Long-term Heart Transplant Recipients Research Articles

Lack of Usefulness of Donor-Derived Cell-Free DNA as a Biomarker for Cardiac Allograft Vasculopathy: A Prospective Study.

BackgroundCardiac allograft vasculopathy (CAV) remains a major cause of morbidity and mortality among long-term heart transplant recipients. There is an unmet need for a non-invasive biomarker of CAV that could obviate the need to perform surveillance coronary angiograms in these patients. Our aim was to evaluate the performance of Donor-derived Cell Free DNA (dd-cfDNA) as a biomarker of CAV.MethodsWe prospectively measured dd-cfDNA levels in all patients undergoing routine coronary angiography >1 year after heart transplant at a single center. Endpoints included the association between dd-cfDNA levels and the presence CAV, according to several prespecified criteria.ResultsWe included 94 heart transplant recipients, a median of 10.9 years after transplant. Coronary angiogram revealed CAV0, CAV1, CAV2, and CAV3 in 61, 19, 14, and 6% of patients, respectively. Comparison of dd-cfDNA levels in patients with CAV0 and CAV1–2–3 (primary end-point) did not show significant differences (0.92%, IQR 0.46–2.0 vs. 0.46%, IQR 0.075–1.5, p = 0.059), nor did the comparison between patients with stable CAV (no new coronary lesions since previous angiogram, n = 77) and progressive CAV (n = 17); dd-cfDNA values 0.735% (IQR 0.195–2.0) vs. 0.9% (IQR 0.12–1.8), p = 0.76. However, we found an association between NTproBNP levels and CAV degree (p = 0.017). Dd-cfDNA levels did not correlate with NTproBNP (ρ = −0.095).ConclusionIn this study, dd-cfDNA did not perform as a useful biomarker to avoid surveillance coronary angiograms for CAV diagnosis.Clinical Trial NotationPotential Role of Donor-derived Cell Free DNA as a Biomarker in Cardiac Allograft Vasculopathy, NCT 04791852.

Long-term heart transplant recipients: heart rate-related effects on augmented transfer function coherence during repeated squat-stand maneuvers in males.

Previous research has highlighted that squat-stand maneuvers (SSMs) augment coherence values within the cerebral pressure-flow relationship to ∼0.99. However, it is not fully elucidated if mean arterial pressure (MAP) leads to this physiological entrainment independently, or if heart rate (HR) and/or the partial pressure of carbon dioxide (Pco2) also have contributing influences. A 2:1 control-to-case model was used in the present investigation [participant number (n) = 40; n = 16 age-matched (AM); n = 16 donor control (DM); n = 8 heart transplant recipients (HTRs)]. The latter group was used to mechanistically isolate the extent to which HR influences the cerebral pressure-flow relationship. Participants completed 5 min of squat-stand maneuvers at 0.05 Hz (10 s) and 0.10 Hz (5 s). Linear transfer function analysis (TFA) examined the relationship between different physiological inputs (i.e., MAP, HR, and Pco2) and output [cerebral blood velocity (CBV)] during SSM; and cardiac baroreceptor sensitivity (BRS). Compared with DM, cardiac BRS was reduced in AM (P < 0.001), which was further reduced in HTR (P < 0.045). In addition, during the SSM, HR was elevated in HTR compared with both control groups (P < 0.001), but all groups had near-maximal coherence metrics ≥0.98 at 0.05 Hz and ≥0.99 at 0.10 Hz (P ≥ 0.399). In contrast, the mean HR-CBV/Pco2-CBV relationships ranged from 0.38 (HTR) to 0.81 (DM). Despite near abolishment of BRS and blunted HR following heart transplantation, long-term HTR exhibited near-maximal coherence within the MAP-CBV relationship, comparable with AM and DM. Therefore, these results show that the augmented coherence with SSM is driven by blood pressure, whereas elevations in TFA coherence as a result of HR contribution are likely correlational in nature.

Prospective evaluation of donor-derived cell-free DNA as a potential biomarker for cardiac allograft vasculopathy

Abstract Background Cardiac allograft vasculopathy (CAV) remains a major cause of morbidity and mortality among long-term heart transplant (HT) recipients. There is clearly an unmet need for a noninvasive biomarker of CAV that could obviate the need to perform surveillance coronary angiograms in these patients. Purpose Our aim was to evaluate the performance of Donor-derived Cell Free DNA (dd-cfDNA) as a biomarker of CAV. Methods We prospectively measured dd-cfDNA levels in all consecutive asymptomatic patients undergoing surveillance coronary angiography &amp;gt;1 year after HT at a single center, between Jan 2019 and Jan 2021. Endpoints included the association between dd-cfDNA levels and the presence CAV, according to ISHLT 2010 classification. Patients with history of acute cellular rejection ≥1R or antibody mediated rejection in the previous 6 months were excluded. Results We included 94 HT recipients, median age 57 years (IQR 50–67), 67% men, a median of 10.9 years after transplant. Coronary angiogram revealed CAV0, CAV1, CAV2 and CAV3 in 61%, 19%, 14% and 6% of patients, respectively. Median dd-cfDNA values for each CAV group were: CAV0 0.92% (IQR 0.46–2.0), CAV1 1.4% (0.38–2.8), CAV2 0.17% (0.07–0.52) and CAV3 0.24% (0.057–0.87); p=0.0535. Figure 1 summarizes baseline characteristics of the cohort and results. Comparison of dd-cfDNA levels in patients with CAV0 and CAV1–2-3 did not show significant differences (0.92%, IQR 0.46–2.0 vs 0.46%, IQR 0.075–1.5, p=0.059) (Figure 2A), nor did the comparison between patients with stable CAV (no new coronary lesions since previous angiogram, n=77) and progressive CAV (patients with new coronary stenoses, n=17); median dd-cfDNA values were 0.735% (IQR 0.195–2.0) vs 0.9% (IQR 0.12–1.8), p=0.76 (Figure 2B). A subanalysis according to time after HT was also found non-significant: less than 5 years (p=0.95), 5 to 10 years (p=0.14) and more than 10 years after HT (p=0.16) (Figure 2C). The AUC ROC curve for the diagnosis of CAV revealed the lack of ability to predict the presence of any degree of CAV (AUC ROC = 0.38). Conclusion In our experience, dd-cfDNA did not perform as a useful biomarker to avoid surveillance coronary angiograms for CAV diagnosis. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): Sociedad Madrileña de Trasplantes

Blood volume and hemoglobin mass in long-term heart transplant recipients with and without Anemia

BackgroundIn systolic chronic heart failure, a heterogeneous blood volume (BV) regulation can be found with plasma volume expansion in many cases, possibly leading to pseudoanemia. Little is known about the volume status after heart transplantation (HTX). So far, anemia of HTX recipients was solely investigated using hemoglobin-concentration that may be misleading in a clinical context. The objective of the study was whether a difference in plasma volume and red cell volume can be observed in clinically stable heart transplant recipients compared to matched control subjects. Secondary, the aim was to describe anemia in the long-term after HTX based on quantitative data.MethodsBlood volume and its constituents red cell volume and plasma volume were quantified using an abbreviated carbon monoxide rebreathing method (aCORM) with focus on its primary measure total hemoglobin mass (Hbmass) and coincidental anemia in 36 (7 women) heart transplant recipients. For comparison, a matched control group of 46 (5 women) healthy subjects was selected.ResultsNeither Hbmass nor blood volumes were significantly different in HTX patients compared to matched healthy control group subjects. The prevalence of anemia 6.3 ± 4.3 years after transplantation was 19%. Hbmass and red cell volume were significantly lower in anemic HTX patients compared to non-anemic patients while plasma volume was not expanded. Various immunosuppressant regimens did not have an effect on Hbmass, plasma volume or red cell volume.ConclusionsThere was no difference in blood volumes and Hbmass between HTX patients and control subjects. The pathophysiologic blood volume regulation in chronic heart failure does not seem to be longer active in long-term HTX recipients. However, in the long-term after HTX, anemia occurs in a considerable number of patients as true anemia without a clear association with immunosuppression.Trial registrationGerman registry for clinical studies, DRKS00006078. Registered 09 May 2014, https://www.drks.de/drks_web/navigate.do?navigationId=trial. HTML&TRIAL_ID=DRKS00006078.

Dynamical Landscape of Heart Rhythm in Long-Term Heart Transplant Recipients: A Way to Discern Erratic Rhythms.

It is commonly believed that higher values of heart rate variability (HRV) indices account for better organization of the network of feedback reflexes driving an organism's response to actual bodily needs. In order to evaluate this organization in heart transplant (HTX) recipients, 58 nocturnal Holter signals of 14 HTX patients were analyzed. Their dynamical properties were evaluated by short-term HRV indices and measures grounded on entropy. Estimates grouped according to the patients' clinical progress: free of complications versus with complications, and arranged in order of the length of time since the HTX, lead us to the conclusion that higher HRV is associated with a worse outcome for HTX patients. Moreover, short-term HRV indices that are constant, rather than increasing over time, serve well in the prognosis of the future state of a HTX patient. These findings suggest that increases observed in HRV indices are related to erratic rhythms resulting from remodeling of the cardiac tissue (including heterogeneous innervation) in long-term HTX patients. Therefore, we hypothesize that dynamical landscape markers (entropy and fragmentation measures together with the short-term HRV indices) can serve as a tool in the exploration of the genesis of (non-respiratory sinus) arrhythmia.

(797) - Gene Expression Profiling to Optimize Immunosuppression in Long-Term Heart Transplant Recipients

(797) - Gene Expression Profiling to Optimize Immunosuppression in Long-Term Heart Transplant Recipients

Relationship between cerebral blood flow and blood pressure in long-term heart transplant recipients.

Heart transplant recipients are at an increased risk for cerebral hemorrhage and ischemic stroke; yet, the exact mechanism for this derangement remains unclear. We hypothesized that alterations in cerebrovascular regulation is principally involved. To test this hypothesis, we studied cerebral pressure-flow dynamics in 8 clinically stable male heart transplant recipients (62±8 years of age and 9±7 years post transplant, mean±SD), 9 male age-matched controls (63±8 years), and 10 male donor controls (27±5 years). To increase blood pressure variability and improve assessment of the pressure-flow dynamics, subjects performed squat-stand maneuvers at 0.05 and 0.10 Hz. Beat-to-beat blood pressure, middle cerebral artery velocity, and end-tidal carbon dioxide were continuously measured during 5 minutes of seated rest and throughout the squat-stand maneuvers. Cardiac baroreceptor sensitivity gain and cerebral pressure-flow responses were assessed with linear transfer function analysis. Heart transplant recipients had reductions in R-R interval power and baroreceptor sensitivity low frequency gain (P<0.01) compared with both control groups; however, these changes were unrelated to transfer function metrics. Thus, in contrast to our hypothesis, the increased risk of cerebrovascular complication after heart transplantation does not seem to be related to alterations in cerebral pressure-flow dynamics. Future research is, therefore, warranted.

Rejection after conversion to a proliferation signal inhibitor in chronic heart transplantation

We sought to determine the incidence, risk factors, and consequences of acute rejection (AR) after conversion from a calcineurin inhibitor (CNI) to a proliferation signal inhibitor (PSI) in maintenance heart transplantation. Relevant clinical data were retrospectively obtained for 284 long-term heart transplant recipients from nine centers in whom CNIs were replaced with a PSI (sirolimus or everolimus) between October 2001 and March 2009. The rejection rate at one yr was 8.3%, stabilizing to 2% per year thereafter. The incidence rate after conversion (4.9 per 100 patient-years) was significantly higher than that observed on CNI therapy in the pre-conversion period (2.2 per 100 patient-years). By multivariate analysis, rejection risk was associated with a history of late AR prior to PSI conversion, early conversion (<5 yr) after transplantation and age <50 yr at the time of conversion. Use of mycophenolate mofetil was a protective factor. Post-conversion rejection did not significantly influence the evolution of left ventricular ejection fraction, renal function, or mortality during further follow-up. Conversion to a CNI-free immunosuppression based on a PSI results in an increased risk of AR. Awareness of the clinical determinants of post-conversion rejection could help to refine the current PSI conversion strategies.

Can Plasma NGAL Predict Renal Response to Conversion from Calcineurin Inhbitor- to Everolimus Based Immunosuppression after Cardiac Transplantation?

Purpose Useful predictors of renal recovery following conversion from calcineurin inhibitor (CNI) to proliferation signal inhibitor based therapy are lacking. We hypothesized that plasma-neutrophil gelatinase-associated lipocalin (P-NGAL) - a new marker of kidney damage - in long term cardiac transplant recipients could predict improvement in glomerular filtration rate one year after conversion to an everolimus based regimen. Methods and Materials P-NGAL was measured at baseline in 88 cardiac transplant patients (median age 62 years, median 5 years post transplant) with mild to moderate renal dysfunction randomized to continuation of conventional immunosuppression (CNI, antiproliferative agent, steroid) or treatment with low dose everolimus, low dose CNI, an antiproliferative agent and steroid. Glomerular filtration rate was measured at baseline and after 1 year using crEDTA clearance (mGFR). Results Median P-NGAL was 109 (97-144) pg/L. Patients with NGAl above median were heavier and had higher white blood cell count and higher hsC-reactive protein levels at baseline. Median mGFR at baseline was 53 ml/min/1.73 m 2 . P-NGAL correlated with mGFR (R 2 =0.21, P 2 =0.32, P 2 ), P=0.006). Baseline P-NGAL predicted mGFR after one year (R 2 =0.18, P Conclusions P-NGAL and GFR correlate in long-term heart transplant recipients with renal dysfunction. P-NGAL did not predict improvement of renal function after conversion to everolimus based immunosuppression.

653 Heart Rate Reduction for 36 Months with Ivabradine Reduces Left Ventricular Mass in Cardiac Allograft Recipients

Purpose: Proliferation signal inhibitors (PSI, sirolimus and everolimus) have been extensively used in renal-sparing immunosuppressive regimes both as substitutes for calcineurin-inhibitors (conversion protocols, CON) or combined with reduced CNI dosages (minimization protocols, MIN). We compare both strategies in a large multi-center cohort of long-term heart transplant recipients. Methods and Materials: We retrospectively studied 394 pts. with a MDRD baseline GFR 60 mL/min/1.73 m2. PSI were initiated 8.2 4.4 years after transplantation. A propensity score was used to account for the differences in baseline covariates between CON and MIN pts. and for obtaining matched cohorts of both strategies. The change rate in GFR was analyzed at a mean of 29 months after PS

Reply to Raza et al. The role of pre-conversion glomerular filtration rate in predicting long-term renal function after conversion to proliferation signal inhibitors in long-term heart transplant recipients

1. Gonzalez-Vilchez F, Vazquez de Prada JA, Castrillo C, Canteli A, Liano MF, Martin-Duran R. Predictors of long-term renal function after conversion to proliferation signal inhibitors in long-term heart transplant recipients. J Heat Lung Transplant 2011;30:552-7. 2. Ayub-Ferreira SM, Avilla MS, Feitosa FS, Souza GE, et al. Recovery of renal function in heart transplantation patients after conversion from a calcineurin inhibitor-based therapy to sirolimus. Transplant Proc 2010; 42; 542-4. 3. Groetzner J, Kaczmarek I, Landwehr P, et al. Renal recovery after conversion to a calcineurin inhibitor-free immunosuppression in late cardiac transplant recipients. Eur J Cardiothorac Surg 2004;25:333-41. 4. Raichlin E, Khalpey Z, Kremers W, et al. Replacement of calcineurininhibitors with sirolimus as primary immunosuppression in stable cardiac transplant recipients. Transplantation 2007;84:467-74.

The role of pre-conversion glomerular filtration rate in predicting long-term renal function after conversion to proliferation signal inhibitors in long-term heart transplant recipients

The role of pre-conversion glomerular filtration rate in predicting long-term renal function after conversion to proliferation signal inhibitors in long-term heart transplant recipients

Effect of High Intensity Exercise on Peak Oxygen Uptake and Endothelial Function in Long-Term Heart Transplant Recipients

Coronary allograft vasculopathy is a well-known long-term complication after cardiac transplantation. Endothelial dysfunction is involved and may be prevented by aerobic exercise. The purpose of this study was to examine whether high intensity aerobic exercise improves peak oxygen uptake (VO(2 peak) ) and endothelial function in heart transplant (HT) recipients. Twenty-seven long-term HT recipients were randomized to either 8-weeks high intensity aerobic exercise or no training. Flow mediated dilation of the brachial artery (FMD) was measured by ultrasound and VO(2 peak) by the analysis of expired air. Blood pressure and biomarkers were measured before and after 8 weeks. VO(2 peak) increased significantly in the exercise group (VO(2 peak) 23.9 ± 1.79 to 28.3 ± 1.63 mL/kg/min compared to controls (VO(2 peak) 24.6 ± 1.38 to 23.4 ± 1.58, p < 0.001 exercise vs. control).FMD increased in the exercise group compared to controls (8.3 ± 1.1% to 11.4 ± 1.2% vs. 5.6 ± 1.0% to 5.3 ± 1.7%, p = 0.024). No increase in nitroglycerin-induced vasodilation was observed. Systolic blood pressure fell in the exercise group (142 ±4.2 mmHg to127 ± 3.4 mmHg, p = 0.01) and was unchanged in controls (141 ± 4.2 mmHg to 142 ±6.4 mmHg, NS). High intensity aerobic exercise reduces systolic blood pressure and improves endothelial function in HT recipients.

Predictors of long-term renal function after conversion to proliferation signal inhibitors in long-term heart transplant recipients

The purpose of this study was to evaluate the change in renal function and its determinants after replacement of calcineurin inhibitors with a proliferation signal inhibitor (sirolimus or everolimus) in long-term heart transplant recipients. We studied 49 consecutive patients in whom a switch to a proliferation signal inhibitor was carried out 9 ± 4 years after transplantation. Evolutive glomerular filtration rate was assessed at a mean of 28 months after conversion by the simplified MDRD equation. Pre-conversion glomerular filtration rate (40 ± 22 ml/min/1.73 m(2)) remained stable at 1 year after conversion (41 ± 22 ml/min/1.73 m(2)), but decreased significantly by the end of follow-up (35 ± 22 ml/min/1.73 m(2); p = 0.008 and p = 0.002 vs pre-conversion and 1-year values, respectively). In a multivariate model, including age, time from transplantation to conversion, pre-conversion glomerular filtration rate, presence of diabetes and use of angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (ACEI/ARB) therapy, the rate of decline in renal function was related only to the presence of diabetes (p = 0.017) and inversely related to the use of ACEI/ARB therapy (p = 0.003). There were no significant differences with respect to age, time between transplantation and replacement and baseline glomerular filtration rate. In long-term heart transplant recipients, late substitution of a calcineurin inhibitor for a proliferation signal inhibitor does not preclude a decrease in renal function in the long-term setting. We identified the presence of diabetes as the main clinical predictor of renal function deterioration. In contrast, we found that the use of ACEI/ARB therapy could exert a protective effect.

Causal relationships between heart period and systolic arterial pressure during graded head-up tilt

In physiological conditions, heart period (HP) affects systolic arterial pressure (SAP) through diastolic runoff and Starling's law, but, the reverse relation also holds as a result of the continuous action of baroreflex control. The prevailing mechanism sets the dominant temporal direction in the HP-SAP interactions (i.e., causality). We exploited cross-conditional entropy to assess HP-SAP causality. A traditional approach based on phases was applied for comparison. The ability of the approach to detect the lack of causal link from SAP to HP was assessed on 8 short-term (STHT) and 11 long-term heart transplant (LTHT) recipients (i.e., less than and more than 2 yr after transplantation, respectively). In addition, spontaneous HP and SAP variabilities were extracted from 17 healthy humans (ages 21-36 yr, median age 29 yr; 9 females) at rest and during graded head-up tilt. The tilt table inclinations ranged from 15 to 75° and were changed in steps of 15°. All subjects underwent recordings at every step in random order. The approach detected the lack of causal relation from SAP to HP in STHT recipients and the gradual restoration of the causal link from SAP to HP with time after transplantation in the LTHT recipients. The head-up tilt protocol induced the progressive shift from the prevalent causal direction from HP to SAP to the reverse causality (i.e., from SAP to HP) with tilt table inclination in healthy subjects. Transformation of phases into time shifts and comparison with baroreflex latency supported this conclusion. The proposed approach is highly efficient because it does not require the knowledge of baroreflex latency. The dependence of causality on tilt table inclination suggests that "spontaneous" baroreflex sensitivity estimated using noncausal methods (e.g., spectral and cross-spectral approaches) is more reliable at the highest tilt table inclinations.

Results With Cyclosporine Monotherapy in Long-Term Cardiac Transplant Recipients

Background Triple therapy is the gold standard after heart transplantation while few reports have described experiences with cyclosporine monotherapy (CM). We have analyzed our experience with CM in long-term heart transplant recipients, surviving >5 years. Methods Of the 219 patients transplanted between January 1990 and December 1998, 143 survived >5 years (mean age, 49.6 ± 10.4). There were 124 (86.7%) male subjects. Matching patients respect to follow-up length, we obtained 2 groups: group A of 41 patients on double therapy (DT; cyclosporine plus Azathioprine) and group B of 41 patients on CM. Results After a mean follow-up of 119.8 ± 32.2 months, we did not observe a significant difference in terms of survival and major events: heart failure, malignancy, dialysis, infections, and CAV. Conclusion We strongly support the use of triple therapy in cardiac transplant recipients because of its known safety and efficacy. However, our experience with CM suggests the utility of this approach.

The impact of everolimus versus mycophenolate on blood and lymphocyte cyclosporine exposure in heart-transplant recipients

Trough- or 2-h post-dose (C2) blood cyclosporine (CsA) concentrations are used for prediction of efficacy and toxicity of CsA in transplant recipients concomitantly treated with antiproliferative agents, but information on utility of blood CsA levels in patients treated with proliferation signal inhibitors (PSIs), such as everolimus, is sparse. Because of the inhibitory effect of PSIs on the P-glycoprotein drug efflux pump present in lymphocytes, we hypothesized that CsA pharmacokinetics in blood and lymphocytes were dissociated in patients concomitantly treated with everolimus. Twelve-hour pharmacokinetic studies of whole-blood and intralymphocytic CsA concentrations were conducted in long-term heart-transplant recipients treated with mycophenolate mofetil (MMF) + CsA (n = 8) and everolimus + CsA (n = 9). There was a highly significant correlation between blood CsA C2 levels and blood CsA AUC(0-12) in groups of patients treated with MMF or everolimus (R(2) 0.93 and 0.96, respectively; P < 0.001 for both). Whereas blood CsA C2 levels were closely associated with lymphocyte CsA AUC(0-12) in patients treated with MMF (R(2) = 0.98), there was poor correlation between whole-blood C2 and lymphocyte AUC(0-12) in patients treated with everolimus (R(2) = 0.24). Standard blood CsA levels accurately predict intralymphocytic exposure to CsA in patients concomitantly treated with MMF but not in patients treated with everolimus.

34: C4d Detection and Outcome in Long-Term Heart Transplant Recipients

Although the concept of antibody mediated rejection (AMR) has been associated with poor outcome in heart transplant (HT) recipients since long ago, only recently pathological criteria for its diagnosis have been standardized. Nevertheless, clinical correlates of criteria for AMR in endomyocardial biopsies (EMB) are poorly characterized. In this report, we analyzed the association of intravascular C4d detection with morphological criteria for AMR, hemodynamic features, and survival in mid and long-term HT recipients.

Serum Testosterone Levels After Cardiac Transplantation

Men undergoing heart transplantation during the early 1990s had declines in testosterone associated with rapid bone loss. It is unclear whether low testosterone still occurs in an era of lower prednisone doses, whether cyclosporine A (CsA) contributes, whether hypothalamic-pituitary-gonadal (HPG) suppression or direct testicular effects are responsible, and whether low testosterone influences bone loss in men receiving therapy to prevent osteoporosis. Serum testosterone, estradiol, sex hormone binding globulin, gonadotropins, and bone density were measured and prednisone and CsA doses and levels for the first 2 years after transplantation were recorded in a more recently transplanted cohort of 108 participants in a trial comparing alendronate and calcitriol for prevention of posttransplant osteoporosis. Total and free testosterone levels were lowest during the first month (257+/-131 and 6.2+/-3 ng/dL, respectively) and normalized by 2 months. Gonadotropins were low in the majority, suggesting HPG suppression. Low total testosterone persisted in 14% at 1 year and 18% at 2 years. Prednisone was the major predictor of serum testosterone. No adverse effect of CsA and no relationship between serum testosterone and bone density change were detected. Low serum testosterone levels still occur in the early posttransplant period, probably related to HPG suppression by prednisone rather than direct testicular effects of CsA. They are not associated with bone loss in men receiving therapies to prevent osteoporosis. At later time points, low testosterone levels are common and apparently related to primary gonadal dysfunction, suggesting that long-term male heart transplant recipients should be evaluated for hypogonadism.

Assessment of Cyclosporine Pharmacokinetic Parameters to Facilitate Conversion From C0 to C2 Monitoring in Heart Transplant Recipients

Background Cyclosporine (CsA) 2-hour postdose (C2) monitoring is recommended to assess CsA exposure and predict clinical outcomes among heart transplant recipients. We correlated pharmacokinetic parameters and clinical outcomes in stable long-term heart transplant recipients monitored with C0 to develop an algorithm to convert patients from C0 to C2 monitoring. Methods Paired CsA C0-C2 measurements and serum creatinine levels were obtained from 35 heart transplant recipients more than 2 years posttransplantation (mean 8.8 ± 4.7 years). Results The mean CsA dose and C0, C2, and C0/C2 ratio were 85 ± 23 mg/12 hours, 123 ± 41 ng/mL, 572 ± 274 ng/mL and 4.8 ± 2.1, respectively. C0 correlated weakly with C2 ( r = .42, P = .011). The CsA dose correlated better with C2 ( r = .58; P < .001) than with C0 ( r = .37; P = .026). A good correlation was noted between C2 and the C2/C0 ratio ( r = .73; P < .001), but none between C0 and the C2/C0 ratio. A borderline significant inverse correlation was noted between C0 and the worst endomyocardial biopsy score ( r = −.34; P = .045), whereas none was noted with C2. Serum creatinine level did not correlate with either C2 or C0. Among patients with C0 within our target of 100 to 150 ug/L, six had C2 above 300 to 600 ug/L as suggested by the literature. Conclusions In long-term heart transplant recipients, we could not identify a single pharmacokinetic parameter that could be used to develop an algorithm to convert from C0 to C2 monitoring; however, C2 may be better than C0 for identifying patients at risk of overexposure to CsA.