fractions (LDL-Chol and HDL-Chol) during the following two years. Methods: Historical cohort study done in 12 Spanish HT centers. 597 HT patients older than 18 years (80.4% males and with a mean age of 52.3 years (standard deviation= 11.2)). All HT were done between 2000 and 2005 and only patients with complete information both on steroids treatment one year after HT and on lipids one and three years after HT were considered in this analysis. Lipids changes between first and third year after HT where analyzed in three different groups depending on steroids treatment one year after HT: A) No steroids; B) Low doses (≤ 5mg/día) y C) High doses (> 5mg/día), and these changes compared among groups. Results: At the one-year visit, 59 (9.9%) patients were without steroids (Group A), 175 (29.3%) with low doses (B) and 363 (60.8%) with high doses (C); Group A had lower levels of total and LDL-cholesterol than the two other groups and HDL-Chol level lower than group C. Group A increased its cholesterol level from year one to year three (mean increase of 9.2 mg/ dL, [95% C.I.= 1.2-17.1]) while the two other groups decreased it (corresponding figures in B= -4.6 mg/dL, [95% C.I= -10.1-0.9] and C= -10.9mg/ dL, [95% C.I.= -15.6- -6.2]), although the decrease was only significant in group C. Changes in the same direction but of smaller size were observed in LDL-Chol and statistically significant only in group C (-4.6mg/dL, [95% C.I= -8.3- -0.9]). HDL-Chol decreased in all groups from year one to year three, but it was a small reduction in groups A and B and only significant in group C (-4.2 mg/dL, [95% C.I.= -5.9- -2.5]). Conclusion: Lipid profile, usually adversely affected by steroids use, does not improve among HT patiens in whom steroids are withdrawn compared to HT patients who continue on steroids. 7( 76) Pioglitazone for the Treatment of Insulin Resistance in Heart Transplant Recipients: Assessment of Efficacy and Safety R. Ray ,1 M. Shih,2 N. Constantz,1 B. Kohli,1 H. Luikart,1 K. Khush.1 1Cardiovascular Medicine, Stanford University, Stanford, CA; 2Health Research & Policiy, Stanford University, Stanford, CA. Purpose: Pioglitazone,a thiazolidinedione, has been successfully used in the treatment of type 2 diabetes mellitus in the general population with the additional benefit of improved cardiovascular outcomes. Many heart transplant recipients develop insulin resistance due to post-transplant medications. Insulin resistance has been linked to the development of cardiac allograft vasculopathy (CAV), a major cause of mortality and morbidity. We hypothesized that pioglitazone is effective and safe in the treatment of insulin resistance in the high risk patient population of heart transplant recipients. Methods: We conducted a pilot double-blind randomized clinical trial of pioglitazone versus placebo from 2010 to 2013 in heart transplant recipients who were 1-4 years post-transplant. The primary efficacy endpoint was change in the area under the curve for insulin (I-AUC; a validated surrogate measure of insulin resistance) in response to an oral glucose challenge from baseline to 1 year follow-up. A secondary efficacy endpoint was progression in CAV, as assessed by coronary angiography with intravascular ultrasound. Safety parameters were monitored at frequent intervals and included ejection fraction, fasting glucose, hemoglobin, liver function tests, and weight. Results: Eighteen heart transplant patients aged 20 to 72 years were randomized (9 to pioglitazone, 9 to placebo). Treatment with pioglitazone showed a trend toward reduction in insulin resistance as measured by I-AUC, although this did not reach statistical significance (pioglitazone: -47.7 ± 123.6; placebo, 10.7± 87.5; p= 0.27). There were no significant differences between the two groups in the secondary efficacy endpoint of progression of CAV at 1 year: maximal intimal thickness (p= 0.97) and intimal volume(p= 0.19), or in the pre-specified safety endpoints (p≥ 0.23).
7( 72) Influence of Junctional-Adhesion-Molecules on Transendothelial Migration Under Hypothermic Conditions: What About the Rewarming During Reperfusion? N.V. Bogert , I. Werner, A. Moritz, A. Beiras-Fernandez. Department of Thoracic and Cardiovascular Surgery, University Hospital Frankfurt, Goethe University, Frankfurt am Main, Germany. Purpose: Patients during circulatory arrest in aortic surgery or organ transplantation are subjected to therapeutic hypothermia. The body is cooled down or organs are perfused with cold preservation solutions and rewarmed again to body temperature. Hypothermia evokes anti-inflammatory responses and rewarming leads to pro-inflammatory responses. The role of hypothermia and the rewarming process on transendothelial migration (t-m) of leukocytes is not clarified yet. We investigated the influence of hypothermia/rewarming on t-m and the influence of Junctional-adhesion-molecules A and B (JAM-A; JAM-B) on this process. Methods: PBMC and endothelial cells (EC) were used for analyzing t-m: 1) normothermic activation (act)+hypothermic t-m 2) hypothermic act+hypothermic t-m 3) hypothermic act+normothermic t-m. Expression of JAM-A/JAM-B was analyzed following hypothermic act+normothermic t-m. In every experimental group 4 treatment subassembly-groups were observed: A) ctr B) act-PBMC C) act-EC D) act-EC/act-PBMCs with 4 different temperature conditions: 37°C, 30°C, 18°C, 4°C. p< 0.05 was considered statistically significant. Results: Hypothermic/normothermic act following hypothermic t-m leads to a significant drop in t-m of non-act-PBMCs through act-EC with falling temperature. Act-PBMCs showed significant increased t-m through non-actEC with falling temperature. Act-EC and PBMCs showed a significant drop of t-m with falling temperature. Hypothermic act following normothermic t-m leads to a significant increase in t-m of non-act-PBMCs through act-EC with falling activation temperature. JAM-A expression correlates reciprocal with the results of t-m during rewarming. JAM-B expression shows only minimal changes. Conclusion: The in vitro re-enactment of clinical practice shows a significant influence of temperature on t-m. Our data show that migration of PBMCs through EC is not only modulated by cell-activation itself-the activation temperature and the rewarming processes are essential. The modifications in JAM-A, provide a potential mechanistic explanation for the observed changes during the rewarming process. EC protection prior to warm reperfusion should be considered in organ transplantation. 7( 73) High Expression of Plasmocytoid Dendritic Cells in Peripheral Blood Lower the Risk of Acute Cellular Rejection in Heart Transplant Recipients M.J. Barten ,1 M. Dieterlen,1 J. Garbade,1 S. Dhein,1 F.W. Mohr,1 H.B. Bittner.2 1Cardiac Surgery, University Leipzig, Heart Center, Leipzig, Germany; 2Department of Cardiothoracic Transplantation and Advanced Cardiac Surgery, Florida Hospital Orlando, Orlando, FL. Purpose: Over the last decade many studies evaluated the potential of certain biomarkers to predict acute cellular rejection (ACR) without finding their way in the clinical routine. Thus, in our study we monitored dendritic cells (DCs) in heart transplant recipients (HTxR) treated either with a tacrolimus (TAC) or cyclosporine A (CsA) -based immunosuppressive regimen in the context of ACR. Methods: Both groups consisted of 14 maintenance HTxR. At different study time points (0, 3 and 6 months after study start) peripheral blood from all HTxR was drawn to analyse for (1) blood CsA or TAC concentration (trough value) and (2) to analyse myeloid and plasmocytoid (m and p) DCs with FACS. Histological rejection grading was performed of endomyocardial biopsies. Results: TAC treated HTxR had significantly higher values of pDCs (CsAgroup 53.9± 13.0%, TAC-group 67.5±8.4%, p< 0.05) and significantly lower values of mDCs than CsA treated HTxR (CsA-group 57.9±19.0%, TACgroup 45.2±10.7%, p< 0.05). In general, HTxR with rejection grade of ≥ 2 ISHLT 1990 had significant (p< 0.05) lower values of pDCs (55.1±16.2%) compared to HTxR without rejection (63.6±10.5%). TAC treated HTxR had
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The Journal of Heart and Lung Transplantation, Vol 32, No 4S, April 2014
significantly less rejections compared to CsA treated HTxR (CsA-group 0.86±0.95%, TAC- group 0.2±0.4%, p< 0.05). Conclusion: Our results showed that HTxR with high pDCs have a lower risk of rejection and that TAC treated HTxR had higher pDCs valuescompared to CsA treated HTxR. Future studies are needed to confirm if monitoring pDCs and mDCs have the potential value as biomarkers to identify HTxR at risk to develop ACR. 7( 74) Usefulness of ECMO for Cardiac Transplanted Patients Suffering From Early Cardiac Dysfunction A. Defontaine , T. Le Poivre, M. Treilhaud, P. Bizouarn, S. Pattier, J. Roussel, O. Baron. CHU Nantes, Nantes, France. Purpose: Use of ExtraCorporeal Membrane Oxygenation (ECMO) as a circulatory support during early postoperative period of heart transplantation has increased for the last years adding a new mean to deal with early cardiac dysfunction. The objective was to study survival for heart-transplanted patients requiring ECMO compared to heart-transplanted patients within the same period. Methods: A retrospective review of heart-transplanted patients older than 18 in our centre was leaded. The main objective was to compare survival at one year for two groups of patients (receiving or not ECMO) in terms of mortality and dialysis. The influences of pretransplantation Pulmonary Hypertension (PH), prior Ventricular Assist Device (VAD) as well as the moment of ECMO setup were also analysed. Results: 83 consecutive transplanted patients were included between January 2009 and December 2012: 25 (30%) in the ECMO group and 58 (70%) in the NoECMO group. Populations were comparable in terms of receivers, donors, mismatch gender and graft ischemia duration. Survival at one year was not different between the two groups (19-76% patients in ECMO group, 50-86% in NoECMO group, p= 0.11) as well as the requirement of at least one session of dialysis (18-72% in ECMO group, 29-50% in NoECMO group, p= 0.06). Among patients suffering from pretransplantation PH (15-60% in ECMO group, 29-50% in NoECMO group), survival showed no difference (p= 0.33) whereas there was less dialysis in NoECMO group (p= 0.04). For those with prior VAD (7-28% in ECMO group, 17-29% in NoECMO group), survival was better in NoECMO group (p= 0.02) whereas there was no difference in terms of dialysis (p= 0.34). 15 (60%) ECMOs were set up in intraoperative period while 9 (36%, 1 NA-4%) were set up after transplantation and return in intensive care unit (> = Day0) with no difference in terms of survival regarding the moment of the ECMO setup (p= 0.35) but a reduce of dialysis when ECMO was setup in intraoperative period (p= 0.03). Conclusion: ECMO appears as a first choice hemodynamic support in early postoperative period for heart-transplanted patients suffering from graft dysfunction. Survival at one year is not different for patients requiring ECMO support compared to the other heart-transplanted patients. Moreover, should requirement to ECMO be considered, the trend may be to set it early in intraoperative period in order to reduce dialysis need. 7( 75) Association Between Steroids Withdrawal During the First Year After Heart Transplantation and Changes in Total Cholesterol and Its Fractions in a Two Year Follow-Up. RESTCO Study M.G. Crespo-Leiro ,1 M.J. Paniagua-Martín,1 M. Gómez-Bueno,2 J.L. Lambert-Rodríguez,3 J. Fernández-Yáñez,4 J.M. Arizón del Prado,5 F. González-Vilchez,6 T. Blasco-Peiró,7 L. de la Fuente Galán,8 V. Brossa-Loidi,9 L. Almenar Bonet,10 I. Garrido-Bravo,11 E. Lage-Galle,12 J. Muñiz-García,13 J. Delgado-Jiménez.14 1Heart Transplant Unit, Hospital Universitario A Coruña, La Coruña, Spain; 2Hospital Universitario Puerta de Hierro, Madrid, Spain; 3Hospital Universitario Central de Asturias, Asturias, Spain; 4Hospital General Universitario Gregorio Marañón, Madrid, Spain; 5Hospital Universitario Reina Sofía, Córdoba, Spain; 6Hospital Universitario Marqués de Valdecilla, Santander, Spain; 7Hospital Universitario Miguel Servet, Zaragoza, Spain; 8Hospital Clínico Universitario de Valladolid, Valladolid, Spain; 9Hospital Santa Creu i Sant Pau, Barcelona, Spain; 10Hospital Universitari i Politècnic La Fe, Valencia, Spain; 11Hospital Universitario Virgen de la Arrixaca, Murcia, Spain; 12Hospital Universitario Virgen del Rocio, Sevilla, Spain; 13Instituto Universitario de Ciencias de la Salud.
Universidad de A Coruña, La Coruña, Spain; 14Hospital Universitario 12 de Octubre, Madrid, Spain. Purpose: There is still debate on whether steroids withdrawal is the best option in the immunosuppression of heart transplant patients. While we know the frequency of this practice in Spain, little is known on the magnitude of the potential beneficial effect in different clinical variables (i.e. lipids) really achieved for the extra rejection risk assumed associated with steroids withdrawal. To study the association between steroids withdrawal during the first year after heart transplantation (HT) and changes in serum total cholesterol and its fractions (LDL-Chol and HDL-Chol) during the following two years. Methods: Historical cohort study done in 12 Spanish HT centers. 597 HT patients older than 18 years (80.4% males and with a mean age of 52.3 years (standard deviation= 11.2)). All HT were done between 2000 and 2005 and only patients with complete information both on steroids treatment one year after HT and on lipids one and three years after HT were considered in this analysis. Lipids changes between first and third year after HT where analyzed in three different groups depending on steroids treatment one year after HT: A) No steroids; B) Low doses (≤ 5mg/día) y C) High doses (> 5mg/día), and these changes compared among groups. Results: At the one-year visit, 59 (9.9%) patients were without steroids (Group A), 175 (29.3%) with low doses (B) and 363 (60.8%) with high doses (C); Group A had lower levels of total and LDL-cholesterol than the two other groups and HDL-Chol level lower than group C. Group A increased its cholesterol level from year one to year three (mean increase of 9.2 mg/ dL, [95% C.I.= 1.2-17.1]) while the two other groups decreased it (corresponding figures in B= -4.6 mg/dL, [95% C.I= -10.1-0.9] and C= -10.9mg/ dL, [95% C.I.= -15.6- -6.2]), although the decrease was only significant in group C. Changes in the same direction but of smaller size were observed in LDL-Chol and statistically significant only in group C (-4.6mg/dL, [95% C.I= -8.3- -0.9]). HDL-Chol decreased in all groups from year one to year three, but it was a small reduction in groups A and B and only significant in group C (-4.2 mg/dL, [95% C.I.= -5.9- -2.5]). Conclusion: Lipid profile, usually adversely affected by steroids use, does not improve among HT patiens in whom steroids are withdrawn compared to HT patients who continue on steroids. 7( 76) Pioglitazone for the Treatment of Insulin Resistance in Heart Transplant Recipients: Assessment of Efficacy and Safety R. Ray ,1 M. Shih,2 N. Constantz,1 B. Kohli,1 H. Luikart,1 K. Khush.1 1Cardiovascular Medicine, Stanford University, Stanford, CA; 2Health Research & Policiy, Stanford University, Stanford, CA. Purpose: Pioglitazone,a thiazolidinedione, has been successfully used in the treatment of type 2 diabetes mellitus in the general population with the additional benefit of improved cardiovascular outcomes. Many heart transplant recipients develop insulin resistance due to post-transplant medications. Insulin resistance has been linked to the development of cardiac allograft vasculopathy (CAV), a major cause of mortality and morbidity. We hypothesized that pioglitazone is effective and safe in the treatment of insulin resistance in the high risk patient population of heart transplant recipients. Methods: We conducted a pilot double-blind randomized clinical trial of pioglitazone versus placebo from 2010 to 2013 in heart transplant recipients who were 1-4 years post-transplant. The primary efficacy endpoint was change in the area under the curve for insulin (I-AUC; a validated surrogate measure of insulin resistance) in response to an oral glucose challenge from baseline to 1 year follow-up. A secondary efficacy endpoint was progression in CAV, as assessed by coronary angiography with intravascular ultrasound. Safety parameters were monitored at frequent intervals and included ejection fraction, fasting glucose, hemoglobin, liver function tests, and weight. Results: Eighteen heart transplant patients aged 20 to 72 years were randomized (9 to pioglitazone, 9 to placebo). Treatment with pioglitazone showed a trend toward reduction in insulin resistance as measured by I-AUC, although this did not reach statistical significance (pioglitazone: -47.7 ± 123.6; placebo, 10.7± 87.5; p= 0.27). There were no significant differences between the two groups in the secondary efficacy endpoint of progression of CAV at 1 year: maximal intimal thickness (p= 0.97) and intimal volume(p= 0.19), or in the pre-specified safety endpoints (p≥ 0.23).