A. H. M. M. Balk

Prediction of Improvement of Regional Left Ventricular Function After Surgical Revascularization A Comparison of Low-Dose Dobutamine Echocardiography With 201Tl Single-Photon Emission Computed Tomography

BACKGROUND Although both 201Tl scintigraphy and low-dose dobutamine echocardiography (LDDE) have been proposed as effective methods of assessing myocardial viability, their relative efficacies are unknown. The aim of the present study was to compare the two imaging techniques in the prediction of improvement of regional left ventricular (LV) function after surgical revascularization. METHODS AND RESULTS Thirty-eight patients with severe chronic LV dysfunction (ejection fraction < or = 40%, one or more akinetic [Ak] or severely hypokinetic [SH] segments on resting echocardiogram) who underwent uncomplicated coronary artery bypass graft surgery were studied with simultaneous dobutamine stress echocardiography and poststress reinjection 201Tl single-photon emission computed tomography (SPECT) before surgery. The Ak or SH segments were considered viable by LDDE when wall thickening improved during the infusion of 10 micrograms.kg-1 min 1 dobutamine. Scintigraphic definition of viability was the presence of normal 201Tl uptake, totally reversible defect, partially reversible defect, or moderately severe fixed defect. The postoperative improvement of dyssynergic segments was determined with a rest echocardiogram 3 months after surgery. Of 608 LV segments, 169 were classified as Ak and 51 as SH on resting preoperative echocardiography. Of these, 170 were successfully revascularized. Wall motion during LDDE improved in 33 severely dyssynergic segments and was more frequent in SH than in Ak segments (19 of 44 versus 14 of 126, P < .0001). Viability was detected by 201Tl SPECT criteria in 103 SH or Ak segments. Thirty-two of the 33 segments from LDDE responders were judged viable on 201Tl SPECT, whereas 201Tl viability was also detected in 71 of 137 segments from LDDE nonresponders. The sensitivity and the specificity for the prediction of postoperative improvement of segmental wall motion were 74% (95% confidence interval [CI], 67% to 81%) and 95% (95% CI, 92% to 98%) by LDDE and 89% (95% CI, 84% to 94%) and 48% (95% 40% to 56%) by 201Tl SPECT, respectively. Positive predictive value of LDDE was higher than that of 201Tl SPECT (85%, [95% CI, 80% to 90%] versus 33% [95% CI, 26% to 40%]). Thirty-six patients had angina before and only 1 had angina 3 months after revascularization. High-dose dobutamine echocardiography demonstrated significant reduction in stress-induced ischemia (new or worsening of preexisting wall motion abnormalities) after surgery (from 163 to 23 LV segments). CONCLUSIONS In patients with severe chronic LV dysfunction, LDDE is a good predictor of the improvement of dyssynergic segments after revascularization. Because 201Tl SPECT overestimates the probability of postoperative improvement of dyssynergic segments, LDDE should be the preferred imaging technique for preoperative assessment of these patients.

Differential effect of calcineurin inhibitors, anti-CD25 antibodies and rapamycin on the induction of FOXP3 in human T cells.

Background. The transcription factor FOXP3 has been identified as the molecule associated with the regulatory function of CD25+ T cells. Methods. To understand the biology of FOXP3+ T cells in allogeneic reactions, we measured FOXP3 mRNA expression levels in allostimulated CD25 bright+ cells and CD25 intermediate( int)/- cells and in peripheral blood mononuclear cells (PBMC). The effect of immunosuppressive drugs on FOXP3 expression was studied in mixed lymphocyte reactions (MLR) in the presence and absence of calcineurin inhibitors (CNI), &agr;CD25 mAb, and Rapamycin (Rapa), and analyzed in biopsies from cardiac allograft recipients during acute rejection by quantitative (Q)-PCR. Results. FOXP3 mRNA expression was restricted to the CD25 bright+ population that inhibited the proliferation of allostimulated CD25 int/- cells. In the MLR FOXP3 was readily induced after allostimulation. Kinetic examination of the MLR showed a 10–20-fold higher FOXP3 mRNA expression level after 5 days of culture. The CNI Cyclosporin and Tacrolimus, and &agr;CD25 mAb inhibited in vitro induced FOXP3 gene transcription (range 70%–90%), whereas Rapa did not inhibit the induction. After clinical heart transplantation the highest FOXP3 mRNA expression levels were measured in biopsies during acute rejection (P=0.03). Conclusions. The high FOXP3 mRNA levels during allogeneic responses in vivo and in vitro suggests that regulatory activities of CD25 bright+ T cells or the generation of these cells is an intrinsic part of activation. CNI and &agr;CD25 mAb in contrast to Rapa, did interfere with this immunosuppressive counter-mechanism and as a result might have an inhibitory effect to tolerance induction after transplantation.

Population pharmacokinetics of cyclosporine in kidney and heart transplant recipients and the influence of ethnicity and genetic polymorphisms in the MDR-1, CYP3A4, and CYP3A5 genes

Our objective was to determine the relationship between single nucleotide polymorphisms (SNPs) in the multidrug resistance 1 (MDR‐1) gene and the cytochrome P450 (CYP) genes CYP3A4 and CYP3A5 and the pharmacokinetics of cyclosporine (INN, ciclosporin).

Management of Chronic Heart Failure Guided by Individual N-Terminal Pro-B-Type Natriuretic Peptide Targets Results of the PRIMA (Can PRo-brain-natriuretic peptide guided therapy of chronic heart failure IMprove heart fAilure morbidity and mortality?) Study

OBJECTIVES The purpose of this study was to assess whether management of heart failure (HF) guided by an individualized N-terminal pro-B-type natriuretic peptide (NT-proBNP) target would lead to improved outcome compared with HF management guided by clinical assessment alone. BACKGROUND Natriuretic peptides may be attractive biomarkers to guide management of heart failure (HF) and help select patients in need of more aggressive therapy. The PRIMA (Can PRo-brain-natriuretic peptide guided therapy of chronic heart failure IMprove heart fAilure morbidity and mortality?) study is, to our knowledge, the first large, prospective randomized study to address whether management of HF guided by an individualized target NT-proBNP level improves outcome. METHODS A total of 345 patients hospitalized for decompensated, symptomatic HF with elevated NT-proBNP levels at admission were included. After discharge, patients were randomized to either clinically-guided outpatient management (n = 171), or management guided by an individually set NT-proBNP (n = 174) defined by the lowest level at discharge or 2 weeks thereafter. The primary end point was defined as number of days alive outside the hospital after index admission. RESULTS HF management guided by this individualized NT-proBNP target increased the use of HF medication (p = 0.006), and 64% of HF-related events were preceded by an increase in NT-proBNP. Nevertheless, HF management guided by this individualized NT-proBNP target did not significantly improve the primary end point (685 vs. 664 days, p = 0.49), nor did it significantly improve any of the secondary end points. In the NT-proBNP-guided group mortality was lower, as 46 patients died (26.5%) versus 57 (33.3%) in the clinically-guided group, but this was not statistically significant (p = 0.206). CONCLUSIONS Serial NT-proBNP measurement and targeting to an individual NT-proBNP value did result in advanced detection of HF-related events and importantly influenced HF-therapy, but failed to provide significant clinical improvement in terms of mortality and morbidity. (Effect of NT-proBNP Guided Treatment of Chronic Heart Failure [PRIMA]; NCT00149422).

Intracranial hemorrhage in association with thrombolytic therapy : incidence and clinical predictive factors

In a period of 18 months, 2,469 patients with acute myocardial infarction treated with a thrombolytic agent were prospectively registered in 61 hospitals. Most patients (73%) were treated with streptokinase. Intracranial hemorrhage was observed in 24 patients, corresponding to an incidence rate of 1% (95% confidence interval 0.6% to 1.3%). The median time interval between the start of thrombolytic therapy and the first clinical signs of intracranial bleeding was 16 h (range 3 to 36). In total, 16 (66%) of the 24 patients died as a result of cerebral hematoma. To determine clinical predictive factors, a case-control study was conducted. For every patient with intracranial hemorrhage, two control patients who received thrombolytic therapy because of acute infarction in the same hospital and in the same period were selected. Detailed clinical characteristics of 22 of the 24 patients as well as of 7 other patients with documented intracerebral bleeding from the European Cooperative Study Group and of 2 patients who sustained intracranial hemorrhage outside the registry period were compared with 62 control patients. The results of multivariate logistic regression analysis indicate that patients taking an oral anticoagulant before admission, patients with a body weight less than 70 kg and those greater than 65 years old are at higher risk for intracranial hemorrhage during thrombolytic therapy.

Time course of the decline in renal function in cyclosporine-treated heart transplant recipients

The renal side-effects are a major limitation of the use of cyclosporine A (CsA) following heart transplantation. In an effort to define the time course of the decline in renal function and to identify a group of patients especially prone to the nephrotoxic effects of CsA, we studied 187 orthotopic heart transplant recipients who had a follow-up of at least 1 month. All patients received oral CsA in a starting dose of 8 mg/kg and low-dose steroids. Renal function decreased steadily after transplantation. Serum creatinine was > 150 mumol/l in 52% of the patients after 2 years. After 4 years serum creatinine was > 250 mumol/l in 13% of the patients. No relation could be found between the decline in renal function (as defined by the slope of serum creatinine-1 versus time) and age, sex, creatinine levels before transplantation, blood pressure, CsA blood levels, the number of rejections or the use of calcium channel blocking drugs. We conclude that, despite reduction of CsA dosage, progressive renal insufficiency can be observed in an increasing percentage of heart transplant recipients. We were not able to identify patients with a poor renal prognosis in an early phase after transplantation.

Hepatitis E virus infection among solid organ transplant recipients, the Netherlands

We screened 1,200 living heart, lung, liver, and kidney transplant recipients for hepatitis E virus infection by reverse transcription PCR. In 12 (1%) patients, hepatitis E virus infection was identified; in 11 patients, chronic infection developed. This immunocompromised population is at risk for hepatitis E virus infection.

Does aerobic training lead to a more active lifestyle and improved quality of life in patients with chronic heart failure

Due to dyspnea and fatigue, patients with chronic heart failure (CHF) are often restricted in the performance of everyday activities, which gradually may lead to hypoactivity.

VALIDITY OF AMBULATORY ACCELEROMETRY TO QUANTIFY PHYSICAL ACTIVITY IN HEART FAILURE

The purpose was to assess the validity of a novel Activity Monitor to quantify physical activity in congestive heart failure. The Activity Monitor is based on long-term ambulatory monitoring of signals from body-fixed accelerometers. Information can be obtained on which mobility-related activity is performed, when, how intense, and for how long. Ten patients performed several functional activities. Continuous registrations of accelerometer signals were made and the output was compared with visual analysis of simultaneously made video recordings (reference method). Overall results showed an agreement between both methods of 90%. Percentages of sensitivity and predictive value were higher than 80% for most activities. Overall number of transitions was determined well (Activity Monitor, 153; video, 149; p = 0.33). It was concluded that the Activity Monitor is a valid instrument to quantify several aspects of everyday physical activity in congestive heart failure.

Susceptibility of human mesenchymal stem cells to tacrolimus, mycophenolic acid, and rapamycin.

Background. Mesenchymal stem cells (MSC) have multilineage differentiation and immunomodulatory capacities and are potentially useful for therapeutic applications, such as tissue regeneration and control of alloreactivity. MSC are present in most tissues including the transplantable organs. It is therefore unavoidable that MSC will be exposed to immunosuppressive drugs in a clinical transplantation setting. The molecular targets of these drugs are expressed in MSC, but the effect of their inhibition on MSC functioning is unknown. Methods. MSC were isolated and expanded from heart tissue and the effects of the calcineurin inhibitor tacrolimus, the cell cycle inhibitor mycophenolic acid (MPA), and the mammalian target of rapamycin inhibitor on MSC survival, proliferation, differentiation, and immunosuppressive capacity were examined. Results. Short-term exposure to the immunosuppressants did not induce toxicity or apoptosis in MSC, but high-dose tacrolimus induced toxicity after 7 days. MPA and rapamycin inhibited MSC proliferation at therapeutic doses. The immunosuppressants had differential effects on the differentiation capacity of MSC. Tacrolimus reduced the expression of troponin T type 2 and desmin during cardiomyogenic differentiation of MSC, whereas MPA decreased the deposition of calcified minerals during osteogenic differentiation. Rapamycin stimulated lipid production during adipogenic differentiation. Unexpectedly, MSC had adverse effects on the immunosuppressive efficacy of tacrolimus and rapamycin. There was no such effect of MSC on the function of MPA. Preincubation of MSC with tacrolimus increased the immunosuppressive capacity of MSC. Discussion. This study demonstrates that therapeutic concentrations of immunosuppressive drugs affect MSC function. MSC affect the efficacy of immunosuppressive medication. These findings are important for potential clinical use of MSC in combination with immunosuppressants.