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1.  Mitochondrial DNA haplogroups and risk of transient ischaemic attack and ischaemic stroke: a genetic association study 
Lancet Neurology  2010;9(5):498-503.
Genetic factors have a role in the pathogenesis of ischaemic stroke, but the main genes involved have yet to be defined. Mitochondrial mechanisms have been implicated in the pathophysiology of acute stroke, but the role of mitochondrial DNA (mtDNA) has not been comprehensively studied. We investigated whether there is an association between mtDNA haplotypes and incidence of stroke.
The major European mtDNA haplogroups were identified in two independent subpopulations (n=950) from a study of occurrence of transient ischaemic attack (TIA) and ischaemic stroke and were compared with those of patients with acute coronary syndromes from the same populations (n=340) and with those of independent population controls (n=2939).
The presence of mtDNA sub-haplogroup K was significantly less frequent in patients with TIA or stroke than in controls in both subpopulations separately and in a pooled analysis (odds ratio 0·54, 95% CI 0·39–0·75, p<0·00001). This association remained highly significant after adjustment for multiple haplogroup comparisons. The association was significant for patients with TIA and stroke separately and was independent of known risk factors, but was not found for patients with acute coronary events. The mtDNA sub-haplogroup K was present in 8·7% of the total UK population controls and therefore confers a 4·0% (95% CI 2·2–5·7) reduction in population attributable risk of TIA and stroke.
Genetic variation of mtDNA sub-haplogroup K is an independent determinant of risk of cerebral, but not coronary, ischaemic vascular events. These findings implicate mitochondrial mechanisms in the aetiology of ischaemic stroke and provide a new means for the identification of individuals with a high susceptibility of developing ischaemic stroke.
Medical Research Council UK, National Institute of Health Research (NIHR), the Stroke Association, the Dunhill Medical Trust, the NIHR-funded Oxford Biomedical Research Centre, the NIHR-funded Newcastle Biomedical Research Centre in Ageing, and the Wellcome Trust.
PMCID: PMC2855429  PMID: 20362514
2.  Y-chromosome Short Tandem Repeat Intermediate Variant Alleles DYS392.2, DYS449.2, and DYS385.2 Delineate New Phylogenetic Substructure in Human Y-chromosome Haplogroup Tree 
Croatian Medical Journal  2009;50(3):239-249.
To determine the human Y-chromosome haplogroup backgrounds of intermediate-sized variant alleles displayed by short tandem repeat (STR) loci DYS392, DYS449, and DYS385, and to evaluate the potential of each intermediate variant to elucidate new phylogenetic substructure within the human Y-chromosome haplogroup tree.
Molecular characterization of lineages was achieved using a combination of Y-chromosome haplogroup defining binary polymorphisms and up to 37 short tandem repeat loci. DNA sequencing and median-joining network analyses were used to evaluate Y-chromosome lineages displaying intermediate variant alleles.
We show that DYS392.2 occurs on a single haplogroup background, specifically I1*-M253, and likely represents a new phylogenetic subdivision in this European haplogroup. Intermediate variants DYS449.2 and DYS385.2 both occur on multiple haplogroup backgrounds, and when evaluated within specific haplogroup contexts, delineate new phylogenetic substructure, with DYS449.2 being informative within haplogroup A-P97 and DYS385.2 in haplogroups D-M145, E1b1a-M2, and R1b*-M343. Sequence analysis of variant alleles observed within the various haplogroup backgrounds showed that the nature of the intermediate variant differed, confirming the mutations arose independently.
Y-chromosome short tandem repeat intermediate variant alleles, while relatively rare, typically occur on multiple haplogroup backgrounds. This distribution indicates that such mutations arise at a rate generally intermediate to those of binary markers and Y-STR loci. As a result, intermediate-sized Y-STR variants can reveal phylogenetic substructure within the Y-chromosome phylogeny not currently detected by either binary or Y-STR markers alone, but only when such variants are evaluated within a haplogroup context.
PMCID: PMC2702739  PMID: 19480020
3.  Job strain as a risk factor for coronary heart disease: a collaborative meta-analysis of individual participant data 
Lancet  2012;380(9852):1491-1497.
Published work assessing psychosocial stress (job strain) as a risk factor for coronary heart disease is inconsistent and subject to publication bias and reverse causation bias. We analysed the relation between job strain and coronary heart disease with a meta-analysis of published and unpublished studies.
We used individual records from 13 European cohort studies (1985–2006) of men and women without coronary heart disease who were employed at time of baseline assessment. We measured job strain with questions from validated job-content and demand-control questionnaires. We extracted data in two stages such that acquisition and harmonisation of job strain measure and covariables occurred before linkage to records for coronary heart disease. We defined incident coronary heart disease as the first non-fatal myocardial infarction or coronary death.
30 214 (15%) of 197 473 participants reported job strain. In 1·49 million person-years at risk (mean follow-up 7·5 years [SD 1·7]), we recorded 2358 events of incident coronary heart disease. After adjustment for sex and age, the hazard ratio for job strain versus no job strain was 1·23 (95% CI 1·10–1·37). This effect estimate was higher in published (1·43, 1·15–1·77) than unpublished (1·16, 1·02–1·32) studies. Hazard ratios were likewise raised in analyses addressing reverse causality by exclusion of events of coronary heart disease that occurred in the first 3 years (1·31, 1·15–1·48) and 5 years (1·30, 1·13–1·50) of follow-up. We noted an association between job strain and coronary heart disease for sex, age groups, socioeconomic strata, and region, and after adjustments for socioeconomic status, and lifestyle and conventional risk factors. The population attributable risk for job strain was 3·4%.
Our findings suggest that prevention of workplace stress might decrease disease incidence; however, this strategy would have a much smaller effect than would tackling of standard risk factors, such as smoking.
Finnish Work Environment Fund, the Academy of Finland, the Swedish Research Council for Working Life and Social Research, the German Social Accident Insurance, the Danish National Research Centre for the Working Environment, the BUPA Foundation, the Ministry of Social Affairs and Employment, the Medical Research Council, the Wellcome Trust, and the US National Institutes of Health.
PMCID: PMC3486012  PMID: 22981903
4.  Genome-Wide Study of Gene Variants Associated with Differential Cardiovascular Event Reduction by Pravastatin Therapy 
PLoS ONE  2012;7(5):e38240.
Statin therapy reduces the risk of coronary heart disease (CHD), however, the person-to-person variability in response to statin therapy is not well understood. We have investigated the effect of genetic variation on the reduction of CHD events by pravastatin. First, we conducted a genome-wide association study of 682 CHD cases from the Cholesterol and Recurrent Events (CARE) trial and 383 CHD cases from the West of Scotland Coronary Prevention Study (WOSCOPS), two randomized, placebo-controlled studies of pravastatin. In a combined case-only analysis, 79 single nucleotide polymorphisms (SNPs) were associated with differential CHD event reduction by pravastatin according to genotype (P<0.0001), and these SNPs were analyzed in a second stage that included cases as well as non-cases from CARE and WOSCOPS and patients from the PROspective Study of Pravastatin in the Elderly at Risk/PHArmacogenomic study of Statins in the Elderly at risk for cardiovascular disease (PROSPER/PHASE), a randomized placebo controlled study of pravastatin in the elderly. We found that one of these SNPs (rs13279522) was associated with differential CHD event reduction by pravastatin therapy in all 3 studies: P = 0.002 in CARE, P = 0.01 in WOSCOPS, P = 0.002 in PROSPER/PHASE. In a combined analysis of CARE, WOSCOPS, and PROSPER/PHASE, the hazard ratio for CHD when comparing pravastatin with placebo decreased by a factor of 0.63 (95% CI: 0.52 to 0.75) for each extra copy of the minor allele (P = 4.8×10−7). This SNP is located in DnaJ homolog subfamily C member 5B (DNAJC5B) and merits investigation in additional randomized studies of pravastatin and other statins.
PMCID: PMC3364212  PMID: 22666496
5.  Y chromosome haplogroups and prostate cancer in populations of European and Ashkenazi Jewish ancestry 
Human Genetics  2012;131(7):1173-1185.
Genetic variation on the Y chromosome has not been convincingly implicated in prostate cancer risk. To comprehensively analyze the role of inherited Y chromosome variation in prostate cancer risk in individuals of European ancestry, we genotyped 34 binary Y chromosome markers in 3,995 prostate cancer cases and 3,815 control subjects drawn from four studies. In this set, we identified nominally significant association between a rare haplogroup, E1b1b1c, and prostate cancer in stage I (P = 0.012, OR = 0.51; 95% confidence interval 0.30–0.87). Population substructure of E1b1b1c carriers suggested Ashkenazi Jewish ancestry, prompting a replication phase in individuals of both European and Ashkenazi Jewish ancestry. The association was not significant for prostate cancer overall in studies of either Ashkenazi Jewish (1,686 cases and 1,597 control subjects) or European (686 cases and 734 control subjects) ancestry (Pmeta = 0.078), but a meta-analysis of stage I and II studies revealed a nominally significant association with prostate cancer risk (Pmeta = 0.010, OR = 0.77; 95% confidence interval 0.62–0.94). Comparing haplogroup frequencies between studies, we noted strong similarities between those conducted in the US and France, in which the majority of men carried R1 haplogroups, resembling Northwestern European populations. On the other hand, Finns had a remarkably different haplogroup distribution with a preponderance of N1c and I1 haplogroups. In summary, our results suggest that inherited Y chromosome variation plays a limited role in prostate cancer etiology in European populations but warrant follow-up in additional large and well characterized studies of multiple ethnic backgrounds.
Electronic supplementary material
The online version of this article (doi:10.1007/s00439-012-1139-5) contains supplementary material, which is available to authorized users.
PMCID: PMC3374121  PMID: 22271044
6.  Mitochondrial DNA haplogroup T is associated with coronary artery disease and diabetic retinopathy: a case control study 
BMC Medical Genetics  2009;10:35.
There is strong and consistent evidence that oxidative stress is crucially involved in the development of atherosclerotic vascular disease. Overproduction of reactive oxygen species (ROS) in mitochondria is an unifying mechanism that underlies micro- and macrovascular atherosclerotic disease. Given the central role of mitochondria in energy and ROS production, mitochondrial DNA (mtDNA) is an obvious candidate for genetic susceptibility studies on atherosclerotic processes. We therefore examined the association between mtDNA haplogroups and coronary artery disease (CAD) as well as diabetic retinopathy.
This study of Middle European Caucasians included patients with angiographically documented CAD (n = 487), subjects with type 2 diabetes mellitus with (n = 149) or without (n = 78) diabetic retinopathy and control subjects without clinical manifestations of atherosclerotic disease (n = 1527). MtDNA haplotyping was performed using multiplex PCR and subsequent multiplex primer extension analysis for determination of the major European haplogroups. Haplogroup frequencies of patients were compared to those of control subjects without clinical manifestations of atherosclerotic disease.
Haplogroup T was significantly more prevalent among patients with CAD than among control subjects (14.8% vs 8.3%; p = 0.002). In patients with type 2 diabetes, the presence of diabetic retinopathy was also significantly associated with a higher prevalence of haplogroup T (12.1% vs 5.1%; p = 0.046).
Our data indicate that the mtDNA haplogroup T is associated with CAD and diabetic retinopathy in Middle European Caucasian populations.
PMCID: PMC2676278  PMID: 19383124
7.  Cigarette smoking in British men and selection for coronary artery bypass surgery. 
Heart  1996;75(6):557-562.
OBJECTIVE: To examine the relation between smoking status, clinical need, and likelihood of coronary artery bypass grafting in middle aged men. DESIGN: A prospective study of cardiovascular disease in British men aged 40 to 59 years, screened in 1978-80 and followed until December 1991. SUBJECTS AND SETTING: 7735 men drawn from one general practice in each of 24 British towns. MAIN OUTCOME MEASURE: Coronary artery bypass graft surgery. RESULTS: Of the 3185 current smokers, 38 (1.03/1000/year) underwent coronary artery bypass surgery compared with 47 of 2715 (1.45/1000/year) ex-smokers, and 19 of 1817 (0.85/1000/year) never-smokers. Ex-smokers had a lower incidence of major ischaemic heart disease during follow up than current smokers. After adjustment for incidence of ischaemic heart disease during follow up, the hazard ratio of coronary artery bypass surgery for ex-smokers compared with smokers was 1.52 (95% confidence interval 0.99 to 2.34). Ex-smokers were more likely at screening to recall a doctor diagnosis of ischaemic heart disease than smokers (7.1% v 5.3%), but among those who recalled a doctor diagnosis, smokers were less likely to undergo coronary artery bypass surgery than ex-smokers (9.4% v 3.5%, P = 0.026). By 1992, men defined as smokers at screening were no less likely than ex-smokers to have been referred to a cardiologist (18.5% v 18.8%), nor to report having undergone coronary angiography less frequently than ex-smokers (12.7% v 11.4%). CONCLUSION: Even allowing for the strong relation between coronary artery bypass surgery and clinical need, continuing smokers were less likely to undergo coronary artery bypass surgery than ex-smokers. A complex interplay exists between the men's experience of heart disease, the decision to stop smoking, and the willingness of doctors to consider coronary artery bypass surgery.
PMCID: PMC484376  PMID: 8697156
8.  Evaluating the Quality of Research into a Single Prognostic Biomarker: A Systematic Review and Meta-analysis of 83 Studies of C-Reactive Protein in Stable Coronary Artery Disease 
PLoS Medicine  2010;7(6):e1000286.
In a systematic review and meta-analysis of 83 prognostic studies of C-reactive protein in coronary disease, Hemingway and colleagues find substantial biases, preventing them from drawing clear conclusions relating to the use of this marker in clinical practice.
Systematic evaluations of the quality of research on a single prognostic biomarker are rare. We sought to evaluate the quality of prognostic research evidence for the association of C-reactive protein (CRP) with fatal and nonfatal events among patients with stable coronary disease.
Methods and Findings
We searched MEDLINE (1966 to 2009) and EMBASE (1980 to 2009) and selected prospective studies of patients with stable coronary disease, reporting a relative risk for the association of CRP with death and nonfatal cardiovascular events. We included 83 studies, reporting 61,684 patients and 6,485 outcome events. No study reported a prespecified statistical analysis protocol; only two studies reported the time elapsed (in months or years) between initial presentation of symptomatic coronary disease and inclusion in the study. Studies reported a median of seven items (of 17) from the REMARK reporting guidelines, with no evidence of change over time.
The pooled relative risk for the top versus bottom third of CRP distribution was 1.97 (95% confidence interval [CI] 1.78–2.17), with substantial heterogeneity (I2 = 79.5). Only 13 studies adjusted for conventional risk factors (age, sex, smoking, obesity, diabetes, and low-density lipoprotein [LDL] cholesterol) and these had a relative risk of 1.65 (95% CI 1.39–1.96), I2 = 33.7. Studies reported ten different ways of comparing CRP values, with weaker relative risks for those based on continuous measures. Adjusting for publication bias (for which there was strong evidence, Egger's p<0.001) using a validated method reduced the relative risk to 1.19 (95% CI 1.13–1.25). Only two studies reported a measure of discrimination (c-statistic). In 20 studies the detection rate for subsequent events could be calculated and was 31% for a 10% false positive rate, and the calculated pooled c-statistic was 0.61 (0.57–0.66).
Multiple types of reporting bias, and publication bias, make the magnitude of any independent association between CRP and prognosis among patients with stable coronary disease sufficiently uncertain that no clinical practice recommendations can be made. Publication of prespecified statistical analytic protocols and prospective registration of studies, among other measures, might help improve the quality of prognostic biomarker research.
Please see later in the article for the Editors' Summary
Editors' Summary
Coronary artery disease is the leading cause of death among adults in developed countries. With age, fatty deposits called atherosclerotic plaques coat the walls of the arteries, the vessels that carry blood to the body's organs. Because they narrow the arteries, atherosclerotic plaques restrict blood flow. If plaques form in the arteries that feed the heart, the result is coronary artery disease, the symptoms of which include shortness of breath and chest pains (angina). If these symptoms only occur during exertion, the condition is called stable coronary artery disease. Coronary artery disease can cause potentially fatal heart attacks (myocardial infarctions). A heart attack occurs when a plaque ruptures and a blood clot completely blocks the artery, thereby killing part of the heart. Smoking, high blood pressure, high blood levels of cholesterol (a type of fat), diabetes, and being overweight are risk factors for coronary artery disease. Treatments for the condition include lifestyle changes and medications that lower blood pressure and blood cholesterol. Narrowed arteries can also be widened using a device called a stent or surgically bypassed.
Why Was This Study Done?
Clinicians can predict whether a patient with coronary artery disease is likely to have a heart attack by considering their risk factors. They then use this “prognosis” to help them manage the patient. To provide further help for clinicians, researchers are trying to identify prognostic biomarkers (molecules whose blood levels indicate how a disease might develop) for coronary artery disease. However, before a biomarker can be used clinically, it must be properly validated and there are concerns that there is insufficient high quality evidence to validate many biomarkers. In this systematic review and meta-analysis, the researchers ask whether the evidence for an association between blood levels of C-reactive protein (CRP, an inflammatory protein) and subsequent fatal and nonfatal events affecting the heart and circulation (cardiovascular events) among patients with stable coronary artery disease supports the routine measurement of CRP as recommended in clinical practice guidelines. A systematic review uses predefined criteria to identify all the research on a given topic; a meta-analysis is a statistical method for combining the results of several studies.
What Did the Researchers Do and Find?
The researchers identified 83 studies that investigated the association between CRP levels measured in people with coronary artery disease and subsequent cardiovascular events. Their examination of these studies revealed numerous reporting and publication short-comings. For example, none of the studies reported a prespecified statistical analysis protocol, yet analyses should be prespecified to avoid the choice of analytical method biasing the study's results. Furthermore, on average, the studies only reported seven of the 17 recommended items in the REMARK reporting guidelines, which were designed to improve the reporting quality of tumor biomarker prognostic studies. The meta-analysis revealed that patients with a CRP level in the top third of the distribution were nearly twice as likely to have a cardiovascular event as patients with a CRP in the bottom third of the distribution (a relative risk of 1.97). However, the outcomes varied considerably between studies (heterogeneity) and there was strong evidence for publication bias—most published studies were small and smaller studies were more likely to report higher relative risks. Adjustment for publication bias reduced the relative risk associated with high CRP levels to 1.19. Finally, nearly all the studies failed to calculate whether CRP measurements discriminated between patients likely and unlikely to have a subsequent cardiovascular event.
What Do These Findings Mean?
These findings suggest that, because of multiple types of reporting and publication bias, the size of the association between CRP levels and prognosis among patients with stable coronary artery disease is extremely uncertain. They also suggest that CRP measurements are unlikely to add anything to the prognostic discrimination achieved by considering blood pressure and other standard clinical factors among this patient group. Thus, the researchers suggest, the recommendation that CRP measurements should be used in the management of patients with stable coronary artery disease ought to be removed from clinical practice guidelines. More generally, these findings increase concerns about the quality of research into prognostic biomarkers and highlight areas that need to be changed, the most fundamental of which is the need to preregister studies on prognostic biomarkers and their analytic protocols.
Additional Information
Please access these Web sites via the online version of this summary at
The MedlinePlus Encyclopedia has pages on coronary artery disease and C-reactive protein (in English and Spanish)
MedlinePlus provides links to other sources of information on heart disease
The American Heart Association provides information for patients and caregivers on all aspects of cardiovascular disease, including information on the role of C-reactive protein in heart disease
Information is available from the British Heart Foundation on heart disease and keeping the heart healthy
Wikipedia has pages on biomarkers and on C-reactive protein (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
The EQUATOR network is a resource center for good reporting of health research studies
PMCID: PMC2879408  PMID: 20532236
9.  Inequalities in coronary revascularisation during the 1990s: evidence from the British regional heart study 
Heart  2005;91(5):635-640.
Objective: To investigate the influence of age and social circumstances on probability of revascularisation among British men.
Design: Prospective population based study
Setting: 24 medium sized British towns, none of which contained a hospital undertaking coronary artery bypass surgery.
Subjects: 5814 surviving participants of the BRHS (British regional heart study), aged 52–73 years, with no history of revascularisation when responding to a questionnaire in November 1992.
Main outcomes: Incident coronary revascularisations, as documented in general practitioner records, over the following 7.1 years and coronary angiography investigations reported by men in a further questionnaire in November 1996.
Results: 160 men underwent at least one revascularisation during this period (4.2/1000 person-years). In multifactorial analysis, which included adjustment for incidence of major coronary heart disease or angina, a lower incidence of revascularisation was found among men aged over 65 years in November 1992 (hazard ratio 0.62, 95% confidence interval (CI) 0.44 to 0.87), among men with manual occupations (0.73, 95% CI 0.53 to 1.02), among men living in households possessing no car (0.44, 95% CI 0.24 to 0.80) or one car (0.60, 95% CI 0.42 to 0.87) compared with two or more cars, among council tenants (0.49, 95% CI 0.25 to 0.97), and among men living outside southern England (0.71, 95% CI 0.51 to 0.99). Only car ownership was related to the incidence of diagnostic angiography: the odds ratio for angiography for those owning fewer than two cars was 0.62 (95% CI 0.42 to 0.89).
Conclusion: During the 1990s, there were major inequalities in the probability of undergoing coronary revascularisation between British men according to socioeconomic status, age, and geographic location.
PMCID: PMC1768900  PMID: 15831650
age group; coronary revascularisation; epidemiology; social inequality
10.  Autosomal and uniparental portraits of the native populations of Sakha (Yakutia): implications for the peopling of Northeast Eurasia 
Sakha – an area connecting South and Northeast Siberia – is significant for understanding the history of peopling of Northeast Eurasia and the Americas. Previous studies have shown a genetic contiguity between Siberia and East Asia and the key role of South Siberia in the colonization of Siberia.
We report the results of a high-resolution phylogenetic analysis of 701 mtDNAs and 318 Y chromosomes from five native populations of Sakha (Yakuts, Evenks, Evens, Yukaghirs and Dolgans) and of the analysis of more than 500,000 autosomal SNPs of 758 individuals from 55 populations, including 40 previously unpublished samples from Siberia. Phylogenetically terminal clades of East Asian mtDNA haplogroups C and D and Y-chromosome haplogroups N1c, N1b and C3, constituting the core of the gene pool of the native populations from Sakha, connect Sakha and South Siberia. Analysis of autosomal SNP data confirms the genetic continuity between Sakha and South Siberia. Maternal lineages D5a2a2, C4a1c, C4a2, C5b1b and the Yakut-specific STR sub-clade of Y-chromosome haplogroup N1c can be linked to a migration of Yakut ancestors, while the paternal lineage C3c was most likely carried to Sakha by the expansion of the Tungusic people. MtDNA haplogroups Z1a1b and Z1a3, present in Yukaghirs, Evens and Dolgans, show traces of different and probably more ancient migration(s). Analysis of both haploid loci and autosomal SNP data revealed only minor genetic components shared between Sakha and the extreme Northeast Siberia. Although the major part of West Eurasian maternal and paternal lineages in Sakha could originate from recent admixture with East Europeans, mtDNA haplogroups H8, H20a and HV1a1a, as well as Y-chromosome haplogroup J, more probably reflect an ancient gene flow from West Eurasia through Central Asia and South Siberia.
Our high-resolution phylogenetic dissection of mtDNA and Y-chromosome haplogroups as well as analysis of autosomal SNP data suggests that Sakha was colonized by repeated expansions from South Siberia with minor gene flow from the Lower Amur/Southern Okhotsk region and/or Kamchatka. The minor West Eurasian component in Sakha attests to both recent and ongoing admixture with East Europeans and an ancient gene flow from West Eurasia.
PMCID: PMC3695835  PMID: 23782551
mtDNA; Y chromosome; Autosomal SNPs; Sakha
11.  Statin Therapy and Risk of Developing Type 2 Diabetes: A Meta-Analysis 
Diabetes Care  2009;32(10):1924-1929.
Although statin therapy reduces cardiovascular risk, its relationship with the development of diabetes is controversial. The first study (West of Scotland Coronary Prevention Study [WOSCOPS]) that evaluated this association reported a small protective effect but used nonstandardized criteria for diabetes diagnosis. However, results from subsequent hypothesis-testing trials have been inconsistent. The aim of this meta-analysis is to evaluate the possible effect of statin therapy on incident diabetes.
A systematic literature search for randomized statin trials that reported data on diabetes through February 2009 was conducted using specific search terms. In addition to the hypothesis-generating data from WOSCOPS, hypothesis-testing data were available from the Heart Protection Study (HPS), the Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) Study, the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER), and the Controlled Rosuvastatin Multinational Study in Heart Failure (CORONA), together including 57,593 patients with mean follow-up of 3.9 years during which 2,082 incident diabetes cases accrued. Weighted averages were reported as risk ratios (RRs) with 95% CIs using a random-effects model. Statistical heterogeneity scores were assessed with the Q and I2 statistic.
In the meta-analysis of the hypothesis-testing trials, we observed a small increase in diabetes risk (RR 1.13 [95% CI 1.03–1.23]) with no evidence of heterogeneity across trials. However, this estimate was attenuated and no longer significant when the hypothesis-generating trial WOSCOPS was included (1.06 [0.93–1.25]) and also resulted in significant heterogeneity (Q 11.8 [5 d.f.], P = 0.03, I2 = 57.7%).
Although statin therapy greatly lowers vascular risk, including among those with and at risk for diabetes, the relationship of statin therapy to incident diabetes remains uncertain. Future statin trials should be designed to formally address this issue.
PMCID: PMC2752935  PMID: 19794004
12.  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
13.  HTT haplotypes contribute to differences in Huntington disease prevalence between Europe and East Asia 
Huntington disease (HD) results from CAG expansion in the huntingtin (HTT) gene. Although HD occurs worldwide, there are large geographic differences in its prevalence. The prevalence in populations derived from Europe is 10–100 times greater than in East Asia. The European general population chromosomes can be grouped into three major haplogroups (group of similar haplotypes): A, B and C. The majority of HD chromosomes in Europe are found on haplogroup A. However, in the East-Asian populations of China and Japan, we find the majority of HD chromosomes are associated with haplogroup C. The highest risk HD haplotypes (A1 and A2), are absent from the general and HD populations of China and Japan, and therefore provide an explanation for why HD prevalence is low in East Asia. Interestingly, both East-Asian and European populations share a similar low level of HD on haplogroup C. Our data are consistent with the hypothesis that different HTT haplotypes have different mutation rates, and geographic differences in HTT haplotypes explain the difference in HD prevalence. Further, the bias for expansion on haplogroup C in the East-Asian population cannot be explained by a higher average CAG size, as haplogroup C has a lower average CAG size in the general East-Asian population compared with other haplogroups. This finding suggests that CAG-tract size is not the only factor important for CAG instability. Instead, the expansion bias may be because of genetic cis-elements within the haplotype that influence CAG instability in HTT, possibly through different mutational mechanisms for the different haplogroups.
PMCID: PMC3083615  PMID: 21248742
Huntington disease; prevalence; CAG expansion; CAG instability; haplotypes; Cis-elements
14.  Disturbances of insulin in British Asian and white men surviving myocardial infarction. 
BMJ : British Medical Journal  1989;299(6698):537-541.
OBJECTIVE--To examine the role of insulin as a cardiovascular risk factor in British Asian and white men. DESIGN--Case-controlled study of survivors of first myocardial infarction. SETTING--District general hospital. PATIENTS--Consecutive series of 76 white and 74 Asian men who survived first myocardial infarction compared with 58 white and 61 Asian male controls without coronary artery disease who were randomly sampled from the community. RESULTS--More Asians than white subjects had impaired glucose tolerance or overt diabetes as measured by the two hour glucose tolerance test (23/74 (32%) v 11/76 (15%) (p less than 0.001) among patients; 17/61 (28%) v 3/58 (6%) (p less than 0.001) among controls). Insulin and C peptide concentrations were higher in both patient groups than in respective controls (p less than 0.001) and higher in Asian than in white subjects, irrespective of their glucose tolerance. Triglyceride concentrations were higher in patients than in controls (1.92 (SD 1.05) v 1.43 (0.82) mmol/l among Asian men; 1.65 (0.83) v 1.3 (0.61) mmol/l among white subjects; p less than 0.001). Total cholesterol concentrations were lower in both groups of Asians than in respective white subjects (5.78 (0.99) v 6.22 (1.04) mmol/l (p less than 0.01) among patients; 5.54 (1.01) v 5.65 (1.11) mmol/l (p less than 0.6) among controls). High density lipoprotein cholesterol concentrations were lower in Asian than in white subjects. The ratio of total cholesterol to high density lipoprotein cholesterol was significantly higher (p less than 0.001) in both patient groups (6.69 (1.81) in Asian patients and 6.31 (1.91) in white patients) than in respective controls (5.24 (1.19) and 4.77 (1.43)). Regression analysis identified C peptide concentration and the ratio of total to high density lipoprotein cholesterol as powerful independent predictors of myocardial infarction in Asian and white men. Total cholesterol concentration predicted infarction in white but not in Asian men. CONCLUSIONS--Secretion and hepatic extraction of insulin are high in survivors of myocardial infarction and especially high in British Asians. Tissue resistance to the action of insulin, giving rise to increased pancreatic secretion, may be an important risk factor for coronary artery disease in both ethnic groups and may be partly responsible for the high incidence of diabetes and coronary artery disease in Asian populations.
PMCID: PMC1837390  PMID: 2507062
15.  Y-chromosomal diversity in the population of Guinea-Bissau: a multiethnic perspective 
The geographic and ethnolinguistic differentiation of many African Y-chromosomal lineages provides an opportunity to evaluate human migration episodes and admixture processes, in a pan-continental context. The analysis of the paternal genetic structure of Equatorial West Africans carried out to date leaves their origins and relationships unclear, and raises questions about the existence of major demographic phenomena analogous to the large-scale Bantu expansions. To address this, we have analysed the variation of 31 binary and 11 microsatellite markers on the non-recombining portion of the Y chromosome in Guinea-Bissau samples of diverse ethnic affiliations, some not studied before.
The Guinea-Bissau Y chromosome pool is characterized by low haplogroup diversity (D = 0.470, sd 0.033), with the predominant haplogroup E3a*-M2 shared among the ethnic clusters and reaching a maximum of 82.2% in the Mandenka people. The Felupe-Djola and Papel groups exhibit the highest diversity of lineages and harbor the deep-rooting haplogroups A-M91, E2-M75 and E3*-PN2, typical of Sahel's more central and eastern areas. Their genetic distinction from other groups is statistically significant (P = 0.01) though not attributable to linguistic, geographic or religious criteria. Non sub-Saharan influences were associated with the presence of haplogroup R1b-P25 and particular lineages of E3b1-M78.
The predominance and high diversity of haplogroup E3a*-M2 suggests a demographic expansion in the equatorial western fringe, possibly supported by a local agricultural center. The paternal pool of the Mandenka and Balanta displays evidence of a particularly marked population growth among the Guineans, possibly reflecting the demographic effects of the agriculturalist lifestyle and their putative relationship to the people that introduced early cultivation practices into West Africa. The paternal background of the Felupe-Djola and Papel ethnic groups suggests a better conserved ancestral pool deriving from East Africa, from where they have supposedly migrated in recent times. Despite the overall homogeneity in a multiethnic sample, which contrasts with their social structure, minor clusters suggest the imprints of multiple peoples at different timescales: traces of ancestral inhabitants in haplogroups A-M91 and B-M60, today typical of hunter-gatherers; North African influence in E3b1-M78 Y chromosomes, probably due to trans-Saharan contacts; and R1b-P25 lineages reflecting European admixture via the North Atlantic slave trade.
PMCID: PMC1976131  PMID: 17662131
16.  Two-stage association study and meta-analysis of mitochondrial DNA variants in Parkinson disease 
Neurology  2013;80(22):2042-2048.
Previous associations between mitochondrial DNA (mtDNA) and idiopathic Parkinson disease (PD) have been inconsistent and contradictory. Our aim was to resolve these inconsistencies and determine whether mtDNA has a significant role in the risk of developing PD.
Two-stage genetic association study of 138 common mtDNA variants in 3,074 PD cases and 5,659 ethnically matched controls followed by meta-analysis of 6,140 PD cases and 13,280 controls.
In the association study, m.2158T>C and m.11251A>G were associated with a reduced risk of PD in both the discovery and replication cohorts. None of the common European mtDNA haplogroups were consistently associated with PD, but pooling of discovery and replication cohorts revealed a protective association with “super-haplogroup” JT. In the meta-analysis, there was a reduced risk of PD with haplogroups J, K, and T and super-haplogroup JT, and an increase in the risk of PD with super-haplogroup H.
In a 2-stage association study of mtDNA variants and PD, we confirm the reduced risk of PD with super-haplogroup JT and resolve this at the J1b level. Meta-analysis explains the previous inconsistent associations that likely arise through sampling effects. The reduced risk of PD with haplogroups J, K, and T is mirrored by an increased risk of PD in super-haplogroup HV, which increases survival after sepsis. Antagonistic pleiotropy between mtDNA haplogroups may thus be shaping the genetic landscape in humans, leading to an increased risk of PD in later life.
PMCID: PMC3716399  PMID: 23645593
17.  Predictive accuracy of the Framingham coronary risk score in British men: prospective cohort study 
BMJ : British Medical Journal  2003;327(7426):1267.
Objective To establish the predictive accuracy of the Framingham risk score for coronary heart disease in a representative British population.
Design Prospective cohort study.
Setting 24 towns in the United Kingdom.
Participants 6643 British men aged 40-59 years and free from cardiovascular disease at entry into the British regional heart study.
Main outcome measures Comparison of observed 10 year coronary heart disease mortality and event rates with predicted rates for each individual, using the relevant Framingham risk equation.
Results Of 6643 men, 2.8% (95% confidence interval 2.4% to 3.2%) died from coronary heart disease compared with 4.1% predicted (relative overestimation 47%, P < 0.0001). A fatal or non-fatal coronary heart disease event occurred in 10.2% (9.5% to 10.9%) of the men compared with 16.0% predicted (relative overestimation 57%, P < 0.0001). These relative degrees of overestimation were similar at all levels of coronary heart disease risk, so that overestimation of absolute risk was greatest for those at highest risk. A simple adjustment provided an improved level of accuracy. In a “high risk score” approach, most cases occur in the low risk group. In this case, 84% of the deaths from coronary heart disease and non-fatal events occurred in the 93% of men classified at low risk (< 30% in 10 years) by the Framingham score.
Conclusion Guidelines for the primary prevention of coronary heart disease advocate offering preventive measures to individuals at high risk. Currently recommended risk scoring methods derived from the Framingham study significantly overestimate the absolute coronary risk assigned to individuals in the United Kingdom.
PMCID: PMC286248  PMID: 14644971
18.  Fasting plasma glucose in non-diabetic participants and the risk for incident cardiovascular events, diabetes and mortality: results from WOSCOPS 15 year follow-up 
European heart journal  2010;31(10):1230-1236.
The evidence base for fasting plasma glucose (FPG) in the non-diabetic range as a risk factor for cardiovascular disease (CVD) is inconclusive. We investigated this question in the West of Scotland Coronary Prevention Study (WOSCOPS).
Methods and Results
In WOSCOPS, we related FPG in 6447 men (mean age 55 years) with hypercholesterolaemia, but no history of CVD or diabetes, to risk of cardiovascular events and mortality over 14.7 years follow-up; 2381 non-fatal/fatal cardiovascular events and 1244 deaths occurred. Participants were divided into fifths of baseline FPG, Q1 (≤4.3mmol/L) to Q5 (>5.1-6.9mmol/L). Q2 was designated the referent based on previous studies which have suggested a J-shaped relationship between FPG and CVD. Compared to Q2 (>4.3-4.6mmol/L), men in Q5 had no elevated risk for cardiovascular events (HR 0.95 [0.83-1.08]), or all cause mortality (HR 0.96 [0.80-1.15]) in fully adjusted analyses despite a significant risk for incident diabetes (HR 22.05 [10.75-45.22]). After further dividing Q5 into fifths, Q5a-e, individuals in Q5e (FPG 5.8-6.9mmol/L) were also not at increased risk of cardiovascular events (HR 1.05 [0.82-1.35]) or other endpoints compared to Q2. All results were similar using Q1 as referent.
Elevations in FPG in the non-diabetic range were not associated with long-term risk of cardiovascular events in middle-aged men in WOSCOPS. These data suggest that the current FPG cutoff for diagnosing diabetes also appropriately identifies western men at risk of CVD.
PMCID: PMC4209362  PMID: 20395260
cardiovascular disease; impaired fasting glycaemia; diabetes mellitus; glucose
19.  Genomewide Association Analysis of Coronary Artery Disease 
The New England journal of medicine  2007;357(5):443-453.
Modern genotyping platforms permit a systematic search for inherited components of complex diseases. We performed a joint analysis of two genomewide association studies of coronary artery disease.
We first identified chromosomal loci that were strongly associated with coronary artery disease in the Wellcome Trust Case Control Consortium (WTCCC) study (which involved 1926 case subjects with coronary artery disease and 2938 controls) and looked for replication in the German MI [Myocardial Infarction] Family Study (which involved 875 case subjects with myocardial infarction and 1644 controls). Data on other single-nucleotide polymorphisms (SNPs) that were significantly associated with coronary artery disease in either study (P<0.001) were then combined to identify additional loci with a high probability of true association. Genotyping in both studies was performed with the use of the GeneChip Human Mapping 500K Array Set (Affymetrix).
Of thousands of chromosomal loci studied, the same locus had the strongest association with coronary artery disease in both the WTCCC and the German studies: chromosome 9p21.3 (SNP, rs1333049) (P=1.80×10−14 and P=3.40×10−6, respectively). Overall, the WTCCC study revealed nine loci that were strongly associated with coronary artery disease (P<1.2×10−5 and less than a 50% chance of being falsely positive). In addition to chromosome 9p21.3, two of these loci were successfully replicated (adjusted P<0.05) in the German study: chromosome 6q25.1 (rs6922269) and chromosome 2q36.3 (rs2943634). The combined analysis of the two studies identified four additional loci significantly associated with coronary artery disease (P<1.3×10−6) and a high probability (>80%) of a true association: chromosomes 1p13.3 (rs599839), 1q41 (rs17465637), 10q11.21 (rs501120), and 15q22.33 (rs17228212).
We identified several genetic loci that, individually and in aggregate, substantially affect the risk of development of coronary artery disease.
PMCID: PMC2719290  PMID: 17634449
20.  Y-Chromosome Diversity in Modern Bulgarians: New Clues about Their Ancestry 
PLoS ONE  2013;8(3):e56779.
To better define the structure and origin of the Bulgarian paternal gene pool, we have examined the Y-chromosome variation in 808 Bulgarian males. The analysis was performed by high-resolution genotyping of biallelic markers and by analyzing the STR variation within the most informative haplogroups. We found that the Y-chromosome gene pool in modern Bulgarians is primarily represented by Western Eurasian haplogroups with ∼ 40% belonging to haplogroups E-V13 and I-M423, and 20% to R-M17. Haplogroups common in the Middle East (J and G) and in South Western Asia (R-L23*) occur at frequencies of 19% and 5%, respectively. Haplogroups C, N and Q, distinctive for Altaic and Central Asian Turkic-speaking populations, occur at the negligible frequency of only 1.5%. Principal Component analyses group Bulgarians with European populations, apart from Central Asian Turkic-speaking groups and South Western Asia populations. Within the country, the genetic variation is structured in Western, Central and Eastern Bulgaria indicating that the Balkan Mountains have been permeable to human movements. The lineage analysis provided the following interesting results: (i) R-L23* is present in Eastern Bulgaria since the post glacial period; (ii) haplogroup E-V13 has a Mesolithic age in Bulgaria from where it expanded after the arrival of farming; (iii) haplogroup J-M241 probably reflects the Neolithic westward expansion of farmers from the earliest sites along the Black Sea. On the whole, in light of the most recent historical studies, which indicate a substantial proto-Bulgarian input to the contemporary Bulgarian people, our data suggest that a common paternal ancestry between the proto-Bulgarians and the Altaic and Central Asian Turkic-speaking populations either did not exist or was negligible.
PMCID: PMC3590186  PMID: 23483890
21.  Lipoprotein-Associated Phospholipase A2, Vascular Inflammation and Cardiovascular Risk Prediction 
Circulating lipoprotein-associated phospholipase A2 (Lp-PLA2) is a marker of inflammation that plays a critical role in atherogenesis; its inhibition may have antiatherogenic effects. Studies from the West of Scotland Coronary Prevention Study (WOSCOPS), Monitoring Trends and Determinants in Cardiovascular Diseases (MONICA) and Rotterdam cohorts have shown that Lp-PLA2 is an independent predictor of coronary heart disease (CHD), and the association is not attenuated upon multivariate analysis with traditional risk factors and other inflammatory markers. Studies in subjects with coronary artery disease (CAD) have also shown associations between Lp-PLA2 and cardiovascular risk. At least two recent studies have shown that Lp-PLA2 is a risk predictor for stroke. Overall, epidemiological studies suggest that measurement of Lp-PLA2 in plasma may be a useful in identifying individuals at high risk for cardiovascular events.
PMCID: PMC1994000  PMID: 17319459
Inflammation; vascular; cardiovascular risk; coronary; stroke
22.  Mitochondrial Genetic Background Modifies the Relationship between Traffic-Related Air Pollution Exposure and Systemic Biomarkers of Inflammation 
PLoS ONE  2013;8(5):e64444.
Mitochondria are the main source of reactive oxygen species (ROS). Human mitochondrial haplogroups are linked to differences in ROS production and oxidative-stress induced inflammation that may influence disease pathogenesis, including coronary artery disease (CAD). We previously showed that traffic-related air pollutants were associated with biomarkers of systemic inflammation in a cohort panel of subjects with CAD in the Los Angeles air basin.
We tested whether air pollutant exposure-associated inflammation was stronger in mitochondrial haplogroup H than U (high versus low ROS production) in this panel (38 subjects and 417 observations).
Inflammation biomarkers were measured weekly in each subject (≤12 weeks), including interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), C-reactive protein, interleukin-6 soluble receptor and tumor necrosis factor-soluble receptor II. We determined haplogroup by restriction fragment length polymorphism analysis. Air pollutants included nitrogen oxides (NOx), carbon monoxide (CO), organic carbon, elemental and black carbon (EC, BC); and particulate matter mass, three size fractions (<0.25 µm, 0.25–2.5 µm, and 2.5–10 µm in aerodynamic diameter). Particulate matter extracts were analyzed for organic compounds, including polycyclic aromatic hydrocarbons (PAH), and in vitro oxidative potential of aqueous extracts. Associations between exposures and biomarkers, stratified by haplogroup, were analyzed by mixed-effects models.
IL-6 and TNF-α were associated with traffic-related air pollutants (BC, CO, NOx and PAH), and with mass and oxidative potential of quasi-ultrafine particles <0.25 µm. These associations were stronger for haplogroup H than haplogroup U.
Results suggest that mitochondrial haplogroup U is a novel protective factor for air pollution-related systemic inflammation in this small group of subjects.
PMCID: PMC3662686  PMID: 23717615
23.  Heart rate, ischaemic heart disease, and sudden cardiac death in middle-aged British men. 
British Heart Journal  1993;70(1):49-55.
OBJECTIVE--To examine the relation between resting heart rate and new major ischaemic heart disease events in middle aged men with and without pre-existing ischaemic heart disease. DESIGN--Prospective study of a cohort of men with eight years follow up for cardiovascular morbidity and mortality for all men. SETTING--General practices in 24 British towns (the British Regional Heart study). SUBJECTS--7735 men aged 40-59 years drawn at random from the age-sex registers of one general practice in each town. MAIN OUTCOME MEASURES--Major ischaemic heart disease events such as sudden cardiac death, other deaths attributed to ischaemic heart disease, and non-fatal myocardial infarction. RESULTS--During the follow up period of eight years, 488 men had a major ischaemic heart disease event (217 fatal and 271 non-fatal). Of these, 117 were classified as sudden cardiac death (death within one hour of the start of symptoms). The relation between heart rate and risk of all major ischaemic heart disease events, ischaemic heart disease deaths, and sudden cardiac death was examined separately in men with and without pre-existing ischaemic heart disease. In men with no evidence of ischaemic heart disease, there was a strong positive association between resting heart rate and age adjusted rates of all major ischaemic heart disease events (fatal and non-fatal), ischaemic heart disease deaths, and sudden cardiac death. This association remained significant even after adjustment for age, systolic blood pressure, blood cholesterol, smoking, social class, heavy drinking, and physical activity, with particularly high risk in those with heart rate > or = 90 beats/min. The increased risk seen in those with increased heart rate was largely due to a significantly increased risk of sudden cardiac death, which was five times higher than in those with heart rate < 60 beats/min. The effect of heart rate on sudden cardiac death was present irrespective of blood pressure or smoking state. In men with pre-existing ischaemic heart disease a positive association was seen between raised heart rate and risk of all major ischaemic heart disease events, ischaemic heart disease death, and sudden cardiac death, but the effect was less noticeable than in men without pre-existing ischaemic heart disease. CONCLUSION--In this study of middle aged British men increased heart rate > or = 90 beats/min) is a risk factor for fatal ischaemic heart disease events but particularly for sudden cardiac death. The effect is not dependent on the presence of other established coronary risk factors and is most clearly seen in men free of pre-existing ischaemic heart disease at initial examination.
PMCID: PMC1025228  PMID: 8037998
24.  Intravascular Ultrasound to Guide Percutaneous Coronary Interventions 
Executive Summary
The objective of this health technology policy assessment was to determine the effectiveness and cost-effectiveness of using intravascular ultrasound (IVUS) as an adjunctive imaging tool to coronary angiography for guiding percutaneous coronary interventions.
Intravascular Ultrasound
Intravascular ultrasound is a procedure that uses high frequency sound waves to acquire 3-dimensional images from the lumen of a blood vessel. The equipment for performing IVUS consists of a percutaneous transducer catheter and a console for reconstructing images. IVUS has been used to study the structure of the arterial wall and nature of atherosclerotic plaques, and obtain measurements of the vessel lumen. Its role in guiding stent placement is also being investigated. IVUS is presently not an insured health service in Ontario.
Clinical Need
Coronary artery disease accounts for approximately 55% of cardiovascular deaths, the leading cause of death in Canada. In Ontario, the annual mortality rate due to ischemic heart disease was 141.8 per 100,000 population between 1995 and 1997. Percutaneous coronary intervention (PCI), a less invasive approach to treating coronary artery disease, is used more frequently than coronary bypass surgery in Ontario. The number of percutaneous coronary intervention procedures funded by the Ontario Ministry of Health and Long-term Care is expected to increase from approximately 17, 780 in 2004/2005 to 22,355 in 2006/2007 (an increase of 26%), with about 95% requiring the placement of one or more stents. Restenosis following percutaneous coronary interventions involving bare metal stents occurs in 15% to 30% of the cases, mainly because of smooth muscle proliferation and migration, and production of extracellular matrix. In-stent restenosis has been linked to suboptimal stent expansion and inadequate lesion coverage, while stent thrombosis has been attributed to incomplete stent-to-vessel wall apposition. Since coronary angiography (the imaging tool used to guide stent placement) has been shown to be inaccurate in assessing optimal stent placement, and IVUS can provide better views of the vessel lumen, the clinical utility of IVUS as an imaging tool adjunctive to coronary angiography in coronary intervention procedures has been explored in clinical studies.
A systematic review was conducted to answer the following questions:
What are the procedure-related complications associated with IVUS?
Does IVUS used in conjunction with angiography to guide percutaneous interventions improve patient outcomes compared to angiographic guidance without IVUS?
Who would benefit most in terms of clinical outcomes from the use of IVUS adjunctive to coronary angiography in guiding PCIs?
What is the effectiveness of IVUS guidance in the context of drug-eluting stents?
What is the cost-effectiveness ratio and budget impact of adjunctive IVUS in PCIs in Ontario?
A systematic search of databases OVID MEDLINE, EMBASE, MEDLINE In-Process & Other Non-Indexed Citations, The Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) database for the period beginning in May 2001 until the day of the search, November 4, 2005 yielded 2 systematic reviews, 1 meta-analysis, 6 randomized controlled trials, and 2 non-randomized studies on left main coronary arteries. The quality of the studies ranged from moderate to high. These reports were combined with reports from a previous systematic review for analysis. In addition to qualitative synthesis, pooled analyses of data from randomized controlled studies using a random effect model in the Cochrane Review Manager 4.2 software were conducted when possible.
Findings of Literature Review & Analysis
Intravascular ultrasound appears to be a safe tool when used in coronary interventions. Periprocedural complications associated with the use of IVUS in coronary interventions ranged from 0.5% in the largest study to 4%. Coronary rupture was reported in 1 study (1/54). Other complications included prolonged spasms of the artery after stenting, dissection, and femoral aneurysm.
Based on pooled analyses of data from randomized controlled studies, the use of intravascular ultrasound adjunctive to coronary intervention in percutaneous coronary interventions using bare metal stents yielded the following findings:
For lesions predominantly at low risk of restenosis:
There were no significant differences in preintervention angiographic minimal lumen diameter between the IVUS-guided and angiography-guided groups.
IVUS guidance resulted in a significantly larger mean postintervention angiographic minimal lumen diameter (weighted mean difference of 0.11 mm, P = .0003) compared to angiographic guidance alone.
The benefit in angiographic minimal lumen diameter from IVUS guidance was not maintained at 6-month follow-up, when no significant difference in angiographic minimal lumen diameter could be detected between the two arms (weighted mean difference 0.08, P = .13).
There were no statistically significant differences in angiographic binary restenosis rates between IVUS-guidance and no IVUS guidance (Odds ratio [OR] 0.87 in favour of IVUS, 95% Confidence Interval [CI] [0.64–1.18], P = 0.37).
IVUS guidance resulted in a reduction in the odds of target lesion revascularization (repeat percutaneous coronary intervention or coronary bypass graft) compared to angiographic guidance alone. The reduction was statistically significant at a follow-up period of 6 months to 1 year, and at a follow-up period of 18 month to 2 years (OR 0.52 in favour of IVUS, 95% CI [0.33–0.81], P = .004).
Total revascularization rate (either target lesion or target vessel revascularization) was significantly lower for IVUS-guided patients at 18 months to 2.5 years after intervention (OR 0.43 in favour of IVUS, 95% CI [0.29–0.63], p < .0001).
There were no statistically significant differences in the odds of death (OR 1.36 in favour of no IVUS, P =0.65) or myocardial infarction (OR 0.95 in favour of IVUS, P = 0.93) between IVUS-guidance and angiographic guidance alone at up to 2.5 years of follow-up
The odds of having a major cardiac event (defined as death, myocardial infarction, and target lesion or target vessel revascularization) were significantly lower for patients with IVUS guidance compared to angiographic guidance alone during follow-up periods of up to 2.5 years (OR 0.53, 95% CI [0.36–0.78], P = 0.001). Since there were no significant reductions in the odds of death or myocardial infarction, the reduction in the odds of combined events reflected mainly the reduction in revascularization rates.
For lesions at High Risk of Restenosis:
There is evidence from one small, randomized controlled trial (n=150) that IVUS-guided percutaneous coronary intervention in long de novo lesions (>20 mm) of native coronary arteries resulted in statistically significant larger minimal lumen Diameter, and statistically significant lower 6-month angiographic binary restenosis rate. Target vessel revascularization rate and the rate of combined events were also significantly reduced at 12 months.
A small subgroup analysis of a randomized controlled trial reported no benefit in clinical or angiographic outcomes for IVUS-guided percutaneous coronary interventions in patients with diabetes compared to those guided by angiography. However, due to the nature and size of the analysis, no firm conclusions could be reached.
Based on 2 small, prospective, non-randomized controlled studies, IVUS guidance in percutaneous coronary interventions of left main coronary lesions using bare metal stents or drug-eluting stents did not result in any benefits in angiographic or clinical outcomes. These findings need to be confirmed.
Interventions Using Drug-Eluting Stents
There is presently no evidence on whether the addition of IVUS guidance during the implantation of drug-eluting stents would reduce incomplete stent apposition, or improve the angiographic or clinical outcomes of patients.
Ontario-Based Economic Analysis
Cost-effectiveness analysis showed that PCIs using IVUS guidance would likely be less costly and more effective than PCIs without IVUS guidance. The upfront cost of adjunctive use of IVUS in PCIs ranged from $1.56 million at 6% uptake to $13.04 million at 50% uptake. Taking into consideration cost avoidance from reduction in revascularization associated with the use of IVUS, a net saving of $0.63 million to $5.2 million is expected. However, since it is uncertain whether the reduction in revascularization rate resulting from the use of IVUS can be generalized to clinical settings in Ontario, further analysis on the budget impact and cost-effectiveness need to be conducted once Ontario-specific revascularization rates are verified.
Factors to be Considered in the Ontario Context
Applicability of Findings to Ontario
The interim analysis of an Ontario field evaluation that compared drug-eluting stents to bare metal stents showed that the revascularization rates in low-risk patients with bare metal stents were much lower in Ontario compared to rates reported in randomized controlled trials (7.2% vs >17 %). Even though IVUS is presently not routinely used in the stenting of low-risk patients in Ontario, the revascularization rates in these patients in Ontario were shown to be lower than those reported for the IVUS groups reported in published studies. Based on this information and previous findings from the Ontario field evaluation on stenting, it is uncertain whether the reduction in revascularization rates from IVUS guidance can be generalized to Ontario. In light of the above findings, it is advisable to validate the reported benefits of IVUS guidance in percutaneous coronary interventions involving bare metal stents in the Ontario context.
Licensing Status
As of January 16, 2006, Health Canada has licensed 10 intravascular ultrasound imaging systems/catheters for transluminal intervention procedures, most as class 4 medical devices.
Current Funding
IVUS is presently not an insured procedure under the Ontario Health Insurance Plan and there are no professional fees for this procedure. All costs related to the use of IVUS are covered within hospitals’ global budgets. A single use IVUS catheter costs approximately $900CDN and the procedure adds approximately 20 minutes to 30 minutes to a percutaneous coronary intervention procedure.
According to an expert consultant, current use of IVUS in coronary interventions in Ontario is probably limited to high-risk cases such as interventions in long lesions, small vessels, and bifurcated lesions for which images from coronary angiography are indeterminate. It was estimated that IVUS is being used in about 6% of all percutaneous coronary interventions at a large Ontario cardiac centre.
Expert Opinion
IVUS greatly enhances the cardiac interventionists’ ability to visualize and assess high-risk lesions such as long lesions, narrow lesions, and bifurcated lesions that may have indeterminate angiographic images. Information from IVUS in these cases facilitates the choice of the most appropriate approach for the intervention.
The use of adjunctive IVUS in PCIs using bare metal stents in lesions predominantly at low risk for restenosis had no significant impact on survival, myocardial infarction, or angiographic restenosis rates up to 2.5 years after intervention.
The use of IVUS adjunctive to coronary angiography in percutaneous coronary interventions using bare metal stents in lesions predominantly at low risk for restenosis significantly reduced the target lesion and target vessel revascularization at a follow-up period of 18 months to 2.5 years.
One small study suggests that adjunctive IVUS in PCIs using bare metal stents in long lesions (>20 mm) significantly improved the 6-month angiographic restenosis rate and one-year target lesion revascularization rate. These results need to be confirmed with large randomized controlled trials.
Based on information from the Ontario field evaluation on stenting, it is uncertain whether the reduction in revascularization rate resulting from the use of IVUS in the placement of bare metal stents can be generalized to clinical settings in Ontario.
There is presently insufficient evidence available to determine the impact of adjunctive IVUS in percutaneous interventions in high-risk lesions (other than long lesions) or in PCIs using drug-eluting stents.
PMCID: PMC3379536  PMID: 23074482
25.  Unrecognized Non-Q-Wave Myocardial Infarction: Prevalence and Prognostic Significance in Patients with Suspected Coronary Disease 
PLoS Medicine  2009;6(4):e1000057.
Using delayed-enhancement cardiovascular magnetic resonance, Han Kim and colleagues show that in patients with suspected coronary disease the prevalence of unrecognized myocardial infarction without Q-waves is more than 3-fold higher than that with Q-waves and predicts subsequent mortality.
Unrecognized myocardial infarction (UMI) is known to constitute a substantial portion of potentially lethal coronary heart disease. However, the diagnosis of UMI is based on the appearance of incidental Q-waves on 12-lead electrocardiography. Thus, the syndrome of non-Q-wave UMI has not been investigated. Delayed-enhancement cardiovascular magnetic resonance (DE-CMR) can identify MI, even when small, subendocardial, or without associated Q-waves. The aim of this study was to investigate the prevalence and prognosis associated with non-Q-wave UMI identified by DE-CMR.
Methods and Findings
We conducted a prospective study of 185 patients with suspected coronary disease and without history of clinical myocardial infarction who were scheduled for invasive coronary angiography. Q-wave UMI was determined by electrocardiography (Minnesota Code). Non-Q-wave UMI was identified by DE-CMR in the absence of electrocardiographic Q-waves. Patients were followed to determine the prognostic significance of non-Q-wave UMI. The primary endpoint was all-cause mortality. The prevalence of non-Q-wave UMI was 27% (50/185), compared with 8% (15/185) for Q-wave UMI. Patients with non-Q-wave UMI were older, were more likely to have diabetes, and had higher Framingham risk than those without MI, but were similar to those with Q-wave UMI. Infarct size in non-Q-wave UMI was modest (8%±7% of left ventricular mass), and left ventricular ejection fraction (LVEF) by cine-CMR was usually preserved (52%±18%). The prevalence of non-Q-wave UMI increased with the extent and severity of coronary disease on angiography (p<0.0001 for both). Over 2.2 y (interquartile range 1.8–2.7), 16 deaths occurred: 13 in non-Q-wave UMI patients (26%), one in Q-wave UMI (7%), and two in patients without MI (2%). Multivariable analysis including New York Heart Association class and LVEF demonstrated that non-Q-wave UMI was an independent predictor of all-cause mortality (hazard ratio [HR] 11.4, 95% confidence interval [CI] 2.5–51.1) and cardiac mortality (HR 17.4, 95% CI 2.2–137.4).
In patients with suspected coronary disease, the prevalence of non-Q-wave UMI is more than 3-fold higher than Q-wave UMI. The presence of non-Q-wave UMI predicts subsequent mortality, and is incremental to LVEF.
Trial Registration NCT00493168
Editors' Summary
Coronary artery disease (CAD; also called coronary heart disease) is the leading cause of death among adults in developed countries. In the USA alone, it kills nearly half a million people every year. CAD is caused by narrowing of the coronary arteries, the blood vessels that supply the heart with oxygen and nutrients. With age, fatty deposits (atherosclerotic plaques) coat the walls of these arteries and restrict the heart's blood supply, which causes the characteristic symptoms of CAD—angina (chest pains that are usually relieved by rest) and shortness of breath. In addition, if a plaque breaks off the wall of a coronary artery, it can completely block that artery and kill part of the heart, which causes a potentially fatal heart attack (doctors call this a myocardial infarction or MI). Heart attacks are often characterized by long-lasting chest pain that is not relieved by rest. Risk factors for CAD include smoking, high blood pressure, high blood levels of cholesterol (a type of fat), and being overweight. Treatments for the condition include lifestyle changes (for example, losing weight), and medications that lower blood pressure and blood cholesterol. The narrowed arteries can also be widened using a device called a stent or surgically bypassed.
Why Was This Study Done?
Not everyone who has a heart attack has chest pain. In fact, some studies suggest that 40–60% of MIs have no obvious symptoms. It is important, however, that these “unrecognized” MIs (UMIs) are diagnosed because they have death rates similar to those of MIs with clinical symptoms and need to be treated in a similar way. Traditionally, UMIs have been diagnosed using an electrocardiogram (ECG). When the heart beats, it generates small electric waves that can be picked up by electrodes attached to the skin. The pattern of these waves (the ECG) provides information about the heart's health. Alterations in the ECG, leading to so-called Q-waves, indicate that a UMI has occurred some time previously. However, not all UMIs result in Q-waves. In this study, the researchers use a recently developed technique—delayed enhancement cardiovascular magnetic resonance (DE-CMR), which can detect heart damage even in patients whose Q-waves are absent—to measure the prevalence (the fraction of a population that has a disorder) of non-Q-wave UMI. The researchers also investigate whether non-Q-wave UMI increases the risk of death.
What Did the Researchers Do and Find?
The researchers used electrocardiography and DE-CMR to look for Q-wave and non-Q-wave UMI, respectively, in 185 patients with suspected CAD but no history of MI. They then followed the patients for 2 years to discover whether a diagnosis of non-Q-wave UMI predicted their likelihood of dying from any cause or from a heart problem. 27% of the patients had evidence of non-Q-wave UMI whereas only 8% had evidence of Q-wave UMI. Patients with non-Q-wave UMI tended to have only a small area of heart damage and, consistent with this limited damage, their hearts pumped near-normal volumes of blood. Examination of the patients' arteries with a technique called coronary angiography indicated that the patients with widespread and/or severe CAD had a higher prevalence of non-Q-wave UMI than those with limited CAD. Finally, patients with non-Q-wave UMI had an 11-fold higher risk of death from any cause and a 17-fold higher risk of death from a heart problem than patients without UMI.
What Do These Findings Mean?
These findings indicate that non-Q-wave UMI occurs more than 3-times as often in patients with suspected CAD than Q-wave UMI and that patients with non-Q-wave UMI have a much greater risk of dying than patients without MI. Thus, if all cases of UMI—both Q-wave and non-Q-wave UMI—could be identified, it might be possible to reduce the number of deaths among people with CAD. However, before any recommendations are made to include DE-CMR in the routine examination of people with suspected CAD to achieve this aim, additional studies must be undertaken to confirm that non-Q-wave UMI is a common feature of CAD and to test whether the early diagnosis of non-Q-wave UMI does extend the life expectancy of people with CAD.
Additional Information
Please access these Web sites via the online version of this summary at
This study is further discussed in a PLoS Medicine Perspective by Clara Chow
The MedlinePlus encyclopedia has pages on coronary heart disease, heart attacks, and electrocardiograms (in English and Spanish). MedlinePlus also provides links to further information on all aspects of heart disease (in English and Spanish)
Information is available from the US National Heart Lung and Blood Institute on coronary heart disease
The UK National Health Service Choices website also provides information about coronary heart disease (in several languages).
The Nobel Foundation provides an interactive electrocardiogram game
PMCID: PMC2661255  PMID: 19381280

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