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Biomedical subjects

P A Doevendans

Publications and source records attributed to P A Doevendans.

At least 19 recordsLinked to original sources
PubMed2006

Interleukin 10: a new risk marker for the development of restenosis after percutaneous coronary intervention.

Genetic factors appear to be important in the process of restenosis after percutaneous coronary intervention (PCI), as well as in inflammation, a pivotal factor in restenosis. An important mediator in the inflammatory response is interleukin (IL)-10. Our aim was to study whether genetic variants in IL-10 predispose to the risk of restenosis. The GENetic DEterminants of Restenosis (GENDER) study included 3104 patients treated with successful PCI. Target vessel revascularization (TVR) was chosen as primary end point. Genotyping of the -2849G/A, -1082G/A, -592C/A and +4259A/G polymorphisms of the IL-10 gene was performed by MassArray platform. After adjusting for clinical variables, three polymorphisms significantly increased the risk of restenosis (-2849AA: relative risk (RR), 1.7, 95% confidence interval (CI), 1.2-2.5; -1082AA: RR, 1.4, 95% CI, 1.1-1.8 and +4259GG: RR, 2.0, 95% CI, 1.4-2.8). To further exclude possible involvement of neighboring genes due to LD in the IL-10 locus, additional polymorphisms were genotyped. The results reveal that association of the IL-10 gene with restenosis is independent of flanking genes. Our findings demonstrate that IL-10 is associated with restenosis and therefore support the hypothesis that anti-inflammatory genes also may be involved in developing restenosis. Furthermore, they may provide a new targeting gene for drug-eluting stents.

3' Untranslated Regions↗
PubMed2006

Coronary collaterals--insights in molecular determinants and prognostic relevance.

In the field of molecular cardiology, recently several determinants of coronary collateral circulation have been identified. Knowing these factors may aid risk-stratification and put forward targets for intervention by stimulating development of collateral blood vessels (arteriogenesis). However, prognostic importance of coronary collaterals is not yet beyond debate, and seems to be modified by the extent of atherosclerotic burden. Combining these insights is essential to increase our understanding of these mechanisms and to proceed with developing strategies for risk-stratification and therapeutic stimulation of arteriogenesis.

Collateral Circulation↗
PubMed2006

Early and transient gene expression changes in pressure overload-induced cardiac hypertrophy in mice.

Cardiac hypertrophy is an important risk factor for cardiac morbidity and mortality. To unravel the underlying pathogenic genetic pathways, we hybridized left ventricular RNA from Transverse Aortic Constriction mice at 48 h, 1 week, and 2, 3, and 8 weeks after surgery to microarrays containing a 15K fetal cDNA collection. Key processes involved an early restriction in the expression of metabolic genes, accompanied by increased expression of genes related to growth and reactivation of fetal genes. Most of these genes returned to basal expression levels during the later, compensated hypertrophic phase. Our findings suggest that compensated hypertrophy in these mice is established by rapid adaptation of the heart at the cost of gene expression associated with metabolic activity, with only temporary expression of possible maladaptive processes. Therefore, the transient early changes may reflect a beneficial response to pressure overload, as deterioration of cardiac hemodynamic function or heart failure does not occur.

Animals↗
PubMed2006

Common variants of multiple genes that control reverse cholesterol transport together explain only a minor part of the variation of HDL cholesterol levels.

It is assumed that the combined effects of multiple common genetic variants explain a large part of variation of high-density lipoprotein cholesterol (HDL-C) plasma levels, but little evidence exists to corroborate this assumption. It was our objective to study the contribution of multiple common genetic variants of HDL-C-related genes to variation of HDL-C plasma levels. A well-characterized cohort of 546 Caucasian men with documented coronary artery disease was genotyped for common functional variants in genes that control reverse cholesterol transport: ATP-binding cassette transporter A1, apolipoprotein A-I and apolipoprotein-E, cholesteryl ester transfer protein, hepatic lipase, lecithin : cholesterol-acyl transferase, lipoprotein lipase, and scavenger receptor class B type 1. Multivariate linear regression showed that these variants, in conjunction, explain 12.4% (95% confidence interval: 6.9-17.9%) of variation in HDL-C plasma levels. When the covariates smoking and body mass index were taken into account, the explained variation increased to 15.3% (9.4-21.2%), and when 10 two-way interactions were incorporated, this percentage rose to 25.2% (18.9-31.5%). This study supports the hypothesis that multiple, mildly penetrant, but highly prevalent genetic variants explain part of the variation of HDL-C plasma levels, albeit to a very modest extent. Multiple environmental and genetic influences on HDL-C plasma levels still have to be elucidated.

ATP Binding Cassette Transporter 1↗
PubMed2004

Acromegaly and heart failure: revisions of the growth hormone/insulin-like growth factor axis and its relation to the cardiovascular system.

Cardiomyopathy is a major cause of death in overt acromegaly. Recent progress in research has increasingly revealed the molecular mechanisms concerning growth hormone and insulin-like growth factor in the development of heart failure. In this article, we propose mechanisms according to which heart failure occurs, and we aim to extrapolate this knowledge to more general processes involved in heart failure.

Acromegaly↗
PubMed2004

New and viable cells to replace lost and malfunctioning myocardial tissue.

The use of stem cells for cardiac repair is a promising opportunity for developing new treatment strategies as the applications are theoretically unlimited and lead to actual cardiac tissue regeneration. Human embryonic stem cells were only recently cloned and their capacity to differentiate into true cardiomyocytes makes them in principle an unlimited source of transplantable cells for cardiac repair, although practical and ethical constraints exist. Also, the study of embryonic stem cells and their differentiation into cardiomyocytes will bring forth new insights into the molecular processes involved in cardiomyocyte-development and -proliferation, which could lead to the development of other strategies to augment in vivo cardiomyocyte numbers. On the other hand, somatic stem cells are alternative cell sources that can be used for cell transplantation purposes. They do not evoke ethical issues and bear less ethical constraints. However, they also appear to be much more restricted in their differentiation potential than the embryonic stem cells. Here we discuss the use of both cell types, embryonic and somatic stem cells, in relation with their importance for the clarification of cardiomyocyte-development and their possible usefulness for clinical therapy.

Humans↗
PubMed2003

[Hypertrophic cardiomyopathy: from diagnosis to prevention].

In a 55-year-old man, his two sons aged 32 and 30 years and a 3-year-old grandchild, a gene mutation related to an increased chance of hypertrophic cardiomyopathy was found. The adults had complaints of cardiac arrhythmias varying from dizziness to cardiac arrest and received medication; a defibrillator was also implanted in the case of the sons. Familial hypertrophic cardiomyopathy can be diagnosed in an early stage with DNA screening methods. At that time 'patients' (carriers) often do not exhibit symptoms. This offers the possibility of taking therapeutic measures to prevent or slow down the disease process. However, the scientific basis for preventive therapy is inadequate, so that medical-ethical dilemmas arise which can affect the decision-making process with respect to genetic testing. Additional research must lead to satisfactory preventive therapies, so that in the future the genetic diagnosis 'hypertrophic cardiomyopathy' can be effectively translated into disease prevention.

Adult↗
PubMed2003

The human adult cardiomyocyte phenotype.

AIM: Determination of the phenotype of adult human atrial and ventricular myocytes based on gene expression and morphology. METHODS: Atrial and ventricular cardiomyocytes were obtained from patients undergoing cardiac surgery using a modified isolation procedure. Myocytes were isolated and cultured with or without serum. The relative cell attachment promoting efficiency of several reagents was evaluated and compared. Morphological changes during long-term culture were assessed with phase contrast microscopy, morphometric analysis and immunocytochemistry or RT-PCR of sarcomeric markers including alpha-actinin, myosin light chain-2 (MLC-2) and the adhesion molecule, cadherin. RESULTS: The isolation method produced viable rod-shaped atrial (16.6+/-6.0%, mean+/-S.E.; n=5) and ventricular cells (22.4+/-8.0%, mean+/-S.E.; n=5) in addition to significant numbers of apoptotic and necrotic cells. Cell dedifferentiation was characterized by the loss of sarcomeric structure, condensation and extrusion of sarcomeric proteins. Cells cultured with low serum recovered and assumed a flattened, spread form with two distinct morphologies apparent. Type I cells were large, had extensive sarcolemmal spreading, with stress fibers and nascent myofibrils, whilst type II cells appeared smaller, with more mature myofibril organisation and focal adhesions. CONCLUSION: Characterization of the redifferentiation capabilities of cultured adult cardiac myocytes in culture, provides an important system for comparing cardiomyocytes differentiating from human stem cells and provides the basis for an in vitro transplantation model to study interaction and communication between primary adult and stem cell-derived cardiomyocytes.

Actinin↗
PubMed2003

Coordinated down-regulation of KCNQ1 and KCNE1 expression contributes to reduction of I(Ks) in canine hypertrophied hearts.

OBJECTIVE: In animal models of hypertrophy, electrical remodeling giving rise to QT prolongation occurs rapidly and is associated with the development of torsade de pointes (TdP) arrhythmias and sudden death. Chronic AV block (CAVB)-induced hypertrophy in dogs has been associated with a reduction in the slow component (I(Ks)) of the delayed rectifier potassium current (I(K)), which contributes to a prolongation of ventricular repolarization, the development of an acquired form of long QT, and the substrate for triggered activity and TdP. The present study was designed to probe the molecular basis for the decrease in I(Ks) by studying the characteristics of KCNE1 and KCNQ1, the putative genes responsible for formation of the channel. METHODS AND RESULTS: Using a combination of Northern blot, competitive multiplex PCR and immunoblot assays, we found that CAVB reduces KCNE1 and KCNQ1 RNA in the canine ventricles by 70 and 80%, respectively. Protein levels of KCNE1 and KCNQ1 were reduced by 60 and 50%, respectively. We also demonstrate at the molecular level the basis for inter-ventricular difference in I(Ks) density previously reported in hearts of normal dogs and show the basis for reduction of this difference in the CAVB dog. CONCLUSIONS: Our results indicate that the CAVB-induced reduction in I(Ks) is due to a down-regulation of KCNE1 and KCNQ1 transcription. The data suggest that electrical remodeling of the cardiac ventricle during hypertrophy involves regulation of the gene expression through modulation of transcriptional and translational regulatory pathways. The reduction in KCNE1 and KCNQ1 expression increases the dependence of ventricular repolarization on the rapid component of I(K) and may potentiate the action of Class III antiarrhythmic agents.

Animals↗
PubMed2002

Expression of the smoothelin gene is mediated by alternative promoters.

OBJECTIVE: Two major isoforms of smoothelin have been reported, a 59-kDa smoothelin-A in visceral smooth muscle cells and a 110-kDa smoothelin-B in vascular smooth muscle cells. The present study was undertaken to investigate the expression of these smoothelin isoforms in different smooth muscle tissues and to determine how they are generated. METHODS: Western blotting with a new, well-defined, smoothelin antibody was used to confirm the existence of two major smoothelin isoforms. Northern blotting, RT-PCR, primer extension and 5'RACE were applied to analyse the expression of these isoforms in human and mouse. Promoter reporter assays were carried out to establish the existence of a dual promoter system governing the expression pattern of the gene. RESULTS: Antibody C6G confirmed the existence of two smoothelin proteins. Northern blotting showed that in vascular tissues a larger smoothelin transcript is generated than in visceral tissue. The cDNA of this larger smoothelin-B was cloned. Computer analysis of the open reading frame suggests an alpha-helical structure of 130 amino acids at the amino terminus of smoothelin-B. The smoothelin gene was cloned and sequenced. It comprises about 25 kb and contains 21 exons. The translational start of smoothelin-B is located in exon 2, whereas transcription and translation of the previously described smoothelin-A starts inside exon 10. Smoothelin-A and -B were demonstrated to be generated by two physically separated promoters. Splice variants within the calponin homology domain at the 3' end of the gene were found for both isoforms. CONCLUSIONS: Two major smoothelin isoforms are generated from a single gene by a dual promoter system in a tissue specific manner. Further variation in the smoothelin proteins is achieved by alternative splicing in the calponin homology domain.

Alternative Splicing↗
PubMed2002

Cardiomyocyte differentiation of mouse and human embryonic stem cells.

Ischaemic heart disease is the leading cause of morbidity and mortality in the western world. Cardiac ischaemia caused by oxygen deprivation and subsequent oxygen reperfusion initiates irreversible cell damage, eventually leading to widespread cell death and loss of function. Strategies to regenerate damaged cardiac tissue by cardiomyocyte transplantation may prevent or limit post-infarction cardiac failure. We are searching for methods for inducing pluripotent stem cells to differentiate into transplantable cardiomyocytes. We have already shown that an endoderm-like cell line induced the differentiation of embryonal carcinoma cells into immature cardiomyocytes. Preliminary results show that human and mouse embryonic stem cells respond in a similar manner. This study presents initial characterization of these cardiomyocytes and the mouse myocardial infarction model in which we will test their ability to restore cardiac function.

Adult↗
PubMed2001

17beta-estradiol attenuates the development of pressure-overload hypertrophy.

BACKGROUND: Cardiac hypertrophy is an independent risk factor for cardiovascular morbidity and mortality in men and in women. Epidemiological studies indicate that estrogen replacement therapy is cardioprotective; the mechanisms involved in this process, however, are poorly understood. We therefore studied the effect of 17beta-estradiol (E(2)) on the development of pressure-overload hypertrophy. METHODS AND RESULTS: Ovariectomized mice receiving E(2) or placebo underwent transverse aortic constriction (TAC) or sham operation. TAC led to a significant increase in ventricular mass compared with sham operation. E(2) treatment reduced cardiac hypertrophy by 31% and 26% compared with placebo 4 and 8 weeks after TAC, whereas it had no effect on the degree of pressure overload, as determined by hemodynamic measurements. Furthermore, E(2) blocked the increased phosphorylation of p38-mitogen-activated protein kinase (MAPK) observed in the placebo-treated animals with TAC. No differences were observed in the phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 and c-Jun N-terminal kinase (JNK) 1/2 between the groups. E(2) had no effect on the expression of angiotensin-converting enzyme (ACE) or the angiotensin II type 1 receptor. Ventricular atrial natriuretic peptide (ANP) expression was detected only in the animals with TAC. Compared with placebo, E(2) treatment led to an increased expression of ANP in animals with pressure overload. CONCLUSIONS: Here, we show that E(2) attenuates the hypertrophic response to pressure overload in mice. This observation demonstrates that hormone replacement therapy with E(2) has direct effects on the heart and may be beneficial in the treatment of postmenopausal women to reduce cardiac hypertrophy.

Animals↗
PubMed2001

Cardiac remodeling after myocardial infarction is impaired in IGF-1 deficient mice.

OBJECTIVE: To obtain more insight in the role of IGF-1 in cardiac remodeling and function after experimental myocardial infarction. We hypothesized that cardiac remodeling is altered in IGF-1 deficient mice, which may affect cardiac function. METHODS: A myocardial infarction was induced by surgical coronary artery ligation in heterozygous IGF-1 deficient mice. One week after surgery, left ventricular function was analyzed, and parameters of cardiac remodeling were measured. RESULTS: No significant difference in cardiac function was found between infarcted wildtype and knock-out animals, despite a marked reduction in capillarization and blunting of the hypertrophic response of the interventricular septum in the IGF-1 deficient group. Furthermore, decreased DNA synthesis and increased apoptosis rates were observed in the IGF-1 knock-out mice. CONCLUSION: IGF-1 deficient mice show preservation of cardiac function 1 week after MI, despite an altered cardiac remodeling process.

Animals↗