Prevalence and management of familial hypercholesterolaemia in patients with chest pain admitted to hospital: a retrospective observational study.

OBJECTIVES: Patients with familial hypercholesterolaemia (FH) are genetically burdened by a lifelong elevation of the low-density lipoprotein cholesterol (LDL-C) level, putting them at a very high risk of premature ischaemic heart disease (IHD). This study aims to assess the prevalence of FH among patients admitted for IHD and the preventive treatment status before admission. DESIGN: Observational, retrospective, register-based study. SETTING: Individuals discharged with a diagnosis of IHD were enrolled consecutively throughout 2012-2016 from the cardiac care units of two hospitals in Copenhagen. PARTICIPANTS: 4223 individuals were discharged during the period. Inclusion criteria for further investigation were the availability of one measurement of LDL-C at the time of admission. In total, 2797 individuals were included for further investigation. There were no exclusion criteria. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary objective has been to determine the prevalence of FH in the population. The secondary objective has been to determine the use of lipid-lowering therapy and to which extend the individuals reach their treatment goal. RESULTS: Among the 2797 consecutive patients evaluated, the prevalence of potential FH was 7.7% (1: 13) and 6.8% (1:15) had probably or definite FH. The prevalence of FH was age-dependent: Among the 680 patients (24.3%) with premature IHD (men <55 years/women <60 years), 136 patients (20.0%) had potential FH and 21 (3.1%) had probable/definite FH. None were diagnosed and almost none attained their treatment goal. CONCLUSIONS: There is still a massive lack of recognition of FH in patients admitted to a cardiac care unit with a diagnosis of IHD. Despite a measured high LDL-C, the diagnosis was not made for any patients not even in patients who were admitted at an early age or had a previous cardiovascular event.

European Society of Cardiology guidance for the diagnosis and management of cardiovascular disease during the COVID-19 pandemic: part 1-epidemiology, pathophysiology, and diagnosis.

AIMS: Since its emergence in early 2020, the novel severe acute respiratory syndrome coronavirus 2 causing coronavirus disease 2019 (COVID-19) has reached pandemic levels, and there have been repeated outbreaks across the globe. The aim of this two-part series is to provide practical knowledge and guidance to aid clinicians in the diagnosis and management of cardiovascular disease (CVD) in association with COVID-19. METHODS AND RESULTS: A narrative literature review of the available evidence has been performed, and the resulting information has been organized into two parts. The first, reported here, focuses on the epidemiology, pathophysiology, and diagnosis of cardiovascular (CV) conditions that may be manifest in patients with COVID-19. The second part, which will follow in a later edition of the journal, addresses the topics of care pathways, treatment, and follow-up of CV conditions in patients with COVID-19. CONCLUSION: This comprehensive review is not a formal guideline but rather a document that provides a summary of current knowledge and guidance to practicing clinicians managing patients with CVD and COVID-19. The recommendations are mainly the result of observations and personal experience from healthcare providers. Therefore, the information provided here may be subject to change with increasing knowledge, evidence from prospective studies, and changes in the pandemic. Likewise, the guidance provided in the document should not interfere with recommendations provided by local and national healthcare authorities.

Doppler Echocardiography Assessment of Coronary Microvascular Function in Patients With Angina and No Obstructive Coronary Artery Disease.

Echocardiographic evaluation is an essential part of the diagnostic work-up in patients with known or suspected cardiovascular disease. Transthoracic Doppler echocardiography (TTDE) enables straightforward and reliable visualization of flow in the left anterior descending artery. In the absence of obstructive coronary artery disease, low TTDE-derived coronary flow velocity reserve (CFVR) is considered a marker of coronary microvascular dysfunction (CMD). TTDE CFVR is free from ionizing radiation and widely available, utilizing high-frequency transducers, pharmacologic vasodilator stress, and pulsed-wave Doppler quantification of diastolic peak flow velocities. European Society of Cardiology guidelines recommend TTDE CFVR evaluation only following preceding anatomic invasive or non-invasive coronary imaging excluding obstructive CAD. Accordingly, clinical use of TTDE CFVR is limited and CMD frequently goes undiagnosed. An evolving body of evidence underlines that low CFVR is an important and robust predictor of adverse prognosis and continuing symptoms in angina patients both with and without obstructive CAD. The majority of angina patients have no obstructive CAD, particularly among women. This has led to the suggestion that there may be a gender-specific female atherosclerotic phenotype with less epicardial obstruction, and a low CFVR signifying CMD instead. Nevertheless, available evidence indicates low CFVR is an equally important prognostic marker in both men and women. In this review, TTDE CFVR was evaluated regarding indication, practical and technical aspects, and interpretation of results. Association with symptoms and prognosis, comparison with alternative invasive and non-invasive imaging modalities, and possible interventions in angina patients with low CFVR were discussed, and key research questions were proposed.

Cost-effectiveness of adding a non-invasive acoustic rule-out test in the evaluation of patients with symptoms suggestive of coronary artery disease: rationale and design of the prospective, randomised, controlled, parallel-group multicenter FILTER-SCAD trial.

INTRODUCTION: Most patients with symptoms suggestive of chronic coronary syndrome (CCS) have no obstructive coronary artery disease (CAD) and better selection of patients to be referred for diagnostic tests is needed. The CAD-score is a non-invasive acoustic measure that, when added to pretest probability of CAD, has shown good rule-out capabilities. We aimed to test whether implementation of CAD-score in clinical practice reduces the use of diagnostic tests without increasing major adverse cardiac events (MACE) rates in patients with suspected CCS. METHODS AND ANALYSIS: FILTER-SCAD is a randomised, controlled, multicenter trial aiming to include 2000 subjects aged ≥30 years without known CAD referred for outpatient assessment for symptoms suggestive of CCS. Subjects are randomised 1:1 to either the control group: standard diagnostic examination (SDE) according to the current guidelines, or the intervention group: SDE plus a CAD-score. The subjects are followed for 12 months for the primary endpoint of cumulative number of diagnostic tests and a safety endpoint (MACE). Angina symptoms, quality of life and risk factor modification will be assessed with questionnaires at baseline, 3 months and 12 months after randomisation. The study is powered to detect superiority in terms of a reduction of ≥15% in the primary endpoint between the two groups with a power of 80%, and non-inferiority on the secondary endpoint with a power of 90%. The significance level is 0.05. The non-inferiority margin is set to 1.5%. Randomisation began on October 2019. Follow-up is planned to be completed by December 2022. ETHICS AND DISSEMINATION: This study has been approved by the Danish Medical Agency (2019024326), Danish National Committee on Health Research Ethics (H-19012579) and Swedish Ethical Review Authority (Dnr 2019-04252). All patients participating in the study will sign an informed consent. All study results will be attempted to be published as soon as possible. TRIAL REGISTRATION NUMBER: NCT04121949; Pre-results.

Assessment of functional sit-to-stand muscle power: Cross-sectional trajectories across the lifespan.

BACKGROUND: The 30-s sit-to-stand (STS) muscle power test is a valid test to assess muscle power in older people; however, whether it may be used to assess trajectories of lower-limb muscle power through the adult lifespan is not known. This study evaluated the pattern and time course of variations in relative, allometric and specific STS muscle power throughout the lifespan. METHODS: Subjects participating in the Copenhagen Sarcopenia Study (729 women and 576 men; aged 20 to 93 years) were included. Lower-limb muscle power was assessed with the 30-s version of the STS muscle power test. Allometric, relative and specific STS power were calculated as absolute STS power normalized to height squared, body mass and leg lean mass as assessed by DXA, respectively. RESULTS: Relative STS muscle power tended to increase in women (0.08 ±â€¯0.05 W·kg-1·yr-1; p = 0.082) and increased in men (0.14 ±â€¯0.07 W·kg-1·yr-1; p = 0.046) between 20 and 30 years, followed by a slow decline (-0.05 ±â€¯0.05 W·kg-1·yr-1 and -0.06 ±â€¯0.08 W·kg-1·yr-1, respectively; both p > 0.05) between 30 and 50 years. Then, relative STS power declined at an accelerated rate up to oldest age in men (-0.09 ±â€¯0.02 W·kg-1·yr-1) and in women until the age of 75 (-0.09 ±â€¯0.01 W·kg-1·yr-1) (both p < 0.001). A lower rate of decline was observed in women aged 75 and older (-0.04 ±â€¯0.02 W·kg-1·yr-1; p = 0.039). Similar age-related patterns were noted for allometric and specific STS power. CONCLUSIONS: The STS muscle power test appears to provide a feasible and inexpensive tool to monitor cross-sectional trajectories of muscle power throughout the lifespan.

Temporal trends and sex differences in sudden cardiac death in the Copenhagen City Heart Study.

OBJECTIVE: More knowledge about the development of sudden cardiac death (SCD) in the general population is needed to develop meaningful predictors of SCD. Our aim with this study was to estimate the incidence of SCD in the general population and examine the temporal changes, demographics and clinical characteristics. METHODS: All participants in the Copenhagen City Heart Study were followed from 1993 to 2016. All death certificates, autopsy reports and national registry data were used to identify all cases of SCD. RESULTS: A total of 14 562 subjects were included in this study. There were 8394 deaths with all information available, whereof 1335 were categorised as SCD. The incidence of SCD decreased during the study period by 41% for persons aged 40-90 years, and the standardised incidence rates decreased from 504 per 100 000 person-years (95% CI 447 to 569) to 237 per 100 000 person-years (95% CI 195 to 289). The incidence rate ratio of SCD between men and women ≤75 years was 1.99 (95% CI 1.62 to 2.46). The proportion of SCD of all cardiac deaths decreased during the observation period and decreased with increasing age. Men had more cardiovascular comorbidities (OR 1.34, 95% CI 1.07 to 1.68, p<0. 01), and SCD was the first registered manifestation of cardiac disease in 50% of all cases. CONCLUSION: The incidence of SCD in the general population has declined significantly during the study period but should be further investigated for more recent variations as well as novel risk predictors for persons with low to medium risk of SCD.

Greater burden of risk factors and less effect of cardiac rehabilitation in elderly with low educational attainment: The Eu-CaRE study.

AIMS: Socioeconomic status is a strong predictor of cardiovascular health. The aim of this study was to describe the immediate and long-term effects of cardiac rehabilitation (CR) across socioeconomic strata in elderly cardiac patients in Europe. METHODS AND RESULTS: The observational EU-CaRE study is a prospective study with eight CR sites in seven European countries. Patients ≥65 years with coronary heart disease or heart valve surgery participating in CR were consecutively included. Data were obtained at baseline, end of CR and at one-year follow up. Educational level as a marker for socioeconomic status was divided into basic, intermediate and high. The primary endpoint was exercise capacity (peak oxygen consumption (VO2peak)). Secondary endpoints were cardiovascular risk factors, medical treatment and scores for depression, anxiety and quality of life (QoL). A total of 1626 patients were included; 28% had basic, 48% intermediate and 24% high education. A total of 1515 and 1448 patients were available for follow-up analyses at end of CR and one-year, respectively. Patients with basic education were older and more often female. At baseline we found a socioeconomic gradient in VO2peak, lifestyle-related cardiovascular risk factors, anxiety, depression and QoL. The socioeconomic gap in VO2peak increased following CR (p for interaction <0.001). The socioeconomic gap in secondary outcomes was unaffected by CR. The use of evidence-based medication was good in all socioeconomic groups. CONCLUSIONS: We found a strong socioeconomic gradient in VO2peak and cardiovascular risk factors that was unaffected or worsened after CR. To address inequity in cardiovascular health, the individual adaption of CR according to socioeconomic needs should be considered.

Screening for potential familial hypercholesterolaemia in general practice: an observational study on prevalence and management.

BACKGROUND: Familial hypercholesterolaemia (FH) is a common genetic disorder causing premature cardiovascular disease (CVD). The estimated prevalence of probable or definite FH is 1:200-250 individuals, according to the Dutch Lipid Clinic Network (DLCN) criteria for FH. In Denmark approximately 12% of cases are identified. AIM: To provide knowledge of the prevalence and management of FH in general practice. DESIGN & SETTING: A collaboration between six general practice clinics and the department of cardiology at Bispebjerg hospital in Denmark. METHOD: A total of 9652 patient records were screened for hypercholesterolaemia. All patients with a low-density lipoprotein cholesterol (LDL-C) ≥5.0 mmol/l were included in the study population and their records were investigated in order to perform a diagnostic score according to the DLCN criteria. RESULTS: It was found that 2382 individuals had a lipid measurement available, and 236 of those had an LDL-C ≥5.0 mmol/l. In total, 34 individuals were found to have probable or definite FH (DLCN score ≥5). Only three individuals had been diagnosed and treated with lipid-lowering therapy. Of 236 individuals with high LDL-C, only 25 individuals met their treatment target. By excluding patients with signs of secondary hypercholesterolaemia, a subgroup of 115 individuals with potential primary hypercholesterolaemia was established. Among those, 21 individuals were found to have probable or definite FH (1:114 individuals). CONCLUSION: The study shows that there is a massive lack of recognition of FH in general practice. Despite a measured high LDL-C, the diagnosis is rarely made and only a few patients are treated accordingly. Of the patients undergoing treatment, only a few reached their treatment target.

Cardiac rehabilitation availability and delivery in Europe: How does it differ by region and compare with other high-income countries?: Endorsed by the European Association of Preventive Cardiology.

AIMS: The aims of this study were to establish cardiac rehabilitation availability and density, as well as the nature of programmes, and to compare these by European region (geoscheme) and with other high-income countries. METHODS: A survey was administered to cardiac rehabilitation programmes globally. Cardiac associations were engaged to facilitate programme identification. Density was computed using global burden of disease study ischaemic heart disease incidence estimates. Four high-income countries were selected for comparison (N = 790 programmes) to European data, and multilevel analyses were performed. RESULTS: Cardiac rehabilitation was available in 40/44 (90.9%) European countries. Data were collected in 37 (94.8% country response rate). A total of 455/1538 (29.6% response rate) programme respondents initiated the survey. Programme volumes (median 300) were greatest in western European countries, but overall were higher than in other high-income countries (P < 0.001). Across all Europe, there was on average only 1 CR spot per 7 IHD patients, with an unmet regional need of 3,449,460 spots annually. Most programmes were funded by social security (n = 25, 59.5%; with significant regional variation, P < 0.001), but in 72 (16.0%) patients paid some or all of the programme costs (or ∼18.5% of the ∼€150.0/programme) out of pocket. Guideline-indicated conditions were accepted in 70% or more of programmes (lower for stable coronary disease), with no regional variation. Programmes had a multidisciplinary team of 6.5 ± 3.0 staff (number and type varied regionally; and European programmes had more staff than other high-income countries), offering 8.5 ± 1.5/10 core components (consistent with other high-income countries) over 24.8 ± 26.0 hours (regional differences, P < 0.05). CONCLUSION: European cardiac rehabilitation capacity must be augmented. Where available, services were consistent with guidelines, but varied regionally.

Explaining trends in coronary heart disease mortality in different socioeconomic groups in Denmark 1991-2007 using the IMPACTSEC model.

AIM: To quantify the contribution of changes in different risk factors population levels and treatment uptake on the decline in CHD mortality in Denmark from 1991 to 2007 in different socioeconomic groups. DESIGN: We used IMPACTSEC, a previously validated policy model using data from different population registries. PARTICIPANTS: All adults aged 25-84 years living in Denmark in 1991 and 2007. MAIN OUTCOME MEASURE: Deaths prevented or postponed (DPP). RESULTS: There were approximately 11,000 fewer CHD deaths in Denmark in 2007 than would be expected if the 1991 mortality rates had persisted. Higher mortality rates were observed in the lowest socioeconomic quintile. The highest absolute reduction in CHD mortality was seen in this group but the highest relative reduction was in the most affluent socioeconomic quintile. Overall, the IMPACTSEC model explained nearly two thirds of the decline in. Improved treatments accounted for approximately 25% with the least relative mortality reduction in the most deprived quintile. Risk factor improvements accounted for approximately 40% of the mortality decrease with similar gains across all socio-economic groups. The 36% gap in explaining all DPPs may reflect inaccurate data or risk factors not quantified in the current model. CONCLUSIONS: According to the IMPACTSEC model, the largest contribution to the CHD mortality decline in Denmark from 1991 to 2007 was from improvements in risk factors, with similar gains across all socio-economic groups. However, we found a clear socioeconomic trend for the treatment contribution favouring the most affluent groups.

Challenges in secondary prevention after acute myocardial infarction: A call for action.

Worldwide, each year more than 7 million people experience myocardial infarction, in which one-year mortality rates are now in the range of 10%, but vary with patient characteristics. The consequences are even more dramatic: among patients who survive, 20% suffer a second cardiovascular event in the first year and approximately 50% of major coronary events occur in those with a previous hospital discharge diagnosis of ischaemic heart disease. The people behind these numbers spur this call for action. Prevention after myocardial infarction is crucial to reduce risk and suffering. Evidence-based interventions include optimal medical treatment with anti-platelets and statins, achievement of blood pressure, lipid and blood glucose targets, and appropriate lifestyle changes. The European Society of Cardiology and its constituent bodies are determined to embrace this challenge by developing a consensus document in which the existing gaps for secondary prevention strategies are reviewed. Effective interventions in relation to the patients, healthcare providers and healthcare systems are proposed and discussed. Finally, innovative strategies in hospital as well as in outpatient and long-term settings are endorsed.

Role of the polypill for secondary prevention in ischaemic heart disease.

In 2011, for the first time in the history of humankind, non-communicable diseases became the leading cause of death worldwide. This change in trend is obviously multifactorial and very complex, as it is the paradoxical result of social, economic and health system growth worldwide. Vaccination and infectious diseases control, changing dietary habits worldwide, sedentary behaviour, globalisation, industrialisation (resulting in a shift from manual to sedentary labour), tobacco and sugary beverage surges in low- and middle-income countries and rapid urbanisation have all played a role in this epidemic transition. At the same time, the increase in cardiovascular risk factors, together with a decline in mortality in high-income countries in the past two decades, has led to a significant upsurge in the prevalence of secondary prevention of ischaemic heart disease. With this, the effect that non-adherence to cardioprotective drugs is having has become progressively clear, both in terms of clinical outcomes and as a driver of increased healthcare expenditure. The cardiovascular polypill, which was originally proposed as a strategy to improve accessibility to cardioprotective drugs worldwide, has proven to be a mainstay therapeutic approach for improving medication adherence in cardiovascular disease. In the current paper, we aim to review the need for a polypill strategy in the present scenario of cardiovascular disease, the available data that support such a strategy and the various clinical trials that are in progress that will help further shape future indications for the cardiovascular polypill.

Transthoracic Doppler echocardiography compared with positron emission tomography for assessment of coronary microvascular dysfunction: The iPOWER study.

BACKGROUND: Coronary microvascular function can be assessed by transthoracic Doppler echocardiography as a coronary flow velocity reserve (TTDE CFVR) and by positron emission tomography as a myocardial blood flow reserve (PET MBFR). PET MBFR is regarded the noninvasive reference standard for measuring coronary microvascular function but has limited availability. We compared TTDE CFVR with PET MBFR in women with angina pectoris and no obstructive coronary artery disease and assessed repeatability of TTDE CFVR. METHODS: From a cohort of women with angina and no obstructive coronary artery stenosis at invasive coronary angiography, TTDE CFVR by dipyridamole induced stress and MBFR by rubidium-82 PET with adenosine was successfully measured in 107 subjects. Repeatability of TTDE CFVR was assessed in 10 symptomatic women and in 10 healthy individuals. RESULTS: MBFR was systematically higher than CFVR. Median MBFR (interquartile range, IQR) was 2.68 (2.29-3.10) and CFVR (IQR) was 2.31 (1.89-2.72). Pearson's correlation coefficient was 0.36 (p<0.01). Limits of agreement (2·standard deviation) assessed by the Bland-Altman (confidence interval, CI) method was 1.49 (1.29;1.69) and unaffected by time-interval between examinations. Results were similar when adjusting for rate pressure product or focusing on perfusion of the left anterior descending artery region. Limits of agreement (CI) for repeated CFVR in 10 healthy individuals and in 10 women with angina was 0.44 (0.21;0.68) and 0.48 (0.22; 0.74), respectively. CONCLUSION: CFVR had a good repeatability, but the agreement between CFVR and MBFR was modest. Divergence could be due to methodology differences; TTDE estimates flow velocities whereas PET estimates myocardial blood flow.

A EUropean study on effectiveness and sustainability of current Cardiac Rehabilitation programmes in the Elderly: Design of the EU-CaRE randomised controlled trial.

BACKGROUND: Cardiac rehabilitation (CR) is an evidence-based intervention to increase survival and quality of life. Yet studies consistently show that elderly patients are less frequently referred to CR, show less uptake and more often drop out of CR programmes. DESIGN: The European study on effectiveness and sustainability of current cardiac rehabilitation programmes in the elderly (EU-CaRE) project consists of an observational study and an open prospective, investigator-initiated multicentre randomised controlled trial (RCT) involving mobile telemonitoring guided CR (mCR). OBJECTIVE: The aim of EU-CaRE is to map the efficiency of current CR of the elderly in Europe, and to investigate whether mCR is an effective alternative in terms of efficacy, adherence and sustainability. METHODS AND RESULTS: The EU-CaRE study includes patients aged 65 years or older with ischaemic heart disease or who have undergone heart valve surgery. A total of 1760 patients participating in existing CR programmes in eight regions of Europe will be included. Of patients declining regular CR, 238 will be included in the RCT and randomised in two study arms. The experimental group (mCR) will receive a personalised home-based programme while the control group will receive no advice or coaching throughout the study period. Outcomes will be assessed after the end of CR and at 12 months follow-up. The primary outcome is VO2peak and secondary outcomes include variables describing CR uptake, adherence, efficacy and sustainability. CONCLUSION: The study will provide important information to improve CR in the elderly. The EU-CaRE RCT is the first European multicentre study of mCR as an alternative for elderly patients not attending usual CR.

Socio-economic position and time trends in invasive management and case fatality after acute myocardial infarction in Denmark.

BACKGROUND: Lower case fatality and increased use of evidence-based invasive management incl. coronary angiography (CAG) have been reported for patients admitted with acute myocardial infarction (AMI) in the last 25 years. This article seeks to investigate whether these advances have benefitted patients in all socio-economic groups and how this has impacted on inequality in case fatality. METHODS: Forty three thousand eight hundred and forty three patients admitted with AMI in the period from 2001 to 2009 were included. Socio-economic position was measured using individual information on education. Age-standardized cumulative incidence of CAG within 1, 3 and 30 days along with age-standardized case fatality within 30 and 365 days were estimated. Cox regression models were used to model the relative inequality over time. RESULTS: Use of CAG within 1, 3 and 30 days increased for all educational groups over time and the inequality in CAG within 1 and 3 days seen in the beginning of the time frame was eliminated. Case fatality decreased in all educational groups and the relative inequality in 30 days case fatality decreased for women but not 365 days case fatality. No change was seen for inequality in case fatality for men. CONCLUSION: Increased use of CAG within the evidence based time frame was observed along with a decrease in inequality. However, a reduction in inequality was only observed for short term case fatality, and only for women. These results suggest that inequality in case fatality is not primarily driven by inequality in invasive management of AMI.

Does access to invasive examination and treatment influence socioeconomic differences in case fatality for patients admitted for the first time with non-ST-elevation myocardial infarction or unstable angina?

AIMS: Our aim was to investigate whether there is social inequality in access to invasive examination and treatment, and whether access explains social inequality in case fatality in a nationwide sample of patients admitted for the first time with unstable angina or non-ST-elevation myocardial infarction (NSTEMI) in Denmark. METHODS AND RESULTS: All patients admitted for the first time with NSTEMI (n=16,625) or unstable angina (n=8,800) from 2001 to 2009 in Denmark were included. We measured time from admission to coronary angiography (CAG), percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG). The outcomes were 30-day and one-year case fatality. We found social inequality in access to CAG and one-year case fatality for both NSTEMI and unstable angina patients, but the time waited for CAG did not explain the social inequality in case fatality. CONCLUSIONS: Despite nominal equal access to health care, social inequality in case fatality after NSTEMI and unstable angina exists in Denmark. The patients with the shortest education waited longer for angio-graphy; however, this did not seem to explain inequality in case fatality. This register-based study was approved by the Danish Data Protection Agency (Approval number 2010-41-5263). Register-based studies do not need approval by a medical ethics committee in Denmark.

Burden of hospital admission and repeat angiography in angina pectoris patients with and without coronary artery disease: a registry-based cohort study.

AIMS: To evaluate risk of hospitalization due to cardiovascular disease (CVD) and repeat coronary angiography (CAG) in stable angina pectoris (SAP) with no obstructive coronary artery disease (CAD) versus obstructive CAD, and asymptomatic reference individuals. METHODS AND RESULTS: We followed 11,223 patients with no prior CVD having a first-time CAG in 1998-2009 due to SAP symptoms and 5,695 asymptomatic reference individuals from the Copenhagen City Heart Study through registry linkage for 7.8 years (median). In recurrent event survival analysis, patients with SAP had 3-4-fold higher risk of hospitalization for CVD irrespective of CAG findings and cardiovascular comorbidity. Multivariable adjusted hazard ratios(95%CI) for patients with angiographically normal coronary arteries was 3.0(2.5-3.5), for angiographically diffuse non-obstructive CAD 3.9(3.3-4.6) and for 1-3-vessel disease 3.6-4.1(range)(all P<0.001). Mean accumulated hospitalization time was 3.5(3.0-4.0)(days/10 years follow-up) in reference individuals and 4.5(3.8-5.2)/7.0(5.4-8.6)/6.7(5.2-8.1)/6.1(5.2-7.4)/8.6(6.6-10.7) in patients with angiographically normal coronary arteries/angiographically diffuse non-obstructive CAD/1-, 2-, and 3-vessel disease, respectively (all P<0.05, age-adjusted). SAP symptoms predicted repeat CAG with multivariable adjusted hazard ratios for patients with angiographically normal coronary arteries being 2.3(1.9-2.9), for angiographically diffuse non-obstructive CAD 5.5(4.4-6.8) and for obstructive CAD 6.6-9.4(range)(all P<0.001). CONCLUSIONS: Patients with SAP symptoms and angiographically normal coronary arteries or angiographically diffuse non-obstructive CAD suffer from considerably greater CVD burdens in terms of hospitalization for CVD and repeat CAG compared with asymptomatic reference individuals even after adjustment for cardiac risk factors and exclusion of cardiovascular comorbidity as cause. Contrary to common perception, excluding obstructive CAD by CAG in such patients does not ensure a benign cardiovascular prognosis.

Education and cause-specific mortality: the mediating role of differential exposure and vulnerability to behavioral risk factors.

BACKGROUND: Differential exposures to behavioral risk factors have been shown to play an important mediating role on the education-mortality relation. However, little is known about the extent to which educational attainment interacts with health behavior, possibly through differential vulnerability. METHODS: In a cohort study of 76,294 participants 30 to 70 years of age, we estimated educational differences in cause-specific mortality from 1980 through 2009 and the mediating role of behavioral risk factors (smoking, alcohol intake, physical activity, and body mass index). With the use of marginal structural models and three-way effect decomposition, we simultaneously regarded the behavioral risk factors as intermediates and clarified the role of their interaction with educational exposure. RESULTS: Rate differences in mortality comparing participants with low to high education were 1,277 (95% confidence interval = 1,062 to 1,492) per 100,000 person-years for men and 746 (598 to 894) per 100,000 person-years for women. Smoking was the strongest mediator for cardiovascular disease, cancer, and respiratory disease mortality when conditioning on sex, age, and cohort. The proportion mediated through smoking was most pronounced in cancer mortality as a combination of the pure indirect effect, owing to differential exposure (men, 42% [25% to 75%]; women, 36% [17% to 74%]) and the mediated interactive effect, owing to differential vulnerability (men, 18% [2% to 35%], women, 26% [8% to 50%]). The mediating effects through body mass index, alcohol intake, or physical activity were partial and varied for the causes of deaths. CONCLUSION: Differential exposure and vulnerability should be addressed simultaneously, as these mechanisms are not mutually exclusive and may operate at the same time.

Cohort profile: the Social Inequality in Cancer (SIC) cohort study.

The Social Inequality in Cancer (SIC) cohort study was established to determine pathways through which socioeconomic position affects morbidity and mortality, in particular common subtypes of cancer. Data from seven well-established cohort studies from Denmark were pooled. Combining these cohorts provided a unique opportunity to generate a large study population with long follow-up and sufficient statistical power to develop and apply new methods for quantification of the two basic mechanisms underlying social inequalities in cancer-mediation and interaction. The SIC cohort included 83 006 participants aged 20-98 years at baseline. A wide range of behavioural and biological risk factors such as smoking, physical inactivity, alcohol intake, hormone replacement therapy, body mass index, blood pressure and serum cholesterol were assessed by self-administered questionnaires, physical examinations and blood samples. All participants were followed up in nationwide demographic and healthcare registries. For those interested in collaboration, further details can be obtained by contacting the Steering Committee at the Department of Public Health, University of Copenhagen, at inan@sund.ku.dk.