Unbound Plasma, Total Plasma, and Whole-Blood Tacrolimus Pharmacokinetics Early After Thoracic Organ Transplantation.

BACKGROUND AND OBJECTIVE: Therapeutic drug monitoring of tacrolimus whole-blood concentrations is standard care in thoracic organ transplantation. Nevertheless, toxicity may appear with alleged therapeutic concentrations possibly related to variability in unbound concentrations. However, pharmacokinetic data on unbound concentrations are not available. The objective of this study was to quantify the pharmacokinetics of whole-blood, total, and unbound plasma tacrolimus in patients early after heart and lung transplantation. METHODS: Twelve-hour tacrolimus whole-blood, total, and unbound plasma concentrations of 30 thoracic organ recipients were analyzed with high-performance liquid chromatography-tandem mass spectrometry directly after transplantation. Pharmacokinetic modeling was performed using non-linear mixed-effects modeling. RESULTS: Plasma concentration was < 1% of the whole-blood concentration. Maximum binding capacity of erythrocytes was directly proportional to hematocrit and estimated at 2700 pg/mL (95% confidence interval 1750-3835) with a dissociation constant of 0.142 pg/mL (95% confidence interval 0.087-0.195). The inter-individual variability in the binding constants was considerable (27% maximum binding capacity, and 29% for the linear binding constant of plasma). CONCLUSIONS: Tacrolimus association with erythrocytes was high and suggested a non-linear distribution at high concentrations. Monitoring hematocrit-corrected whole-blood tacrolimus concentrations might improve clinical outcomes in clinically unstable thoracic organ transplants. CLINICAL TRIAL REGISTRATION: NTR 3912/EudraCT 2012-001909-24.

High Variability of Whole-Blood Tacrolimus Pharmacokinetics Early After Thoracic Organ Transplantation.

BACKGROUND AND OBJECTIVE: Oral tacrolimus is initiated perioperatively in heart and lung transplantation patients. There have been few studies on oral tacrolimus pharmacokinetics early post-transplantation, even though tacrolimus-related toxicity may occur early, potentially leading to morbidity and mortality. Therefore, we aimed to study the pharmacokinetics of oral tacrolimus in thoracic organ recipients during the first days after transplantation. METHODS: We conducted a pharmacokinetic study in 30 thoracic organ transplants at intensive care at the University Medical Center Utrecht in the first week post-transplantation. Twelve-hour whole-blood tacrolimus profiles were examined using high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) and analysed via population pharmacokinetic modelling. RESULTS: The concentration-time profiles showed high variability. Concentrations at 12 h were outside the target range in 69% of the cases. A two-compartment model with mixed first-order and zero-order absorption adequately described tacrolimus concentrations. The typical value of the apparent clearance was 19.6 L/h (95% CI 16.2-22.9), and the apparent distribution volumes of central and peripheral compartments, V1 and V2, were 231 L (95% CI 199-267) and 521 L (95% CI 441-634), respectively. Inter-occasion (dose-to-dose) variability far exceeded the interindividual variability (IIV), with an estimated variability in relative bioavailability of 55% (95% CI 48.5-64.4). CONCLUSIONS: The high variability of tacrolimus pharmacokinetics early after thoracic organ transplantation is largely due to excessive variability in bioavailability, making individualised dosing based on measured concentrations futile. To bypass this bioavailability issue, we suggest administering tacrolimus intravenously and aiming below the upper therapeutic range early post-transplantation. Clinical Trial Registraion: NTR 3912/EudraCT 2012-001909-24.

Association of Whole Blood Tacrolimus Concentrations with Kidney Injury in Heart Transplantation Patients.

BACKGROUND AND OBJECTIVES: Acute kidney injury (AKI) is frequently observed after heart transplantation and is associated with morbidity and mortality. However, many confounding factors also contribute to the development of AKI in heart transplants. We hypothesized that supratherapeutic whole-blood tacrolimus trough concentrations are associated with AKI. METHODS: In a retrospective observational cohort from April 2005 to December 2012, all adult heart transplantation patients were included. AKI was assessed in the first 2 weeks after transplantation as classified by the Kidney Disease Improving Global Outcomes Network (KDIGO). Whole-blood tacrolimus trough concentrations were determined from day 1 to day 14 and at 1, 3, 6 and 12 months post-transplantation. The therapeutic range was 9 to 15 ng/ml in the first 2 months and tapered to 5-8 ng/ml thereafter. The relationship between supratherapeutic tacrolimus trough concentrations and AKI was evaluated. The impact of various potentially confounding factors on tacrolimus concentrations and AKI was considered. RESULTS: We included 110 patients. AKI occurred in 57% of patients in the first week. Recovery from AKI was seen in 24%. The occurrence of chronic kidney disease (CKD) was 19% at 1 year. Whole-blood tacrolimus trough concentrations were often supratherapeutic and, despite correction for confounding factors, independently associated with AKI (OR 1.66; 95% CI 1.20-2.31). CONCLUSIONS: Supratherapeutic whole-blood tacrolimus trough concentrations are independently associated with the development of AKI in adult heart transplantation patients. More stringent dosing of tacrolimus early after transplantation may be critical in preserving the kidney function.

Heterogeneous Connexin43 distribution in heart failure is associated with dispersed conduction and enhanced susceptibility to ventricular arrhythmias.

AIMS: Sudden arrhythmogenic cardiac death is a major cause of mortality in patients with congestive heart failure (CHF). To investigate determinants of the increased arrhythmogenic susceptibility, we studied cardiac remodelling and arrhythmogenicity in CHF patients and in a mouse model of chronic pressure overload. METHODS AND RESULTS: Clinical and (immuno)histological data of myocardial biopsies from CHF patients with (VT+) and without (VT-) documented ventricular arrhythmia were compared with controls. In CHF patients, ejection fraction was decreased and QRS duration was increased. Cell size and interstitial fibrosis were increased, but Connexin43 (Cx43) levels, the most abundant gap junction in ventricular myocardium, were unchanged. No differences were found between VT+ and VT- patients, except for the distribution pattern of Cx43, which was significantly more heterogeneous in VT+. Mice were subjected to transverse aortic constriction (TAC) or sham operated. At 16 weeks, cardiac function was determined by echocardiography and epicardial ventricular activation mapping was performed. Transverse aortic constriction mice had decreased fractional shortening and prolonged QRS duration. Right ventricular conduction velocity was reduced, and polymorphic VTs were induced in 44% TAC and 0% sham mice. Interstitial fibrosis was increased and Cx43 quantity was unchanged in TAC mice with and without arrhythmias. Similar to CHF patients, heterogeneous Cx43 distribution was significantly associated with arrhythmias in TAC mice and with spatial heterogeneity of impulse conduction. CONCLUSION: Heterogeneous Cx43 expression during CHF is associated with dispersed impulse conduction and may underlie enhanced susceptibility to ventricular tachyarrhythmias.

Unrecognized heart failure in elderly patients with stable chronic obstructive pulmonary disease.

AIMS: To establish the prevalence of unrecognized heart failure in elderly patients with a diagnosis of chronic obstructive pulmonary disease, in a stable phase of their disease. METHODS AND RESULTS: In a cross-sectional study, patients >/=65 years of age, classified as having chronic obstructive pulmonary disease by their general practitioner and not known with a cardiologist-confirmed diagnosis of heart failure, were invited to our out-patient clinic. Four hundred and five participants underwent an extensive diagnostic work-up, including medical history and physical examination, followed by chest radiography, electrocardiography, echocardiography, and pulmonary function tests. As reference (i.e. 'gold') standard the consensus opinion of an expert panel was used. The panel based the diagnosis of heart failure on all available results from the diagnostic assessment, guided by the diagnostic principles of the European Society of Cardiology (ESC) for heart failure (i.e., symptoms and echocardiographic systolic and/or diastolic dysfunction). The diagnosis of chronic obstructive pulmonary disease was based on the diagnostic criteria of the Global Initiative (GOLD) for chronic obstructive pulmonary disease. Of 405 participating patients with a diagnosis of chronic obstructive pulmonary disease, 83 (20.5%, 95% CI 16.7-24.8) had previously unrecognized heart failure (42 patients systolic, 41 'isolated' diastolic, and none right-sided heart failure). In total, 244 (60.2%) patients had chronic obstructive pulmonary disease according to the GOLD criteria and 50 (20.5%, 95% CI 15.6-26.1) patients combined with unrecognized heart failure. CONCLUSION: Unrecognized heart failure is very common in elderly patients with stable chronic obstructive pulmonary disease. Closer co-operation among general practitioners, pulmonologists, and cardiologists is necessary to improve detection and adequate treatment of heart failure in this large patient population.

Gender disparities in cardiac cellular electrophysiology and arrhythmia susceptibility in human failing ventricular myocytes.

Gender disparities in ECG variables and susceptibility to arrhythmia exist. The basis of these sex-related distinctions in cardiac electrophysiology has been extensively studied in various species, but is virtually unexplored in humans. The aim of this study was to clarify the cellular basis of electrophysiological gender disparities in human cardiac myocytes. Human midmyocardial left ventricular myocytes were isolated from explanted hearts of male and female patients in end-stage heart failure at the time of cardiac transplantation. The action potentials, sarcolemmal ion currents, and susceptibility to the generation of early afterdepolarizations were studied using whole-cell patch-clamp methodology. The functional effects of gender disparities in sarcolemmal ion currents were assessed by computer simulations using the Priebe-Beuckelmann or the ten Tusscher-Noble-Noble-Panfilov human ventricular cell models. Female myocytes had significantly longer action potentials and greater susceptibility to early afterdepolarizations than male myocytes. All other action potential parameters (resting membrane potential, amplitude, plateau level, upstroke velocity, maximal velocity of phase-1 and phase-3 repolarization) had similar values for both genders. In female myocytes, the transient outward potassium current (I(to1)) tended to be smaller, while the L-type calcium current (I(Ca,L)) and quasi-steady state current (I(QSS)) tended to be larger. Computer simulations showed that these subtle differences in sarcolemmal ion currents may conspire to cause the observed gender disparities in action potential properties. Female failing myocytes have longer action potentials and a greater susceptibility to early afterdepolarizations than male failing myocytes. These gender disparities may be due to slightly larger depolarizing I(Ca,L) in conjunction with slightly smaller repolarizing I(QSS) and I(to1) in female myocytes.

Clinical efficacy of cardiac resynchronization therapy using left ventricular pacing in heart failure patients stratified by severity of ventricular conduction delay.

OBJECTIVES: We assessed the clinical efficacy of single-site left ventricular (LV) pacing and determined the impact of baseline conduction delay severity on the magnitude of benefit. BACKGROUND: Multisite biventricular pacing can improve heart failure (HF) symptoms in patients with an intraventricular conduction delay by resynchronizing abnormal ventricular contractions and improving LV systolic function. METHODS: Eighty-six patients with at least New York Heart Association functional class II HF, chronic LV systolic dysfunction, normal sinus rhythm, and a QRS interval over 120 ms were implanted for atrial-synchronized LV pacing. The single-blinded, randomized, controlled, crossover study stratified patients 1:1 by the baseline QRS interval into long (QRS >150 ms) and short (QRS 120 to 150 ms) groups, which were compared during a three-month period of active (univentricular) pacing and a three-month period of inactive (ventricular inhibited) pacing. The primary end point was peak oxygen consumption (VO(2)) followed by anaerobic threshold, distance walked in 6 min, and quality-of-life questionnaire score. PATIENTS: Twelve patients were withdrawn before randomization and 17 could not complete both study periods. The short QRS group did not improve in any end point with active pacing. For the long QRS group, peak VO(2) increased 2.46 ml/min/kg (p < 0.001), the anaerobic threshold increased 1.55 ml/min/kg (p < 0.001), the distance walked in 6 min increased 47 m (p = 0.024), and the quality-of-life score improved 8.1 points (p = 0.004). CONCLUSIONS: Left ventricular pacing significantly improves exercise tolerance and quality of life in patients with chronic HF, LV systolic dysfunction, and a QRS interval over 150 ms.