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Nicolaas de Jonge

Publications and source records attributed to Nicolaas de Jonge.

11 recordsLinked to original sources
PubMed2006

The chemokine and chemokine receptor profile of infiltrating cells in the wall of arteries with cardiac allograft vasculopathy is indicative of a memory T-helper 1 response.

BACKGROUND: Despite improvement in short-term patient survival after heart transplantation (HTx), long-term survival rates have not improved much, mainly because of cardiac allograft vasculopathy (CAV). Cytokines and chemokines are considered to play an important role in CAV development. METHODS AND RESULTS: We focused on coronary arteries of HTx patients and made an inventory of the infiltrating cells and the expression of cytokines as well as chemokines and chemokine receptors (C+CR) in the different layers of the vessel wall with CAV. Tissue slides were stained for a variety of cell markers (CD3, CD4, CD8, CD20, CD68, CD79a), chemokines (monokine induced by interferon [MIG], interferon-inducible protein 10 [IP-10], interferon-inducible T cell-alpha chemoattractant [ITAC], RANTES [regulated on activation normal T cell expressed and secreted], and fractalkine), and chemokine receptors (CXCR3, CCR5, and CX3CR1). In reference coronary arteries (not transplanted), almost no infiltrating cells were found, and in transplanted hearts with CAV (HTx+CAV), a large number of T cells were observed (CD4:CD8=2:1), mainly localized in the neointima and adventitia. Most of these T cells appeared to be activated (human leukocyte antigen DR positive). Coronary arteries from transplanted hearts without CAV (HTx-CAV), HTx+CAV, and references were also analyzed for cytokine and C+CR mRNA expression with the use of quantitative polymerase chain reaction. Interferon-gamma was highly expressed in HTx+CAV compared with HTx-CAV. Interleukin-4 and interleukin-10 were expressed at the same level in both HTx groups and references. In HTx+CAV, all C+CR, but especially the T-helper 1 (TH1) C+CR, were more abundant than in the HTx-CAV and references. However, TH2 CCR4 expression did not differ significantly between both HTx groups. CONCLUSIONS: In coronary arteries with CAV, most T cells are CD4+ and express human leukocyte antigen DR. These activated TH cells are mainly memory TH1 cells on the basis of their C+CR profile and cytokine expression.

Adolescent↗
PubMed2006

Reverse remodeling of the myocardial extracellular matrix after prolonged left ventricular assist device support follows a biphasic pattern.

BACKGROUND: Collagens are important components of the extracellular matrix (ECM). Alterations in collagen structure and composition can lead to end-stage heart failure. Left ventricular assist devices (LVADs) are frequently used as a bridge to heart transplantation (HTx). In this study, we analyzed changes in composition of the collagens as well as the synthesis or degradation of these collagens after prolonged LVAD support. METHODS: The ECM volume was quantified after Picro-Sirius red staining. With immunohistochemistry (IHC), Type I and Type III collagen proteins were analyzed and, using quantitative polymerase chain reaction (PCR), collagen mRNA expression was analyzed. Collagen synthesis and degradation was studied by measuring N-terminal pro-peptide for Type I collagen (PINP), N-terminal pro-peptide for Type III collagen (PIIINP) and carboxyterminal telopeptide for Type I collagen (ICTP) in plasma. Collagen composition was measured using the hydroxyproline/Sircol assay. RESULTS: The ECM volume increased in the first 200 days after LVAD implantation. At between 200 and 400 days the ECM volume decreased, but remained higher than pre-LVAD. After 400 days the ECM volume was smaller than the pre-LVAD volume. IHC did not show a significant difference pre- and post-LVAD for collagen composition. Collagen mRNA expression did not change but an augmented synthesis of collagen during the first month after LVAD support was detected upon measurement of plasma PINP and PIIINP levels. In addition, the quality of the collagen network improved. CONCLUSIONS: Reverse remodeling during LVAD support follows a biphasic pattern. Initially, an increase in Type I and Type III collagen turnover occurs, which is paralleled by a volume increase of the ECM. Subsequently, this turnover decreases as ECM volume decreases, which results in a restoration of the collagen network.

Adolescent↗
PubMed2006

Brain natriuretic peptide is produced both by cardiomyocytes and cells infiltrating the heart in patients with severe heart failure supported by a left ventricular assist device.

BACKGROUND: Brain natriuretic peptide (BNP) is a cardiac neurohormone synthesized in cardiac ventricles as a result of increased wall stress. Left ventricular assist device (LVAD) support in patients with end-stage heart failure results in reduced wall stress and therefore may change BNP levels in the heart. METHODS: BNP plasma levels were measured in 17 patients with end-stage HF before LVAD implantation and at 1 week, 1 month, and 3 months after LVAD support. BNP-messenger RNA (mRNA) expression in cardiac biopsy specimens of 27 patients before and after LVAD support was determined by quantitative polymerase chain reaction. Immunohistochemistry (IHC) and IHC-double staining was used in biopsy specimens from 32 patients before and after LVAD support to localize the BNP protein expression in the heart. RESULTS: BNP plasma levels significantly decreased from 1,872 +/- 1,098 pg/ml before implantation to 117 +/- 91 pg/ml at 3 months after LVAD implantation. This decrease in plasma levels was accompanied by a significant decrease in mRNA expression (relative quantity) in the heart. IHC and IHC-double staining showed BNP immunoreactivity in the cardiomyocytes, endothelial cells, infiltrating T cells, and macrophages. CONCLUSIONS: The significant decrease in serum BNP concentration after LVAD support coincides with a decrease in BNP mRNA and protein expression in the heart. BNP is produced in the left ventricle not only by cardiomyocytes but also by endothelial cells, T cells, and macrophages. Unloading of the left ventricle by a LVAD results in decreased BNP expression in the heart and plasma and may play an important role in the reverse remodeling process of the heart.

Adult↗
PubMed2006

Controlling cardiomyocyte survival.

Gradually the distinction between signalling pathways originally believed to be specific for either hypertrophy, cell cycle control, apoptosis and cell survival are fading. The subtle variations in stimuli to a cell and the microenvironment will determine cell fate. In cardiomyocytes the entrance into the cell cycle is efficiently blocked. Therefore attention has focused on pathways involved in hypertrophy to assess effects in ischaemic models and vice versa. Interventions at different levels have been shown to be cardiomyocyte protective. Various growth factors (including IGF1 and FGF1,2) have shown to prevent or delay cardiomyocyte loss in and ex vivo. Similar results have been reported for downstream interventions in the signalling pathways. Strong effects after MAPK activation have been shown in gene targeted mice. Especially constitutive activation of the ERK proteins prevents ischemic damage of the heart with conservation of left ventricular function. Evidence for a key role of nuclear Akt in preventing apoptosis is accumulating from various genetic and pharmacological sources. Development of techniques to measure the level of cardiomyocyte death depends on further improvements in molecular imaging in mouse and human. In addition to studying cardiomyocyte cell death, it is crucial to measure myocardial function. Whether hypertrophy following ischaemia is adaptive or maladaptive and whether all apoptosis is detrimental will have to be determined by assessment of left ventricular function through invasive and noninvasive methods.

Animals↗
PubMed2005

Similar left and right ventricular sarcomere structure after support with a left ventricular assist device suggests the utility of right ventricular biopsies to monitor left ventricular reverse remodeling.

BACKGROUND: To evaluate whether the morphology of the contractile filaments in cardiomyocytes of patients with end-stage heart failure, treated with a left ventricular assist device (LVAD), is identical in the left- and right ventricle (LV, RV) and in the interventricular septum (IVS) and can be monitored by biopsies taken with a bioptome. The application of an LVAD as a bridge to recovery of cardiac function requires monitoring of myocyte recovery. The use of RV biopsies for this purpose might be feasible, if morphologic findings in the RV coincide with those in the LV. METHODS AND RESULTS: At the time of heart transplantation, myocardial biopsies of LV, RV and IVS from 13 patients after LVAD support were compared using immunohistochemistry with monoclonal antibodies against contractile proteins. Additionally, in five of these patients, small biopsies obtained with a diagnostic bioptome were compared with large transmural biopsies of the same region. Hemodynamic monitoring was performed when the patients were fully recovered from the implantation, to rule out persistent RV failure. The staining pattern of actin, myosin, tropomyosin, troponin T and C was identical in the biopsies of LV, RV and IVS. Small biopsies taken with a bioptome appeared to be representative for the larger biopsies. Hemodynamic monitoring showed absence of RV failure in our study group. CONCLUSION: In the absence of RV failure, morphology of the contractile myofilaments after LVAD support for 215+/-143 days is identical in LV, RV and IVS. This may allow monitoring of the possible occurrence of LV reverse remodeling by RV biopsies.

Adolescent↗
PubMed2003

Cardiomyocyte death in patients with end-stage heart failure before and after support with a left ventricular assist device: low incidence of apoptosis despite ubiquitous mediators.

BACKGROUND: Left ventricular assist device (LVAD) implantation in patients with end-stage heart failure results in impressive hemodynamic improvement. The effects on myocardial apoptosis and its mediators are unknown. METHODS: Myocardial biopsies from 17 patients at the time of LVAD implantation and after explantation, at the time of heart transplantation (HTx), were examined by terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling (TUNEL) reaction and with antibodies against Fas ligand (FasL), Fas, tumor necrosis factor (TNF)-alpha receptor 1 (TNF-R1), TNF-alpha receptor 2 (TNF-R2), TNF-alpha, TNF-alpha-converting enzyme (TACE), poly(ADP-ribose) polymerase (PARP), poly(ADP-ribose) (PAR), caspase-3 and FLICE inhibitory protein (FLIP). RESULTS: Apoptosis incidence was low: 0.8% (range 0% to 3%) positive cardiomyocytes nuclei before support, and 0.1% (range 0% to 0.6%) after support (p < 0.01). This was accompanied by low expression of caspase-3 and high expression of the DNA repair enzyme, PARP. Its product, PAR, increased after support. Mediators and receptors inducing apoptosis as well as FLIP were widely present before and after support. CONCLUSIONS: Despite the abundant presence of mediators and receptors inducing apoptosis, the incidence of apoptosis itself was low before and after mechanical support. The abundant expression of FLIP may suggest an important role for this protein in the inhibition of cardiomyocyte death.

Adult↗
PubMed2002

Left ventricular assist device in end-stage heart failure: persistence of structural myocyte damage after unloading. An immunohistochemical analysis of the contractile myofilaments.

OBJECTIVES: We sought to evaluate the contractile proteins in cardiomyocytes of patients with end-stage heart failure (HF) before and after mechanical support with a left ventricular assist device (LVAD). BACKGROUND: Improvement of myocyte dysfunction has been suggested after LVAD support. METHODS: Fourteen patients' myocardial biopsies taken at the time of LVAD implantation and after explantation, at the time of heart transplantation, were processed for routine hematoxylin-eosin staining and immunohistochemistry using monoclonal antibodies against actin, myosin, tropomyosin, troponin C and T and titin. A grading scale from 1 (abnormal staining of all myocytes, no cross-striation) to 5 (normal fiber anatomy and striation) was used. The cross-sectional area of cardiomyocytes was also measured. RESULTS: The cardiomyocytes' cross-sectional area decreased after support, from 519 +/- 94 microm(2) to 319 +/- 53 microm(2) (p < 0.001). Actin, tropomyosin, troponin C, troponin T and titin at the time of LVAD implantation showed widespread distortion of architecture; their grades were 1.4 +/- 0.6, 2.3 +/- 1.0, 2.1 +/- 0.9, 2.1 +/- 1.2 and 2.0 +/- 0.6, respectively. In contrast, myosin morphology was preserved (4.6 +/- 0.7). After LVAD support, actin, tropomyosin, troponin C, troponin T and titin showed improvement (grades 2.7 +/- 1.3 [p = 0.004], 3.2 +/- 1.2 [p = 0.021], 3.3 +/- 0.9 [p = 0.004], 3.0 +/- 1.1 [p = 0.048] and 3.1 +/- 0.9 [p = 0.001], respectively), but no normalization. The myosin pattern deteriorated slightly (3.6 +/- 1.6 [p = 0.058]). CONCLUSIONS: After LVAD support, during a period of 213 +/- 135 days in patients with end-stage HF, despite a decrease in the size of the cardiomyocytes, severe structural myocyte damage persisted. This does not support complete recovery of myocyte histologic features.

Actin Cytoskeleton↗
PubMed2002

Acute cardiac transplant rejection is associated with low frequencies of interleukin-4 producing helper T-lymphocytes rather than with interleukin-4 promoter or splice variants.

Interleukin-4 (IL-4) is a cytokine of the Th2 subtype. It is suggested that Th2 cytokines are involved in induction of tolerance towards the graft after organ transplantation. Therefore, we studied the association between the frequencies of IL-4 producing helper T lymphocytes (IL-4 HTL) and acute rejection in a panel of 31 cardiac transplant patients. It was also investigated whether these frequencies were influenced by: (1) a single nucleotide polymorphism (SNP) at position -590 in the promoter region of the IL-4 gene, which influences the production level of IL-4; and (2) the expression of an IL-4 splice variant (IL-4delta2), which inhibits the IL-4 receptor. Frequencies of IL-4 HTL were determined by limiting dilution analysis. Genotyping for the SNP was carried out by sequencing. The ratio of wild type versus IL-4delta2 mRNA was determined by quantitative RT-PCR of mRNA isolated from stimulated MNC of cardiac transplant patients. Frequencies of IL-4 HTL were significantly higher in patients who did not suffer from acute cardiac transplant rejection, than in patients that suffered from at least one rejection episode requiring treatment in the first year after heart transplantation. The genotype of the promoter SNP and the ratio between wild type/splice variant IL-4 mRNA did not influence the measured frequencies of IL-4 HTL or the presence of transplant rejection itself.

Acute Disease↗
PubMed2002

No association between transforming growth factor beta gene polymorphism and acute allograft rejection after cardiac transplantation.

Transforming growth factor-beta1 (TGF-beta1) is a multifunctional cytokine, which inhibits both development of Th1 and Th2 subsets and the Th1 proinflammatory response. TGF-beta1 production is influenced through several single nucleotide polymorphisms (SNP) in the structural gene and promoter region. Acute rejection of transplants depends on the Th1/Th2 balance within the graft, high levels of TGF-beta1 shift this balance towards Th2. We investigated whether genotypes of 4 SNP (-800 and -509 in the promoter region, codon 10 and codon 25 in the first exon) were correlated with cardiac disease or with incidence of rejection after heart transplantation (HTX). Genotypes were determined for 70 HTX patients and 61 donors by sequencing or oligonucleotide ligation assay. No association between SNP genotypes and heart disease or acute transplant rejection was observed. We conclude that genetic variation in the TGF-beta1 gene neither influences the existence of cardiomyopathy nor the incidence of rejection upon HTX.

Acute Disease↗