Search

Supplementary Table S3 from Lack of p53 Ser389 Phosphorylation Predisposes Mice to Develop 2-Acetylaminofluorene–Induced Bladder Tumors but not Ionizing Radiation–Induced Lymphomas

Supplementary Figure S3 from Lack of p53 Ser389 Phosphorylation Predisposes Mice to Develop 2-Acetylaminofluorene–Induced Bladder Tumors but not Ionizing Radiation–Induced Lymphomas

Supplementary Figure Legends from Lack of p53 Ser389 Phosphorylation Predisposes Mice to Develop 2-Acetylaminofluorene–Induced Bladder Tumors but not Ionizing Radiation–Induced Lymphomas

Background: Heart failure (HF) is a common cause of hospitalisation and mortality in elderly. The frequent rehospitalisations put a serious burden on patients, health-care budgets, and health-care capacity. Frequent hospital admissions are also associated with a substantial additional hazard for serious complications and reduced quality of life. The NWE-Chance project will explore the feasibility and scalability of providing home hospitalisation supported by a newly developed digital health-supported platform and daily visits of specialised nurses. Methods/Design: Hundred patients with chronic HF will be recruited over a 1-year period. The digital health-supported home hospitalisation strategy will be tested in 3 hospitals with different experience in delivering home hospitalisation: Isala Zwolle, Maastricht UMC+, both in The Netherlands, and Jessa Hospital, Hasselt in Belgium. The home hospitalisation intervention will have a maximal duration of 14 days. Feasibility will be measured with acceptability, satisfaction, and usability questionnaires for patients, nurses, and physicians. Furthermore, safety and costs will be assessed for 30 days after the start of the home hospitalisation intervention. Discussion: The NWE-Chance project will be one of the first studies to examine the feasibility of a digital health-supported home hospitalisation platform for HF patients. It has the potential to augment current standard HF care and quality of life of HF patients and to innovate the standard HF care to potentially lower the hospitalisation-related complications, the burden of HF on health-care systems, and to potentially implement more patient-centred care strategies.

Aims Cardiac rehabilitation (CR) is strongly recommended but participation of elderly patients has not been well characterized. This study aims to analyse current rates and determinants of CR referral, participation, adherence, and compliance in a contemporary European cohort of elderly patients. Methods and results The EU-CaRE observational study included data from consecutive patients aged ≥ 65 with acute coronary syndrome, revascularization, stable coronary artery disease, or heart valve replacement, recruited in eight European centres. Rates and factors determining offering, participation, and adherence to CR programmes and compliance with training sessions were studied across centres, under consideration of extensive-outpatient vs. intensive-inpatient programmes. Three thousand, four hundred, and seventy-one patients were included in the offering and participation analysis. Cardiac rehabilitation was offered to 80.8% of eligible patients, formal contraindications being the main reason for not offering CR. Mean participation was 68.0%, with perceived lack of usefulness and transport issues being principal barriers. Mean adherence to CR programmes of participants in the EU-CaRE study (n = 1663) was 90.3%, with hospitalization/physical impairment as principal causes of dropout. Mean compliance with training sessions was 86.1%. Older age was related to lower offering and participation, and comorbidity was associated with lower offering, participation, adherence, and compliance. Intensive-inpatient programmes displayed higher adherence (97.1% vs. 85.9%, P Conclusion In this European cohort of elderly patients, older age and comorbidity tackled patients’ referral and uptake of CR programmes. Intensive-inpatient CR programmes showed higher completion than extensive-outpatient CR programmes, suggesting this formula could suit some elderly patients.

Introduction Studies on effectiveness of cardiac rehabilitation (CR) in elderly cardiovascular disease patients are rare, and it is unknown, which patients benefit most. We aimed to identify predictors for 1-year outcomes of cardiorespiratory fitness and CV risk factor (CVRF) control in patients after completing CR programs offered across seven European countries. Methods Cardiovascular disease patients with minimal age 65 years who participated in comprehensive CR were included in this observational study. Peak oxygen uptake (VO2), body mass index (BMI), resting systolic blood pressure (BPsys), and low-density lipoprotein-cholesterol (LDL-C) were assessed before CR (T0), at termination of CR (T1), and 12 months after start of CR (T2). Predictors for changes were identified by multivariate regression models. Results Data was available from 1241 out of 1633 EU-CaRE patients. The strongest predictor for improvement in peak VO2 was open chest surgery, with a nearly four-fold increase in surgery compared to non-surgery patients. In patients after surgery, age, female sex, physical inactivity and time from index event to T0 were negative predictors for improvement in peak VO2. In patients without surgery, previous acute coronary syndrome and higher exercise capacity at T0 were the only negative predictors. Neither number of attended training sessions nor duration of CR were significantly associated with change in peak VO2. Non-surgery patients were more likely to achieve risk factor targets (BPsys, LDL-C, BMI) than surgery patients. Conclusions In a previously understudied population of elderly CR patients, time between index event and start of CR in surgery and disease severity in non-surgery patients were the most important predictors for long-term improvement of peak VO2. Non-surgery patients had better CVRF control.

Objective We aimed 1) to test the applicability of the previously suggested prognostic value of CPET to elderly cardiac rehabilitation patients and 2) to explore the underlying mechanism of the greater improvement in exercise capacity (peak oxygen consumption, VO2) after CR in surgical compared to non-surgical cardiac patients. Methods Elderly patients (≥65 years) commencing CR after coronary artery bypass grafting, surgical valve replacement (surgery-group), percutaneous coronary intervention, percutaneous valve replacement or without revascularisation (non-surgery group) were included in the prospective multi-center EU-CaRE study. CPETs were performed at start of CR, end of CR and 1-year-follow-up. Logistic models and receiver operating characteristics were used to determine prognostic values of CPET parameters for major adverse cardiac events (MACE). Linear models were performed for change in peak VO2 (start to follow-up) and parameters accounting for the difference between surgery and non-surgery patients were sought. Results 1421 out of 1633 EU-CaRE patients performed a valid CPET at start of CR (age 73±5.4, 81% male). No CPET parameter further improved the receiver operation characteristics significantly beyond the model with only clinical parameters. The higher improvement in peak VO2 (25% vs. 7%) in the surgical group disappeared when adjusted for changes in peak tidal volume and haemoglobin. Conclusion CPET did not improve the prediction of MACE in elderly CR patients. The higher improvement of exercise capacity in surgery patients was mainly driven by restoration of haemoglobin levels and improvement in respiratory function after sternotomy. Trial registration Netherlands Trial Register, Trial NL5166.

Importance: Although nonparticipation in cardiac rehabilitation is known to increase cardiovascular mortality and hospital readmissions, more than half of patients with coronary artery disease in Europe are not participating in cardiac rehabilitation. Objective: To assess whether a 6-month guided mobile cardiac rehabilitation (MCR) program is an effective therapy for elderly patients who decline participation in cardiac rehabilitation. Design, Setting, and Participants: Patients were enrolled in this parallel multicenter randomized clinical trial from November 11, 2015, to January 3, 2018, and follow-up was completed on January 17, 2019, in a secondary care system with 6 cardiac institutions across 5 European countries. Researchers assessing primary outcome were masked for group assignment. A total of 4236 patients were identified with a recent diagnosis of acute coronary syndrome, coronary revascularization, or surgical or percutaneous treatment for valvular disease, or documented coronary artery disease, of whom 996 declined to start cardiac rehabilitation. Subsequently, 179 patients who met the inclusion and exclusion criteria consented to participate in the European Study on Effectiveness and Sustainability of Current Cardiac Rehabilitation Programmes in the Elderly trial. Data were analyzed from January 21 to October 11, 2019. Interventions: Six months of home-based cardiac rehabilitation with telemonitoring and coaching based on motivational interviewing was used to stimulate patients to reach exercise goals. Control patients did not receive any form of cardiac rehabilitation throughout the study period. Main Outcomes and Measures: The primary outcome parameter was peak oxygen uptake (Vo2peak) after 6 months. Results: Among 179 patients randomized (145 male [81%]; median age, 72 [range, 65-87] years), 159 (89%) were eligible for primary end point analysis. Follow-up at 1 year was completed for 151 patients (84%). Peak oxygen uptake improved in the MCR group (n = 89) at 6 and 12 months (1.6 [95% CI, 0.9-2.4] mL/kg-1/min-1and 1.2 [95% CI, 0.4-2.0] mL/kg-1/min-1, respectively), whereas there was no improvement in the control group (n = 90) (+0.2 [95% CI, -0.4 to 0.8] mL/kg-1/min-1and +0.1 [95% CI, -0.5 to 0.7] mL/kg-1/min-1, respectively). Changes in Vo2peak were greater in the MCR vs control groups at 6 months (+1.2 [95% CI, 0.2 to 2.1] mL/kg-1/min-1) and 12 months (+0.9 [95% CI, 0.05 to 1.8] mL/kg-1/min-1). The incidence of adverse events was low and did not differ between the MCR and control groups. Conclusions and Relevance: These results suggest that a 6-month home-based MCR program for patients 65 years or older with coronary artery disease or a valvular intervention was safe and beneficial in improving Vo2peak when compared with no cardiac rehabilitation. Trial Registration: trialregister.nl Identifier: NL5168.

Aims Functional capacity is an important endpoint for therapies oriented to older adults with cardiovascular diseases. The literature on predictors of exercise capacity is sparse in the elderly population. In a longitudinal European study on effectiveness of cardiac rehabilitation of seven European countries in elderly (>65 years) coronary artery disease or valvular heart disease patients, predictors for baseline exercise capacity were determined, and reference ranges for elderly cardiac patients provided. Methods Mixed models were performed in 1282 patients (mean age 72.9 ± 5.4 years, 79% male) for peak oxygen consumption relative to weight (peak VO2; ml/kg per min) with centre as random factor and patient anthropometric, demographic, social, psychological and nutritional parameters, as well as disease aetiology, procedure, comorbidities and cardiovascular risk factors as fixed factors. Results The most important predictors for low peak VO2 were coronary artery bypass grafting or valve surgery, low resting forced expiratory volume, reduced left ventricular ejection fraction, nephropathy and peripheral arterial disease. Each cumulative comorbidity or cardiovascular risk factors reduced exercise capacity by 1.7 ml/kg per min and 1.1 ml/kg per min, respectively. Males had a higher peak VO2 per body mass but not per lean mass. Haemoglobin was significantly linked to peak VO2 in both surgery and non-surgery patients. Conclusions Surgical procedures, cumulative comorbidities and cardiovascular risk factors were the factors with the strongest relation to reduced exercise capacity in the elderly. Expression of peak VO2 per lean mass rather than body mass allows a more appropriate comparison between sexes. Haemoglobin is strongly related to peak VO2 and should be considered in studies assessing exercise capacity, especially in studies on patients after cardiac surgery.

Background The prevalence of patients with concomitant cardiovascular disease and diabetes mellitus (DM) is increasing rapidly. We aimed to compare the effectiveness of current cardiac rehabilitation (CR) programs across seven European countries between elderly cardiac patients with and without DM. Methods 1633 acute and chronic coronary artery disease (CAD) patients and patients after valve intervention with an age 65 or above who participated in comprehensive CR (3 weeks to 3 months, depending on centre) were included. Peak oxygen uptake (VO2 peak), body mass index, resting systolic blood pressure, low-density lipoprotein-cholesterol (LDL-C), and glycated haemoglobin (HbA1c) were assessed before start of CR, at termination of CR (variable time point), and 12 months after start of CR, with no intervention after CR. Baseline values and changes from baseline to 12-month follow-up were compared between patients with and without DM using mixed models, and mortality and hospitalisation rates using logistic regression. Results 430 (26.3%) patients had DM. Patients with DM had more body fat, lower educational level, more comorbidities, cardiovascular risk factors, and more advanced CAD. Both groups increased their VO2 peak over the study period but with a significantly lower improvement from baseline to follow-up in patients with DM. In the DM group, change in HbA1c was associated with weight change but not with change in absolute VO2 peak. 12-month cardiac mortality was higher in patients with DM. Conclusions While immediate improvements in VO2 peak after CR in elderly patients with and without DM were similar, 12-month maintenance of this improvement was inferior in patients with DM, possibly related to disease progression. Glycemic control was less favourable in diabetic patients needing insulin in the short- and long-term. Since glycemic control was only related to weight loss but not to increase in exercise capacity, this highlights the importance of weight loss in obese DM patients during CR. Trial registration NTR5306 at trialregister.nl; trial registered 07/16/2015; https://www.trialregister.nl/trial/5166

ObjectivesGuidelines for exercise intensity prescription in Cardiac Rehabilitation (CR) are inconsistent and have recently been discussed controversially. We aimed (1) to compare training intensities between European CR centres and (2) to assess associations between training intensity and improvement in peak oxygen consumption (V˙O2) in elderly CR patients.MethodsPeakV˙O2, heart rate and work rate (WR) at the first and second ventilatory thresholds were measured at start of CR. Training heart rate was measured during three sessions spread over the CR. Multivariate models were used to compare training characteristics between centres and to assess the effect of training intensity on change in peakV˙O2.ResultsTraining intensity was measured in 1011 out of 1633 EU-CaRE patients in 7 of 8 centers and the first and secondary ventilatory threshold were identified in 1166 and 817 patients, respectively. The first and second ventilatory threshold were found at 44% (SD 16%) and 78% (SD 9%) of peak WR and 78% (SD 9%) and 89% (SD 5%) of peak heart rate, respectively. Training intensity and session duration varied significantly between centres but change in peakV˙O2over CR did not. Training above the first individual threshold (β 0.62, 95% confidence interval [0.25–1.02]) and increase in training volume per hour (β 0.06, 95%CI [0.01–0.12]) were associated with a higher change in peakV˙O2.ConclusionWhile training intensity and volume varied greatly amongst current European CR programs, changes in peakV˙O2were similar and the effect of training characteristics on these changes were small.

INTRODUCTION: The aim of the EuReCa ONE study was to determine the incidence, process, and outcome for out of hospital cardiac arrest (OHCA) throughout Europe.METHODS: This was an international, pr ...

AIMS: Inherited cardiac diseases play an important role in sudden death (SD) in the young. Autopsy and cardiogenetic evaluation of relatives of young SD victims identifies relatives at risk. We studied the usual care after SD in the young aimed at identifying inherited cardiac disease, and assessed the efficacy of two interventions to improve this usual care.METHODS AND RESULTS: We conducted a community-based intervention study to increase autopsy rates of young SD victims aged 1-44 years and referral of their relatives to cardiogenetic clinics. In the Amsterdam study region, a 24/7 central telephone number and a website were available to inform general practitioners and coroners. In the Utrecht study region, they were informed by a letter and educational meetings. In two control regions usual care was monitored. Autopsy was performed in 169 of 390 registered SD cases (43.3%). Cardiogenetic evaluation of relatives was indicated in 296 of 390 cases (75.9%), but only 25 of 296 families (8.4%) attended a cardiogenetics clinic. Autopsy rates were 38.7% in the Amsterdam study region, 45.5% in the Utrecht study region, and 49.0% in the control regions. The proportion of families evaluated at cardiogenetics clinics in the Amsterdam study region, the Utrecht study region, and the control regions was 7.3, 9.9, and 8.8%, respectively.CONCLUSIONS: The autopsy rate in young SD cases in the Netherlands is low and few families undergo cardiogenetic evaluation to detect inherited cardiac diseases. Two different interventions did not improve this suboptimal situation substantially.

Phosphorylation is important in p53-mediated DNA damage responses. After UV irradiation, p53 is phosphorylated specifically at murine residue Ser389. Phosphorylation mutant p53.S389A cells and mice show reduced apoptosis and compromised tumor suppression after UV irradiation. We investigated the underlying cellular processes by time-series analysis of UV-induced gene expression responses in wild-type, p53.S389A, and p53(-/-) mouse embryonic fibroblasts. The absence of p53.S389 phosphorylation already causes small endogenous gene expression changes for 2,253, mostly p53-dependent, genes. These genes showed basal gene expression levels intermediate to the wild type and p53(-/-), possibly to readjust the p53 network. Overall, the p53.S389A mutation lifts p53-dependent gene repression to a level similar to that of p53(-/-) but has lesser effect on p53-dependently induced genes. In the wild type, the response of 6,058 genes to UV irradiation was strictly biphasic. The early stress response, from 0 to 3 h, results in the activation of processes to prevent the accumulation of DNA damage in cells, whereas the late response, from 12 to 24 h, relates more to reentering the cell cycle. Although the p53.S389A UV gene response was only subtly changed, many cellular processes were significantly affected. The early response was affected the most, and many cellular processes were phase-specifically lost, gained, or altered, e.g., induction of apoptosis, cell division, and DNA repair, respectively. Altogether, p53.S389 phosphorylation seems essential for many p53 target genes and p53-dependent processes.

BACKGROUND: For chest pain patients without ST-segment elevation in the pre-hospital setting, current clinical guidelines merely offer in-hospital risk stratification and management, as opposed to chest pain patients with ST-segment elevation for whom there is a straightforward pre-hospital strategy for diagnosis, medication regimen and logistics. The FAMOUS TRIAGE study will assess the effects of introducing a pre-hospital triage system that reliably stratifies chest pain patients without ST-segment elevation into 1) patients at high risk for NSTEMI requiring a direct transfer to a PCI-hospital; 2) patients at intermediate risk for a major adverse cardiac event (MACE) who could be evaluated at the nearest non-PCI hospital; and 3) patients at low risk for MACE (benign non-cardiac chest pain) who could have further evaluation at home or in a primary care setting. METHODS: The FAMOUS TRIAGE study will be performed in three phases. In the first phase an appropriate pre-hospital risk stratification tool will be designed for chest pain patients without ST-segment elevation by means of a retrospective and a prospective study. The second phase of the project represents the external validation of the risk stratification models, and in the third and final phase an optimal risk stratification tool will be implemented into clinical practice. Clinical and economical endpoints before and after implementation of the pre-hospital risk stratification tool will be compared to assess clinical benefit and cost-effectiveness. CONCLUSION: The FAMOUS TRIAGE project is a triple phase study that aims to optimize the pre-hospital management of chest pain patients without ST-segment elevation by providing tools for pre-hospital identification of NSTEMI or exclusion of acute coronary syndrome at home. TRIAL ID: NTR4205. Dutch Trial Register [http://www.trialregister.nl]: trial number 4205.

Objective To perform two predefined sub-group analyses within the LINC study and evaluate if the results were supportive of the previous reported intention to treat (ITT) analysis. Methods Predefined subgroup analyses from the previously published LINC study were performed. The Per-Protocol population (PPP) included the randomized patients included in the ITT-population but excluding those with violated inclusion or exclusion criteria and those that did not get the actual treatment to which the patient was randomized. In the Pre-Defined population (PDP) analyses patients were also excluded if the dispatch time to ambulance arrival at the address exceeded 12min, there was a non-witnessed cardiac arrest, or if it was not possible to determine whether the arrest was witnessed or not, and those cases where LUCAS was not brought to the scene at the first instance. Results After exclusion from the 2589 patients within the ITT-population, the Per-Protocol analysis was performed in 2370 patients and the Pre-Defined analysis within 1133 patients. There was no significant difference in 4-h survival of patients between the mechanical-CPR group and the manual-CPR group in the Per-Protocol population; 279 of 1172 patients (23.8%) versus 281 of 1198 patients (23.5%) (risk difference −0.35%, 95% C.I. −3.1 to 3.8, p =0.85) or in the Pre-Defined population; 176 of 567 patients (31.0%) versus 192 of 566 patients (33.9%) (risk difference −2.88%, 95% C.I. −8.3 to 2.6, p =0.31). There was no difference in any of the second outcome variables analyzed in the Pre-Protocol or Pre-Defined populations. Conclusions The results from these predefined sub-group analyses of the LINC study population did not show any difference in 4h survival or in secondary outcome variables between patients treated with mechanical-CPR or manual-CPR. This is consistent with the previously published ITT analysis.

Combined oral benzo[a]pyrene and inhalatory ozone exposure have no effect on lung tumor development in DNA repair-deficient Xpa mice.Hoogervorst EM, de Vries A, Beems RB, van Oostrom CT, Wester PW, Vos JG, Bruins W, Roodbergen M, Cassee FR, Vijg J, van Schooten FJ, van Steeg H.National Institute of Public Health and the Environment, Laboratory of Toxicology, Center for Environment and Health Research, Bilthoven, The Netherlands.There is considerable concern about an enhanced risk of lung tumor development upon exposure of humans to polycyclic aromatic hydrocarbons (PAHs), like benzo[a] pyrene (B[a]P), in combination with induced lung cell proliferation by toxic agents like ozone. We studied this issue in wild-type (WT) C57BL/6 mice, the cancer prone nucleotide excision repair-deficient Xeroderma pigmentosum complementation group A mice (Xpa-/-) and the even more sensitive Xpa-/-/p53+/- mice. The mice were treated with B[a]P through the diet at a dose of 75 p.p.m., in combination with intermittent ozone exposures (0.8 p.p.m.). First, a dose-range finding study with WT and Xpa-/- mice was conducted to determine the optimal ozone concentration giving high cell proliferation and low toxic side effects. We show by BrdU incorporation that cell proliferation in the lung was induced by ozone, with an optimal concentration of 0.8 p.p.m., which was subsequently used in the (sub)chronic studies. In the subchronic study, in which lacZ mutant frequency and BPDE-DNA adduct formation were measured, the mice were treated for 13 weeks with B[a]P and/or ozone, whereas in the chronic study this treatment protocol was followed by a 6 month period on control feed and filtered air. As expected, oral B[a]P exposure appeared to be highly carcinogenic to Xpa-/- and Xpa-/-/p53+/- mice and to a lesser extent to WT mice. A high incidence of forestomach tumors and some tumors of the esophagus were found. In the lung, a clear genotoxic effect of B[a]P was found as shown by the presence of BPDE-DNA adducts. However, these DNA adducts in combination with induction of cell proliferation did not result in increased lacZ mutations, nor in lung tumor formation not even in the highly sensitive Xpa-/- and Xpa-/-/p53+/- mice. The implication of these findings for tumor risk assessment will be discussed.

Reanalysis of our UV study of p53-mutant mouse embryonic fibroblasts revealed an intriguing orchestration of massive transcriptome responses. However, close scrutiny of the data uncovered an affected mRNA/rRNA ratio, effectively inhibiting valid data analysis. UV-dose range-finding showed low-dose UV specific- and high-dose stress-related responses, which represent a plea for UV dose range-finding in experimental design.

Mice with non-phosphorylated serine 389 in p53 are susceptible for bladder tumors induced by 2-acetylaminofluorene (2-AAF). Since p53 is a transcription factor, this might well be preceded by differences in the regulation of gene expression. Microarray analysis was used to determine early transcriptional changes that might underlie this cancer-prone phenotype. Interestingly, lack of Ser389 phosphorylation led to endogenously different gene expression levels. The number of genes affected was, however, rather small. Conversely, after short-term exposure to 2-AAF, wild-type and p53.S389A bladders demonstrated a significant number of differentially expressed genes. Differences between wild-type and p53.S389A could mainly be attributed to a delayed, rather than complete absence of, transcriptional response of a group of genes, including well-known p53 target genes involved in apoptosis and cell-cycle control like Bax, Perp and P21. An analysis of differentially expressed genes in non-tumorigenic tissue and bladder tumors of p53.S389A after long-term exposure to 2-AAF revealed 319 genes. Comparison of these with those found after short-term exposure resulted in 23 transcripts. These possible marker genes might be useful for the early prediction of bladder tumor development. In conclusion, our data indicate that lack of Ser389 phosphorylation results in aberrant expression of genes needed to execute vital responses to DNA damage. Post-translational modifications, like Ser389 phosphorylation, seem crucial for fine-tuning the transcription of a specific set of genes and do not appear to give rise to major changes in transcription patterns. As such, Ser389 phosphorylation is needed for some, but certainly not all, p53 functions.

Phosphorylation is important for p53 protein stabilization and activation after DNA damage. Serine 389 of p53 is specifically phosphorylated after UV irradiation, whereas gamma radiation activates p53 through a different pathway. To study the in vivo significance of p53 phosphorylation at serine 389, we generated a physiological mouse model in which p53 phosphorylation at serine 389 is abolished by alanine substitution. Homozygous mutant p53.S389A mice are viable and have an apparently normal phenotype. However, cells isolated from these mice are partly compromised in transcriptional activation of p53 target genes and apoptosis after UV irradiation, whereas gamma radiation-induced responses are not affected. Moreover, p53.S389A mice show increased sensitivity to UV-induced skin tumor development, signifying the importance of serine 389 phosphorylation for the tumor-suppressive function of p53.

Background The LUCAS™ device delivers mechanical chest compressions that have been shown in experimental studies to improve perfusion pressures to the brain and heart as well as augmenting cerebral blood flow and end tidal CO2, compared with results from standard manual cardiopulmonary resuscitation (CPR). Two randomised pilot studies in out-of-hospital cardiac arrest patients have not shown improved outcome when compared with manual CPR. There remains evidence from small case series that the device can be potentially beneficial compared with manual chest compressions in specific situations. This multicentre study is designed to evaluate the efficacy and safety of mechanical chest compressions with the LUCAS™ device whilst allowing defibrillation during on-going CPR, and comparing the results with those of conventional resuscitation. Methods/design This article describes the design and protocol of the LINC-study which is a randomised controlled multicentre study of 2500 out-of-hospital cardiac arrest patients. The study has been registered at ClinicalTrials.gov (http://clinicaltrials.gov/ct2/show/NCT00609778?term=LINC&rank=1). Results Primary endpoint is four-hour survival after successful restoration of spontaneous circulation. The safety aspect is being evaluated by post mortem examinations in 300 patients that may reflect injuries from CPR. Conclusion This large multicentre study will contribute to the evaluation of mechanical chest compression in CPR and specifically to the efficacy and safety of the LUCAS™ device when used in association with defibrillation during on-going CPR.