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author:("auwera, Jan A")
1.  The effect of a comprehensive lifestyle intervention on cardiovascular risk factors in pharmacologically treated patients with stable cardiovascular disease compared to usual care: a randomised controlled trial 
The additional benefit of lifestyle interventions in patients receiving cardioprotective drug treatment to improve cardiovascular risk profile is not fully established.
The objective was to evaluate the effectiveness of a target-driven multidisciplinary structured lifestyle intervention programme of 6 months duration aimed at maximum reduction of cardiovascular risk factors in patients with cardiovascular disease (CVD) compared with usual care.
A single centre, two arm, parallel group randomised controlled trial was performed. Patients with stable established CVD and at least one lifestyle-related risk factor were recruited from the vascular and cardiology outpatient departments of the university hospital. Blocked randomisation was used to allocate patients to the intervention (n = 71) or control group (n = 75) using an on-site computer system combined with allocations in computer-generated tables of random numbers kept in a locked computer file. The intervention group received the comprehensive lifestyle intervention offered in a specialised outpatient clinic in addition to usual care. The control group continued to receive usual care. Outcome measures were the lifestyle-related cardiovascular risk factors: smoking, physical activity, physical fitness, diet, blood pressure, plasma total/HDL/LDL cholesterol concentrations, BMI, waist circumference, and changes in medication.
The intervention led to increased physical activity/fitness levels and an improved cardiovascular risk factor profile (reduced BMI and waist circumference). In this setting, cardiovascular risk management for blood pressure and lipid levels by prophylactic treatment for CVD in usual care was already close to optimal as reflected in baseline levels. There was no significant improvement in any other risk factor.
Even in CVD patients receiving good clinical care and using cardioprotective drug treatment, a comprehensive lifestyle intervention had a beneficial effect on some cardiovascular risk factors. In the present era of cardiovascular therapy and with the increasing numbers of overweight and physically inactive patients, this study confirms the importance of risk factor control through lifestyle modification as a supplement to more intensified drug treatment in patients with CVD.
Trial registration
ISRCTN69776211 at
PMCID: PMC3479017  PMID: 22962863
Cardiovascular diseases; Lifestyle intervention; Smoking; Physical activity; Diet; Health behaviour; Randomised controlled trial; Cardiology; Therapy; Cardiovascular risk management
2.  Homocysteine-Induced Apoptosis in Endothelial Cells Coincides With Nuclear NOX2 and Peri-nuclear NOX4 Activity 
Apoptosis of endothelial cells related to homocysteine (Hcy) has been reported in several studies. In this study, we evaluated whether reactive oxygen species (ROS)-producing signaling pathways contribute to Hcy-induced apoptosis induction, with specific emphasis on NADPH oxidases. Human umbilical vein endothelial cells were incubated with 0.01–2.5 mM Hcy. We determined the effect of Hcy on caspase-3 activity, annexin V positivity, intracellular NOX1, NOX2, NOX4, and p47phox expression and localization, nuclear nitrotyrosine accumulation, and mitochondrial membrane potential (ΔΨm). Hcy induced caspase-3 activity and apoptosis; this effect was concentration dependent and maximal after 6-h exposure to 2.5 mM Hcy. It was accompanied by a significant increase in ΔΨm. Cysteine was inactive on these parameters excluding a reactive thiol group effect. Hcy induced an increase in cellular NOX2, p47phox, and NOX4, but not that of NOX1. 3D digital imaging microscopy followed by image deconvolution analysis showed nuclear accumulation of NOX2 and p47phox in endothelial cells exposed to Hcy, but not in control cells, which coincided with accumulation of nuclear nitrotyrosine residues. Furthermore, Hcy enhanced peri-nuclear localization of NOX4 coinciding with accumulation of peri-nuclear nitrotyrosine residues, a reflection of local ROS production. p47phox was also increased in the peri-nuclear region. The Hcy-induced increase in caspase-3 activity was prevented by DPI and apocynin, suggesting involvement of NOX activity. The data presented in this article reveal accumulation of nuclear NOX2 and peri-nuclear NOX4 accumulation as potential source of ROS production in Hcy-induced apoptosis in endothelial cells.
PMCID: PMC3825580  PMID: 22038300
Homocysteine; Endothelial cell; NOX2; NOX4; Apoptosis; Nitrotyrosine; Reactive oxygen species
3.  Transjugular intrahepatic portosystemic shunt-placement increases arginine/asymmetric dimethylarginine ratio in cirrhotic patients 
AIM: To analyze the change of dimethylarginine plasma levels in cirrhotic patients receiving transjugular intrahepatic portosystemic shunt (TIPS).
METHODS: To determine arginine, asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and nitric oxide (NO) plasma levels, blood samples were collected from the superior cava, hepatic, and portal vein just before, directly after, and 3 mo after TIPS-placement.
RESULTS: A significant increase in the arginine/ADMA ratio after TIPS placement was shown. Moreover, TIPS placement enhanced renal function and thereby decreased systemic SDMA levels. In patients with renal dysfunction before TIPS placement, both the arginine/ADMA ratio and creatinine clearance rate increased significantly, while this was not the case in patients with normal renal function before TIPS placement. Hepatic function did not change significantly after TIPS placement and no significant decline in ADMA plasma levels was measured.
CONCLUSION: The increase of the arginine/ADMA ratio after TIPS placement suggests an increase in intracellular NO bioavailability. In addition, this study suggests that TIPS placement does not alter dimethylarginine dimethylaminohydrolase (DDAH) activity and confirms the major role of the liver as an ADMA clearing organ.
PMCID: PMC2776879  PMID: 19084936
Asymmetric dimethylarginine; Symmetric dimethylarginine; Arginine; Liver cirrhosis; Transjugular intrahepatic portosystemic shunt
4.  Motives for (not) participating in a lifestyle intervention trial 
Non-participants can have a considerable influence on the external validity of a study. Therefore, we assessed the socio-demographic, health-related, and lifestyle behavioral differences between participants and non-participants in a comprehensive CVD lifestyle intervention trial, and explored the motives and barriers underlying the decision to participate or not.
We collected data on participants (n = 50) and non-participants (n = 50) who were eligible for inclusion in a comprehensive CVD lifestyle interventional trial. Questionnaires and a hospital patient records database were used to assess socio-demographic, health-related and lifestyle behavioral variables. Univariate and multivariate logistic regression was used to describe the relationship between explanatory variables and study participation. Furthermore, motives and barriers that underlie study participation were investigated by means of questionnaires.
Participants were younger, single, had a higher level of education and were employed. No statistically significant differences were found in health measures and behavioral variables. The motives for participation that were most frequently reported were: the perception of being unhealthy and willingness to change their lifestyle. The main barriers reported by non-participants were financial arguments and time investment.
The differences between participants and non-participants in a lifestyle intervention trial are in mainly demographic factors. The participants consent in order to alter their lifestyle, and/or because they want to improve their health. To minimize non-participation, it is recommended that access to a lifestyle intervention program should be easy and cause no financial restraints.
Trial registration
PMCID: PMC2365955  PMID: 18402683
5.  Homocysteine affects cardiomyocyte viability: concentration-dependent effects on reversible flip-flop, apoptosis and necrosis 
Apoptosis  2007;12(8):1407-1418.
Hyperhomocysteinaemia (HHC) is thought to be a risk factor for cardiovascular disease including heart failure. While numerous studies have analyzed the role of homocysteine (Hcy) in the vasculature, only a few studies investigated the role of Hcy in the heart. Therefore we have analyzed the effects of Hcy on isolated cardiomyocytes.
H9c2 cells (rat cardiomyoblast cells) and adult rat cardiomyocytes were incubated with Hcy and were analyzed for cell viability. Furthermore, we determined the effects of Hcy on intracellular mediators related to cell viability in cardiomyocytes, namely NOX2, reactive oxygen species (ROS), mitochondrial membrane potential (ΔΨm) and ATP concentrations.
We found that incubation of H9c2 cells with 0.1 mM D,L-Hcy (= 60 μM l-Hcy) resulted in an increase of ΔΨm as well as ATP concentrations. 1.1 mM d,l-Hcy (= 460 μM l-Hcy) induced reversible flip-flop of the plasma membrane phospholipids, but not apoptosis. Incubation with 2.73 mM d,l-Hcy (= 1.18 mM l-Hcy) induced apoptosis and necrosis. This loss of cell viability was accompanied by a thread-to-grain transition of the mitochondrial reticulum, ATP depletion and nuclear NOX2 expression coinciding with ROS production as evident from the presence of nitrotyrosin residues. Notably, only at this concentration we found a significant increase in S-adenosylhomocysteine which is considered the primary culprit in HHC.
We found concentration-dependent effects of Hcy in cardiomyocytes, varying from induction of reversible flip-flop of the plasma membrane phospholipids, to apoptosis and necrosis.
PMCID: PMC1914234  PMID: 17440815
Hyperhomocysteinaemia; Cardiomyocytes; Heart failure; Oxidant stress; Apoptosis
6.  Novel applications of therapeutic hypothermia: report of three cases 
Critical Care  2004;8(5):R343-R346.
Therapeutic hypothermia can provide neuroprotection in various situations where global or focal neurological injury has occurred. Hypothermia has been shown to be effective in a large number of animal experiments. In clinical trials, hypothermia has been used in patients with postanoxic injury following cardiopulmonary resuscitation, in traumatic brain injury with high intracranial pressure, in the perioperative setting during various surgical procedures and for various other indications. There is thus evidence that hypothermia can be effective in various situations of neurological injury, although a number of questions remain unanswered. We describe three patients with unusual causes of neurological injury, whose clinical situation was in fundamental aspects analogous to conditions where hypothermia has been shown to be effective.
PMCID: PMC1065027  PMID: 15469578
neurological injury; neuroprotection; outcome; postanoxic injury; spinal cord ischaemia; therapeutic hypothermia

Results 1-6 (6)