The plasma proteome is linked with left ventricular and left atrial function parameters in patients with chronic heart failure.

BACKGROUND: Examining the systemic biological processes in the heterogeneous syndrome of heart failure with reduced ejection fraction (HFrEF), as reflected by circulating proteins, in relation to echocardiographic characteristics, may provide insights into HF pathophysiology. OBJECTIVE: We investigated the link of 4210 repeatedly measured circulating proteins with repeatedly measured echocardiographic parameters, as well as with elevated left atrial pressure (LAP), in HFrEF patients, to provide insights into underlying mechanisms. METHODS: In 173 HFrEF patients, we performed six-monthly echocardiography and trimonthly blood sampling during a median follow-up of 2.7(IQR:2.5-2.8) years. We investigated circulating proteins in relation to echocardiographic parameters of left ventricular (left ventricular ejection fraction[LVEF], global longitudinal strain[GLS]), and left atrial function (left atrial reservoir strain[LASr]) and elevated LAP(E/e' ratio >15), and used gene enrichment analyses to identify underlying pathophysiological processes. RESULTS: We found 723, 249, 792 and 427 repeatedly measured proteins, with significant associations with LVEF, GLS, LASr and E/e' ratio, respectively. Proteins associated with LASr reflected pathophysiological mechanisms mostly related to the extracellular matrix (ECM). Proteins associated with GLS reflected cardiovascular biological processes and diseases, whereas those associated with LVEF reflected processes involved in the sympathetic nervous system. Moreover, 49 proteins were associated with elevated LAP; after correction for LVEF, three proteins remained: Cystatin-D, Fibulin-5 and HSP40. CONCLUSION: Circulating proteins show varying associations with different echocardiographic parameters in HFrEF patients. These findings suggest that pathways involved in atrial and ventricular dysfunction, as reflected by the plasma proteome, are distinct.

A critical appreciation of pathway analysis in atherosclerotic disease. Cellular phenotypic plasticity as an illustrative example.

The rapid advancements in genome-scale (omics) techniques has created significant opportunities to investigate complex disease mechanisms in tissues and cells. Nevertheless, interpreting -omics data can be challenging, and pathway enrichment analysis is a frequently used method to identify candidate molecular pathways that drive gene expression changes. With a growing number of -omics studies dedicated to atherosclerosis, there has been a significant increase in studies and hypotheses relying on enrichment analysis. This brief review discusses the benefits and limitations of pathway enrichment analysis within atherosclerosis research. We highlight the challenges of identifying complex biological processes, such as cell phenotypic switching, within -omics data. Additionally, we emphasize the need for more comprehensive and curated gene sets that reflect the biological complexity of atherosclerosis. Pathway enrichment analysis is a valuable tool for gaining insights into the molecular mechanisms of atherosclerosis. Nevertheless, it is crucial to remain aware of the intrinsic limitations of this approach. By addressing these weaknesses, enrichment analysis in atherosclerosis can lead to breakthroughs in identifying the mechanisms of disease progresses, the identification of key driver genes, and consequently, advance personalized patient care.

Microvascular endothelial dysfunction in skin is associated with higher risk of heart failure with preserved ejection fraction in women with type 2 diabetes: the Hoorn Diabetes Care System Cohort.

BACKGROUND: Microvascular dysfunction plays a crucial role in complications of type 2 diabetes and might contribute to heart failure with preserved ejection fraction (HFpEF), a disease that disproportionally affects women. We aimed to investigate if presence and degree of microvascular dysfunction (MVD) in skin relates to markers of left ventricular diastolic dysfunction (LVDD) and HFpEF risk in adults with type 2 diabetes, and whether sex modifies this association. METHODS: We recruited 154 participants (50% women) from the Hoorn Diabetes Care System Cohort, a prospective cohort study, for in vivo evaluation of skin MVD, echocardiography and blood sampling. MVD was assessed by laser speckle contrast analysis combined with iontophoresis of insulin, acetylcholine and sodium nitroprusside (SNP). We performed a cross-sectional analysis of the association between perfusion responses and echocardiographic and clinical markers of LVDD and the H2FPEF score by multivariable linear regression analysis adjusted for confounders. Sex was evaluated as a potential effect modifier and the analysis was stratified. RESULTS: Mean age was 67 ± 6y, mean HbA1c 7.6 ± 1.3%. Women were more frequently obese (54.5 vs. 35.1%), had higher NT-proBNP plasma levels (80, IQR:34-165 vs. 46, 27-117 pg/ml) and E/E'(13.3 ± 4.3 vs. 11.4 ± 3.0) than men. Eleven women and three men were diagnosed with HFpEF, and showed lower perfusion response to insulin than those without HFpEF. A lower perfusion response to insulin and acetylcholine was associated with higher HFpEF risk in women, but not men (10% decreased perfusion response was associated with 5.8% [95%CI: 2.3;9.4%] and 5.9% [1.7;10.1%] increase of the H2FPEF score, respectively). A lower perfusion response to SNP was associated with higher pulmonary arterial systolic pressure in men while a lower perfusion response to acetylcholine associated with higher LV mass index in women and with worse LV longitudinal strain in the total population. No significant associations were found between perfusion responses and conventional LVDD markers. CONCLUSIONS: Impaired microvascular responses to insulin and acetylcholine in skin confers a higher risk of HFpEF in women with type 2 diabetes. In vivo measures of systemic MVD could represent novel risk markers for HFpEF, opening new avenues for the prevention of HFpEF in type 2 diabetes.

Design and rationale of the NetherLands registry of invasive Coronary vasomotor Function Testing (NL-CFT).

BACKGROUND: Angina without angiographic evidence of obstructive coronary artery disease (ANOCA) is a highly prevalent condition with insufficient pathophysiological knowledge and lack of evidence-based medical therapies. This affects ANOCA patients prognosis, their healthcare utilization and quality of life. In current guidelines, performing a coronary function test (CFT) is recommended to identify a specific vasomotor dysfunction endotype. The NetherLands registry of invasive Coronary vasomotor Function testing (NL-CFT) has been designed to collect data on ANOCA patients undergoing CFT in the Netherlands. METHODS: The NL-CFT is a web-based, prospective, observational registry including all consecutive ANOCA patients undergoing clinically indicated CFT in participating centers throughout the Netherlands. Data on medical history, procedural data and (patient reported) outcomes are gathered. The implementation of a common CFT protocol in all participating hospitals promotes an equal diagnostic strategy and ensures representation of the entire ANOCA population. A CFT is performed after ruling out obstructive coronary artery disease. It comprises of both acetylcholine vasoreactivity testing as well as bolus thermodilution assessment of microvascular function. Optionally, continuous thermodilution or Doppler flow measurements can be performed. Participating centers can perform research using own data, or pooled data will be made available upon specific request via a secure digital research environment, after approval of a steering committee. CONCLUSION: NL-CFT will be an important registry by enabling both observational and registry based (randomized) clinical trials in ANOCA patients undergoing CFT.

Evaluation of non-invasive imaging parameters in coronary microvascular disease: a systematic review.

BACKGROUND: Coronary microvascular dysfunction (CMD) is an important underlying cause of angina pectoris. Currently, no diagnostic tool is available to directly visualize the coronary microvasculature. Invasive microvascular reactivity testing is the diagnostic standard for CMD, but several non-invasive imaging techniques are being evaluated. However, evidence on reported non-invasive parameters and cut-off values is limited. Thus, we aimed to provide an overview of reported non-invasive parameters and corresponding cut-off values for CMD. METHODS: Pubmed and EMBASE databases were systematically searched for studies enrolling patients with angina pectoris without obstructed coronary arteries, investigating at least one non-invasive imaging technique to quantify CMD. Methodological quality assessment of included studies was performed using QUADAS-2. RESULTS: Thirty-seven studies were included. Ten cardiac magnetic resonance studies reported MPRI and nine positron emission tomography (PET) and transthoracic echocardiography (TTE) studies reported CFR. Mean MPRI ranged from 1.47 ± 0.36 to 2.01 ± 0.41 in patients and from 1.50 ± 0.47 to 2.68 ± 0.49 in controls without CMD. Reported mean CFR in PET and TTE ranged from 1.39 ± 0.31 to 2.85 ± 1.35 and 1.69 ± 0.40 to 2.40 ± 0.40 for patients, and 2.68 ± 0.83 to 4.32 ± 1.78 and 2.65 ± 0.65 to 3.31 ± 1.10 for controls, respectively. CONCLUSIONS: This systematic review summarized current evidence on reported parameters and cut-off values to diagnose CMD for various non-invasive imaging modalities. In current clinical practice, CMD is generally diagnosed with a CFR less than 2.0. However, due to heterogeneity in methodology and reporting of outcome measures, outcomes could not be compared and no definite reference values could be provided.

Mortality after hospital admission for heart failure: improvement over time, equally strong in women as in men.

BACKGROUND: To assess the trend in age- and sex-stratified mortality after hospitalization for heart failure (HF) in the Netherlands. METHODS: Two nationwide cohorts of patients, hospitalized for new onset heart failure between 01.01.2000-31.12.2002 and between 01.01.2008-31.12.2010, were constructed by linkage of the Dutch Hospital Discharge Registry and the National Cause of Death registry. 30-day, 1-year and 5 -year overall and cause-specific mortality rates stratified by age and sex were assessed and compared over time. RESULTS: We identified 40,230 men and 41,582 women. In both cohorts, men were on average younger than women (74-75 and 78-79 years, respectively) and more often had comorbid conditions (37 and 30%, respectively). In the 2008-10 cohort, mortality rates for men were 13, 32 and 64% for respectively 30-day, 1-year and 5-year mortality and 14, 33 and 66% for women. Mortality rates increased considerably with age similarly in men and women (e.g. from 10.5% in women aged 25-54 to 46.1% in those aged 85 and older after 1 year). Between the two time periods, mortality rates dropped across all ages, equally strong in women as in men. The 1-year absolute risk of death declined by 4.0% (from 36.1 to 32.1%) in men and 3.2% (from 36.2 to 33.0%) in women. CONCLUSIONS: Mortality after hospitalization for new onset HF remains high, however, both short-term and long-term survival is improving over time. This improvement was similar across all ages and equally strong in women as in men.

Enhancing cardiovascular artificial intelligence (AI) research in the Netherlands: CVON-AI consortium.

BACKGROUND: Machine learning (ML) allows the exploration and progressive improvement of very complex high-dimensional data patterns that can be utilised to optimise specific classification and prediction tasks, outperforming traditional statistical approaches. An enormous acceleration of ready-to-use tools and artificial intelligence (AI) applications, shaped by the emergence, refinement, and application of powerful ML algorithms in several areas of knowledge, is ongoing. Although such progress has begun to permeate the medical sciences and clinical medicine, implementation in cardiovascular medicine and research is still in its infancy. OBJECTIVES: To lay out the theoretical framework, purpose, and structure of a novel AI consortium. METHODS: We have established a new Dutch research consortium, the CVON-AI, supported by the Netherlands Heart Foundation, to catalyse and facilitate the development and utilisation of AI solutions for existing and emerging cardiovascular research initiatives and to raise AI awareness in the cardiovascular research community. CVON-AI will connect to previously established CVON consortia and apply a cloud-based AI platform to supplement their planned traditional data-analysis approach. RESULTS: A pilot experiment on the CVON-AI cloud was conducted using cardiac magnetic resonance data. It demonstrated the feasibility of the platform and documented excellent correlation between AI-generated ventricular function estimates as compared to expert manual annotations. The resulting AI solution was then integrated in a web application. CONCLUSION: CVON-AI is a new consortium meant to facilitate the implementation and raise awareness of AI in cardiovascular research in the Netherlands. CVON-AI will create an accessible cloud-based platform for cardiovascular researchers, demonstrate the clinical applicability of AI, optimise the analytical methodology of other ongoing CVON consortia, and promote AI awareness through education and training.

Meta-analysis of the outcomes of treatment of internal carotid artery near occlusion.

BACKGROUND: Guidelines recommend treating patients with an internal carotid artery near occlusion (ICANO) with best medical therapy (BMT) based on weak evidence. Consequently, patients with ICANO were excluded from randomized trials. The aim of this individual-patient data (IPD) meta-analysis was to determine the optimal treatment approach. METHODS: A systematic search was performed in MEDLINE, EMBASE and the Cochrane Library databases in January 2018. The primary outcome was the occurrence of any stroke or death within the first 30 days of treatment, analysed by multivariable mixed-effect logistic regression. The secondary outcome was the occurrence of any stroke or death beyond 30 days up to 1 year after treatment, evaluated by Kaplan-Meier survival analysis. RESULTS: The search yielded 1526 articles, of which 61 were retrieved for full-text review. Some 32 studies met the inclusion criteria and pooled IPD were available from 11 studies, including some 703 patients with ICANO. Within 30 days, any stroke or death was reported in six patients (1·8 per cent) in the carotid endarterectomy (CEA) group, five (2·2 per cent) in the carotid artery stenting (CAS) group and seven (4·9 per cent) in the BMT group. This resulted in a higher 30-day stroke or death rate after BMT than after CEA (odds ratio 5·63, 95 per cent c.i. 1·30 to 24·45; P = 0·021). No differences were found between CEA and CAS. The 1-year any stroke- or death-free survival rate was 96·1 per cent for CEA, 94·4 per cent for CAS and 81·2 per cent for BMT. CONCLUSION: These data suggest that BMT alone is not superior to CEA or CAS with respect to 30-day or 1-year stroke or death prevention in patients with ICANO. These patients do not appear to constitute a high-risk group for surgery, and consideration should made to including them in future RCTs of internal carotid artery interventions.

Publisher Correction: Optimization of large animal MI models; a systematic analysis of control groups from preclinical studies.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Cardiovascular and all-cause mortality in patients with intermittent claudication and critical limb ischaemia.

BACKGROUND: The aim of this study was to evaluate absolute mortality risks and to determine whether changes in mortality risk occurred in patients with intermittent claudication (IC) or critical limb ischaemia (CLI) in the Netherlands between 1998 and 2010. METHODS: Data for patients treated between 1998 and 2010 were obtained from Dutch nationwide registers: the Hospital Discharge Register, Population Register and Cause of Death Register. The registers were used to obtain information regarding IC and CLI hospitalizations, co-morbidities, demographic factors, and date and cause of death. The cohort was split into two time intervals for comparison: 1998-2004 (period 1) and 2005-2010 (period 2). Thirty-day mortality was excluded to eliminate per-admission complications. One- and 5-year cardiovascular and all-cause mortality rates were compared with those of a representative sample of the general Dutch population (28 494 persons) by Cox proportional hazards models. RESULTS: Some 47 548 patients were included, 34 078 with IC and 13 470 with CLI. In patients with IC, the age-adjusted 5-year mortality risk for cardiovascular disease decreased significantly in period 2 (14·1 per cent) compared with that in period 1 (16·1 per cent) in men only (5-year adjusted hazard ratio (HR) 0·76, 95 per cent c.i. 0·69 to 0·83; P < 0·001). In patients with CLI, the cardiovascular mortality risk decreased significantly only in women, with the 5-year risk reducing from 31·2 per cent in period 1 to 29·2 per cent in period 2 (adjusted HR 0·84, 0·74 to 0·94; P = 0·004). Compared with the general population, the mortality risk in patients with IC was increased between 1·70 (1·58 to 1·83) and 3·20 (2·69 to 3·81) times, and in those with CLI the risk was increased between 2·24 (2·09 to 2·40) and 5·19 (4·30 to 6·26) times. CONCLUSION: The risk of premature death in patients with IC and CLI declined significantly in the Netherlands, in a sex-specific manner, over the period from 1998 to 2010. The absolute risk of cardiovascular mortality remains high in these patients.

Optimization of large animal MI models; a systematic analysis of control groups from preclinical studies.

Large animal models are essential for the development of novel therapeutics for myocardial infarction. To optimize translation, we need to assess the effect of experimental design on disease outcome and model experimental design to resemble the clinical course of MI. The aim of this study is therefore to systematically investigate how experimental decisions affect outcome measurements in large animal MI models. We used control animal-data from two independent meta-analyses of large animal MI models. All variables of interest were pre-defined. We performed univariable and multivariable meta-regression to analyze whether these variables influenced infarct size and ejection fraction. Our analyses incorporated 246 relevant studies. Multivariable meta-regression revealed that infarct size and cardiac function were influenced independently by choice of species, sex, co-medication, occlusion type, occluded vessel, quantification method, ischemia duration and follow-up duration. We provide strong systematic evidence that commonly used endpoints significantly depend on study design and biological variation. This makes direct comparison of different study-results difficult and calls for standardized models. Researchers should take this into account when designing large animal studies to most closely mimic the clinical course of MI and enable translational success.

Meta-analysis of the costs of carotid artery stenting and carotid endarterectomy.

BACKGROUND: Carotid artery stenting (CAS) is currently associated with an increased risk of 30-day stroke compared with carotid endarterectomy (CEA), whereas both interventions seem equally durable beyond the periprocedural period. Although the clinical outcomes continue to be scrutinized, there are few data summarizing the costs of both techniques. METHODS: A systematic search was conducted in MEDLINE, Embase and Cochrane databases in August 2016 identifying articles comparing the costs or cost-effectiveness of CAS and CEA in patients with carotid artery stenosis. Combined overall effect sizes were calculated using random-effects models. The in-hospital costs were specified to gain insight into the main heads of expenditure associated with both procedures. RESULTS: The literature search identified 617 unique articles, of which five RCTs and 12 cohort studies were eligible for analysis. Costs of the index hospital admission were similar for CAS and CEA. Costs of the procedure itself were 51 per cent higher for CAS, mainly driven by the higher costs of devices and supplies, but were balanced by higher postprocedural costs of CEA. Long-term cost analysis revealed no difference in costs or quality of life after 1 year of follow-up. CONCLUSION: Hospitalization and long-term costs of CAS and CEA appear similar. Economic considerations should not influence the choice of stenting or surgery in patients with carotid artery stenosis being considered for revascularization.

Time-dependent trends in cardiovascular adverse events during follow-up after carotid or iliofemoral endarterectomy.

BACKGROUND: Recent observations have suggested a decline in vulnerable carotid artery and iliofemoral atherosclerotic plaque characteristics over the past decade. The aim of this study was to determine whether, in the presence of clinically manifest carotid or peripheral artery disease, secondary adverse cardiovascular events decreased over this period. METHODS: Patients included in the Athero-Express biobank between 2003 and 2012 were analysed. During 3-year follow-up, composite cardiovascular endpoints were documented yearly, including: myocardial infarction, coronary interventions, stroke, peripheral interventions and cardiovascular death. The major cardiovascular endpoint consisted of myocardial infarction, stroke and cardiovascular death. RESULTS: Some 1684 patients who underwent carotid endarterectomy (CEA) and another 530 who had iliofemoral endarterectomy (IFE) were analysed. In total, 405 (25·2 per cent) and 236 (45·9 per cent) patients had a composite cardiovascular endpoint within 3 years after CEA and IFE respectively. Corrected for possible confounders, the percentage of patients with a secondary cardiovascular event after CEA did not change over time (hazard ratio (HR) 0·91, 95 per cent c.i. 0·65 to 1·28; P = 0·590, for 2011-2012 versus 2003-2004). In patients who had IFE, the incidence of secondary cardiovascular events significantly decreased only in the last 2 years (HR 0·62, 0·41 to 0·94; P = 0·024), owing to a decrease in peripheral (re)interventions in 2011-2012 (HR 0·59, 0·37 to 0·94; P = 0·028). No decrease in major cardiovascular events was observed in either group. CONCLUSION: In patients who had undergone either CEA or IFE there was no evidence of a decrease in all secondary cardiovascular events. There were no differences in major cardiovascular events.

Lack of Evidence for Dual Antiplatelet Therapy after Endovascular Arterial Procedures: A Meta-analysis.

INTRODUCTION: Dual antiplatelet therapy (DAPT) has mainly replaced mono antiplatelet therapy (MAPT) and is recommended after arterial endovascular revascularization. The aim of this meta-analysis was to summarize the available evidence for DAPT after endovascular revascularization throughout the arterial system. METHODS: A systematic search was performed in Medline, Embase, and the Cochrane Register. Two reviewers independently performed data extraction and quality assessment using the Cochrane Collaboration risk of bias assessment tool. Included in the search were randomized controlled trials (RCTs) comparing DAPT with MAPT after endovascular procedures for the treatment of coronary, carotid, or peripheral artery disease, reporting at least one clinical outcome. Articles were excluded if patients received anticoagulation in addition to antiplatelet therapy in the post-procedural phase. The primary outcome was restenosis or stent thrombosis, and secondary outcomes were major adverse cardiac events (MACE), target lesion revascularization, cerebrovascular accident or transient ischemic attack, bleeding, and death. Meta-analyses of binary outcomes were performed using the random effects model and described as risk ratios (RRs) and 95% confidence intervals (95% CIs). Chi-square tests were used to test for heterogeneity. RESULTS: Nine articles were included in this study, involving lower limb peripheral arteries (1), carotid arteries (2), and coronary arteries (6). The pooled results of coronary trials showed a RR for restenosis with DAPT of 0.60 (95% CI 0.28-1.31) and for myocardial infarction 0.49 (95% CI 0.12-2.03). In the carotid artery trials the RR for restenosis was 0.22 (95% CI 0.04-1.20) and for peripheral arteries 1.02 (95% CI 0.56-1.82). A meta-analysis of bleeding risk of all the included trials showed a RR of 1.06 (95% CI 0.32-3.52) with DAPT. CONCLUSION: The available evidence comparing DAPT with MAPT after endovascular arterial revascularization is limited and the majority of trials were conducted in the cardiology field. No significant evidence for superiority of DAPT compared with MAPT was found, but there was also no evidence of an increased bleeding risk with DAPT over MAPT.

High On-Treatment Platelet Reactivity in Peripheral Arterial Disease: A Pilot Study to Find the Optimal Test and Cut Off Values.

OBJECTIVE: Restenosis and stent thrombosis after endovascular intervention in patients with peripheral arterial disease (PAD) can potentially be tackled by more intensive antiplatelet therapy, such as dual antiplatelet therapy (DAPT) consisting of aspirin and P2Y12 inhibitor. Despite clopidogrel treatment, some patients still display high platelet reactivity (HCPR). Tailored antiplatelet therapy, based on platelet reactivity testing, might overcome HCPR. However, more data are warranted regarding the proportion of patients with HCPR in the PAD population, different platelet reactivity tests, their correlation, and the optimal timing for these tests as a stepping stone for a future trial investigating the potential benefit of tailored antiplatelet therapy in PAD patients. METHODS: Thirty patients on DAPT after percutaneous transluminal angioplasty underwent platelet reactivity testing by VerifyNow, vasodilator-stimulated phosphoprotein (VASP) and platelet activation assay, and CYP2C19-polymorphism testing. RESULTS: The proportion of patients with HCPR measured by VerifyNow varied between 43.3% and 83.3%, depending on the cut off values used. Testing within 24 hours of initiation of DAPT gave a higher proportion of HCPR than testing after more than 24 hours. According to DNA testing, 14.8% were CYP2C19*2 homozygote, 22.2% heterozygote, and 63% CYP2C19*2 negative. VASP assay revealed 24% HCPR. The highest HCPR rate was found with a VerifyNow cut off of less than 40% inhibition, whereas the lowest HCPR rate was found with the VASP assay. There was a low correlation between the tests. CONCLUSION: HCPR is present in PAD patients and research on HCPR is needed in this population; timing of tests is relevant and standardisation of tests is needed. The optimal conditions for platelet function testing should be determined.

The ethnicity-specific association of biomarkers with the angiographic severity of coronary artery disease.

BACKGROUND: Risk factor burden and clinical characteristics of patients with coronary artery disease (CAD) differ among ethnic groups. We related biomarkers to CAD severity in Caucasians, Chinese, Indians and Malays. METHODS: In the Dutch-Singaporean UNICORN coronary angiography cohort (n = 2033) we compared levels of five cardiovascular biomarkers: N-terminal pro-brain natriuretic peptide (NTproBNP), high-sensitivity C-reactive protein (hsCRP), cystatin C (CysC), myeloperoxidase (MPO) and high-sensitivity troponin I (hsTnI). We assessed ethnicity-specific associations of biomarkers with CAD severity, quantified by the SYNTAX score. RESULTS: Adjusted for baseline differences, NTproBNP levels were significantly higher in Malays than in Chinese and Caucasians (72.1 vs. 34.4 and 41.1 pmol/l, p < 0.001 and p = 0.005, respectively). MPO levels were higher in Caucasians than in Indians (32.8 vs. 27.2 ng/ml, p = 0.026), hsTnI levels were higher in Malays than in Caucasians and Indians (33.3 vs. 16.4 and 17.8 ng/l, p < 0.001 and p = 0.029) and hsTnI levels were higher in Chinese than in Caucasians (23.3 vs. 16.4, p = 0.031). We found modifying effects of ethnicity on the association of biomarkers with SYNTAX score. NTproBNP associated more strongly with the SYNTAX score in Malays than Caucasians (ß 0.132 vs. ß 0.020 per 100 pmol/l increase in NTproBNP, p = 0.032). For MPO levels the association was stronger in Malays than Caucasians (ß 1.146 vs. ß 0.016 per 10 ng/ml increase, p = 0.017). Differing biomarker cut-off levels were found for the ethnic groups. CONCLUSION: When corrected for possible confounders we observe ethnicity-specific differences in biomarker levels. Moreover, biomarkers associated differently with CAD severity, suggesting that ethnicity-specific cut-off values should be considered.

Patient selection for cardiac surgery: Time to consider subgroups within risk categories?

BACKGROUND: Medical guidelines increasingly use risk stratification and implicitly assume that individuals classified in the same risk category form a homogeneous group, while individuals with similar, or even identical, predicted risks can still be very different. We evaluate a strategy to identify homogeneous subgroups typically comprising predicted risk categories to allow further tailoring of treatment allocation and illustrate this strategy empirically for cardiac surgery patients with high postoperative mortality risk. METHODS: Using a dataset of cardiac surgery patients (n=6517) we applied cluster analysis to identify homogenous subgroups of patients comprising the high postoperative mortality risk group (EuroSCORE ≥ 15%). Cluster analyses were performed separately within younger (<75 years) and older (≥ 75 years) patients. Validity measures were calculated to evaluate quality and robustness of the identified subgroups. RESULTS: Within younger patients two distinct and robust subgroups were identified, differing mainly in preoperative state and indication of recent myocardial infarction or unstable angina. In older patients, two distinct and robust subgroups were identified as well, differing mainly in preoperative state, presence of chronic pulmonary disease, previous cardiac surgery, neurological dysfunction disease and pulmonary hypertension. CONCLUSIONS: We illustrated a feasible method to identify homogeneous subgroups of individuals typically comprising risk categories. This allows a single treatment strategy--optimal only on average, across all individuals in a risk category--to be replaced by subgroup-specific treatment strategies, bringing us another step closer to individualized care. Discussions on allocation of cardiac surgery patients to different interventions may benefit from focusing on such specific subgroups.

Clinical Relevance of Cardiac Troponin Assessment in Patients Undergoing Carotid Endarterectomy.

OBJECTIVE: Myocardial infarction (MI) is a frequent complication of carotid endarterectomy (CEA), yet most events are silent. Routine post-operative monitoring of cardiac troponin was implemented to facilitate timely recognition of MI and stratify high risk patients. The aim was to evaluate the incidence of troponin elevation after CEA and its association with adverse cardiovascular events. METHODS: This analysis included patients ≥60 years old who underwent CEA, whose troponin-I levels were routinely monitored post-operatively and were included in a cohort study that assessed clinical outcomes. A clinical troponin cutoff of 60 ng/L was used. The primary endpoint was the composite of MI, stroke, and cardiovascular death. Secondary endpoints were MI, stroke, coronary intervention, cardiovascular death, and all cause death. RESULTS: 225 consecutive patients were included in the analysis. Troponin elevation occurred in 34 patients (15%) and a post-operative MI was diagnosed in eight patients. After a median follow up of 1.8 years (IQR 1.0-2.6), the primary endpoint occurred in 29% of patients with troponin elevation versus 6.3% without (HR 5.6, 95% CI 2.4-13), MI in 24% versus 1.6% (HR 18.0, 95% CI 4.7-68), stroke in 5.9% versus 4.2% (HR 1.4, 95% CI 0.3-6.7), coronary intervention in 5.9% versus 2.6% (HR 2.7, 95% CI 0.5-14), cardiovascular death in 5.9% versus 0.5% (HR 11.8, 95% CI 1.1-131), and all cause death in 15% versus 5.8% (HR 3.0, 95% CI 1.0-8.7), respectively. Incidences of the primary endpoint and all cause mortality in patients with a post-operative MI versus "troponin only" were 25% versus 7.7% and 25% versus 12%, respectively. CONCLUSION: Troponin elevation after CEA occurred in 15% of patients. The incidence of adverse cardiovascular events was significantly higher in patients with troponin elevation, which was mainly attributable to silent non-ST segment elevation MIs that occurred in the early post-operative phase.

Vascular age to determine cardiovascular disease risk: A systematic review of its concepts, definitions, and clinical applications.

BACKGROUND: Vascular age is an alternate means of representing an individual's cardiovascular risk. Little consensus exists on what vascular age represents and its clinical utility has not been determined. We systematically reviewed the literature to provide a comprehensive overview of different methods that have been used to define vascular age, and to examine its potential clinical value in patient communication and risk prediction. DESIGN: This was a systematic review with data sources of PubMed and Embase. RESULTS: We identified 39 articles on vascular age, 20 proposed to use vascular age as a communication tool and 19 proposed to use vascular age as a means to improve cardiovascular risk prediction. Eight papers were methodological and 31 papers reported on vascular age in study populations. Of these 31 papers, vascular age was a direct translation of the absolute risk estimated by existing cardiovascular risk prediction models in 15 papers, 12 derived vascular age from the reference values of an additional test, and in three papers vascular age was defined as the age at which the estimated cardiovascular risk equals the risk from non-invasive imaging observed degree of atherosclerosis. One trial found a small effect on risk factor levels when vascular age was communicated instead of cardiovascular risk. CONCLUSION: Despite sharing a common name, various studies have proposed distinct ways to define and measure vascular age. Studies into the effects of vascular age as a tool to improve cardiovascular risk prediction or patient communication are scarce but will be required before its clinical use can be justified.

Quality of Life After Treatment with Autologous Bone Marrow Derived Cells in No Option Severe Limb Ischemia.

OBJECTIVE: Quality of life (QoL) is an important outcome in evaluating treatment effect in severe limb ischemia. The randomized, double blind, placebo controlled JUVENTAS trial, investigating the effect of bone marrow derived mononuclear cell (BMMNC) administration in no option severe limb ischemia, showed an improved QoL at 6 months compared with baseline in both the treatment and placebo groups. The aim of the present study was to evaluate whether the improved QoL persisted beyond 6 months' follow up, whether this differed in both trial arms, and if major amputation influenced QoL. METHODS: Short form 36 (SF-36) and EuroQol 5D (EQ5D), including the EQ Visual Analogue Scale (EQ-VAS), questionnaires were sent to JUVENTAS trial participants. In the JUVENTAS trial, a norm based scoring method was applied to report the results of the SF-36. The results of the long-term follow up were compared with baseline and 6 month follow up and the results of both trial arms were compared, as were the results of patients with and without amputation. RESULTS: One hundred and nine patients (86.5% of surviving patients) responded to the questionnaires. Median follow up after inclusion was 33 months (interquartile range [IQR] 21.2-50.6) for the BMMNC and 36 months (IQR 21.4-50.9) for the placebo group. The improvement in QoL at 6 months persisted in both arms at a median follow up of 35 months. The long-term QoL did not differ between the BMMNC and placebo group in any of the SF-36 or EQ5D domains. Patients with and without a major amputation had similar QoL scores. CONCLUSIONS: The increased QoL in patients with no option severe limb ischemia persisted until 3 years after inclusion, but did not differ between the BMMNC and placebo arms or between patients with and without a major amputation.