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1.  The Relationship between Proteinuria and Coronary Risk: A Systematic Review and Meta-Analysis 
PLoS Medicine  2008;5(10):e207.
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.
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
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
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
PMCID: PMC2570419  PMID: 18942886
2.  Homocysteine and Coronary Heart Disease: Meta-analysis of MTHFR Case-Control Studies, Avoiding Publication Bias 
PLoS Medicine  2012;9(2):e1001177.
Robert Clarke and colleagues conduct a meta-analysis of unpublished datasets to examine the causal relationship between elevation of homocysteine levels in the blood and the risk of coronary heart disease. Their data suggest that an increase in homocysteine levels is not likely to result in an increase in risk of coronary heart disease.
Moderately elevated blood levels of homocysteine are weakly correlated with coronary heart disease (CHD) risk, but causality remains uncertain. When folate levels are low, the TT genotype of the common C677T polymorphism (rs1801133) of the methylene tetrahydrofolate reductase gene (MTHFR) appreciably increases homocysteine levels, so “Mendelian randomization” studies using this variant as an instrumental variable could help test causality.
Methods and Findings
Nineteen unpublished datasets were obtained (total 48,175 CHD cases and 67,961 controls) in which multiple genetic variants had been measured, including MTHFR C677T. These datasets did not include measurements of blood homocysteine, but homocysteine levels would be expected to be about 20% higher with TT than with CC genotype in the populations studied. In meta-analyses of these unpublished datasets, the case-control CHD odds ratio (OR) and 95% CI comparing TT versus CC homozygotes was 1.02 (0.98–1.07; p = 0.28) overall, and 1.01 (0.95–1.07) in unsupplemented low-folate populations. By contrast, in a slightly updated meta-analysis of the 86 published studies (28,617 CHD cases and 41,857 controls), the OR was 1.15 (1.09–1.21), significantly discrepant (p = 0.001) with the OR in the unpublished datasets. Within the meta-analysis of published studies, the OR was 1.12 (1.04–1.21) in the 14 larger studies (those with variance of log OR<0.05; total 13,119 cases) and 1.18 (1.09–1.28) in the 72 smaller ones (total 15,498 cases).
The CI for the overall result from large unpublished datasets shows lifelong moderate homocysteine elevation has little or no effect on CHD. The discrepant overall result from previously published studies reflects publication bias or methodological problems.
Please see later in the article for the Editors' Summary
Editors' Summary
Coronary heart disease (CHD) is the leading cause of death among adults in developed countries. With age, fatty deposits (atherosclerotic plaques) coat the walls of the coronary arteries, the blood vessels that supply the heart with oxygen and nutrients. The resultant restriction of the heart's blood supply causes shortness of breath, angina (chest pains that are usually relieved by rest), and sometimes fatal heart attacks. Many established risk factors for CHD, including smoking, physical inactivity, being overweight, and eating a fat-rich diet, can be modified by lifestyle changes. Another possible modifiable risk factor for CHD is a high blood level of the amino acid homocysteine. Methylene tetrahydofolate reductase, which is encoded by the MTHFR gene, uses folate to break down and remove homocysteine so fortification of cereals with folate can reduce population homocysteine blood levels. Pooled results from prospective observational studies that have looked for an association between homocysteine levels and later development of CHD suggest that the reduction in homocysteine levels that can be achieved by folate supplementation is associated with an 11% lower CHD risk.
Why Was This Study Done?
Prospective observational studies cannot prove that high homocysteine levels cause CHD because of confounding, the potential presence of other unknown shared characteristics that really cause CHD. However, an approach called “Mendelian randomization” can test whether high blood homocysteine causes CHD. A common genetic variant of the MTHFR gene—the C677T polymorphism—reduces MTHFR efficiency so TT homozygotes (individuals in whom both copies of the MTHFR gene have the nucleotide thymine at position 677; the human genome contains two copies of most genes) have 25% higher blood homocysteine levels than CC homozygotes. In meta-analyses (statistical pooling of the results of several studies) of published Mendelian randomized studies, TT homozygotes have a higher CHD risk than CC homozygotes. Because gene variants are inherited randomly, they are not subject to confounding, so this result suggests that high blood homocysteine causes CHD. But what if only Mendelian randomization studies that found an association have been published? Such publication bias would affect this aggregate result. Here, the researchers investigate the association of the MTHFR C677T polymorphism with CHD in unpublished datasets that have analyzed this polymorphism incidentally during other genetic studies.
What Did the Researchers Do and Find?
The researchers obtained 19 unpublished datasets that contained data on the MTHFR C677T polymorphism in thousands of people with and without CHD. Meta-analysis of these datasets indicates that the excess CHD risk in TT homozygotes compared to CC homozygotes was 2% (much lower than predicted from the prospective observational studies), a nonsignificant difference (that is, it could have occurred by chance). When the probable folate status of the study populations (based on when national folic acid fortification legislation came into effect) was taken into account, there was still no evidence that TT homozygotes had an excess CHD risk. By contrast, in an updated meta-analysis of 86 published studies of the association of the polymorphism with CHD, the excess CHD risk in TT homozygotes compared to CC homozygotes was 15%. Finally, in a meta-analysis of randomized trials on the use of vitamin B supplements for homocysteine reduction, folate supplementation had no significant effect on the 5-year incidence of CHD.
What Do These Findings Mean?
These analyses of unpublished datasets are consistent with lifelong moderate elevation of homocysteine levels having no significant effect on CHD risk. In other words, these findings indicate that circulating homocysteine levels within the normal range are not causally related to CHD risk. The meta-analysis of the randomized trials of folate supplementation also supports this conclusion. So why is there a discrepancy between these findings and those of meta-analyses of published Mendelian randomization studies? The discrepancy is too large to be dismissed as a chance finding, suggest the researchers, but could be the result of publication bias—some studies might have been prioritized for publication because of the positive nature of their results whereas the unpublished datasets used in this study would not have been affected by any failure to publish null results. Overall, these findings reveal a serious example of publication bias and argue against the use of folate supplements as a means of reducing CHD risk.
Additional Information
Please access these Web sites via the online version of this summary at
The American Heart Association provides information about CHD and tips on keeping the heart healthy; it also provides information on homocysteine, folic acid, and CHD, general information on supplements and heart health, and personal stories about CHD
The UK National Health Service Choices website provides information about CHD, including personal stories about CHD
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 CHD (in English and Spanish)
MedlinePlus provides links to many other sources of information on CHD (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)
PMCID: PMC3283559  PMID: 22363213
3.  Renal Function and Risk of Coronary Heart Disease in General Populations: New Prospective Study and Systematic Review 
PLoS Medicine  2007;4(9):e270.
End-stage chronic kidney disease is associated with striking excesses of cardiovascular mortality, but it is uncertain to what extent renal function is related to risk of subsequent coronary heart disease (CHD) in apparently healthy adults. This study aims to quantify the association of markers of renal function with CHD risk in essentially general populations.
Methods and Findings
Estimated glomerular filtration rate (eGFR) was calculated using standard prediction equations based on serum creatinine measurements made in 2,007 patients diagnosed with nonfatal myocardial infarction or coronary death during follow-up and in 3,869 people without CHD in the Reykjavik population-based cohort of 18,569 individuals. There were small and nonsignificant odds ratios (ORs) for CHD risk over most of the range in eGFR, except in the lowest category of the lowest fifth (corresponding to values of <60 ml/min/1.73m2), in which the OR was 1.33 (95% confidence interval 1.01–1.75) after adjustment for several established cardiovascular risk factors. Findings from the Reykjavik study were reinforced by a meta-analysis of six previous reports (identified in electronic and other databases) involving a total of 4,720 incident CHD cases (including Reykjavik), which yielded a combined risk ratio of 1.41 (95% confidence interval 1.19–1.68) in individuals with baseline eGFR less than 60 ml/min/1.73m2 compared with those with higher values.
Although there are no strong associations between lower-than-average eGFR and CHD risk in apparently healthy adults over most of the range in renal function, there may be a moderate increase in CHD risk associated with very low eGFR (i.e., renal dysfunction) in the general population. These findings could have implications for the further understanding of CHD and targeting cardioprotective interventions.
John Danesh and colleagues conclude there may be a moderate increase in risk of coronary heart disease associated with very low estimated glomerular filtration rate.
Editors' Summary
Coronary heart disease (CHD), the leading cause of death in most Western countries, is a “cardiovascular” disease—literally a disorder affecting the heart and/or blood vessels. In CHD, the blood vessels that supply the heart become increasingly narrow. Eventually, the flow of blood to the heart slows or stops, causing chest pains (angina), breathlessness, and heart attacks. Many factors increase the risk of developing CHD and other cardiovascular diseases, including high blood pressure, high blood levels of cholesterol (a type of fat), or being overweight. Individuals can reduce their chances of developing cardiovascular disease by taking drugs to reduce their blood pressure or cholesterol levels or by making lifestyle changes (so-called cardioprotective interventions). Another important risk factor for cardiovascular disease is end-stage chronic kidney disease (CKD), a condition in which the kidneys stop working. (In healthy people, the kidneys remove waste products and excess fluid from the body.) People with end-stage CKD (which is treated by dialysis) have about a five times higher risk of dying from cardiovascular disease compared with healthy people.
Why Was This Study Done?
End-stage CKD is preceded by a gradual loss of kidney function. There is a clear association between non-dialysis–dependent CKD and the incidence of cardiovascular events (such as heart attacks) in people who already have signs of cardiovascular disease. But are people with slightly dysfunctional kidneys (often because of increasing age) but without any obvious cardiovascular disease at greater risk of developing cardiovascular diseases than people with fully functional kidneys? If the answer is yes, it might be possible to reduce CHD deaths by minimizing the exposure of people with CKD to other risk factors for cardiovascular disease. In this study, the researchers have taken two approaches to answer this question. In a population-based study, they have examined whether there is any association in healthy adults between kidney function measured at the start of the study and incident CHD (the first occurrence of CHD) over subsequent years. In addition, they have systematically searched the published literature for similar studies and combined the results of these studies using statistical methods, a so-called “meta-analysis.”
What Did the Researchers Do and Find?
Between 1967 and 1991, nearly 19,000 middle-aged men and women without a history of heart attacks living in Reykjavik, Iceland, enrolled in a prospective study of cardiovascular disease. Baseline blood samples were taken at enrollment and the participants' health monitored for 20 years on average. The researchers identified 2,007 participants who suffered a nonfatal heart attack or died of CHD during follow-up and 3,869 who remained disease free. They then calculated the estimated glomerular filtration rate (eGFR; a measure of kidney function) for each participant from baseline creatinine measurements (creatinine is a muscle waste product). There was no association between lower-than-average eGFRs and the risk of developing CHD over most of the range of eGFR values. However, people whose eGFR was below approximately 60 units had about a 40% higher risk of developing CHD after allowing for established cardiovascular risk factors than individuals with higher eGFRs. This finding was confirmed by the meta-analysis of six previous studies, which included a further 2,700 incident CHD cases.
What Do These Findings Mean?
These findings indicate that people with an eGFR below about 60 units (the cut-off used to define CKD) may have an increased risk of developing CHD. They also indicate a nonliner association between kidney function and CHD risk. That is, any association with CHD became evident only when the eGFR dropped below about 60 units. These findings need confirming in different ethnic groups and by using more accurate methods to measure eGFRs. Nevertheless, they suggest that improving kidney function across the board is unlikely to have much effect on the overall incidence of CHD. Instead, they suggest that targeting cardioprotective interventions at the one in ten adults in Western countries whose eGFR is below 60 units might be a good way to reduce the burden of CHD.
Additional Information.
Please access these Web sites via the online version of this summary at
MedlinePlus encyclopedia pages on coronary heart disease, chronic kidney failure, and end-stage kidney disease (in English and Spanish).
Information for patients and carers from the American Heart Association on all aspects of heart disease, including prevention of CHD
Information from the British Heart Foundation on heart disease and on keeping the heart healthy
Information on chronic kidney disease from the US National Kidney Foundation, and the US National Kidney and Urologic Diseases Information Clearing House (in English and Spanish)
Information on chronic kidney disease from the UK National Kidney Foundation
PMCID: PMC1961630  PMID: 17803353
4.  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.
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.
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
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
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)
PMCID: PMC2843598  PMID: 20351774
5.  Occurrence of symptoms and depressive mood among working-aged coronary heart disease patients 
The typical symptoms of coronary heart disease (CHD), chest pain and breathlessness, are well-known. They are considered quite dramatic, and can thus be fairly reliably mapped by a survey. However, people might have other clearly unpleasant symptoms impairing quality of life. The aim of this study is to evaluate the appearance of these complaints of working-aged people with self-reported CHD.
The study consists of a postal questionnaire of randomly selected Finns in age groups 30–34, 40–44 and 50–54, a response rate of 39% (N = 15,477). The subjects were asked whether or not a doctor had told them that they had angina pectoris or had had myocardial infarction. Four randomly selected age and sex matched controls were chosen for every patient. The occurrence of self-reported dyspnoea, chest pain during anger or other kind of emotion, palpitation and perspiration without physical exercise, irregular heartbeats, flushing, trembling of hands and voice, jerking of muscles, depression and day-time sleepiness were examined. Odds ratios (OR) with 95% confidence intervals (CI), between occurrence of symptoms and CHD with and without heart infarction, were computed by multivariate logistic regression analysis.
The sample eventually comprised 319 CHD patients. Dyspnoea, chest pain during anger or other kind of emotion, palpitation, perspiration without physical exercise, irregular heartbeats daily or almost daily, trembling of hands and voice, and jerking of muscles occurred statistically significantly more frequently among CHD patients than among controls. The CHD patients also reported more depressive mood according to Beck's inventory scores and poorer sleep and more frequent day-time sleepiness than controls. In the multivariate logistic regression analysis chest pain during anger or other kind of emotion (ORs 4.12 and 3.61) and dyspnoea (ORs 2.33 and 3.81) were the symptoms most associated with CHD.
Working-aged people with self-reported coronary heart disease evince a number of symptoms limiting the quality of their every day life. This aspect should be paid attention to when evaluating functional capacity of these patients.
PMCID: PMC534791  PMID: 15533254
6.  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.
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.
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
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
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
PMCID: PMC3389034  PMID: 22802735
7.  Is access to specialist assessment of chest pain equitable by age, gender, ethnicity and socioeconomic status? An enhanced ecological analysis 
BMJ Open  2012;2(3):e001025.
To determine whether access to rapid access chest pain clinics of people with recent onset symptoms is equitable by age, socioeconomic status, ethnicity and gender, according to need.
Retrospective cohort study with ecological analysis.
Patients referred from primary care to five rapid access chest pain clinics in secondary care, across England.
Of 8647 patients aged ≥35 years referred to chest pain clinics with new-onset stable chest pain but no known cardiac history, 7570 with documented census ward codes, age, gender and ethnicity comprised the study group. Patients excluded were those with missing date of birth, gender or ethnicity (n=782) and those with missing census ward codes (n=295).
Outcome measures
Effects of age, gender, ethnicity and socioeconomic status on clinic attendance were calculated as attendance rate ratios, with number of attendances as the outcome and resident population-years as the exposure in each stratum, using Poisson regression. Attendance rate ratios were then compared with coronary heart disease (CHD) mortality ratios to determine whether attendance was equitable according to need.
Adjusted attendance rate ratios for patients aged >65 years were similar to younger patients (1.1, 95% CI 1.05 to 1.16), despite population CHD mortality rate ratios nearly 15 times higher in the older age group. Women had lower attendance rate ratios (0.81, 95% CI 0.77 to 0.84) and also lower population CHD mortality rate ratios compared with men. South Asians had higher attendance rates (1.67, 95% CI 1.57 to 1.77) compared with whites and had a higher standardised CHD mortality ratio of 1.46 (95% CI 1.41 to 1.51). Although univariable analysis showed that the most deprived patients (quintile 5) had an attendance rate twice that of less deprived quintiles, the adjusted analysis showed their attendance to be 13% lower (0.87, 95% CI 0.81 to 0.94) despite a higher population CHD mortality rate.
There is evidence of underutilisation of chest pain clinics by older people and those from lower socioeconomic status. More robust and patient focused administrative pathways need to be developed to detect inequity, correction of which has the potential to substantially reduce coronary mortality.
Article summary
Article focus
Is access to chest pain clinics of people with recent onset symptoms equitable according to local need and consistent with national policy.
Key messages
Need for evaluation in chest pain clinics will vary according to the variable incidence of heart disease in different age, gender, socioeconomic and ethnic groups.
There is evidence of underutilisation of chest pain clinics by older people and those from lower socioeconomic status.
Strengths and limitations of this study
Large, diverse and unselected patient population with uniformly collected patient-level data, allowing robust comparisons between demographic and clinical groups.
Ecological fallacy with respect to age and sex has been avoided by applying an enhanced ecological analysis.
Need to use census wards, not postcodes, as the smallest geographical areas for which mortality and demographic data were available.
Ethnicity was not based on self-ascription.
PMCID: PMC3378943  PMID: 22700834
8.  Impact of socioeconomic status on coronary mortality in people with symptoms, electrocardiographic abnormalities, both or neither: the original Whitehall study 25 year follow up 
OBJECTIVES—To determine the impact of socioeconomic status (SES) on coronary heart disease (CHD) mortality in people with and without prevalent CHD at baseline.
DESIGN—Cohort study with 25 year follow up; prevalent CHD was defined by Q, ST or T wave electrocardiographic (ECG) abnormalities or symptoms (defined by the Rose chest pain questionnaire and self reported doctor diagnosis) or both. SES was defined by four civil service employment grades.
PARTICIPANTS—17 907 male civil servants aged 40-69 years.
MAIN OUTCOME MEASURES—CHD mortality (n=2695 deaths).
RESULTS—The lowest versus highest employment grade was associated with increased CHD mortality (age adjusted hazard ratio 1.56 (95% CI 1.2, 2.1)), prevalence of symptoms and, among symptomatic participants only, the prevalence of Q, ST or T abnormalities. Thirty one per cent of CHD deaths occurred in participants with prevalent CHD at baseline. Among participants without Q, ST or T abnormality employment grade was associated with CHD mortality; the hazard ratios (lowest v highest grade) adjusted for age, systolic and diastolic blood pressure were 1.72 (95% CI 1.4, 2.1) for asymptomatic and 1.52 (95% CI 1.1, 2.1) for symptomatic participants; among participants with Q, ST or T abnormality the corresponding hazard ratios were 1.46 (95% CI 0.7, 2.9) and 1.14 (95% CI 0.6, 2.0) respectively.
CONCLUSIONS—SES was inversely associated with CHD mortality in civil servants with and without prevalent CHD at baseline. Further distinguishing the relative contribution of SES to the initiation and progression of CHD requires repeated measures studies of pre-clinical and clinical measures of CHD.

Keywords: socioeconomic status; coronary mortality
PMCID: PMC1731713  PMID: 10846193
9.  Gender differences in presentation and diagnosis of chest pain in primary care 
BMC Family Practice  2009;10:79.
Chest pain is a common complaint and reason for consultation in primary care. Research related to gender differences in regard to Coronary Heart Disease (CHD) has been mainly conducted in hospital but not in primary care settings. We aimed to analyse gender differences in aetiology and clinical characteristics of chest pain and to provide gender related symptoms and signs associated with CHD.
We included 1212 consecutive patients with chest pain aged 35 years and older attending 74 general practitioners (GPs). GPs recorded symptoms and findings of each patient and provided follow up information. An independent interdisciplinary reference panel reviewed clinical data of every patient and decided about the aetiology of chest pain at the time of patient recruitment. Multivariable regression analysis was performed to identify clinical predictors that help to rule in or out CHD in women and men.
Women showed more psychogenic disorders (women 11,2%, men 7.3%, p = 0.02), men suffered more from CHD (women 13.0%, men 17.2%, p = 0.04), trauma (women 1.8%, men 5.1%, p < 0.001) and pneumonia/pleurisy (women 1.3%, men 3.0%, p = 0.04) Men showed significantly more often chest pain localised on the right side of the chest (women 9.1%, men 25.0%, p = 0.01). For both genders known clinical vascular disease, pain worse with exercise and age were associated positively with CHD. In women pain duration above one hour was associated positively with CHD, while shorter pain durations showed an association with CHD in men. In women negative associations were found for stinging pain and in men for pain depending on inspiration and localised muscle tension.
We found gender differences in regard to aetiology, selected clinical characteristics and association of symptoms and signs with CHD in patients presenting with chest pain in a primary care setting. Further research is necessary to elucidate whether these differences would support recommendations for different diagnostic approaches for CHD according to a patient's gender.
PMCID: PMC2801475  PMID: 20003406
10.  Inducible ischemia and the risk of recurrent cardiovascular events in outpatients with stable coronary heart disease: The Heart and Soul Study 
Archives of internal medicine  2008;168(13):1423-1428.
To compare the prognosis of stable coronary heart disease (CHD) patients with self-reported angina symptoms, inducible ischemia, or both.
Current guidelines do not recommend routine cardiac stress testing in patients with stable CHD unless they report symptoms of angina.
We measured self-reported angina by questionnaire and inducible ischemia using treadmill stress echocardiography in 937 outpatients with stable CHD. We used Cox proportional hazards models to evaluate the independent association of angina and inducible ischemia with CHD events (myocardial infarction or CHD death) during an average 3.9 years of follow-up, adjusted for traditional cardiovascular risk factors.
Of the study participants, 129 (14%) had angina alone, 188 (20%) had inducible ischemia alone, and 40 (4%) had both angina and ischemia. Recurrent CHD events occurred in 7% of participants without angina or inducible ischemia, 10% of those with angina alone, 21% of those with inducible ischemia alone, and 23% of those with both angina and inducible ischemia (p<0.0001). The presence of angina alone was not associated with recurrent CHD events (HR 1.4, 95% CI 0.7–2.9; p=.3). However, the presence of inducible ischemia without self-reported angina strongly predicted recurrent CHD events (HR 2.2, 95% CI, 1.4–3.5; p=.001).
We found that 24% of patients with stable CHD have inducible ischemia and over 80% of these do not report angina. The presence of inducible ischemia without self-reported angina is associated with a greater than 2-fold increased rate of recurrent CHD events.
PMCID: PMC2675881  PMID: 18625923
11.  Role of risk factors for major coronary heart disease events with increasing length of follow up 
Heart  1999;81(4):374-379.
BACKGROUND—It has been suggested that the predictive value of certain risk factors for coronary heart disease (CHD) measured at one point in time diminishes with increasing length of follow up.
DESIGNS AND METHODS—The relation was examined between a wide range of risk factors and the risk of major CHD events over 15 years' total (cumulative) follow up and for three separate five year periods (0-5.0, 5.1-10.0, and 10.1-15.0 years) in men with and without diagnosed CHD in a large prospective study of 7735 men aged 40-59 years.
SETTING—General practices in 24 towns in the UK.
RESULTS—The cumulative CHD event rate for all men was 9.4/1000 person-years for the 15 years of follow up. In men with no recall of a diagnosis of CHD, the established risk factors—serum total cholesterol, high density lipoprotein cholesterol, systolic and diastolic blood pressure, physical activity, body mass index (BMI), alcohol intake, diabetes mellitus, parental history, and evidence of CHD on chest pain questionnaire or on ECG—were predictive of CHD events occurring in the three specific periods after baseline measurement. Blood pressure (systolic and diastolic) was still predictive of events occurring 10.1-15.0 years later with some attenuation in the relative risk associated with systolic blood pressure. The risks associated with blood glucose and serum insulin concentration, factors measured with greater imprecision, attenuated with longer follow up and were not predictive of events occurring 10.1-15.0 years later. In men with recall of diagnosed CHD, the absolute risk was very high (38.8/1000 person-years); only cigarette smoking, BMI, total cholesterol, and serum insulin were predictive of CHD events occurring 10.1-15.0 years later. 
CONCLUSION—In men without recall of diagnosed CHD most major risk factors measured in middle age predict risk of CHD events occurring in up to 15 years of follow up, both cumulatively and in the three separate five year periods. Risk factors measured at one point in time in middle age may be regarded as reliable indicators for long term prognosis of major CHD events on a group basis, despite the changes that may take place in these risk factors in some individuals during prolonged follow up.

 Keywords: coronary heart disease, risk factors; epidemiology
PMCID: PMC1729008  PMID: 10092563
12.  Coronary heart disease: prevalence and dietary sugars in Scotland. 
STUDY OBJECTIVE--The aim was to investigate the effects of dietary intakes of different types of sugars (extrinsic, intrinsic, and lactose) and the dietary fat to sugar ratio on prevalent coronary heart disease (CHD). DESIGN--This was a baseline cross sectional survey of CHD risk factors. SETTING--Twenty two Scottish health districts were surveyed between 1984 and 1986. PARTICIPANTS--A total of 10,359 men and women aged 40-59 years were screened as part of the Scottish Heart Health Study, and a further 1267 men and women aged 25-39 and 60-64 years were screened as part of the Scottish MONICA (monitoring trends and determinants in cardiovascular disease) Study. The response rates were 74% and 64% respectively. METHODS--Subjects completed a questionnaire which included sociodemographic, health, and food frequency information. Medical history, response to the Rose chest pain questionnaire, and results of a 12 lead ECG recording were used to categorize subjects into CHD diagnosed, previously CHD undiagnosed, or no CHD groups. The chi 2 statistic was used to determine whether the CHD groups differed in their sugar consumption, and multiple logistic regression analysis, with adjustment for other potential coronary risk factors, was used to calculate odds ratios for prevalent CHD by intake fifths of dietary sugars. MAIN RESULTS--Men, but not women, differed in their sugar consumption by CHD group. The odds ratios showed a tendency for a U shaped relationship for extrinsic sugar intake with CHD prevalence, but no significant effect of the fat to sugar ratio (possible marker of obesity) on CHD was seen. CONCLUSIONS--The results suggest that neither extrinsic sugar, intrinsic sugar, nor the fat to sugar ratio are significant independent predictors of prevalent CHD in the Scottish population, when the other major risk factors such as cigarette smoking, blood cholesterol concentration, and antioxidant vitamins intake are accounted for. These new data for different sugar types agree with the consensus view that total sugar intake is not a major marker of coronary heart disease.
PMCID: PMC1059918  PMID: 8189163
13.  Performance of the WHO Rose angina questionnaire in post-menopausal women: Are all of the questions necessary? 
Objective: To assess the performance of a shortened version of the Rose angina questionnaire focusing on exertional chest pain.
Methods: Cross sectional analysis of 3987 women aged 60 to 79 years from 23 British towns. The performances of definite Rose angina (using data from the full Rose angina questionnaire) and exertional chest pain (using data from a subset of three questions from the Rose angina questionnaire) were assessed against a medical record of angina.
Results: The sensitivity (the proportion with a medical record of angina who were identified as having angina by the questionnaire) was 29.9% (95% confidence intervals 25.7% to 34.4%) comparing definite Rose angina to any medical record of angina since 1978 and 50.7% (45.9% to 55.5%) comparing exertional chest pain to any medical record diagnosis of angina. The positive predictive values of both questionnaires were similar. When the two questionnaires were compared with a gold standard of a primary care consultation for angina symptoms within the past five years the sensitivity of definite Rose angina was 33.0% (26.9% to 39.6%) and that of exertional chest pain was 51.8% (45.1% to 58.5%). Although the sensitivity of both versions of the questionnaire was greater in those aged 60–69 years compared with those aged 70–79 years, it remained higher in the exertional chest pain version of the questionnaire than for definite Rose angina based on the full version of the questionnaire in both age groups. Performance of either version of the questionnaire was not affected by occupational social class.
Conclusions: With respect to identifying women with a medical diagnosis of angina or those presenting to primary care with anginal symptoms, these results suggest that a shortened version of the Rose angina questionnaire focusing on exertional chest pain performs better than the full version. Other studies suggest that exertional chest pain is the crucial element of the Rose angina questionnaire with respect to predicting future coronary events. It is concluded that using a shortened version of the Rose angina questionnaire is adequate in epidemiological studies.
PMCID: PMC1732510  PMID: 12821705
14.  Markers of Dysglycaemia and Risk of Coronary Heart Disease in People without Diabetes: Reykjavik Prospective Study and Systematic Review 
PLoS Medicine  2010;7(5):e1000278.
Associations between circulating markers of dysglycaemia and coronary heart disease (CHD) risk in people without diabetes have not been reliably characterised. We report new data from a prospective study and a systematic review to help quantify these associations.
Methods and Findings
Fasting and post-load glucose levels were measured in 18,569 participants in the population-based Reykjavik study, yielding 4,664 incident CHD outcomes during 23.5 y of mean follow-up. In people with no known history of diabetes at the baseline survey, the hazard ratio (HR) for CHD, adjusted for several conventional risk factors, was 2.37 (95% CI 1.79–3.14) in individuals with fasting glucose ≥7.0 mmol/l compared to those <7 mmol/l. At fasting glucose values below 7 mmol/l, adjusted HRs were 0.95 (0.89–1.01) per 1 mmol/l higher fasting glucose and 1.03 (1.01–1.05) per 1 mmol/l higher post-load glucose. HRs for CHD risk were generally modest and nonsignificant across tenths of glucose values below 7 mmol/l. We did a meta-analysis of 26 additional relevant prospective studies identified in a systematic review of Western cohort studies that recorded fasting glucose, post-load glucose, or glycated haemoglobin (HbA1c) levels. In this combined analysis, in which participants with a self-reported history of diabetes and/or fasting blood glucose ≥7 mmol/l at baseline were excluded, relative risks for CHD, adjusted for several conventional risk factors, were: 1.06 (1.00–1.12) per 1 mmol/l higher fasting glucose (23 cohorts, 10,808 cases, 255,171 participants); 1.05 (1.03–1.07) per 1 mmol/l higher post-load glucose (15 cohorts, 12,652 cases, 102,382 participants); and 1.20 (1.10–1.31) per 1% higher HbA1c (9 cohorts, 1639 cases, 49,099 participants).
In the Reykjavik Study and a meta-analysis of other Western prospective studies, fasting and post-load glucose levels were modestly associated with CHD risk in people without diabetes. The meta-analysis suggested a somewhat stronger association between HbA1c levels and CHD risk.
Please see later in the article for the Editors' Summary
Editors' Summary
Among people diagnosed with type 2 diabetes mellitus (the commonest type of diabetes worldwide), poor management or lack of appropriate treatment can lead to long-term complications resulting from persistently high sugar levels in the blood. The long-term complications of type 2 diabetes are generally divided into two main groups: microvascular problems (such as nerve damage, kidney disease, and eye disorders), and macrovascular disease (such as heart disease, strokes, and peripheral vascular disease). A major goal of diabetes treatment is to keep glucose control as normal as possible through diet, weight control, exercise, and pharmacological treatments. However, it is unclear whether the link between high blood sugar and macrovascular disease (principally heart disease and strokes) also holds for people who have slightly higher than normal blood sugar levels, but in whom this level does not reach the diabetic threshold. Some previous research studies have suggested that a continuous relationship exists between blood sugar level and the risk of heart disease across the spectrum, i.e., below the diabetic threshold as well as above it. If such a relationship were confirmed this might have important implications for the management of high blood sugar levels even among people who would not normally meet the usual definition for a diagnosis of diabetes (the “diabetic threshold”).
Why Was This Study Done?
Studies which examine the risk of serious, but relatively common, outcomes (such as a nonfatal heart attack or fatal heart disease), often suffer from insufficient statistical power: a large number of participants need to be recruited, and followed up over a long time, to find out whether certain factors measured at baseline (e.g., fasting glucose) are indeed associated with a particular outcome (e.g., heart attack) or not during follow up. Given the inconclusive nature of some previous studies in this area, the researchers who carried out this work wanted to gather evidence from a large prospective cohort, and a reappraisal of all existing evidence, in relation to the possible link between high blood sugar and risk of heart disease in people without diabetes.
What Did the Researchers Do and Find?
In this study, the researchers report results from a prospective population-based study (in which participants are followed forward in time) from Reykjavik, Iceland. In the study, men and women without history of heart disease aged between 31 and 57 in 1966 were first invited to join the cohort, and were followed forward in time using national registries that recorded deaths (and causes of death), and incidence of heart disease. A total of 8,888 male and 9,681 female participants were recruited. At baseline, laboratory measurements were taken to record blood sugar levels using two different methods: fasting blood glucose and post-load glucose. Among the group of participants, 4,664 people were recorded as having either a nonfatal heart attack or fatal heart disease, during approximately 23 years of follow-up. In addition, the researchers attempted to identify from the published medical literature previous prospective studies conducted in Western populations that had looked at the association between blood sugar levels and risk of coronary heart disease. They requested, and obtained, re-analyses of data conducted in accordance with a common protocol for most of the identified studies and then analysed these, together with the results of the Reykjavik cohort, to produce a summary estimate (meta-analysis) of the association between blood sugar levels and risk of coronary heart disease in people without diabetes.
In the Reykjavik cohort, the researchers confirmed an increased risk of coronary heart disease among individuals with blood sugar above the diabetic threshold, as compared to those below it. However, when they looked at blood sugar in people below the diabetic threshold, they found no evidence that higher levels were strongly linked with greater risk of coronary heart disease. This held for both methods of measuring blood sugar levels (fasting and post-load).
In the meta-analysis, the researchers obtained data for 27 different studies, comprising 303,961 participants and 16,982 cases of heart disease. In this meta-analysis, very small increases in risk of heart disease were found with higher levels of blood sugar, when measured using fasting blood glucose or post-load glucose. However, studies using glycated haemoglobin (a measure of average sugar levels over the past 1–3 months or so) found this measure to be associated with a somewhat higher risk of heart disease.
What Do these Findings Mean?
In this prospective cohort and wider meta-analysis, the researchers did not find evidence of a strong or continuous association between blood sugar levels and risk of heart disease amongst people without diabetes. The prospective study, and analysis of other cohorts, was large, but only looked at participants of European decent, so it is not clear whether the findings will also hold for non-European groups.
Additional Information
Please access these Web sites via the online version of this summary at
Information is available from the US National Diabetes Information Clearinghouse about diabetes, heart disease, and stroke
Centers for Disease Control provides information for the public and professionals about diabetes on their diabetes minisite
Medline Plus encyclopedia has an entry about coronary heart disease
PMCID: PMC2876150  PMID: 20520805
15.  Women and Non-Cardiac Chest Pain: Gender Differences in Symptom Presentation 
Archives of women's mental health  2008;11(4):287-293.
A substantial number of individuals evaluated for complaints of chest pain do not suffer from coronary heart disease (CHD). Studies show that many patients who complain of symptoms that might be caused by CHD, such as shortness of breath or chest pain, may actually have an anxiety disorder. Gender differences in how patients present with these symptoms have not been adequately explored. The purpose of this study was to explore possible gender differences in the presentation of patients with CHD-like symptoms. Two groups were examined, one comprising 6,381 individuals self-referred for electron beam tomography (EBT) studies and a subset of these individuals who defined a “low-risk” group based on the absence of risk factors for CHD and low coronary artery calcium (CAC) scores. We explored gender differences in symptom presentation in each group after controlling for relevant variables by using logistic regression models.
These analyses showed that women were significantly more likely than men to endorse CHD symptoms that might also be caused by an anxiety disorder. Women in the low risk group reported CHD symptoms also referable to anxiety more often than men, but unlike men did not complain primarily of chest pain. Women were also more likely to have been prescribed antianxiety or antidepressant medication. In previous studies, non-cardiac chest pain has been considered a hallmark of anxiety in individuals seen in medical settings. This study suggests that in individuals with low risk for CHD chest pain was not related to gender, but other anxiety-related symptoms including heart flutter, lightheadedness, nausea, and shortness of breath were more likely to be reported in women than in men.
PMCID: PMC2574964  PMID: 18592345
Non-cardiac chest pain; anxiety; coronary heart disease; gender; symptom
16.  Does the patient with chest pain have a coronary heart disease? Diagnostic value of single symptoms and signs – a meta-analysis 
Croatian Medical Journal  2012;53(5):432-441.
To determine the diagnostic value of single symptoms and signs for coronary heart disease (CHD) in patients with chest pain.
Searches of two electronic databases (EMBASE 1980 to March 2008, PubMed 1970 to May 2009) and hand searching in seven journals were conducted. Eligible studies recruited patients presenting with acute or chronic chest pain. The target disease was CHD, with no restrictions regarding case definitions, eg, stable CHD, acute coronary syndrome (ACS), acute myocardial infarction (MI), or major cardiac event (MCE). Diagnostic tests of interest were items of medical history and physical examination. Bivariate random effects model was used to derive summary estimates of positive (pLR) and negative likelihood ratios (nLR).
We included 172 studies providing data on the diagnostic value of 42 symptoms and signs. With respect to case definition of CHD, diagnostically most useful tests were history of CHD (pLR = 3.59), known MI (pLR = 3.21), typical angina (pLR = 2.35), history of diabetes mellitus (pLR = 2.16), exertional pain (pLR = 2.13), history of angina pectoris (nLR = 0.42), and male sex (nLR = 0.49) for diagnosing stable CHD; pain radiation to right arm/shoulder (pLR = 4.43) and palpitation (pLR = 0.47) for diagnosing MI; visceral pain (pLR = 2.05) for diagnosing ACS; and typical angina (pLR = 2.60) and pain reproducible by palpation (pLR = 0.13) for predicting MCE.
We comprehensively reported the accuracy of a broad spectrum of single symptoms and signs for diagnosing myocardial ischemia. Our results suggested that the accuracy of several symptoms and signs varied in the published studies according to the case definition of CHD.
PMCID: PMC3490454  PMID: 23100205
17.  New and known type 2 diabetes as coronary heart disease equivalent: results from 7.6 year follow up in a middle east population 
To investigate whether the known diabetes mellitus (KDM) or newly diagnosed diabetes mellitus (NDM) could be regarded as a coronary heart disease (CHD) risk equivalent among a relatively young Middle East population with high prevalence of diabetes mellitus (DM).
A population based cohort study of 2267 men and 2931 women, aged ≥ 30 years. Prior CHD was defined as self-reported or ECG positive CHD at baseline, KDM as subjects using any kind of glucose-lowering medications and NDM according to fasting plasma glucose and 2-h postchallenge glycemia.
Participants were categorized to six groups according to the presence of known or newly diagnosed DM and CHD at baseline (DM-/CHD-, DM-/CHD+, NDM+/CHD-, NDM+/CHD+, KDM+/CHD-, KDM+/CHD+) and Cox regression analysis were used to estimate the hazard ratio (HR) of CHD events for these DM/CHD groups, given DM-/CHD-as the reference.
During 7.6-year follow up, 358 CHD events occurred. After controlling traditional risk factors, HRs of CHD events for DM-/CHD+ group were 2.1 (95% CI: 1.4-3.1) and 5.2 (3.2-8.3) in men and women respectively. Corresponding HRs for NDM+/CHD-were 1.7 (1.1-2.7) and 3.1 (1.8-5.6) and for KDM+/CHD-were 1.7 (0.9-3.3) and 6.2 (3.6-10.6) in men and women respectively. The HRs for NDM+/CHD+ and KDM+/CHD+ groups (i.e. participants with history of both diabetes and CHD) were 6.4 (3.2-12.9) and 8.0 (4.3-14.8) in women and 3.2 (1.9-5.6) and 4.2 (2.2-7.8) in men, respectively.
The hazard of CHD events did not differ between KDM+/CHD-and DM-/CHD+ in both genders using paired homogeneity test, however the HR for NDM+/CHD-was marginally lower than the HR for DM-/CHD+ in women (p = 0.085).
KDM patients in both genders and NDM especially in men exhibited a CHD risk comparable to nondiabetics with a prior CHD, furthermore diabetic subjects with prior CHD had the worst prognosis, by far more harmful in women than men; reinforcing the urgent need for intensive care and prophylactic treatment for cardiovascular diseases.
PMCID: PMC3016329  PMID: 21129219
18.  Is the prevalence of coronary heart disease falling in British men? 
Heart  2001;86(5):499-505.
OBJECTIVE—To assess whether long term trends over time in acute coronary heart disease (CHD) event rates have influenced the burden of prevalent CHD in British men.
DESIGN—Longitudinal cohort study.
PARTICIPANTS—7735 men, aged 40-59 at entry (1978-80), selected from 24 British towns.
METHODS—The prevalences of current angina symptoms and history of diagnosed CHD were ascertained by questionnaire in 1978-80, 1983-85, 1992, and 1996. New major CHD events (fatal and non-fatal) were ascertained throughout the study from National Health Service central registers and general practice record reviews. Age adjusted trends in CHD prevalence were compared with trends in major CHD event rates.
RESULTS—From 1978-1996 there was a clear decline in the prevalence of current angina symptoms: the age adjusted annual percentage change in odds was -1.8% (95% confidence interval (CI) -2.8% to -0.8%). However, there was no evidence of a trend in the prevalence of history of diagnosed CHD (annual change in odds 0.1%, 95% CI -1.0% to 1.2%). Over the same period, the CHD mortality rate fell substantially (annual change -4.1%, 95% CI -6.5% to -1.6%); rates of non-fatal myocardial infarction, all major CHD events, and first major CHD event fell by -1.7% (95% CI -3.9% to 0.5%), -2.5% (95% CI -4.1% to -0.8%), and -2.4% (95% CI% -4.3 to -0.4%), respectively.
CONCLUSIONS—These results suggest that middle aged British men are less likely to experience symptoms of angina than in previous decades but are just as likely to have a history of diagnosed CHD. Despite falling rates of new major events and falling symptom prevalence, the need for secondary prevention among middle aged men with established CHD is as great as ever.

Keywords: coronary heart disease; angina; prevalence; trends
PMCID: PMC1729960  PMID: 11602539
19.  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.
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).
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
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
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)
PMCID: PMC2288623  PMID: 18399716
20.  Use of global coronary heart disease risk assessment in practice: a cross-sectional survey of a sample of U.S. physicians 
Global coronary heart disease (CHD) risk assessment is recommended to guide primary preventive pharmacotherapy. However, little is known about physicians' understanding and use of global CHD risk assessment. Our objective was to examine US physicians' awareness, use, and attitudes regarding global CHD risk assessment in clinical practice, and how these vary by provider specialty.
Using a web-based survey of US family physicians, general internists, and cardiologists, we examined awareness of tools available to calculate CHD risk, method and use of CHD risk assessment, attitudes towards CHD risk assessment, and frequency of using CHD risk assessment to guide recommendations of aspirin, lipid-lowering and blood pressure (BP) lowering therapies for primary prevention. Characteristics of physicians indicating they use CHD risk assessments were compared in unadjusted and adjusted analyses.
A total of 952 physicians completed the questionnaire, with 92% reporting awareness of tools available to calculate CHD global risk. Among those aware of such tools, over 80% agreed that CHD risk calculation is useful, improves patient care, and leads to better decisions about recommending preventive therapies. However, only 41% use CHD risk assessment in practice. The most commonly reported barrier to CHD risk assessment is that it is too time consuming. Among respondents who calculate global CHD risk, 69% indicated they use it to guide lipid lowering therapy recommendations; 54% use it to guide aspirin therapy recommendations; and 48% use it to guide BP lowering therapy. Only 40% of respondents who use global CHD risk routinely tell patients their risk. Use of a personal digital assistant or smart phone was associated with reported use of CHD risk assessment (adjusted OR 1.58; 95% CI 1.17-2.12).
Reported awareness of tools to calculate global CHD risk appears high, but the majority of physicians in this sample do not use CHD risk assessments in practice. A minority of physicians in this sample use global CHD risk to guide prescription decisions or to motivate patients. Educational interventions and system improvements to improve physicians' effective use of global CHD risk assessment should be developed and tested.
PMCID: PMC3292915  PMID: 22273080
21.  The UPBEAT Nurse-Delivered Personalized Care Intervention for People with Coronary Heart Disease Who Report Current Chest Pain and Depression: A Randomised Controlled Pilot Study 
PLoS ONE  2014;9(6):e98704.
Depression is common in people with coronary heart disease (CHD) and associated with worse outcome. This study explored the acceptability and feasibility of procedures for a trial and for an intervention, including its potential costs, to inform a definitive randomized controlled trial (RCT) of a nurse-led personalised care intervention for primary care CHD patients with current chest pain and probable depression.
Multi-centre, outcome assessor-blinded, randomized parallel group study. CHD patients reporting chest pain and scoring 8 or more on the HADS were randomized to personalized care (PC) or treatment as usual (TAU) for 6 months and followed for 1 year. Primary outcome was acceptability and feasibility of procedures; secondary outcomes included mood, chest pain, functional status, well being and psychological process variables.
1001 people from 17 General Practice CHD registers in South London consented to be contacted; out of 126 who were potentially eligible, 81 (35% female, mean age = 65 SD11 years) were randomized. PC participants (n = 41) identified wide ranging problems to work on with nurse-case managers. Good acceptability and feasibility was indicated by low attrition (9%), high engagement and minimal nurse time used (mean/SD = 78/19 mins assessment, 125/91 mins telephone follow up). Both groups improved on all outcomes. The largest between group difference was in the proportion no longer reporting chest pain (PC 37% vs TAU 18%; mixed effects model OR 2.21 95% CI 0.69, 7.03). Some evidence was seen that self efficacy (mean scale increase of 2.5 vs 0.9) and illness perceptions (mean scale increase of 7.8 vs 2.5) had improved in PC vs TAU participants at 1 year. PC appeared to be more cost effective up to a QALY threshold of approximately £3,000.
Trial and intervention procedures appeared to be feasible and acceptable. PC allowed patients to work on unaddressed problems and appears cheaper than TAU.
Trial Registration ISRCTN21615909
PMCID: PMC4047012  PMID: 24901956
22.  Perceptions of Coronary Heart Disease Risk in Korean Immigrants with Type 2 Diabetes 
The Diabetes educator  2008;34(3):484-492.
The purpose of this study was to examine coronary heart disease (CHD) risk perception, risk factor status, and factors associated with CHD risk perception in Korean immigrants with type 2 diabetes mellitus.
A community sample of 143 Korean adults with type 2 diabetes, aged 30 to 80 years old, completed questionnaires and biological measures. A multiple regression analysis was conducted to evaluate the relationships between CHD knowledge, general health, smoking, medications for CHD risk factors, demographic variables (independent variables) and the perception of CHD risk (dependent variable).
Participants had low perception of CHD risk, with most (76.9%) indicating their risk to be the same or lower than people of the same age and sex in the the general population. Overall, CHD risk- factor control was suboptimal according to American Diabetes Association guidelines. Only 41.3% of participants met the HbA1c goal of less than 7%. More than half (55%) had uncontrolled blood pressure, and a similar proportion (53.6%) had higher low density lipoprotein cholesterol than the target goal. CHD knowledge and self-reported general health influenced the perception of CHD risk. More CHD knowledge and poor general health were associated with higher perception of CHD risk.
To increase the perception of CHD risk in Korean immigrants with type 2 diabetes, diabetes educators and clinicians should educate such patients about CHD risk factors and discuss their risk status at every visit. Those who report their health to be good deserve particular attention.
PMCID: PMC3795773  PMID: 18535321
type 2 diabetes mellitus; coronary heart disease; risk factors; risk perception; immigrant; Korean Americans
23.  History of kidney stones and risk of coronary heart disease 
Kidney stone disease is common and may be associated with an increased risk of coronary heart disease (CHD). However, previous studies of the association between kidney stones and CHD have often not controlled for important risk factors, and the results have been inconsistent.
We examined the association between a history of kidney stones and the risk of CHD in three large prospective cohorts.
Design, setting, and participants
Prospective study of 45,748 men and 196,357 women in the United States without a history of CHD at baseline who were participants in the Health Professionals Follow-Up Study (HPFS, 51,529 men aged 40–75 years followed since 1986), Nurses’ Health Study (NHS) I (121,700 women aged 30–55 years followed since 1976) and II (116,430 women aged 25–42 years followed since 1989). The diagnoses of kidney stones and CHD were updated biennially during follow-up.
Main outcome measure
CHD was defined as fatal or non-fatal myocardial infarction (MI) or coronary revascularization. The outcome was identified by biennial questionnaires and confirmed through review of medical records (fatal and non-fatal MI).
Out of a total of 242,105 participants, 19,678 reported a history of kidney stones. After up to 24 years of follow-up in men and 18 years in women, 16,838 incident cases of CHD occurred. After adjusting for potential confounders, among women, those with a reported history of kidney stones compared with those without had an increased risk of CHD in NHS I (incidence rate (IR) 754 vs 514/100,000 person-years; multivariate HR 1.18, 95% CI 1.08 to 1.28) and NHS II (IR 144 vs 55/100,000 person-years; multivariate HR 1.48, 95% CI 1.23 to 1.78); there was no significant association in men (IR 1,355 vs 1,022/100,000 person-years; multivariate HR 1.06, 95% CI 0.99 to 1.13). Similar results were found when analyzing the individual end-points (fatal and non-fatal MI, revascularization).
Among two cohorts of women, a history of kidney stones was associated with a modest but statistically significant increased risk of CHD; there was no significant association in a separate cohort of men. Further research is needed to determine whether the association is sex-specific.
PMCID: PMC4019927  PMID: 23917291
24.  Independent Associations of Fasting Insulin, Glucose, and Glycated Haemoglobin with Stroke and Coronary Heart Disease in Older Women 
PLoS Medicine  2007;4(8):e263.
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.
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
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
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
PMCID: PMC1952205  PMID: 17760500
25.  Informal Caregiving and the Risk for Coronary Heart Disease: The Whitehall II Study 
The stress associated with informal caregiving has been shown to be associated with poor health, including coronary heart disease (CHD). However, it is unclear if the risk of CHD is attributable to caregiving or prior poor health of the caregiver.
We used data from the Whitehall II cohort study. Caregiving and caregiver’s health (using 3 measures: self-rated health, mental health using the General Health Questionnaire, and physical component score of the SF-36) were assessed in 1991–1993 among 5,468 men and 2,457 women aged 39–63 years. CHD (fatal CHD, clinically verified nonfatal myocardial infarction, and definite angina) incidence was recorded for a mean 17 years; sociodemographic variables, health behaviors, and cardiovascular risk factors were included as covariates.
Cox regression showed the risk of CHD in caregivers not to be higher (hazard ratio = 1.18; 95% CI: 0.96, 1.45) compared with noncaregivers. Analyses stratified by health status showed that compared with noncaregivers in good health, caregivers with poor self-rated (hazard ratio = 2.00; 95% CI: 1.44, 2.78), mental (hazard ratio = 1.63; 95% CI: 1.16, 2.30), or physical (hazard ratio =1.87; 95% CI: 1.34, 2.62) health had greater risk of CHD. A similar elevated risk was observed in noncaregivers with poor health; no excess risk was observed among caregivers reporting good health, and the combined effect of poor health and caregiving did not exceed their independent effects.
Caregiving in midlife is not in itself associated with greater risk of CHD, but it is associated with increased risk for CHD among caregivers who report being in poor health.
PMCID: PMC3779628  PMID: 23525476
Coronary heart disease; Stress; Caregiver.

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