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1.  Analysing Recent Socioeconomic Trends in Coronary Heart Disease Mortality in England, 2000–2007: A Population Modelling Study 
PLoS Medicine  2012;9(6):e1001237.
A modeling study conducted by Madhavi Bajekal and colleagues estimates the extent to which specific risk factors and changes in uptake of treatment contributed to the declines in coronary heart disease mortality in England between 2000 and 2007, across and within socioeconomic groups.
Background
Coronary heart disease (CHD) mortality in England fell by approximately 6% every year between 2000 and 2007. However, rates fell differentially between social groups with inequalities actually widening. We sought to describe the extent to which this reduction in CHD mortality was attributable to changes in either levels of risk factors or treatment uptake, both across and within socioeconomic groups.
Methods and Findings
A widely used and replicated epidemiological model was used to synthesise estimates stratified by age, gender, and area deprivation quintiles for the English population aged 25 and older between 2000 and 2007. Mortality rates fell, with approximately 38,000 fewer CHD deaths in 2007. The model explained about 86% (95% uncertainty interval: 65%–107%) of this mortality fall. Decreases in major cardiovascular risk factors contributed approximately 34% (21%–47%) to the overall decline in CHD mortality: ranging from about 44% (31%–61%) in the most deprived to 29% (16%–42%) in the most affluent quintile. The biggest contribution came from a substantial fall in systolic blood pressure in the population not on hypertension medication (29%; 18%–40%); more so in deprived (37%) than in affluent (25%) areas. Other risk factor contributions were relatively modest across all social groups: total cholesterol (6%), smoking (3%), and physical activity (2%). Furthermore, these benefits were partly negated by mortality increases attributable to rises in body mass index and diabetes (−9%; −17% to −3%), particularly in more deprived quintiles. Treatments accounted for approximately 52% (40%–70%) of the mortality decline, equitably distributed across all social groups. Lipid reduction (14%), chronic angina treatment (13%), and secondary prevention (11%) made the largest medical contributions.
Conclusions
The model suggests that approximately half the recent CHD mortality fall in England was attributable to improved treatment uptake. This benefit occurred evenly across all social groups. However, opposing trends in major risk factors meant that their net contribution amounted to just over a third of the CHD deaths averted; these also varied substantially by socioeconomic group. Powerful and equitable evidence-based population-wide policy interventions exist; these should now be urgently implemented to effectively tackle persistent inequalities.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Coronary heart disease is a chronic medical condition in which the blood vessels supplying the heart muscle become narrowed or even blocked by fatty deposits on the inner linings of the blood vessels—a process known as arthrosclerosis; this restricts blood flow to the heart, and if the blood vessels completely occlude, it may cause a heart attack. Lifestyle behaviors, such as unhealthy diets high in saturated fat, smoking, and physical inactivity, are the main risk factors for coronary heart disease, so efforts to reduce this condition are directed towards these factors. Global rates of coronary heart disease are increasing and the World Health Organization estimates that by 2030, it will be the biggest cause of death worldwide. However, in high-income countries, such as England, deaths due to coronary heart disease have actually fallen substantially over the past few decades with an accelerated reduction in annual death rates since 2000.
Why Was This Study Done?
Socioeconomic factors play an important role in chronic diseases such as coronary heart disease, with mortality rates almost twice as high in deprived than affluent areas. However, the potential effect of population-wide interventions on reducing inequalities in deaths from coronary heart disease remains unclear. So in this study, the researchers investigated the role of behavioral (changing lifestyle) and medical (treatments) management of coronary heart disease that contributed to the decrease in deaths in England for the period 2000–2007, within and between socioeconomic groups.
What Did the Researchers Do and Find?
The researchers used a well-known, tried and tested epidemiological model (IMPACT) but adapted it to include socioeconomic inequalities to analyze the total population of England aged 25 and older in 2000 and in 2007. The researchers included all the major risk factors for coronary heart disease plus 45 current medical and surgical treatments in their model. They used the Index of Multiple Deprivation 2007 as a proxy indicator of socioeconomic circumstances of residents in neighborhoods. Using the postal code of residence, the researchers matched deaths from, and patients treated for, coronary heart disease to the corresponding deprivation category (quintile). Changes in risk factor levels in each quintile were also calculated using the Health Survey for England. Using their model, the researchers calculated the total number of deaths prevented or postponed for each deprivation quintile by measuring the difference between observed deaths in 2007 and expected deaths based on 2000 data, if age, sex, and deprivation quintile death rates had remained the same.
The researchers found that between 2000 and 2007, death rates from coronary heart disease fell from 229 to 147 deaths per 100,000—a decrease of 36%. Both death rates and the number of deaths were lowest in the most affluent quintile and the pace of fall was also faster, decreasing by 6.7% per year compared to just 4.9% in the most deprived quintile. Furthermore, the researchers found that overall, about half of the decrease in death rates was attributable to improvements in uptake of medical and surgical treatments. The contribution of medical treatments to the deaths averted was very similar across all quintiles, ranging from 50% in the most affluent quintile to 53% in the most deprived. Risk factor changes accounted for approximately a third fewer deaths in 2007 than occurred in 2000, but were responsible for a smaller proportion of deaths prevented in the most affluent quintile compared with the most deprived (approximately 29% versus 44%, respectively). However, the benefits of improvements in blood pressure, cholesterol, smoking, and physical activity were partly negated by rises in body mass index and diabetes, particularly in more deprived quintiles.
What Do These Findings Mean?
These findings suggest that approximately half the recent substantial fall in deaths from coronary heart disease in England was attributable to improved treatment uptake across all social groups; this is consistent with equitable service delivery across the UK's National Health Service. However, opposing trends in major risk factors, which varied substantially by socioeconomic group, meant that their net contribution accounted for just a third of deaths averted. Other countries have implemented effective, evidence-based interventions to tackle lifestyle risk factors; the most powerful measures involve legislation, regulation, taxation, or subsidies, all of which tend to be equitable. Such measures should be urgently implemented in England to effectively tackle persistent inequalities in deaths due to coronary heart disease.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001237.
The World Health Organization has information about the global statistics of coronary heart disease
The National Heart Lung and Blood Institute provides a patient-friendly description of coronary heart disease
The National Heart Forum is the leading UK organization facilitating the prevention of coronary heart disease and other chronic diseases
The British Heart Foundation supports research and promotes preventative activity
Heart of Mersey is the UK's largest regional organization promoting the prevention of coronary heart disease and other chronic diseases
More information about the social determinants of health is available from WHO
doi:10.1371/journal.pmed.1001237
PMCID: PMC3373639  PMID: 22719232
2.  The Relationship between Proteinuria and Coronary Risk: A Systematic Review and Meta-Analysis 
PLoS Medicine  2008;5(10):e207.
Background
Markers of kidney dysfunction such as proteinuria or albuminuria have been reported to be associated with coronary heart disease, but the consistency and strength of any such relationship has not been clearly defined. This lack of clarity has led to great uncertainty as to how proteinuria should be treated in the assessment and management of cardiovascular risk. We therefore undertook a systematic review of published cohort studies aiming to provide a reliable estimate of the strength of association between proteinuria and coronary heart disease.
Methods and Findings
A meta-analysis of cohort studies was conducted to obtain a summary estimate of the association between measures of proteinuria and coronary risk. MEDLINE and EMBASE were searched for studies reporting an age- or multivariate-adjusted estimate and standard error of the association between proteinuria and coronary heart disease. Studies were excluded if the majority of the study population had known glomerular disease or were the recipients of renal transplants. Two independent researchers extracted the estimates of association between proteinuria (total urinary protein >300 mg/d), microalbuminuria (urinary albumin 30–300 mg/d), macroalbuminuria (urinary albumin >300 mg/d), and risk of coronary disease from individual studies. These estimates were combined using a random-effects model. Sensitivity analyses were conducted to examine possible sources of heterogeneity in effect size. A total of 26 cohort studies were identified involving 169,949 individuals and 7,117 coronary events (27% fatal). The presence of proteinuria was associated with an approximate 50% increase in coronary risk (risk ratio 1.47, 95% confidence interval [CI] 1.23–1.74) after adjustment for known risk factors. For albuminuria, there was evidence of a dose–response relationship: individuals with microalbuminuria were at 50% greater risk of coronary heart disease (risk ratio 1.47, 95% CI 1.30–1.66) than those without; in those with macroalbuminuria the risk was more than doubled (risk ratio 2.17, 1.87–2.52). Sensitivity analysis indicated no important differences in prespecified subgroups.
Conclusion
These data confirm a strong and continuous association between proteinuria and subsequent risk of coronary heart disease, and suggest that proteinuria should be incorporated into the assessment of an individual's cardiovascular risk.
Vlado Perkovic and colleagues show, through a systematic review and meta-analysis of cohort studies, that there is a strong and continuous association between proteinuria and subsequent risk of coronary heart disease.
Editors' Summary
Background.
Coronary heart disease (CHD) is the leading cause of death among adults in developed countries. With age, fatty deposits called atherosclerotic plaques coat the walls of arteries, the vessels that nourish the organs of the body by carrying blood and oxygen to them. Because they narrow the arteries, atherosclerotic plaques restrict the blood flow to the body's organs. If these plaques form in the arteries that feed the heart muscle (the coronary arteries), the result is CHD. The symptoms of CHD include shortness of breath and chest pains (angina). In addition, if a plaque breaks off the wall of a coronary artery, it can completely block that artery, which kills part of the heart muscle and causes a potentially fatal heart attack. Smoking, high blood pressure, high blood levels of cholesterol (a type of fat), having diabetes, being overweight, and being physically inactive are established risk factors for CHD. Treatments for CHD include lifestyle changes (for example, losing weight) and medications that lower blood pressure and blood cholesterol. The narrowed arteries can also be widened using a device called a stent or surgically bypassed.
Why Was This Study Done?
In addition to the established risk factors for CHD, several other factors may also increase a person's risk of developing CHD, including kidney disease, which affects one in six adults to some degree. An early sign of kidney dysfunction is high amounts of a protein called albumin or of total proteins in the urine (albuminuria and proteinuria, respectively). Some studies have suggested that proteinuria is associated with an increased risk of CHD, but the results of these studies are inconsistent. Consequently, it is unclear whether proteinuria should be considered when assessing and managing an individual's CHD risk. In this study, the researchers undertake a systematic review (a study in which predefined search criteria are used to identify all the research on a specific topic) and a meta-analysis (a statistical method for combining the results of several studies) of published studies that have investigated the association between proteinuria and CHD.
What Did the Researchers Do and Find?
The researchers' systematic review identified 26 published studies that provided estimates of the association between CHD risk and proteinuria and albuminuria by measuring baseline urinary protein and albumin levels in people who were then followed for several years to see whether they developed CHD. Nearly 170,000 individuals participated in these studies, which recorded more 7,000 fatal and nonfatal heart attacks and other coronary events. In the meta-analysis, proteinuria (urinary protein of more than 300 mg/d or dipstick 1+ or more) increased CHD risk by 50% after adjustment for other known CHD risk factors. Furthermore, individuals with microalbuminuria (a urinary albumin of 30–300 mg/d) were 50% more likely to develop CHD than those with normal amounts of urinary albumin; people with macroalbuminuria (urinary albumin of more than 300 mg/d) were more than twice as likely to develop CHD. Finally, the association between proteinuria and CHD did not differ substantially between specific subgroups of participants such as people with and without diabetes.
What Do These Findings Mean?
These findings suggest that there is a strong, possibly dose-dependent association between proteinuria and the risk of CHD and that this association is independent of other known CHD risk factors, including diabetes. The finding that people with proteinuria have a 50% or greater increased risk of developing CHD than people without proteinuria may be a slight overestimate of the strength of the association between proteinuria because of publication bias. That is, studies that failed to show an association may not have been published. However, because this systematic review and meta-analysis includes several large population-based studies done in various parts of the world, these findings are likely to be generalizable. Thus, these findings support the inclusion of an evaluation of proteinuria in the assessment of CHD risk and suggest that medications and other strategies that reduce proteinuria might help to reduce the overall burden of CHD.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050207.
The MedlinePlus encyclopedia has pages on coronary heart disease, atherosclerosis, and chronic kidney failure (in English and Spanish)
Information is available from the US National Heart Lung and Blood Institute on coronary heart disease
The UK National Health Service Direct health encyclopedia also provides information about coronary heart disease (in several languages)
Information for patients and caregivers is provided by the American Heart Association on all aspects of heart disease.
The British Heart Foundation also provides information on heart disease and on keeping the heart healthy
doi:10.1371/journal.pmed.0050207
PMCID: PMC2570419  PMID: 18942886
3.  The Effect of Tobacco Control Measures during a Period of Rising Cardiovascular Disease Risk in India: A Mathematical Model of Myocardial Infarction and Stroke 
PLoS Medicine  2013;10(7):e1001480.
In this paper from Basu and colleagues, a simulation of tobacco control and pharmacological interventions to prevent cardiovascular disease mortality in India predicted that Smokefree laws and increased tobacco taxation are likely to be the most effective measures to avert future cardiovascular deaths in India.
Please see later in the article for the Editors' Summary
Background
We simulated tobacco control and pharmacological strategies for preventing cardiovascular deaths in India, the country that is expected to experience more cardiovascular deaths than any other over the next decade.
Methods and Findings
A microsimulation model was developed to quantify the differential effects of various tobacco control measures and pharmacological therapies on myocardial infarction and stroke deaths stratified by age, gender, and urban/rural status for 2013 to 2022. The model incorporated population-representative data from India on multiple risk factors that affect myocardial infarction and stroke mortality, including hypertension, hyperlipidemia, diabetes, coronary heart disease, and cerebrovascular disease. We also included data from India on cigarette smoking, bidi smoking, chewing tobacco, and secondhand smoke. According to the model's results, smoke-free legislation and tobacco taxation would likely be the most effective strategy among a menu of tobacco control strategies (including, as well, brief cessation advice by health care providers, mass media campaigns, and an advertising ban) for reducing myocardial infarction and stroke deaths over the next decade, while cessation advice would be expected to be the least effective strategy at the population level. In combination, these tobacco control interventions could avert 25% of myocardial infarctions and strokes (95% CI: 17%–34%) if the effects of the interventions are additive. These effects are substantially larger than would be achieved through aspirin, antihypertensive, and statin therapy under most scenarios, because of limited treatment access and adherence; nevertheless, the impacts of tobacco control policies and pharmacological interventions appear to be markedly synergistic, averting up to one-third of deaths from myocardial infarction and stroke among 20- to 79-y-olds over the next 10 y. Pharmacological therapies could also be considerably more potent with further health system improvements.
Conclusions
Smoke-free laws and substantially increased tobacco taxation appear to be markedly potent population measures to avert future cardiovascular deaths in India. Despite the rise in co-morbid cardiovascular disease risk factors like hyperlipidemia and hypertension in low- and middle-income countries, tobacco control is likely to remain a highly effective strategy to reduce cardiovascular deaths.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Cardiovascular diseases (CVDs) are conditions that affect the heart and/or the circulation. In coronary heart disease, for example, narrowing of the heart's blood vessels by fatty deposits slows the blood supply to the heart and may eventually cause a heart attack (myocardial infarction). Stroke, by contrast, is a CVD in which the blood supply to the brain is interrupted. CVD has been a major cause of illness and death in high-income countries for many years, but the burden of CVD is now rapidly rising in low- and middle-income countries. Indeed, worldwide, three-quarters of all deaths from heart disease and stroke occur in low- and middle-income countries. Smoking, high blood pressure (hypertension), high blood cholesterol (hyperlipidemia), diabetes, obesity, and physical inactivity all increase an individual's risk of developing CVD. Prevention strategies and treatments for CVD include lifestyle changes (for example, smoking cessation) and taking drugs that lower blood pressure (antihypertensive drugs) or blood cholesterol levels (statins) or thin the blood (aspirin).
Why Was This Study Done?
Because tobacco use is a key risk factor for CVD and for several other noncommunicable diseases, the World Health Organization has developed an international instrument for tobacco control called the Framework Convention on Tobacco Control (FCTC). Parties to the FCTC (currently 176 countries) agree to implement a set of core tobacco control provisions including legislation to ban tobacco advertising and to increase tobacco taxes. But will tobacco control measures reduce the burden of CVD effectively in low- and middle-income countries as other risk factors for CVD are becoming more common? In this mathematical modeling study, the researchers investigated this question by simulating the effects of tobacco control measures and pharmacological strategies for preventing CVD on CVD deaths in India. Notably, many of the core FCTC provisions remain poorly implemented or unenforced in India even though it became a party to the convention in 2005. Moreover, experts predict that, over the next decade, this middle-income country will contribute more than any other nation to the global increase in CVD deaths.
What Did the Researchers Do and Find?
The researchers developed a microsimulation model (a computer model that operates at the level of individuals) to quantify the likely effects of various tobacco control measures and pharmacological therapies on deaths from myocardial infarction and stroke in India between 2013 and 2022. They incorporated population-representative data from India on risk factors that affect myocardial infarction and stroke mortality and on tobacco use and exposure to secondhand smoke into their model. They then simulated the effects of five tobacco control measures—smoke-free legislation, tobacco taxation, provision of brief cessation advice by health care providers, mass media campaigns, and advertising bans—and increased access to aspirin, antihypertensive drugs, and statins on deaths from myocardial infarction and stroke. Smoke-free legislation and tobacco taxation are likely to be the most effective strategies for reducing myocardial infarction and stroke deaths over the next decade, according to the model, and the effects of these strategies are likely to be substantially larger than those achieved by drug therapies under current health system conditions. If the effects of smoke-free legislation and tobacco taxation are additive, the model predicts that these two measures alone could avert about 9 million deaths, that is, a quarter of the expected deaths from myocardial infarction and stroke in India over the next 10 years, and that a combination of tobacco control policies and pharmacological interventions could avert up to a third of these deaths.
What Do These Findings Mean?
These findings suggest that the implementation of smoke-free laws and the introduction of increased tobacco taxes in India would yield substantial and rapid health benefits by averting future CVD deaths. The accuracy of these findings is likely to be affected by the many assumptions included in the mathematical model and by the quality of the data fed into it. Importantly, however, these finding suggest that, despite the rise in other CVD risk factors such as hypertension and hyperlipidemia, tobacco control is likely to be a highly effective strategy for the reduction of CVD deaths over the next decade in India and probably in other low- and middle-income countries. Policymakers in these countries should, therefore, work towards fuller and faster implementation of the core FCTC provisions to boost their efforts to reduce deaths from CVD.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001480.
The American Heart Association provides information on all aspects of cardiovascular disease; its website includes personal stories about heart attacks and stroke
The US Centers for Disease Control and Prevention has information on heart disease and on stroke (in English and Spanish
The UK National Health Service Choices website provides information about cardiovascular disease and stroke
MedlinePlus provides links to other sources of information on heart diseases, vascular diseases, and stroke (in English and Spanish)
The World Health Organization provides information (in several languages) about the dangers of tobacco, about the Framework Convention on Tobacco Control, and about noncommunicable diseases; its Global Noncommunicable Disease Network (NCDnet) aims to help low- and middle- income countries reduce illness and death caused by CVD and other noncommunicable diseases
SmokeFree, a website provided by the UK National Health Service, offers advice on quitting smoking and includes personal stories from people who have stopped smoking
Smokefree.gov, supported by the US National Cancer Institute and other US agencies, offers online tools and resources to help people quit smoking
doi:10.1371/journal.pmed.1001480
PMCID: PMC3706364  PMID: 23874160
4.  Unrecognized Non-Q-Wave Myocardial Infarction: Prevalence and Prognostic Significance in Patients with Suspected Coronary Disease 
PLoS Medicine  2009;6(4):e1000057.
Using delayed-enhancement cardiovascular magnetic resonance, Han Kim and colleagues show that in patients with suspected coronary disease the prevalence of unrecognized myocardial infarction without Q-waves is more than 3-fold higher than that with Q-waves and predicts subsequent mortality.
Background
Unrecognized myocardial infarction (UMI) is known to constitute a substantial portion of potentially lethal coronary heart disease. However, the diagnosis of UMI is based on the appearance of incidental Q-waves on 12-lead electrocardiography. Thus, the syndrome of non-Q-wave UMI has not been investigated. Delayed-enhancement cardiovascular magnetic resonance (DE-CMR) can identify MI, even when small, subendocardial, or without associated Q-waves. The aim of this study was to investigate the prevalence and prognosis associated with non-Q-wave UMI identified by DE-CMR.
Methods and Findings
We conducted a prospective study of 185 patients with suspected coronary disease and without history of clinical myocardial infarction who were scheduled for invasive coronary angiography. Q-wave UMI was determined by electrocardiography (Minnesota Code). Non-Q-wave UMI was identified by DE-CMR in the absence of electrocardiographic Q-waves. Patients were followed to determine the prognostic significance of non-Q-wave UMI. The primary endpoint was all-cause mortality. The prevalence of non-Q-wave UMI was 27% (50/185), compared with 8% (15/185) for Q-wave UMI. Patients with non-Q-wave UMI were older, were more likely to have diabetes, and had higher Framingham risk than those without MI, but were similar to those with Q-wave UMI. Infarct size in non-Q-wave UMI was modest (8%±7% of left ventricular mass), and left ventricular ejection fraction (LVEF) by cine-CMR was usually preserved (52%±18%). The prevalence of non-Q-wave UMI increased with the extent and severity of coronary disease on angiography (p<0.0001 for both). Over 2.2 y (interquartile range 1.8–2.7), 16 deaths occurred: 13 in non-Q-wave UMI patients (26%), one in Q-wave UMI (7%), and two in patients without MI (2%). Multivariable analysis including New York Heart Association class and LVEF demonstrated that non-Q-wave UMI was an independent predictor of all-cause mortality (hazard ratio [HR] 11.4, 95% confidence interval [CI] 2.5–51.1) and cardiac mortality (HR 17.4, 95% CI 2.2–137.4).
Conclusions
In patients with suspected coronary disease, the prevalence of non-Q-wave UMI is more than 3-fold higher than Q-wave UMI. The presence of non-Q-wave UMI predicts subsequent mortality, and is incremental to LVEF.
Trial Registration
Clinicaltrials.gov NCT00493168
Editors' Summary
Background
Coronary artery disease (CAD; also called coronary heart disease) is the leading cause of death among adults in developed countries. In the USA alone, it kills nearly half a million people every year. CAD is caused by narrowing of the coronary arteries, the blood vessels that supply the heart with oxygen and nutrients. With age, fatty deposits (atherosclerotic plaques) coat the walls of these arteries and restrict the heart's blood supply, which causes the characteristic symptoms of CAD—angina (chest pains that are usually relieved by rest) and shortness of breath. In addition, if a plaque breaks off the wall of a coronary artery, it can completely block that artery and kill part of the heart, which causes a potentially fatal heart attack (doctors call this a myocardial infarction or MI). Heart attacks are often characterized by long-lasting chest pain that is not relieved by rest. Risk factors for CAD include smoking, high blood pressure, high blood levels of cholesterol (a type of fat), and being overweight. Treatments for the condition include lifestyle changes (for example, losing weight), and medications that lower blood pressure and blood cholesterol. The narrowed arteries can also be widened using a device called a stent or surgically bypassed.
Why Was This Study Done?
Not everyone who has a heart attack has chest pain. In fact, some studies suggest that 40–60% of MIs have no obvious symptoms. It is important, however, that these “unrecognized” MIs (UMIs) are diagnosed because they have death rates similar to those of MIs with clinical symptoms and need to be treated in a similar way. Traditionally, UMIs have been diagnosed using an electrocardiogram (ECG). When the heart beats, it generates small electric waves that can be picked up by electrodes attached to the skin. The pattern of these waves (the ECG) provides information about the heart's health. Alterations in the ECG, leading to so-called Q-waves, indicate that a UMI has occurred some time previously. However, not all UMIs result in Q-waves. In this study, the researchers use a recently developed technique—delayed enhancement cardiovascular magnetic resonance (DE-CMR), which can detect heart damage even in patients whose Q-waves are absent—to measure the prevalence (the fraction of a population that has a disorder) of non-Q-wave UMI. The researchers also investigate whether non-Q-wave UMI increases the risk of death.
What Did the Researchers Do and Find?
The researchers used electrocardiography and DE-CMR to look for Q-wave and non-Q-wave UMI, respectively, in 185 patients with suspected CAD but no history of MI. They then followed the patients for 2 years to discover whether a diagnosis of non-Q-wave UMI predicted their likelihood of dying from any cause or from a heart problem. 27% of the patients had evidence of non-Q-wave UMI whereas only 8% had evidence of Q-wave UMI. Patients with non-Q-wave UMI tended to have only a small area of heart damage and, consistent with this limited damage, their hearts pumped near-normal volumes of blood. Examination of the patients' arteries with a technique called coronary angiography indicated that the patients with widespread and/or severe CAD had a higher prevalence of non-Q-wave UMI than those with limited CAD. Finally, patients with non-Q-wave UMI had an 11-fold higher risk of death from any cause and a 17-fold higher risk of death from a heart problem than patients without UMI.
What Do These Findings Mean?
These findings indicate that non-Q-wave UMI occurs more than 3-times as often in patients with suspected CAD than Q-wave UMI and that patients with non-Q-wave UMI have a much greater risk of dying than patients without MI. Thus, if all cases of UMI—both Q-wave and non-Q-wave UMI—could be identified, it might be possible to reduce the number of deaths among people with CAD. However, before any recommendations are made to include DE-CMR in the routine examination of people with suspected CAD to achieve this aim, additional studies must be undertaken to confirm that non-Q-wave UMI is a common feature of CAD and to test whether the early diagnosis of non-Q-wave UMI does extend the life expectancy of people with CAD.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000057.
This study is further discussed in a PLoS Medicine Perspective by Clara Chow
The MedlinePlus encyclopedia has pages on coronary heart disease, heart attacks, and electrocardiograms (in English and Spanish). MedlinePlus also provides links to further information on all aspects of heart disease (in English and Spanish)
Information is available from the US National Heart Lung and Blood Institute on coronary heart disease
The UK National Health Service Choices website also provides information about coronary heart disease (in several languages).
The Nobel Foundation provides an interactive electrocardiogram game
doi:10.1371/journal.pmed.1000057
PMCID: PMC2661255  PMID: 19381280
5.  Secondary prevention in coronary heart disease: baseline survey of provision in general practice 
BMJ : British Medical Journal  1998;316(7142):1430-1434.
Objective: To determine secondary preventive treatment and habits among patients with coronary heart disease in general practice.
Design: Process of care data on a random sample of patients were collected from medical records. Health and lifestyle data were collected by postal questionnaire (response rate 71%).
Setting: Stratified, random sample of general practices in Grampian.
Subjects: 1921 patients aged under 80 years with coronary heart disease identified from pre-existing registers of coronary heart disease and nitrate prescriptions.
Main outcome measures: Treatment with aspirin, β blockers, and angiotensin converting enzyme inhibitors. Management of lipid concentrations and hypertension according to local guidelines. Dietary habits (dietary instrument for nutritional evaluation score), physical activity (health practice indices), smoking, and body mass index.
Results: 825/1319 (63%) patients took aspirin. Of 414 patients with recent myocardial infarction, 131 (32%) took β blockers, and of 257 with heart failure, 102 (40%) took angiotensin converting enzyme inhibitors. Blood pressure was managed according to current guidelines for 1566 (82%) patients but lipid concentrations for only 133 (17%). 673 of 1327 patients (51%) took little or no exercise, 245 of 1333 (18%) were current smokers, 808 of 1264 (64%) were overweight, and 627 of 1213 (52%) ate more fat than recommended.
Conclusion: In terms of secondary prevention, half of patients had at least two aspects of their medical management that were suboptimal and nearly two thirds had at least two aspects of their health behaviour that would benefit from change. There seems to be considerable potential to increase secondary prevention of coronary heart disease in general practice.
Key messages Patients with coronary heart disease can benefit from both medical and lifestyle secondary prevention measures This study found that half of patients with coronary heart disease in general practice had at least two missed opportunities for effective medical interventions Nearly two thirds of patients with coronary heart disease in general practice had two or more high risk lifestyle factors that would benefit from change There seems to be plenty of opportunity for improving secondary prevention of coronary heart disease in general practice
PMCID: PMC28543  PMID: 9572757
6.  Multidetector Computed Tomography for Coronary Artery Disease Screening in Asymptomatic Populations 
Executive Summary
Objective
This evidence-based health technology assessment systematically reviewed the published literature on multidetector computed tomography (MDCT) angiography (with contrast) as a diagnostic tool for coronary artery disease (CAD), and applied the results of the assessment to health care practices in Ontario.
Clinical Need
Coronary artery disease is the leading cause of death in the western world. Occlusion of coronary arteries reduces coronary blood flow and oxygen delivery to the myocardium (heart muscle). The rupture of an unstable atherosclerotic plaque may result in myocardial infarction. If left untreated, CAD can result in heart failure and, subsequently, death. According to the Heart and Stroke Foundation of Canada, 54% of all cardiovascular deaths are due to CAD. Patient characteristics (e.g., age, sex, and genetics), underlying clinical conditions that predispose to cardiac conditions (e.g., diabetes, hypertension, and elevated cholesterol), lifestyle characteristics, (e.g., obesity, smoking, and physical inactivity), and, more recently, determinants of health (e.g., socioeconomic status) may predict the risk of getting CAD.
In 2004/2005, The Ontario government funded approximately 15,400 percutaneous (through the skin) coronary interventions and 7,840 coronary bypass procedures for the treatment of CAD. These numbers are expected to reach 22,355 for percutaneous coronary interventions and 12,323 for coronary bypass procedures in 2006/2007. It was noted that more than one-half of all first coronary events occur in people without symptoms of CAD. In Ontario in 2000/2001, $457.9 million (Cdn) was spent on invasive ($237.4 million) and noninvasive ($220.5 million) cardiac services. The use of noninvasive cardiac tests, in particular, is rising rapidly.
The Technology
Computed tomography (CT) is a medical imaging method employing tomography where digital geometry processing is used to generate a 3-dimensional image of the internals of an object from a large series of 2-dimensional X-ray images taken around a single axis of rotation. Multidetector computed tomography is performed for noninvasive imaging of the coronary arteries. Computer software quantifies the amount of calcium within the coronary arteries and calculates a coronary artery calcium score.
Compared with conventional CT scanning, MDCT can provide smaller pieces of information and cover a larger area faster. Advanced MDCT technology (that is, 8-, 16-, 32-, and 64-slice systems) can produce more images in less time. For general CT scanning, this faster capability can reduce the length of time people are required to be still during the procedure and thereby reduce potential movement artifact. However, the additional clinical utility of images obtained from faster scanners compared with the images obtained from conventional CT scanners for current CT indications (i.e., nonmoving body parts) is unknown.
Review Strategy
The Medical Advisory Secretariat completed a computer-aided search limited to English-language studies in humans from 1998 to 2007 in multiple medical literature databases, including MEDLINE, EMBASE, The Cochrane Library, and INAHTA/CRD. Case reports, letters, editorials, nonsystematic reviews, and comments were excluded. Additional studies that met the inclusion and exclusion criteria were obtained from reference lists of included studies. Inclusion and exclusion criteria were applied to the results according to the criteria listed below.
The Grading of Recommendations Assessment, Development and Evaluation (GRADE) system was used to evaluate the overall quality of the body of evidence (defined as 1 or more studies) supporting the research questions explored in this systematic review.
Summary of Findings and Conclusions
Screening the asymptomatic population for CAD using MDCT does not meet World Health Organization criteria for screening; hence, it is not justifiable. Coronary artery calcification measured by MDCT is a good predictor of future cardiovascular events. However, MDCT exhibits only moderately high sensitivity and specificity for detection of CAD in an asymptomatic population. If population-based screening were implemented, a high rate of false positives would result in increased downstream costs and interventions. Additionally, some cases of CAD would be missed, as they may not be developed, or not yet have progressed to detectable levels. There is no evidence for the impact of screening on patient management. Cardiovascular risk factors are positively associated with the presence of coronary artery calcification and cardiovascular events; however, risk factor stratification to identify high-risk asymptomatic individuals is unclear given the current evidence-base.
Safety of MDCT screening is also an issue because of the introduction of increased radiation doses for the initial screening scan and possible follow-up interventions.
No large randomized controlled trials of MDCT screening have been published, which indicates an important area of future research.
Lastly, the policy implications for MDCT screening for CAD in the asymptomatic population are significant. There is no evidence on the long-term implications of screening, and the potential impact on the resources of the health care system is considerable.
PMCID: PMC3377586  PMID: 23074503
7.  Evaluating the Quality of Research into a Single Prognostic Biomarker: A Systematic Review and Meta-analysis of 83 Studies of C-Reactive Protein in Stable Coronary Artery Disease 
PLoS Medicine  2010;7(6):e1000286.
In a systematic review and meta-analysis of 83 prognostic studies of C-reactive protein in coronary disease, Hemingway and colleagues find substantial biases, preventing them from drawing clear conclusions relating to the use of this marker in clinical practice.
Background
Systematic evaluations of the quality of research on a single prognostic biomarker are rare. We sought to evaluate the quality of prognostic research evidence for the association of C-reactive protein (CRP) with fatal and nonfatal events among patients with stable coronary disease.
Methods and Findings
We searched MEDLINE (1966 to 2009) and EMBASE (1980 to 2009) and selected prospective studies of patients with stable coronary disease, reporting a relative risk for the association of CRP with death and nonfatal cardiovascular events. We included 83 studies, reporting 61,684 patients and 6,485 outcome events. No study reported a prespecified statistical analysis protocol; only two studies reported the time elapsed (in months or years) between initial presentation of symptomatic coronary disease and inclusion in the study. Studies reported a median of seven items (of 17) from the REMARK reporting guidelines, with no evidence of change over time.
The pooled relative risk for the top versus bottom third of CRP distribution was 1.97 (95% confidence interval [CI] 1.78–2.17), with substantial heterogeneity (I2 = 79.5). Only 13 studies adjusted for conventional risk factors (age, sex, smoking, obesity, diabetes, and low-density lipoprotein [LDL] cholesterol) and these had a relative risk of 1.65 (95% CI 1.39–1.96), I2 = 33.7. Studies reported ten different ways of comparing CRP values, with weaker relative risks for those based on continuous measures. Adjusting for publication bias (for which there was strong evidence, Egger's p<0.001) using a validated method reduced the relative risk to 1.19 (95% CI 1.13–1.25). Only two studies reported a measure of discrimination (c-statistic). In 20 studies the detection rate for subsequent events could be calculated and was 31% for a 10% false positive rate, and the calculated pooled c-statistic was 0.61 (0.57–0.66).
Conclusion
Multiple types of reporting bias, and publication bias, make the magnitude of any independent association between CRP and prognosis among patients with stable coronary disease sufficiently uncertain that no clinical practice recommendations can be made. Publication of prespecified statistical analytic protocols and prospective registration of studies, among other measures, might help improve the quality of prognostic biomarker research.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Coronary artery disease is the leading cause of death among adults in developed countries. With age, fatty deposits called atherosclerotic plaques coat the walls of the arteries, the vessels that carry blood to the body's organs. Because they narrow the arteries, atherosclerotic plaques restrict blood flow. If plaques form in the arteries that feed the heart, the result is coronary artery disease, the symptoms of which include shortness of breath and chest pains (angina). If these symptoms only occur during exertion, the condition is called stable coronary artery disease. Coronary artery disease can cause potentially fatal heart attacks (myocardial infarctions). A heart attack occurs when a plaque ruptures and a blood clot completely blocks the artery, thereby killing part of the heart. Smoking, high blood pressure, high blood levels of cholesterol (a type of fat), diabetes, and being overweight are risk factors for coronary artery disease. Treatments for the condition include lifestyle changes and medications that lower blood pressure and blood cholesterol. Narrowed arteries can also be widened using a device called a stent or surgically bypassed.
Why Was This Study Done?
Clinicians can predict whether a patient with coronary artery disease is likely to have a heart attack by considering their risk factors. They then use this “prognosis” to help them manage the patient. To provide further help for clinicians, researchers are trying to identify prognostic biomarkers (molecules whose blood levels indicate how a disease might develop) for coronary artery disease. However, before a biomarker can be used clinically, it must be properly validated and there are concerns that there is insufficient high quality evidence to validate many biomarkers. In this systematic review and meta-analysis, the researchers ask whether the evidence for an association between blood levels of C-reactive protein (CRP, an inflammatory protein) and subsequent fatal and nonfatal events affecting the heart and circulation (cardiovascular events) among patients with stable coronary artery disease supports the routine measurement of CRP as recommended in clinical practice guidelines. A systematic review uses predefined criteria to identify all the research on a given topic; a meta-analysis is a statistical method for combining the results of several studies.
What Did the Researchers Do and Find?
The researchers identified 83 studies that investigated the association between CRP levels measured in people with coronary artery disease and subsequent cardiovascular events. Their examination of these studies revealed numerous reporting and publication short-comings. For example, none of the studies reported a prespecified statistical analysis protocol, yet analyses should be prespecified to avoid the choice of analytical method biasing the study's results. Furthermore, on average, the studies only reported seven of the 17 recommended items in the REMARK reporting guidelines, which were designed to improve the reporting quality of tumor biomarker prognostic studies. The meta-analysis revealed that patients with a CRP level in the top third of the distribution were nearly twice as likely to have a cardiovascular event as patients with a CRP in the bottom third of the distribution (a relative risk of 1.97). However, the outcomes varied considerably between studies (heterogeneity) and there was strong evidence for publication bias—most published studies were small and smaller studies were more likely to report higher relative risks. Adjustment for publication bias reduced the relative risk associated with high CRP levels to 1.19. Finally, nearly all the studies failed to calculate whether CRP measurements discriminated between patients likely and unlikely to have a subsequent cardiovascular event.
What Do These Findings Mean?
These findings suggest that, because of multiple types of reporting and publication bias, the size of the association between CRP levels and prognosis among patients with stable coronary artery disease is extremely uncertain. They also suggest that CRP measurements are unlikely to add anything to the prognostic discrimination achieved by considering blood pressure and other standard clinical factors among this patient group. Thus, the researchers suggest, the recommendation that CRP measurements should be used in the management of patients with stable coronary artery disease ought to be removed from clinical practice guidelines. More generally, these findings increase concerns about the quality of research into prognostic biomarkers and highlight areas that need to be changed, the most fundamental of which is the need to preregister studies on prognostic biomarkers and their analytic protocols.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000286.
The MedlinePlus Encyclopedia has pages on coronary artery disease and C-reactive protein (in English and Spanish)
MedlinePlus provides links to other sources of information on heart disease
The American Heart Association provides information for patients and caregivers on all aspects of cardiovascular disease, including information on the role of C-reactive protein in heart disease
Information is available from the British Heart Foundation on heart disease and keeping the heart healthy
Wikipedia has pages on biomarkers and on C-reactive protein (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
The EQUATOR network is a resource center for good reporting of health research studies
doi:10.1371/journal.pmed.1000286
PMCID: PMC2879408  PMID: 20532236
8.  Socio-medical Characteristics of Coronary Disease in Bosnia and Herzegovina and the World 
Materia Socio-Medica  2011;23(3):171-183.
Introduction:
Coronary heart disease and its etiology are complex socio-medical and clinical problem in this century. World Health Organization defined coronary artery disease as acute and chronic heart ailments due to disruption of flow and myocardial blood supply. Diseases of the cardiovascular system in spite of preventable risk factors are responsible for approximately 50% of all deaths in the developed world, and this ratio is higher in developing countries.
Risk factors:
Coronary heart disease risk factors can be divided in those which are not preventable such as: personal and family history of cardiovascular diseases, age and gender and preventable risk factors including: high blood pressure, elevated blood cholesterol, smoking, reduced physical activity, elevated blood sugar, increased body weight, alcohol use, psychosocial factors and nutrition. There are also newly emerging risk factors which includes increased homocysteine, thrombogenic and inflammatory factors. Prevention of coronary heart disease risk factors: The concept of risk assessment factors, their reduction, initially begun in the Framingham Heart Study and refined in other models. Primary prevention relates to changing lifestyle and influencing preventable risk factors. Numerous studies and meta-analysis showed that lifestyle modification, risk reduction factors, particularly by changing diet, stopping smoking, increasing physical activity, blood pressure control can be effective in the prevention and reduction of coronary heart disease. Primary health care physicians i.e. family physicians need to take an active role in assessment of risk factors for coronary heart disease.
Conclusion:
The data in this paper, based on the findings from other studies, suggest the importance of using a modified algorithm in order to estimates the overall risk of coronary disease in high-risk groups among the patients in the primary health care settings.
doi:10.5455/msm.2011.23.171-183
PMCID: PMC3732343  PMID: 23922510
heart attack; coronary disease; risk factors; prevention of heart diseases.
9.  Primary prevention of coronary heart disease: integration of new data, evolving views, revised goals, and role of rosuvastatin in management. A comprehensive survey 
A recent explosion in the amount of cardiovascular risk and incipient, undetected subclinical cardiovascular pathology has swept across the globe. Nearly 70% of adult Americans are overweight or obese; the prevalence of visceral obesity stands at 53% and continues to rise. At any one time, 55% of the population is on a weight-loss diet, and almost all fail. Fewer than 15% of adults or children exercise sufficiently, and over 60% engage in no vigorous activity. Among adults, 11%–13% have diabetes, 34% have hypertension, 36% have prehypertension, 36% have prediabetes, 12% have both prediabetes and prehypertension, and 15% of the population with either diabetes, hypertension, or dyslipidemia are undiagnosed. About one-third of the adult population, and 80% of the obese, have fatty livers. With 34% of children overweight or obese, prevalence having doubled in just a few years, type 2 diabetes, hypertension, dyslipidemia, and fatty livers in children are at their highest levels ever. Half of adults have at least one cardiovascular risk factor. Not even 1% of the population attains ideal cardiovascular health. Despite falling coronary death rates for decades, coronary heart disease (CHD) death rates in US women 35 to 54 years of age may now be increasing because of the obesity epidemic. Up to 65% of patients do not have their conventional risk biomarkers under control. Only 30% of high risk patients with CHD achieve aggressive low density lipoprotein (LDL) targets. Of those patients with multiple risk factors, fewer than 10% have all of them adequately controlled. Even when patients are titrated to evidence-based targets, about 70% of cardiac events remain unaddressed. Undertreatment is also common. About two-thirds of high risk primary care patients are not taking needed medications for dyslipidemia. Poor patient adherence, typically below 50%, adds further difficulty. Hence, after all such fractional reductions are multiplied, only a modest portion of total cardiovascular risk burden is actually being eliminated, and the full potential of risk reduction remains unrealized. Worldwide the situation is similar, with the prevalence of metabolic syndrome approaching 50%. Primordial prevention, resulting from healthful lifestyle habits that do not permit the appearance of risk factors, is the preferred method to lower cardiovascular risk. Lowering the prevalence of obesity is the most urgent matter, and is pleiotropic since it affects blood pressure, lipid profiles, glucose metabolism, inflammation, and atherothrombotic disease progression. Physical activity also improves several risk factors, with the additional potential to lower heart rate. Given the current obstacles, success of primordial prevention remains uncertain. At the same time, the consequences of delay and inaction will inevitably be disastrous, and the sense of urgency mounts. Since most CHD events arise in a large subpopulation of low- to moderate-risk individuals, identifying a high proportion of those who will go on to develop events with accuracy remains unlikely. Without a refinement in risk prediction, the current model of targeting high-risk individuals for aggressive therapy may not succeed alone, especially given the rising burden of risk. Estimating cardiovascular risk over a period of 10 years, using scoring systems such as Framingham or SCORE, continues to enjoy widespread use and is recommended for all adults. Limitations in the former have been of concern, including the under- or over-estimation of risk in specific populations, a relatively short 10-year risk horizon, focus on myocardial infarction and CHD death, and exclusion of family history. Classification errors may occur in up to 37% of individuals, particularly women and the young. Several different scoring systems are discussed in this review. The use of lifetime risk is an important conceptual advance, since ≥90% of young adults with a low 10-year risk have a lifetime risk of ≥39%; over half of all American adults have a low 10-year risk but a high lifetime risk. At age 50 the absence of traditional risk factors is associated with extremely low lifetime risk and significantly greater longevity. Pathological and epidemiological data confirm that atherosclerosis begins in early childhood, and advances seamlessly and inexorably throughout life. Risk factors in childhood are similar to those in adults, and track between stages of life. When indicated, aggressive treatment should begin at the earliest indication, and be continued for years. For those patients at intermediate risk according to global risk scores, C-reactive protein (CRP), coronary artery calcium (CAC), and carotid intima-media thickness (CIMT) are available for further stratification. Using statins for primary prevention is recommended by guidelines, is prevalent, but remains underprescribed. Statin drugs are unrivaled, evidence-based, major weapons to lower cardiovascular risk. Even when low density lipoprotein cholesterol (LDL-C) targets are attained, over half of patients continue to have disease progression and clinical events. This residual risk is of great concern, and multiple sources of remaining risk exist. Though clinical evidence is incomplete, altering or raising the blood high density lipoprotein cholesterol (HDL-C) level continues to be pursued. Of all agents available, rosuvastatin produces the greatest reduction in LDL-C, LDL-P, and improvement in apoA-I/apoB, together with a favorable safety profile. Several recent proposals and methods to lower cardiovascular risk are reviewed. A combination of approaches, such as the addition of lifetime risk, refinement of risk prediction, guideline compliance, novel treatments, improvement in adherence, and primordial prevention, including environmental and social intervention, will be necessary to lower the present high risk burden.
doi:10.2147/DDDT.S14934
PMCID: PMC3140289  PMID: 21792295
primary prevention; cardiovascular risk; coronary heart disease; primordial prevention; rosuvastatin; JUPITER study; statin drugs; C-reactive protein; inflammation; low-density lipoprotein; high-density lipoprotein; diabetes; metabolic syndrome; Framingham risk score; Reynolds risk score; SCORE; coronary artery calcification; carotid intima-media thickness; hypertension; obesity; non-HDL-cholesterol; LDL-P; dysfunctional HDL; lifetime risk; advanced lipid testing; Bogalusa Heart Study
10.  Independent Associations of Fasting Insulin, Glucose, and Glycated Haemoglobin with Stroke and Coronary Heart Disease in Older Women 
PLoS Medicine  2007;4(8):e263.
Background
Evidence suggests that variations in fasting glucose and insulin amongst those without frank type 2 diabetes mellitus are important determinants of cardiovascular disease. However, the relative importance of variations in fasting insulin, glucose, and glycated haemoglobin as risk factors for cardiovascular disease in women without diabetes is unclear. Our aim was to determine the independent associations of fasting insulin, glucose, and glycated haemoglobin with coronary heart disease and stroke in older women.
Methods and Findings
We undertook a prospective cohort study of 3,246 British women aged 60–79 y, all of whom were free of baseline coronary heart disease, stroke, and diabetes, and all of whom had fasting glucose levels below 7 mmol/l. Fasting insulin and homeostasis model assessment for insulin sensitivity (HOMA-S) were linearly associated with a combined outcome of coronary heart disease or stroke (n = 219 events), but there was no association of fasting glucose or glycated haemoglobin with these outcomes. Results were similar for coronary heart disease and stroke as separate outcomes. The age, life-course socioeconomic position, smoking, and physical activity adjusted hazard ratio for a combined outcome of incident coronary heart disease or stroke per one standard deviation of fasting insulin was 1.14 (95% CI 1.02–1.33). Additional adjustment for other components of metabolic syndrome, low-density lipoprotein cholesterol, fasting glucose, and glycated haemoglobin had little effect on this result.
Conclusions
Our findings suggest that in women in the 60–79 y age range, insulin resistance, rather than insulin secretion or chronic hyperglycaemia, is a more important risk factor for coronary heart disease and stroke. Below currently used thresholds of fasting glucose for defining diabetes, neither fasting glucose nor glycated haemoglobin are associated with cardiovascular disease.
From a prospective study of women aged 60-79 years, Debbie Lawlor and colleagues conclude that insulin resistance is an important risk factor for coronary heart disease and stroke.
Editors' Summary
Background.
Narrowing of the vessels that take blood to the heart and brain is a common form of cardiovascular disease—i.e., a disorder of the heart and blood vessels. It is a major cause of illness and death. By starving the heart and brain of oxygen, this condition causes coronary heart disease (CHD; heart problems such as angina and heart attacks) and strokes. A major risk factor for CHD and strokes is diabetes, a common chronic disease characterized by high levels of sugar (glucose) in the blood. In people who don't have diabetes, the hormone insulin controls blood-sugar levels. Insulin, which is released by the pancreas after eating, “instructs” insulin-responsive muscle and fat cells to absorb the glucose (released from food) from the bloodstream. In the very early stages of type 2 diabetes (the commonest type of diabetes, also called “adult onset” or “noninsulin-dependent” diabetes”), muscle and fat cells become unresponsive to insulin, so blood-sugar levels increase. This is called “insulin resistance.” The pancreas responds by making more insulin. As a result, people with insulin resistance have high blood levels of both insulin (hyperinsulinemia) and glucose (hyperglycemia). Eventually, the insulin-producing cells in the pancreas start to malfunction, insulin secretion decreases, and type 2 diabetes is the result.
Why Was This Study Done?
It is not yet clear whether it is insulin resistance or reduced insulin secretion that is responsible for the association between diabetes and cardiovascular disease. Physicians would like to know this information to help them to prevent CHD and strokes in their patients. There is evidence that variations in fasting glucose levels (blood glucose measured more than 8 h after eating), which provide an indication of how well pancreatic cells are producing insulin, and in fasting insulin levels, which provide an indication of insulin resistance, determine cardiovascular disease risk among people without type 2 diabetes, but the relative importance of these risk factors is unclear. In this study, the researchers have investigated whether markers of insulin resistance (fasting hyperinsulinemia) and of altered insulin secretion (fasting hyperglycemia, and increased glycated hemoglobin, which indicates how much sugar has been in the blood over the past few months) are associated with CHD and strokes in elderly women without diabetes. Their aim is to gain new insights into how diabetes affects cardiovascular disease risk.
What Did the Researchers Do and Find?
The researchers measured glucose, insulin, and glycated hemoglobulin in fasting blood samples taken from about 3,000 women aged 60–79 y when they enrolled in the British Women's Heart and Health Study. None of the women had CHD at enrollment, none had had a stroke, none had diagnosed diabetes, and all had a fasting blood glucose below 7 mmol/l (a higher reading indicates diabetes). After monitoring the women for nearly 5 y for CHD and strokes, the researchers looked for statistical associations between the occurrence of cardiovascular disease and markers of insulin resistance and reduced insulin secretion. They found that fasting insulin levels, but not fasting glucose or glycated hemoglobin levels, were associated with CHD and stroke, even after allowing for other factors that affect cardiovascular disease risk such as smoking and physical activity. In other words, raised fasting insulin levels increased the women's risk of developing cardiovascular disease.
What Do These Findings Mean?
These results indicate that in elderly women without diabetes, fasting insulin (a marker of insulin resistance) is a better predictor of future cardiovascular disease risk than fasting glucose or glycated hemoglobin (markers of reduced insulin secretion). This suggests that insulin resistance might be the main mechanism linking type 2 diabetes to CHD and stroke in elderly women. (Elderly women are known to run a high risk of developing these conditions, but they have been relatively neglected in previous studies of the risk factors for cardiovascular disease.) However, because relatively few women developed CHD during the study and even fewer had a stroke, this conclusion needs confirming in larger studies, preferably ones that include more rigorous tests of insulin resistance and secretion and also include women from more ethnic backgrounds than this study did. If the association between fasting insulin levels and cardiovascular disease risk is confirmed, therapeutic interventions or lifestyle interventions (for example, increased physical activity or weight loss) that prevent or reverse insulin resistance might reduce cardiovascular disease risk better than interventions that prevent chronic hyperglycemia.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040263.
MedlinePlus encyclopedia page on coronary heart disease, stroke, and diabetes (in English and Spanish)
Information for patients and caregivers from the US National Diabetes Information Clearinghouse on diabetes, including information on insulin resistance and on diabetes, heart disease, and stroke
Information on the British Women's Heart and Health Study
doi:10.1371/journal.pmed.0040263
PMCID: PMC1952205  PMID: 17760500
11.  Reduced Glomerular Filtration Rate and Its Association with Clinical Outcome in Older Patients at Risk of Vascular Events: Secondary Analysis 
PLoS Medicine  2009;6(1):e1000016.
Background
Reduced glomerular filtration rate (GFR) is associated with increased cardiovascular risk in young and middle aged individuals. Associations with cardiovascular disease and mortality in older people are less clearly established. We aimed to determine the predictive value of the GFR for mortality and morbidity using data from the 5,804 participants randomized in the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER).
Methods and Findings
Glomerular filtration rate was estimated (eGFR) using the Modification of Diet in Renal Disease equation and was categorized in the ranges ([20–40], [40–50], [50–60]) ≥ 60 ml/min/1.73 m2. Baseline risk factors were analysed by category of eGFR, with and without adjustment for other risk factors. The associations between baseline eGFR and morbidity and mortality outcomes, accrued after an average of 3.2 y, were investigated using Cox proportional hazard models adjusting for traditional risk factors. We tested for evidence of an interaction between the benefit of statin treatment and baseline eGFR status. Age, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol, C-reactive protein (CRP), body mass index, fasting glucose, female sex, histories of hypertension and vascular disease were associated with eGFR (p = 0.001 or less) after adjustment for other risk factors. Low eGFR was independently associated with risk of all cause mortality, vascular mortality, and other noncancer mortality and with fatal and nonfatal coronary and heart failure events (hazard ratios adjusted for CRP and other risk factors (95% confidence intervals [CIs]) for eGFR < 40 ml/min/1.73m2 relative to eGFR ≥ 60 ml/min/1.73m2 respectively 2.04 (1.48–2.80), 2.37 (1.53–3.67), 3.52 (1.78–6.96), 1.64 (1.18–2.27), 3.31 (2.03–5.41). There were no nominally statistically significant interactions (p < 0.05) between randomized treatment allocation and eGFR for clinical outcomes, with the exception of the outcome of coronary heart disease death or nonfatal myocardial infarction (p = 0.021), with the interaction suggesting increased benefit of statin treatment in subjects with impaired GFRs.
Conclusions
We have established that, in an elderly population over the age of 70 y, impaired GFR is associated with female sex, with presence of vascular disease, and with levels of other risk factors that would be associated with increased risk of vascular disease. Further, impaired GFR is independently associated with significant levels of increased risk of all cause mortality and fatal vascular events and with composite fatal and nonfatal coronary and heart failure outcomes. Our analyses of the benefits of statin treatment in relation to baseline GFR suggest that there is no reason to exclude elderly patients with impaired renal function from treatment with a statin.
Using data from the PROSPER trial, Ian Ford and colleagues investigate whether reduced glomerular filtration rate is associated with cardiovascular and mortality risk among elderly people.
Editors' Summary
Background.
Cardiovascular disease (CVD)—disease that affects the heart and/or the blood vessels—is a common cause of death in developed countries. In the USA, for example, the single leading cause of death is coronary heart disease, a CVD in which narrowing of the heart's blood vessels slows or stops the blood supply to the heart and eventually causes a heart attack. Other types of CVD include stroke (in which narrowing of the blood vessels interrupts the brain's blood supply) and heart failure (a condition in which the heart can no longer pump enough blood to the rest of the body). Many factors increase the risk of developing CVD, including high blood pressure (hypertension), high blood cholesterol, having diabetes, smoking, and being overweight. Tools such as the “Framingham risk calculator” assess an individual's overall CVD risk by taking these and other risk factors into account. CVD risk can be minimized by taking drugs to reduce blood pressure or cholesterol levels (for example, pravastatin) and by making lifestyle changes.
Why Was This Study Done?
Another potential risk factor for CVD is impaired kidney (renal) function. In healthy people, the kidneys filter waste products and excess fluid out of the blood. A reduced “estimated glomerular filtration rate” (eGFR), which indicates impaired renal function, is associated with increased CVD in young and middle-aged people and increased all-cause and cardiovascular death in people who have vascular disease. But is reduced eGFR also associated with CVD and death in older people? If it is, it would be worth encouraging elderly people with reduced eGFR to avoid other CVD risk factors. In this study, the researchers determine the predictive value of eGFR for all-cause and vascular mortality (deaths caused by CVD) and for incident vascular events (a first heart attack, stroke, or heart failure) using data from the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER). This clinical trial examined pravastatin's effects on CVD development among 70–82 year olds with pre-existing vascular disease or an increased risk of CVD because of smoking, hypertension, or diabetes.
What Did the Researchers Do and Find?
The trial participants were divided into four groups based on their eGFR at the start of the study. The researchers then investigated the association between baseline CVD risk factors and baseline eGFR and between baseline eGFR and vascular events and deaths that occurred during the 3-year study. Several established CVD risk factors were associated with a reduced eGFR after allowing for other risk factors. In addition, people with a low eGFR (between 20 and 40 units) were twice as likely to die from any cause as people with an eGFR above 60 units (the normal eGFR for a young person is 100 units; eGFR decreases with age) and more than three times as likely to have nonfatal coronary heart disease or heart failure. A low eGFR also increased the risk of vascular mortality, other noncancer deaths, and fatal coronary heart disease and heart failure. Finally, pravastatin treatment reduced coronary heart disease deaths and nonfatal heart attacks most effectively among participants with the greatest degree of eGFR impairment.
What Do These Findings Mean?
These findings suggest that, in elderly people, impaired renal function is associated with levels of established CVD risk factors that increase the risk of vascular disease. They also suggest that impaired kidney function increases the risk of all-cause mortality, fatal vascular events, and fatal and nonfatal coronary heat disease and heart failure. Because the study participants were carefully chosen for inclusion in PROSPER, these findings may not be generalizable to all elderly people with vascular disease or vascular disease risk factors. Nevertheless, increased efforts should probably be made to encourage elderly people with reduced eGFR and other vascular risk factors to make lifestyle changes to reduce their overall CVD risk. Finally, although the effect of statins in elderly patients with renal dysfunction needs to be examined further, these findings suggest that this group of patients should benefit at least as much from statins as elderly patients with healthy kidneys.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000016.
The MedlinePlus Encyclopedia has pages on coronary heart disease, stroke, and heart failure (in English and Spanish)
MedlinePlus provides links to many other sources of information on heart disease, vascular disease, and stroke (in English and Spanish)
The US National Institute of Diabetes and Digestive and Kidney Diseases provides information on how the kidneys work and what can go wrong with them, including a list of links to further information about kidney disease
The American Heart Association provides information on all aspects of cardiovascular disease for patients, caregivers, and professionals (in several languages)
More information about PROSPER is available on the Web site of the Vascular Biochemistry Department of the University of Glasgow
doi:10.1371/journal.pmed.1000016
PMCID: PMC2628400  PMID: 19166266
12.  Personalized Prediction of Lifetime Benefits with Statin Therapy for Asymptomatic Individuals: A Modeling Study 
PLoS Medicine  2012;9(12):e1001361.
In a modeling study conducted by Myriam Hunink and colleagues, a population-based cohort from Rotterdam is used to predict the possible lifetime benefits of statin therapy, on a personalized basis.
Background
Physicians need to inform asymptomatic individuals about personalized outcomes of statin therapy for primary prevention of cardiovascular disease (CVD). However, current prediction models focus on short-term outcomes and ignore the competing risk of death due to other causes. We aimed to predict the potential lifetime benefits with statin therapy, taking into account competing risks.
Methods and Findings
A microsimulation model based on 5-y follow-up data from the Rotterdam Study, a population-based cohort of individuals aged 55 y and older living in the Ommoord district of Rotterdam, the Netherlands, was used to estimate lifetime outcomes with and without statin therapy. The model was validated in-sample using 10-y follow-up data. We used baseline variables and model output to construct (1) a web-based calculator for gains in total and CVD-free life expectancy and (2) color charts for comparing these gains to the Systematic Coronary Risk Evaluation (SCORE) charts. In 2,428 participants (mean age 67.7 y, 35.5% men), statin therapy increased total life expectancy by 0.3 y (SD 0.2) and CVD-free life expectancy by 0.7 y (SD 0.4). Age, sex, smoking, blood pressure, hypertension, lipids, diabetes, glucose, body mass index, waist-to-hip ratio, and creatinine were included in the calculator. Gains in total and CVD-free life expectancy increased with blood pressure, unfavorable lipid levels, and body mass index after multivariable adjustment. Gains decreased considerably with advancing age, while SCORE 10-y CVD mortality risk increased with age. Twenty-five percent of participants with a low SCORE risk achieved equal or larger gains in CVD-free life expectancy than the median gain in participants with a high SCORE risk.
Conclusions
We developed tools to predict personalized increases in total and CVD-free life expectancy with statin therapy. The predicted gains we found are small. If the underlying model is validated in an independent cohort, the tools may be useful in discussing with patients their individual outcomes with statin therapy.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Cardiovascular disease (CVD) affects the heart and/or the blood vessels and is a major cause of illness and death worldwide. In the US, for example, coronary heart disease—a CVD in which narrowing of the heart's blood vessels by fatty deposits slows the blood supply to the heart and may eventually cause a heart attack—is the leading cause of death, and stroke—a CVD in which the brain's blood supply is interrupted—is the fourth leading cause of death. Established risk factors for CVD include smoking, high blood pressure, obesity, and high blood levels of a fat called low-density lipoprotein (“bad cholesterol”). Because many of these risk factors can be modified by lifestyle changes and by drugs, CVD can be prevented. Thus, physicians can assess a healthy individual's risk of developing CVD using a CVD prediction model (equations that take into account the CVD risk factors to which the individual is exposed) and can then recommend lifestyle changes and medications to reduce that individual's CVD risk.
Why Was This Study Done?
Current guidelines recommend that asymptomatic (healthy) individuals whose likely CVD risk is high should be encouraged to take statins—cholesterol-lowering drugs—as a preventative measure. Statins help to prevent CVD in healthy people with a high predicted risk of CVD, but, like all medicines, they have some unwanted side effects, so it is important that physicians can communicate both the benefits and drawbacks of statins to their patients in a way that allows them to make an informed decision about taking these drugs. Telling a patient that statins will reduce his or her short-term risk of CVD is not always helpful—patients really need to know the potential lifetime benefits of statin therapy. That is, they need to know how much longer they might live if they take statins. Here, the researchers use a mathematical model to predict the personalized lifetime benefits (increased total and CVD-free life expectancy) of statin therapy for individuals without a history of CVD.
What Did the Researchers Do and Find?
The researchers used the Rotterdam Ischemic Heart Disease & Stroke Computer Simulation (RISC) model, which simulates the life courses of individuals through six health states, from well through to CVD or non-CVD death, to estimate lifetime outcomes with and without statin therapy in a population of healthy elderly individuals. They then used these outcomes and information on baseline risk factors to develop a web-based calculator suitable for personalized prediction of the lifetime benefits of statins in routine clinical practice. The model estimated that statin therapy increases average life expectancy in the study population by 0.3 years and average CVD-free life expectancy by 0.7 years. The gains in total and CVD-free life expectancy associated with statin therapy increased with blood pressure, unfavorable cholesterol levels, and body mass index (an indicator of body fat) but decreased with age. Notably, the web-based calculator predicted that some individuals with a low ten-year CVD risk might achieve a similar or larger gain in CVD-free life expectancy with statin therapy than some individuals with a high ten-year risk. So, for example, both a 55-year-old non-smoking woman with a ten-year CVD mortality risk of 2% (a two in a hundred chance of dying of CVD within ten years) and a 65-year-old male smoker with a ten-year CVD mortality risk of 15% might both gain one year of CVD-free life expectancy with statin therapy.
What Do These Findings Mean?
These findings suggest that statin therapy can lead on average to small gains in total life expectancy and slightly larger gains in CVD-free life expectancy among healthy individuals, and show that life expectancy benefits can be predicted using an individual's risk factor profile. The accuracy and generalizability of these findings is limited by the assumptions included in the model (in particular, the model did not allow for the known side effects of statin therapy) and by the data fed into it—importantly, the risk prediction model needs to be validated using an independent dataset. If future research confirms the findings of this study, the researchers' web-based calculator could provide complementary information to the currently recommended ten-year CVD mortality risk assessment. Whether communication of personalized outcomes will ultimately result in better clinical outcomes remains to be seen, however, because patients may be less likely to choose statin therapy when provided with more information about its likely benefits.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001361.
The web-based calculator for personalized prediction of lifetime benefits with statin therapy is available (after agreement to software license)
The American Heart Association provides information about many types of cardiovascular disease for patients, carers, and professionals, including information about drug therapy for cholesterol and a heart attack risk calculator
The UK National Health Service Choices website provides information about cardiovascular disease and about statins
Information is available from the British Heart Foundation on heart disease and keeping the heart healthy; information is also available on statins, including personal stories about deciding to take statins
The US National Heart Lung and Blood Institute provides information on a wide range of cardiovascular diseases
The European Society of Cardiology's cardiovascular disease risk assessment model (SCORE) is available
MedlinePlus provides links to many other sources of information on heart diseases, vascular diseases, stroke, and statins (in English and Spanish)
doi:10.1371/journal.pmed.1001361
PMCID: PMC3531501  PMID: 23300388
13.  Long-Term Interleukin-6 Levels and Subsequent Risk of Coronary Heart Disease: Two New Prospective Studies and a Systematic Review 
PLoS Medicine  2008;5(4):e78.
Background
The relevance to coronary heart disease (CHD) of cytokines that govern inflammatory cascades, such as interleukin-6 (IL-6), may be underestimated because such mediators are short acting and prone to fluctuations. We evaluated associations of long-term circulating IL-6 levels with CHD risk (defined as nonfatal myocardial infarction [MI] or fatal CHD) in two population-based cohorts, involving serial measurements to enable correction for within-person variability. We updated a systematic review to put the new findings in context.
Methods and Findings
Measurements were made in samples obtained at baseline from 2,138 patients who had a first-ever nonfatal MI or died of CHD during follow-up, and from 4,267 controls in two cohorts comprising 24,230 participants. Correction for within-person variability was made using data from repeat measurements taken several years apart in several hundred participants. The year-to-year variability of IL-6 values within individuals was relatively high (regression dilution ratios of 0.41, 95% confidence interval [CI] 0.28–0.53, over 4 y, and 0.35, 95% CI 0.23–0.48, over 12 y). Ignoring this variability, we found an odds ratio for CHD, adjusted for several established risk factors, of 1.46 (95% CI 1.29–1.65) per 2 standard deviation (SD) increase of baseline IL-6 values, similar to that for baseline C-reactive protein. After correction for within-person variability, the odds ratio for CHD was 2.14 (95% CI 1.45–3.15) with long-term average (“usual”) IL-6, similar to those for some established risk factors. Increasing IL-6 levels were associated with progressively increasing CHD risk. An updated systematic review of electronic databases and other sources identified 15 relevant previous population-based prospective studies of IL-6 and clinical coronary outcomes (i.e., MI or coronary death). Including the two current studies, the 17 available prospective studies gave a combined odds ratio of 1.61 (95% CI 1.42–1.83) per 2 SD increase in baseline IL-6 (corresponding to an odds ratio of 3.34 [95% CI 2.45–4.56] per 2 SD increase in usual [long-term average] IL-6 levels).
Conclusions
Long-term IL-6 levels are associated with CHD risk about as strongly as are some major established risk factors, but causality remains uncertain. These findings highlight the potential relevance of IL-6–mediated pathways to CHD.
John Danesh and colleagues show that long-term IL-6 levels are associated with coronary heart disease risk, thus highlighting the potential relevance of IL-6−mediated pathways to coronary heart disease.
Editors' Summary
Background.
Coronary heart disease (CHD), the leading cause of death among adults in developed countries, kills one person in the US every minute. With age, “atherosclerotic plaques”—deposits of fats, calcium, and various cellular waste products—coat the walls of arteries, causing them to narrow and harden, interrupting blood flow through the body. When this occurs in the coronary arteries, which nourish the heart muscle, the end result is CHD. If a plaque breaks off the artery wall, it can get trapped in the arteries and completely stop the blood flow, causing death of the heart muscle. The technical term for this is “myocardial infarction” (MI), although it is more commonly known as a heart attack. Smoking, high blood pressure, high blood levels of cholesterol (a type of fat), being overweight, and being physically inactive all increase the risk of developing CHD, as do some inherited factors. Treatments for CHD include lifestyle changes (for example, losing weight and exercising regularly) and medications that lower blood pressure and blood cholesterol. In the worst cases, the narrowed artery can be widened using a device called a stent or surgically bypassed.
Why Was This Study Done?
Atherosclerosis might, at least partly, be an inflammatory condition. Inflammation—an immune response to injury characterized by swelling and redness—involves the production of proteins called “cytokines,” which attract cells of the immune system to the site of injury. In atherosclerosis, damage to the artery walls seems to trigger inflammation, which helps the atherosclerotic plaques grow. Because of the potential involvement of inflammation in atherosclerosis, increased levels of circulating cytokines might be associated with an increased risk of CHD. If they are, cytokines might provide a new therapeutic target for the treatment of CHD. In this study, the researchers have asked whether prolonged moderate increases in the cytokine interleukin-6 (IL-6) in the bloodstream are associated with CHD risk. IL-6, which is produced very early in inflammation, survives only briefly in the human body and its levels fluctuate within individuals. Consequently, its relevance to CHD has been unclear in previous studies.
What Did the Researchers Do and Find?
Between 1967 and 1991, nearly 25,000 healthy, mainly middle-aged people were enrolled into two studies—the Reykjavik Study and the British Regional Heart Study—and followed for about 20 years, during which time 2,138 people had a first-ever nonfatal heart attack or died of CHD. The researchers measured baseline IL-6 blood levels in these participants and in 4,267 similar participants who had not had a CHD event. They also measured IL-6 levels in 558 healthy participants several years into the study to determine a “regression dilution ratio” for IL-6. This ratio gives an idea of the year-to-year consistency of IL-6 levels. When the researchers used this ratio to estimate the impact of prolonged increases in IL-6 levels on CHD, they found that increased long-term IL-6 levels more than doubled the risk for CHD in their study populations. The researchers then combined these new results with those of 15 previous relevant studies. This combined analysis indicated very similar findings to those in the new data.
What Do These Findings Mean?
These findings indicate prolonged moderate increases in IL-6 levels are associated with risk of CHD as strongly as several major established risk factors, including blood pressure and blood cholesterol levels, but whether there is a cause-and-effect relationship remains unknown. More studies are needed to find out whether this result is generalisable to other populations, but the broad agreement between the Icelandic and British studies suggests that they should be. This study renews interest in IL-6–mediated inflammatory pathways and CHD.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050078.
Read a related PLoS Medicine Perspective article
The MedlinePlus encyclopedia has pages on coronary heart disease and atherosclerosis (in English and Spanish)
Information is available from the US National Heart Lung and Blood Institute on coronary heart disease and atherosclerosis
Information for patients and caregivers is provided by the American Heart Association on all aspects of heart disease, including inflammation and heart disease
Information is available from the British Heart Foundation on heart disease and on keeping the heart healthy
Further details are available about the Reykjavik Study and the British Regional Heart Study
Wikipedia has pages on inflammation and on interleukin-6 (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.0050078
PMCID: PMC2288623  PMID: 18399716
14.  Screening for hypercholesterolaemia in primary care: randomised controlled trial of postal questionnaire appraising risk of coronary heart disease 
BMJ : British Medical Journal  1998;316(7139):1208-1213.
Objectives: To validate a self administered postal questionnaire appraising risk of coronary heart disease. To determine whether use of this questionnaire increased the percentage of people at high risk of coronary heart disease and decreased the percentage of people at low risk who had their cholesterol concentration measured.
Design: Validation was by review of medical records and clinical assessment. The questionnaire appraising risk of coronary heart disease encouraged those meeting criteria for cholesterol measurement to have a cholesterol test and was tested in a randomised controlled trial. The intervention group was sent the risk appraisal questionnaire with a health questionnaire that determined risk of coronary heart disease without identifying the risk factors as related to coronary heart disease; the control group was sent the health questionnaire alone.
Setting: One capitation funded primary care practice in Canada with an enrolled patient population of about 12 000.
Subjects: Random sample of 100 participants in the intervention and control groups were included in the validation exercise. 5686 contactable patients aged 20 to 69 years who on the basis of practice records had not had a cholesterol test performed during the preceding 5 years were included in the randomised controlled trial. 2837 were in the intervention group and 2849 were in the control group.
Main outcome measures: Sensitivity and specificity of assessment of risk of coronary heart disease with risk appraisal questionnaire. Rate of cholesterol testing during three months of follow up.
Results: Sensitivity of questionnaire appraising coronary risk was 87.5% (95% confidence interval 73.2% to 95.8%) and specificity 91.7% (81.6% to 97.2%). Of the patients without pre-existing coronary heart disease who met predefined screening criteria based on risk, 45 out of 421 in the intervention group (10.7%) and 9 out of 504 in the control group (1.8%) had a cholesterol test performed during follow up (P<0.0001). Of the patients without a history of coronary heart disease who did not meet criteria for cholesterol testing, 30 out of 1128 in the intervention group (2.7%) and 18 out of 1099 in the control group (1.6%) had a cholesterol test (P=0.175). Of the patients with pre-existing coronary heart disease, 1 out of 15 in the intervention group (6.7%) and 1 out of 23 in the control group (4.3%) were tested during follow up (P=0.851, one tailed Fisher’s exact test).
Conclusions: Although the questionnaire appraising coronary risk increased the percentage of people at high risk who obtained cholesterol testing, the effect was small. Most patients at risk who received the questionnaire did not respond by having a test.
Key messages Of patients at high risk of coronary heart disease, 10.7% who received a risk appraisal questionnaire with a general health questionnaire and 1.8% of those who received the general health questionnaire alone had a cholesterol test within the following three months Of patients at low risk, 2.7% of patients receiving the risk appraisal questionnaire and 1.6% of control subjects had a cholesterol test Most patients at risk who received the risk appraisal questionnaire did not seek a test Further research is needed to identify factors contributing to low uptake of cholesterol testing among people at high risk of coronary heart disease even when encouragement is given
PMCID: PMC28524  PMID: 9552998
15.  The Effect of Elevated Body Mass Index on Ischemic Heart Disease Risk: Causal Estimates from a Mendelian Randomisation Approach 
PLoS Medicine  2012;9(5):e1001212.
A Mendelian randomization analysis conducted by Børge G. Nordestgaard and colleagues using data from observational studies supports a causal relationship between body mass index and risk for ischemic heart disease.
Background
Adiposity, assessed as elevated body mass index (BMI), is associated with increased risk of ischemic heart disease (IHD); however, whether this is causal is unknown. We tested the hypothesis that positive observational associations between BMI and IHD are causal.
Methods and Findings
In 75,627 individuals taken from two population-based and one case-control study in Copenhagen, we measured BMI, ascertained 11,056 IHD events, and genotyped FTO(rs9939609), MC4R(rs17782313), and TMEM18(rs6548238). Using genotypes as a combined allele score in instrumental variable analyses, the causal odds ratio (OR) between BMI and IHD was estimated and compared with observational estimates. The allele score-BMI and the allele score-IHD associations used to estimate the causal OR were also calculated individually. In observational analyses the OR for IHD was 1.26 (95% CI 1.19–1.34) for every 4 kg/m2 increase in BMI. A one-unit allele score increase associated with a 0.28 kg/m2 (95 CI% 0.20–0.36) increase in BMI and an OR for IHD of 1.03 (95% CI 1.01–1.05) (corresponding to an average 1.68 kg/m2 BMI increase and 18% increase in the odds of IHD for those carrying all six BMI increasing alleles). In instrumental variable analysis using the same allele score the causal IHD OR for a 4 kg/m2 increase in BMI was 1.52 (95% CI 1.12–2.05).
Conclusions
For every 4 kg/m2 increase in BMI, observational estimates suggested a 26% increase in odds for IHD while causal estimates suggested a 52% increase. These data add evidence to support a causal link between increased BMI and IHD risk, though the mechanism may ultimately be through intermediate factors like hypertension, dyslipidemia, and type 2 diabetes. This work has important policy implications for public health, given the continuous nature of the BMI-IHD association and the modifiable nature of BMI. This analysis demonstrates the value of observational studies and their ability to provide unbiased results through inclusion of genetic data avoiding confounding, reverse causation, and bias.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Ischemic heart disease (IHD; also known as coronary heart disease) is the leading cause of death among adults in developed countries. In the US alone, IHD kills nearly half a million people every year. With age, fatty deposits (atherosclerotic plaques) build up in the walls of the coronary arteries, the blood vessels that supply the heart with oxygen and nutrients. The resultant reduction in the heart's blood supply causes shortness of breath, angina (chest pains that are usually relieved by rest), and potentially fatal heart attacks (myocardial infarctions). Risk factors for IHD include smoking, high blood pressure (hypertension), abnormal amounts of cholesterol and other fat in the blood (dyslipidemia), type 2 diabetes, and being overweight or obese (having excess body fat). Treatments for IHD include lifestyle changes (for example, losing weight) and medications that lower blood pressure and blood cholesterol levels. The narrowed arteries can also be widened using a device called a stent or surgically bypassed.
Why Was This Study Done?
Prospective observational studies have shown an association between a high body mass index (BMI, a measure of body fat that is calculated by dividing a person's weight in kilograms by their height in meters squared; a BMI greater than 30 kg/m2 indicates obesity) and an increased risk of IHD. Observational studies, which ask whether people who are exposed to a suspected risk factor develop a specific disease more often than people who are not exposed to the risk factor, cannot prove, however, that changes in BMI/adiposity cause IHD. Obese individuals may share other characteristics that cause both IHD and obesity (confounding) or, rather than obesity causing IHD, IHD may cause obesity (reverse causation). Here, the researchers use “Mendelian randomization” to examine whether elevations in BMI across the lifecourse have a causal impact on IHD risk. Three common genetic variants—FTO(rs9939609), MC4R(rs17782313), and TMEM18(rs6548238)—which have the largest single genetic variant associations with BMI were used in this study. Given that gene variants are inherited essentially randomly with respect to conventional confounding factors and are not subject reverse causation, use of these as instruments (or proxy measures) for variation in BMI as a risk factor (as opposed to measuring BMI directly) allows researchers to comment on whether obesity is causally involved in IHD.
What Did the Researchers Do and Find?
The researchers analyzed data from two population-based studies in which adults were physically examined and answered a lifestyle questionnaire before being followed to see how many developed IDH. They also analyzed data from a case-control study on IDH (in a case-control study, people with a disease are matched with similar people without the disease and the occurrence of risk factors in the patients and controls is compared). Overall, the researchers measured the BMI of 75,627 white individuals, among whom 11,056 already had IDH or developed it, and determined which of the BMI-increasing genetic variants each participant carried. On the basis of the observational data, every 4 kg/m2 increase in BMI increased the odds of IDH by 26% (an odds ratio of 1.26). Using a score derived from the combination of the three genetic variants, the researchers confirmed an association between each BMI increasing allele and both BMI (as expected) and IHD (0.28 kg/m2 and an odds ratio for IHD of 1.03, respectively). On average, compared to people carrying no BMI-increasing gene variants, people carrying six BMI-increasing gene variants had a 1.68 kg/m2 increase in BMI and an 18% increase in IHD risk. To extend this and to essentially reassess the original, observational, relationship between BMI and IHD risk, an “instrumental variable analysis” was used to examine the causal effect of a lifetime change in BMI on the risk of IDH. In this, it was found that for every 4 kg/m2 increase in BMI increased the odds of IDH by 52%.
What Do These Findings Mean?
These findings support a causal link between increased BMI and IDH risk, although it may be that BMI affects IDH through intermediate factors such as hypertension, dyslipidemia, and diabetes. The findings also show that observational studies into the impact of elevated BMI on IHD risk were consistent with this, but also that the inclusion of genetic data increases the value of observational studies by making it possible to avoid issues such as confounding and reverse causation. Finally, these findings and those of recent, observational studies have important implications for public-health policy because they show that the association between BMI (which is modifiable by lifestyle changes) and IHD is continuous. That is, any increase in BMI increases the risk of IHD; there is no threshold below which a BMI increase has no effect on IDH risk. Thus, public-health policies that aim to reduce BMI by even moderate levels could substantially reduce the occurrence of IDH in populations.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001212.
The American Heart Association provides information about IHD and tips on keeping the heart healthy, including weight management; it also provides personal stories about IHD
The UK National Health Service Choices website provides information about IHD, including information on prevention and personal stories about IHD
Information is available from the British Heart Foundation on heart disease and keeping the heart healthy
The US National Heart Lung and Blood Institute also provides information on IHD (in English and Spanish)
MedlinePlus provides links to many other sources of information on IHD (in English and Spanish)
Wikipedia has a page on Mendelian randomization (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.1001212
PMCID: PMC3341326  PMID: 22563304
16.  “Unwarranted survivals” and “anomalous deaths” from coronary heart disease: prospective survey of general population 
BMJ : British Medical Journal  2001;323(7327):1487-1491.
Objectives
To assess survival in people who are at apparent high risk who do not develop coronary heart disease (“unwarranted survivals”) and mortality in people at low risk who die from the disease (“anomalous deaths”) and the extent to which these outcomes are explained by other, less visible, risk factors.
Design
Prospective general population survey.
Setting
Renfrew and Paisley, Scotland.
Participants
6068 men aged 45-64 years at screening in 1972-6, allocated to “visible” risk groups on the basis of body mass index and smoking.
Main outcome measures
Survival and death from coronary heart disease by age 70 years.
Results
Visible risk was a good predictor of mortality: 13% (45) of men at low risk and 45% (86) of men at high risk had died by age 70 years. Of these deaths, 12 (4%) and 44 (23%), respectively, were from coronary heart disease. In the group at low visible risk other less visible risk factors accounted for increased risk in 83% (10/12) of men who died from coronary heart disease and 29% (84/292) of men who survived. In the high risk group 81/107 who survived (76%) and 19/44 (43%) who died from coronary heart disease had lower risk after other factors were considered. Different risk factors modified risk (beyond smoking and body mass index) in the two groups. Among men at low visible risk, poor respiratory function, diabetes, previous coronary heart disease, and socioeconomic deprivation modified risk. Among men at high visible risk, height and cholesterol concentration modified risk.
Conclusions
Differences in survival between these extreme risk groups are dramatic. Health promotion messages would be more credible if they discussed anomalies and the limits of prediction of coronary disease at an individual level.
What is already known on this topicPeople pay attention to visible risk factors, such as smoking and weight, in explaining or predicting coronary events but are aware that these behavioural risk factors fail to explain some early deaths from coronary heart disease (in those with “low risk” lifestyles) and long survival (in those with “high risk” lifestyles)Such violations to notions of coronary candidacy undermine people's belief in the worth of modifying behavioural risk factors for coronary heart diseaseWhat this study addsVisible risk status was a good marker for other coronary risk factors at the extremes of the risk distributionMost men at low visible risk (slim, never smoked) who died prematurely from coronary heart disease had poorer risk profiles on other less visible risk factors; similarly, men at high visible risk (obese, heavy smokers) who survived often had more favourable profiles on other risk factors
PMCID: PMC61054  PMID: 11751367
17.  Plasma Phospholipid Fatty Acid Concentration and Incident Coronary Heart Disease in Men and Women: The EPIC-Norfolk Prospective Study 
PLoS Medicine  2012;9(7):e1001255.
Kay-Tee Khaw and colleagues analyze data from a prospective cohort study and show associations between plasma concentrations of saturated phospholipid fatty acids and risk of coronary heart disease, and an inverse association between omega-6 polyunsaturated phospholipid fatty acids and risk of coronary heart disease.
Background
The lack of association found in several cohort studies between dietary saturated fat and coronary heart disease (CHD) risk has renewed debate over the link between dietary fats and CHD.
Methods and Findings
We assessed the relationship between plasma phospholipid fatty acid (PFA) concentration and incident CHD using a nested case control design within a prospective study (EPIC-Norfolk) of 25,639 individuals aged 40–79 years examined in 1993–1997 and followed up to 2009. Plasma PFA concentrations were measured by gas chromatography in baseline samples retrieved from frozen storage. In 2,424 men and women with incident CHD compared with 4,930 controls alive and free of cardiovascular disease, mean follow-up 13 years, saturated PFA (14:0, 16:0,18:0) plasma concentrations were significantly associated with increased CHD risk (odds ratio [OR] 1.75, 95% CI 1.27–2.41, p<0.0001), in top compared to bottom quartiles (Q), and omega-6 polyunsaturated PFA concentrations were inversely related (OR 0.77, 0.60–0.99, p<0.05) after adjusting for age, sex, body mass index, blood pressure, smoking, alcohol intake, plasma vitamin C, social class, education, and other PFAs. Monounsaturated PFA, omega-3 PFA, and trans PFA concentrations were not significantly associated with CHD. Odd chain PFA (15:0, 17:0) concentrations were significantly inversely associated with CHD (OR 0.73, 0.59–0.91, p<0.001, Q4 versus Q1). Within families of saturated PFA or polyunsaturated PFA, significantly heterogeneous relationships with CHD were observed for individual fatty acids.
Conclusions
In this study, plasma concentrations of even chain saturated PFA were found to be positively and omega-6 polyunsaturated PFA inversely related to subsequent coronary heart disease risk. These findings are consistent with accumulating evidence suggesting a protective role of omega-6 fats substituting for saturated fats for CHD prevention.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Coronary heart disease (CHD) is a condition caused by a build-up of fatty deposits on the inner walls of the blood vessels that supply the heart, causing the affected person to experience pain, usually on exertion (angina). A complete occlusion of the vessel by deposits causes a heart attack (myocardial infarction). Lifestyle factors, such as diet (particularly one high in fat), contribute to causing CHD. There are different types of fat, some of which are thought to increase risk of CHD, such as saturated fat, typically found in meat and dairy foods. However, others, such as unsaturated fats (polyunsaturated and monounsaturated fats) found in foods such as vegetable oils, fish, and nuts, may actually help prevent this condition.
Why Was This Study Done?
Although there have been many studies investigating the role of different types of dietary fat in coronary heart disease, it is still not clear whether coronary heart disease can be prevented by changing the type of dietary fat consumed from saturated to unsaturated fats or by lowering all types of dietary fat. Furthermore, many of these studies have relied on participants recalling their dietary intake in questionnaires, which is an unreliable method for different fats. So in this study, the researchers used an established UK cohort to measure the levels of different types of fatty acids in blood to investigate whether a diet high in saturated fatty acids and low in unsaturated fatty acids increases CHD risk.
What Did the Researchers Do and Find?
The researchers used a selection of 10,000 participants (all men and women aged 40–79 years) from the prospective European Prospective Investigation into Cancer (EPIC)-Norfolk cohort. Blood samples from the selected participants taken at the start of the study in 1993–1997 were analyzed to determine levels of specific fatty acids. Participants were followed up till 2011. The researchers identified 2,424 participants who were subsequently diagnosed with CHD using death certificates and hospital discharge data and matched these with 4,930 controls who were still alive and free of known coronary disease. The researchers grouped the type of blood fatty acids identified in the blood samples into six families (even chain saturated fatty acid, odd chain saturated fatty acid, omega-6 polyunsaturated fatty acid, omega-3 polyunsaturated fatty acid, monounsaturated fatty acid, and trans-fatty acid), which represented saturated and unsaturated fatty acids. Using statistical methods, the researchers then compared the risks of developing CHD between cases and controls by the concentration of fatty acid families after adjusting for age and sex and other factors, such as body mass index, physical activity, and smoking. Using these methods, the researchers found that there was no overall significant relationship between total blood fatty acid concentration and CHD but there was a positive association with increasing blood saturated fatty acid concentration after adjusting for other fatty acid concentrations, with an odds ratio of 1.83 comparing higher versus lower concentrations. This risk was attenuated after adjusting for cholesterol levels, indicating that much of the association between saturated fatty acid and CHD is likely to be mediated through blood cholesterol levels. In contrast, blood omega-6 poly-unsaturated fatty acid concentrations were associated with lower CHD risk. Blood monounsaturated fatty acids, omega-3 poly-unsaturated fatty acids, and trans-fatty acids were not consistently associated with CHD risk. The authors also noted that within families of fatty acids, individual fatty acids related differently to CHD risk.
What Do These Findings Mean?
These findings suggest that plasma concentrations of saturated fatty acids are associated with increased risk of CHD and that concentrations of omega-6 poly-unsaturated fatty acids are associated with decreased risk of CHD. These findings are consistent with other studies and with current dietary advice for preventing CHD, which encourages substituting foods high in saturated fat with n-6 polyunsaturated fats. The results also suggest that different fatty acids may relate differently to CHD risk and that the overall balance between different fatty acids is important. However, there are limitations to this study, such as that factors other than diet (genetic differences in metabolism, for example) may cause changes to blood fatty acid levels so a major question is to identify what factors influence blood fatty acid concentrations. Nevertheless, these findings suggest that individual fatty acids play a role in increasing or decreasing risks of CHD.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001255.
Information about the EPIC-Norfolk study is available
The American Heart Foundation provides patient-friendly information about different dietary fats as does Medline
The British Heart Foundation also provides patient-friendly information on heart conditions
doi:10.1371/journal.pmed.1001255
PMCID: PMC3389034  PMID: 22802735
18.  Cluster randomised controlled trial to compare three methods of promoting secondary prevention of coronary heart disease in primary care 
BMJ : British Medical Journal  2001;322(7298):1338.
Objective
To assess the effectiveness of three different methods of promoting secondary prevention of coronary heart disease in primary care.
Design
Pragmatic, unblinded, cluster randomised controlled trial.
Setting
Warwickshire.
Subjects
21 general practices received intervention; outcome measured in 1906 patients aged 55-75 years with established coronary heart disease.
Interventions
Audit of notes with summary feedback to primary health care team (audit group); assistance with setting up a disease register and systematic recall of patients to general practitioner (GP recall group); assistance with setting up a disease register and systematic recall of patients to a nurse led clinic (nurse recall group).
Main outcome measures
At 18 months' follow up: adequate assessment (defined) of 3 risk factors (blood pressure, cholesterol, and smoking status); prescribing of hypotensive agents, lipid lowering drugs, and antiplatelet drugs; blood pressure, serum cholesterol level, and plasma cotinine levels.
Results
Adequate assessment of all 3 risk factors was much more common in the nurse and GP recall groups (85%, 76%) than the audit group (52%). The advantage in the nurse recall compared with the audit group was 33% (95% confidence interval 19% to 46%); in the GP recall group compared with the audit group 23% (10% to 36%), and in the nurse recall group compared with the GP recall group 9% (−3% to 22%). However, these differences in assessment were not reflected in clinical outcomes. Mean blood pressure (148/80, 147/81, 148/81 mm Hg), total cholesterol (5.4, 5.5, 5.5 mmol/l), and cotinine levels (% probable smokers 17%, 16%, 19%) varied little between the nurse recall, GP recall, and audit groups respectively, as did prescribing of hypotensive and lipid lowering agents. Prescribing of antiplatelet drugs was higher in the nurse recall group (85%) than the GP recall or audit groups (80%, 74%). After adjustment for baseline levels, the advantage in the nurse recall group compared with the audit group was 10% (3% to 17%), in the nurse recall group compared with the GP recall group 8% (1% to 15%) and in the GP recall group compared with the audit group 2% (−6% to 10%).
Conclusions
Setting up a register and recall system improved patient assessment at 18 months' follow up but was not consistently better than audit alone in improving treatment or risk factor levels. Understanding the reasons for this is the key next step in improving the quality of care of patients with coronary heart disease.
What is already known on this topicEffective preventive care of patients with any chronic disease requires planned and quality assured follow up on the basis of an up to date registerStrategies for changing clinical practice in primary care have been of limited effectivenessWhat this study addsSetting up a coronary heart disease register for a practice substantially increases follow up and adequate assessment of patients at riskImproved assessment and follow up does not necessarily improve clinical outcomeFollow up by nurses is as effective as, and may be more effective than, follow up by doctorsPatients are being followed up and adequately assessed without the recommended preventive drugs being prescribed
PMCID: PMC32168  PMID: 11387182
19.  Metabolic mediators of the effects of body-mass index, overweight, and obesity on coronary heart disease and stroke: a pooled analysis of 97 prospective cohorts with 1·8 million participants 
Lancet  2014;383(9921):970-983.
Summary
Background
Body-mass index (BMI) and diabetes have increased worldwide, whereas global average blood pressure and cholesterol have decreased or remained unchanged in the past three decades. We quantified how much of the effects of BMI on coronary heart disease and stroke are mediated through blood pressure, cholesterol, and glucose, and how much is independent of these factors.
Methods
We pooled data from 97 prospective cohort studies that collectively enrolled 1·8 million participants between 1948 and 2005, and that included 57 161 coronary heart disease and 31 093 stroke events. For each cohort we excluded participants who were younger than 18 years, had a BMI of lower than 20 kg/m2, or who had a history of coronary heart disease or stroke. We estimated the hazard ratio (HR) of BMI on coronary heart disease and stroke with and without adjustment for all possible combinations of blood pressure, cholesterol, and glucose. We pooled HRs with a random-effects model and calculated the attenuation of excess risk after adjustment for mediators.
Findings
The HR for each 5 kg/m2 higher BMI was 1·27 (95% CI 1·23–1·31) for coronary heart disease and 1·18 (1·14–1·22) for stroke after adjustment for confounders. Additional adjustment for the three metabolic risk factors reduced the HRs to 1·15 (1·12–1·18) for coronary heart disease and 1·04 (1·01–1·08) for stroke, suggesting that 46% (95% CI 42–50) of the excess risk of BMI for coronary heart disease and 76% (65–91) for stroke is mediated by these factors. Blood pressure was the most important mediator, accounting for 31% (28–35) of the excess risk for coronary heart disease and 65% (56–75) for stroke. The percentage excess risks mediated by these three mediators did not differ significantly between Asian and western cohorts (North America, western Europe, Australia, and New Zealand). Both overweight (BMI ≥25 to <30 kg/m2) and obesity (BMI ≥30 kg/m2) were associated with a significantly increased risk of coronary heart disease and stroke, compared with normal weight (BMI ≥20 to <25 kg/m2), with 50% (44–58) of the excess risk of overweight and 44% (41–48) of the excess risk of obesity for coronary heart disease mediated by the selected three mediators. The percentages for stroke were 98% (69–155) for overweight and 69% (64–77) for obesity.
Interpretation
Interventions that reduce high blood pressure, cholesterol, and glucose might address about half of excess risk of coronary heart disease and three-quarters of excess risk of stroke associated with high BMI. Maintenance of optimum bodyweight is needed for the full benefits.
Funding
US National Institute of Health, UK Medical Research Council, National Institute for Health Research Comprehensive Biomedical Research Centre at Imperial College Healthcare NHS Trust, Lown Scholars in Residence Program on cardiovascular disease prevention, and Harvard Global Health Institute Doctoral Research Grant.
doi:10.1016/S0140-6736(13)61836-X
PMCID: PMC3959199  PMID: 24269108
20.  The Dundee coronary risk-disk for management of change in risk factors. 
BMJ : British Medical Journal  1991;303(6805):744-747.
OBJECTIVE--To devise a simplified system for grading and monitoring modifiable coronary risk in primary care, to be used with an action plan. METHODS--The risk equation came from 5203 men aged 40-59 in the United Kingdom heart disease prevention project, who had 331 coronary events over five years; the population rank (reading 1-100) was obtained by scoring 10,359 participants in the Scottish heart health study. Calculation of rank was embodied in the Dundee coronary risk-disk; the formula was tested against the Whitehall study; disk and action plan were evaluated in primary care. RESULTS--The system measures modifiable coronary risk from smoking, blood pressure, and blood cholesterol concentration by a sex and age related rank running from 1 (high risk, priority action) to 100 (low risk, general advice). The formula predicted outcome acceptably in the Whitehall study and is built into a circular slide rule. Only eight (11%) of 76 general practitioners and practice nurses surveyed already used risk factor scores. After evaluation most thought they should use one and proposed to incorporate the Dundee coronary risk-disk and the associated action plan into their routines. CONCLUSION--The Dundee coronary risk-disk readout of Dundee rank, standardised on a scale of 1 to 100 by age and sex, is a simple, valid means of assessing and monitoring modifiable coronary risk. It puts single risk factors (such as cholesterol concentration) in perspective and can aid selective testing. Understood by medical staff and patients, it should improve the efficiency and effectiveness of the high risk approach to coronary prevention.
Images
PMCID: PMC1671016  PMID: 1932933
21.  Risk of ischaemic heart disease and acute myocardial infarction in a Spanish population: observational prospective study in a primary-care setting 
BMC Public Health  2006;6:38.
Background
Ischaemic heart disease is a global priority of health-care policy, because of its social repercussions and its impact on the health-care system. Yet there is little information on coronary morbidity in Spain and on the effect of the principal risk factors on risk of coronary heart disease. The objective of this study is to describe the epidemiology of coronary disease (incidence, mortality and its association with cardiovascular risk factors) using the information gathered by primary care practitioners on cardiovascular health of their population.
Methods
A prospective study was designed. Eight primary-care centres participated, each contributing to the constitution of the cohort with the entire population covered by the centre. A total of 6124 men and women aged over 25 years and free of cardiovascular disease agreed to participate and were thus enrolled and followed-up, with all fatal and non-fatal coronary disease episodes being registered during a 5-year period. Repeated measurements were collected on smoking, blood pressure, weight and height, serum total cholesterol, high-density and low-density lipoproteins and fasting glucose. Rates were calculated for acute myocardial infarction and ischaemic heart disease. Associations between cardiovascular risk factors and coronary disease-free survival were evaluated using Kaplan-Meier and Cox regression analyses.
Results
Mean age at recruitment was 51.6 ± 15, with 24% of patients being over 65. At baseline, 74% of patients were overweight, serum cholesterol over 240 was present in 35% of patients, arterial hypertension in 37%, and basal glucose over 126 in 11%. Thirty-four percent of men and 13% of women were current smokers. During follow-up, 155 first episodes of coronary disease were detected, which yielded age-adjusted rates of 362 and 191 per 100,000 person-years in men and women respectively. Disease-free survival was associated with all risk factors in univariate analyses. After multivariate adjustments, age, male gender, smoking, high total cholesterol, high HDL/LDL ratio, diabetes and overweight remained strongly associated with risk. Relative risks for hypertension in women and for diabetes in men did not reach statistical significance.
Conclusion
Despite high prevalence of vascular risk factors, incidence rates were lower than those reported for other countries and other periods, but similar to those reported in the few population-based studies in Spain. Effect measures of vascular risk factors were mainly as reported worldwide and support the hypothesis that protective factors not considered in this study must exist as to explain low rates. This study shows the feasibility of conducting epidemiological cohort studies in primary-care settings.
doi:10.1186/1471-2458-6-38
PMCID: PMC1402280  PMID: 16503965
22.  Prevention of cardiovascular disease. 
1. Major risk factors for coronary heart disease (CHD) are smoking, blood pressure and blood cholesterol and they interact in a multiplicative fashion. Family history of premature coronary heart disease and lack of exercise also contribute. Obesity increases risk probably mainly by its effect on blood cholesterol and blood pressure. Heavy alcohol consumption is a risk factor for stroke. 2. Prevention may be opportunistic or in specially organized clinics, the latter being less likely to result in the attendance of high risk individuals. 3. Worthwhile reductions in cigarette smoking can be achieved by brief advice and follow-up. Literature on smoking and other aspects of prevention is available from the district health education department. 4. Risk scores can be used to calculate the risk of coronary heart disease. They can help to indicate the advisability of measurement of blood cholesterol and to focus limited resources on those at highest risk by helping to define a 'special care group'. 5. Indications for measuring blood cholesterol are: a family history of premature coronary heart disease or hyperlipidaemia, personal history of coronary heart disease, clinical evidence of raised lipids (xanthelasma, corneal arcus under 50, xanthomas at any age), a high risk of coronary heart disease according to a risk score. Many would also include those under treatment for hypertension and diabetes. 6. Dietary advice can moderately reduce blood cholesterol. The proportion of calories from fat should be reduced from the current average of around 40% to a maximum of 33%. Dietary advice should be tailored to the patient's current diet. An increase in vegetables and fruit can be generally advocated. 7. Regular exercise has a worthwhile role to play in prevention. Rapid walking, jogging and swimming may all be suitable, as may be heavy gardening and housework. 8. A small proportion of patients may require lipid-lowering drugs. These include resins (cholestyramine and colestipol), fibrates (eg bezafibrate and gemfibrozil) and more recently HMG CoA inhibitors (eg simvastatin). The HMG CoA inhibitors produce large falls in cholesterol and may become first line drugs in future. Because of the current controversy about the effect of lipid-lowering drugs on total mortality, many believe that they should be reserved for those at the highest risk, for example patients with familial hypercholesterolaemia or with pre-existing coronary heart disease and a high plasma cholesterol (> 7.8 mmol/L). 9. The special care group defined by the practice should be offered regular follow-up.(ABSTRACT TRUNCATED AT 400 WORDS)
PMCID: PMC2560221  PMID: 1345159
23.  Effects on Coronary Heart Disease of Increasing Polyunsaturated Fat in Place of Saturated Fat: A Systematic Review and Meta-Analysis of Randomized Controlled Trials 
PLoS Medicine  2010;7(3):e1000252.
Dariush Mozaffarian and colleagues conduct a systematic review and meta-analysis to investigate the effect of consuming polyunsaturated fats in place of saturated fats for lowering the risk of coronary heart disease.
Background
Reduced saturated fat (SFA) consumption is recommended to reduce coronary heart disease (CHD), but there is an absence of strong supporting evidence from randomized controlled trials (RCTs) of clinical CHD events and few guidelines focus on any specific replacement nutrient. Additionally, some public health groups recommend lowering or limiting polyunsaturated fat (PUFA) consumption, a major potential replacement for SFA.
Methods and Findings
We systematically investigated and quantified the effects of increased PUFA consumption, as a replacement for SFA, on CHD endpoints in RCTs. RCTs were identified by systematic searches of multiple online databases through June 2009, grey literature sources, hand-searching related articles and citations, and direct contacts with experts to identify potentially unpublished trials. Studies were included if they randomized participants to increased PUFA for at least 1 year without major concomitant interventions, had an appropriate control group, and reported incidence of CHD (myocardial infarction and/or cardiac death). Inclusions/exclusions were adjudicated and data were extracted independently and in duplicate by two investigators and included population characteristics, control and intervention diets, follow-up duration, types of events, risk ratios, and SEs. Pooled effects were calculated using inverse-variance-weighted random effects meta-analysis. From 346 identified abstracts, eight trials met inclusion criteria, totaling 13,614 participants with 1,042 CHD events. Average weighted PUFA consumption was 14.9% energy (range 8.0%–20.7%) in intervention groups versus 5.0% energy (range 4.0%–6.4%) in controls. The overall pooled risk reduction was 19% (RR = 0.81, 95% confidence interval [CI] 0.70–0.95, p = 0.008), corresponding to 10% reduced CHD risk (RR = 0.90, 95% CI = 0.83–0.97) for each 5% energy of increased PUFA, without evidence for statistical heterogeneity (Q-statistic p = 0.13; I2 = 37%). Meta-regression identified study duration as an independent determinant of risk reduction (p = 0.017), with studies of longer duration showing greater benefits.
Conclusions
These findings provide evidence that consuming PUFA in place of SFA reduces CHD events in RCTs. This suggests that rather than trying to lower PUFA consumption, a shift toward greater population PUFA consumption in place of SFA would significantly reduce rates of CHD.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Coronary heart disease (CHD) is the leading cause of death among adults in developed countries. It is caused by disease of the coronary arteries, the blood vessels that supply the heart with oxygen and nutrients. With age, inflammatory deposits (atherosclerotic plaques) coat the walls of these arteries and restrict the heart's blood supply, causing angina (chest pains that are usually relieved by rest), shortness of breath, and, if these plaques rupture or break, heart attacks (myocardial infarctions), which can reduce the heart's function or even be fatal. The key risk factors for CHD are smoking, physical inactivity, and poor diet. Blood cholesterol levels are altered by consuming dietary fats. There are three main types of dietary fats—“saturated” fatty acids (SFA) and unsaturated fatty acids; the latter can be “mono” unsaturated (MUFA) or “poly” unsaturated (PUFA). Eating SFA-rich foods (for example, meat, butter, and cheese) increases the amount of LDL-C in the blood but also increases HDL-C (the “good” cholesterol) and decreases triglycerides. Eating foods that are rich in unsaturated fatty acids (for example, vegetable oils and fatty fish) decreases the amount of LDL-C and triglycerides in the blood and also raises HDL-C.
Why Was This Study Done?
Because of the connection between eating SFA and high blood LDL-C levels, reduced SFA consumption is recommended as a way to avoid CHD. However, the evidence from individual randomized controlled trials that have studied CHD events (such as heart attacks and CHD-related deaths) have been mixed and could not support this recommendation. Furthermore, dietary recommendations to reduce SFA have generally not specified any replacement, i.e., whether SFA should be replaced with carbohydrate, protein, or unsaturated fats. Because of their beneficial effects on blood LDL-C and HDL-C levels, PUFA could be one important replacement for SFA, but, surprisingly, some experts argue that eating PUFA could actually increase CHD risk. Consequently, some guidelines recommend that PUFA consumption should be limited or even reduced. In this systematic review (a study that uses predefined criteria to identify all the research on a specific topic) and meta-analysis (a statistical method for combining the results of several studies) of randomized controlled trials, the researchers assess the impact of increased PUFA consumption as replacement for SFA on CHD events.
What Did the Researchers Do and Find?
The researchers' search of the published literature, “grey” literature (doctoral dissertations, technical reports, and other documents not printed in books and journals), and contacts with relevant experts identified eight trials in which participants were randomized to increase their PUFA intake for at least a year and in which CHD events were reported. 1,042 CHD events were recorded among the 13,614 participants enrolled in these trials. In their meta-analysis, the researchers found that on average the consumption of PUFA accounted for 14.9% of total energy intake in the intervention groups compared with only 5% of total energy intake in the control groups. Participants in the intervention groups had a 19% reduced risk of CHD events compared to participants in the control groups. Put another way, each 5% increase in the proportion of energy obtained from PUFA reduced the risk of CHD events by 10%. Finally, the researchers found that the benefits associated with PUFA consumption increased with longer duration of the trials.
What Do These Findings Mean?
These findings suggest that the replacement of some dietary SFA with PUFA reduces CHD events. Because the trials included in this study looked only at replacing SFA with PUFA, it is not possible from this evidence alone to distinguish between the benefits of reducing SFA and the benefits of increasing PUFA. Furthermore, the small number of trials identified in this study all had design faults, so the risk reductions reported here may be inaccurate. However, other lines of evidence (for example, observational studies that have examined associations between the fat intake of populations and their risk of CHD) also suggest that consumption of PUFA in place of SFA reduces CHD risk. Thus, in the light of these findings, future recommendations to reduce SFA in the diet should stress the importance of replacing SFA with PUFA rather than with other forms of energy, and the current advice to limit PUFA intake should be revised.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000252.
The American Heart Association provides information about all aspects of coronary heart disease for patients, caregivers, and professionals, including advice on dietary fats (in several languages)
The UK National Health Service Choices Web site provides information about coronary heart disease
Eatwell, a resource provided by the UK Food Standards Agency, gives advice on all aspects of healthy eating, including fat consumption
MedlinePlus provides links to further resources on coronary heart disease and on cholesterol (in English and Spanish)
doi:10.1371/journal.pmed.1000252
PMCID: PMC2843598  PMID: 20351774
24.  Readiness for lifestyle advice: self-assessments of coronary risk prior to screening in the British family heart study. Family Heart Study Group. 
BACKGROUND. Where health professionals and patients hold similar views of a problem, health outcomes may be better. AIM. The aims of this paper were to document how attenders at primary care cardiovascular screening clinics perceived their risks of coronary heart disease prior to screening; the degree of similarity between perceived level of risk and an epidemiologically derived risk score; and the relative importance assigned to individual risk factors by subjects compared with those assigned by the risk score. METHOD: These issues were investigated in 3725 middle aged men and women who accepted an invitation to attend health screening as part of the British family heart study. RESULTS. Overall, there was a tendency for subjects to be optimistic (37%) rather than pessimistic (21%) when judging their risk of coronary heart disease. Nevertheless, there were strong significant associations between perceived risk and the levels of individual risk factors, particularly personal and family medical history and body mass index. There was also a strong association with the overall risk score though a large minority (31%) held views of their risk of coronary heart disease that were quite different from those based upon the epidemiologically derived index of risk. Respondents accorded greater importance to smoking and parental death from coronary heart disease and less importance to cholesterol level and blood pressure than did the risk score. CONCLUSION. Possible explanations for the observed disagreement are over-optimism or the relative importance given to individual risk factors. The relationships between patients' perceptions of risk and the epidemiological indices likely to be espoused by health professionals are important in understanding the difficulties in communication that might arise in offering lifestyle advice after screening for cardiovascular risk.
PMCID: PMC1239105  PMID: 7779477
25.  Effect of an intervention to improve the cardiovascular health of family members of patients with coronary artery disease: a randomized trial 
Background:
Family members of patients with coronary artery disease (CAD) have higher risk of vascular events. We conducted a trial to determine if a family heart-health intervention could reduce their risk of CAD.
Methods:
We assessed coronary risk factors and randomized 426 family members of patients with CAD to a family heart-health intervention (n = 211) or control (n = 215). The intervention included feedback about risk factors, assistance with goal setting and counselling from health educators for 12 months. Reports were sent to the primary care physicians of patients whose lipid levels and blood pressure exceeded threshold values. All participants received printed materials about smoking cessation, healthy eating, weight management and physical activity; the control group received only these materials. The main outcomes (ratio of total cholesterol to high-density lipoprotein [HDL] cholesterol; physical activity; fruit and vegetable consumption) were assessed at 3 and 12 months. We examined group and time effects using mixed models analyses with the baseline values as covariates. The secondary outcomes were plasma lipid levels (total cholesterol, low-density lipoprotein cholesterol, HDL cholesterol and triglycerides); glucose level; blood pressure; smoking status; waist circumference; body mass index; and the use of blood pressure, lipid-lowering and smoking cessation medications.
Results:
We found no effect of the intervention on the ratio of total cholesterol to HDL cholesterol. However, participants in the intervention group reported consuming more fruit and vegetables (1.2 servings per day more after 3 mo and 0.8 servings at 12 mo; p < 0.001). There was a significant group by time interaction for physical activity (p = 0.03). At 3 months, those in the intervention group reported 65.8 more minutes of physical activity per week (95% confidence interval [CI] 47.0–84.7 min). At 12 months, participants in the intervention group reported 23.9 more minutes each week (95% CI 3.9–44.0 min).
Interpretation:
A health educator–led heart-health intervention did not improve the ratio of total cholesterol to HDL cholesterol but did increase reported physical activity and fruit and vegetable consumption among family members of patients with CAD. Hospitalization of a spouse, sibling or parent is an opportunity to improve cardiovascular health among other family members. Trial registration: clinicaltrials.gov, no NCT00552591.
doi:10.1503/cmaj.130550
PMCID: PMC3883820  PMID: 24246588

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