Significance of silent ischemia and microalbuminuria in predicting coronary events in asymptomatic patients with type 2 diabetes

OBJECTIVES: The aim of this study was to investigate the relationships between future coronary heart disease (CHD) events and baseline silent myocardial ischemia (SMI) and microalbuminuria (MA) in subjects with type 2 diabetes (T2D) free from known CHD. BACKGROUND: Coronary heart disease is often asymptomatic in subjects with diabetes. There is limited information on the prognostic value of SMI and MA in this group. METHODS: Eighty-six patients with T2D and no history of CHD were studied (43 with MA individually matched with 43 normoalbuminuric patients; mean [SD] age 62 [+/-7] years, 62 men). Metabolic assessment, three timed overnight urine collections for albumin excretion rate, a treadmill exercise test and ankle brachial index (ABI) were performed at baseline. Patients were followed for 2.8 years. RESULTS: Forty-five (52%) patients had SMI during treadmill testing. At review, there had been 23 coronary (CHD) events in 15 patients. Univariate Cox regression analysis showed that CHD events were significantly related to baseline ABI (p = 0.014), SMI (p = 0.020), MA (p = 0.046), 10-year Framingham CHD risk >30% (p = 0.035) and fibrinogen (p = 0.026). In multivariate analysis, SMI was the strongest independent predictor of CHD events (p = 0.008); risk ratio (95% confidence interval) for SMI: 21 (2 to 204). In the prediction of CHD events, SMI showed higher sensitivity and positive predictive value than MA or Framingham calculated CHD risk. CONCLUSIONS: The presence of baseline SMI and MA are associated with future CHD events in asymptomatic patients with T2D and may be of practical use in risk stratification.     

Haemorheological, platelet and endothelial indices in relation to global measures of cardiovascular risk in hypertensive patients: a substudy of the Anglo-Scandinavian Cardiac Outcomes Trial

INTRODUCTION AND METHODS: We tested the hypothesis that there was a significant relationship between haemorheological markers [white blood cell count (WCC), plasma viscosity (PV), haematocrit (HCT) and fibrinogen], as well as plasma von Willebrand factor (vWf, an index of endothelial damage/dysfunction) and soluble P-selectin (sP-sel, an index of platelet activation), to five global measures of cardiovascular risk [i.e. Framingham coronary heart disease (CHD), stroke and cardiovascular death score, the Pocock cardiovascular risk score and the sum of individual risk factors]. RESULTS: Men with a high (> or = median, n = 156) Framingham 10-year CHD risk score had higher levels of WBC (P = 0.027), fibrinogen (P = 0.012) and vWF (P = 0.002) than 153 men with results < median. Men with a high 10-year stroke risk score had significantly higher levels of fibrinogen (P = 0.01) and vWF (P < 0.0001). In stepwise linear regression analysis in men, vWF and fibrinogen were independent predictors of the number of risk factors (P < 0.0001), whilst WCC, vWF and fibrinogen emerged as independent predictors of Framingham CHD risk (P < 0.0001), and fibrinogen and vWF predicted Framingham stroke risk (R(2) = 0.089, P < 0.0001). vWF, PV and fibrinogen were predictors of Pocock cardiovascular death risk (P < 0.0001) but vWF was the only independent predictor of Framingham cardiovascular death risk (P = 0.001). CONCLUSIONS: Abnormal haemorheological factors (particularly high plasma fibrinogen levels) and endothelial damage/dysfunction (high vWF), but not platelet activation (sP-sel), are related to established cardiovascular and death risk scores. This relationship was most evident amongst male 'high-risk' hypertensive subjects.     

Association of high sensitivity C-reactive protein with coronary heart disease prediction, but not with carotid atherosclerosis, in patients with hypertension.

BACKGROUND: Inflammation is believed to predict coronary heart disease (CHD) in healthy subjects and in patients with atherosclerosis. We investigated the association of high sensitivity C-reactive protein (HS-CRP) and other inflammatory markers on cardiovascular outcome, and carotid atherosclerosis in hypertensive patients. METHODS AND RESULTS: We conducted a cross-sectional study of 122 hypertensive patients and compared them with 64 normotensive volunteers. We measured circulating levels of HS-CRP, white blood cells (WBC), albumin, fibrinogen, erythrocyte sedimentation rate, and interleukin-6, and examined the associations with traditional risk factors of CHD, carotid atherosclerosis, and a 10-year risk of CHD, based on the risk prediction algorithm of the Framingham model. The mean of blood pressure (BP) of the hypertensive patients was 163/102 mmHg (normotensives; 118/79 mmHg). The 10-year risk of CHD was higher in the hypertensive patients (9.3 +/- 7.3%) compared with the normotensive volunteers (4.3 +/- 4.2%). Albumin and HS-CRP were significantly higher in the hypertensive patients. Multivariate analysis showed that among markers, only HS-CRP was associated with 10-year risk of CHD (beta=0.13, p=0.03). The BP, body mass index, high-density lipoprotein, WBC count, fibrinogen, and cardiac hypertrophy increased across quartiles of HS-CRP. There was no association between HS-CRP and carotid atherosclerosis in subjects with hypertension and normotension. CONCLUSION: A higher HS-CRP level was associated with a higher risk score of CHD, but not with carotid atherosclerosis, in patients with hypertension.     

Prognostic value of the Framingham cardiovascular risk equation and the UKPDS risk engine for coronary heart disease in newly diagnosed Type 2 diabetes: results from a United Kingdom study.

AIMS: To determine the prognostic value of the Framingham equation and the United Kingdom Prospective Diabetes Study (UKPDS) risk engine in patients with newly diagnosed Type 2 diabetes. METHODS: A community-based cohort (n=428; aged 30-74 years) free of clinically evident CVD and newly diagnosed with Type 2 diabetes were studied over a median 4.2 (sd+/-0.62) years. Predicted (using baseline variables at diagnosis) and observed proportions of primary CVD and CHD events were compared using the Framingham equations and the UKPDS risk engine (only CHD events). The discrimination (c-statistic) and calibration (HLchi2) of the risk equations were calculated. The sensitivity and specificity of the Framingham equation at a 15%, 10-year CHD risk threshold (NICE guidelines) was compared with that of the ADA lipid threshold (LDLc>or=2.6 mmol/l or triglycerides>or=4.5 mmol/l). RESULTS: The Framingham equations underestimated the overall number of cardiovascular events by 33% and coronary events by 32% and showed modest discrimination and poor calibration for CVD [c=0.673; HLchi2=32.8 (P<0.001)] and CHD risk [c=0.657; HLchi2=19.8 (P=0.011)]. Although the overall underestimate was lower and non-significant with the UKPDS risk engine for CHD (13%), its performance in terms of discrimination and calibration were similar [c=0.670; HLchi2=17.1 (P=0.029)]. The 15%, 10-year CHD risk threshold with both the Framingham and UKPDS risk engines had similar sensitivity for primary CVD as the lipid level threshold [85.7 and 89.8% vs. 93.9% (P=0.21 and 0.34)] and both had greater specificity [33.0 and 30.3% vs. 12.1% (P<0.001 and P<0.001)]. CONCLUSIONS: In people with newly diagnosed Type 2 diabetes, both the Framingham equation and UKPDS risk engine are moderately effective at identifying those at high-risk (discrimination) and are poor at quantifying risk (calibration). Nonetheless, at a population level, a 15% 10-year CHD risk threshold using either risk calculator has similar sensitivity as an approach based on a single lipid risk factor level and may have benefits in terms of cost-effectiveness given the improved specificity.     

A coronary heart disease risk score based on patient-reported information

To develop a simple, patient self-report-based coronary heart disease (CHD) risk score for adults without previously diagnosed CHD (Personal Heart Early Assessment Risk Tool [HEART] score), the Atherosclerosis Risk In Communities (ARIC) Study, a prospective cohort of subjects aged 45 to 64 years at baseline, was used to develop a measure for 10-year risk of CHD (n = 14,343). Variables evaluated for inclusion were age, history of diabetes mellitus, history of hypercholesterolemia, history of hypertension, family history of CHD, smoking, physical activity, and body mass index. The 10-year risk of CHD events was defined as myocardial infarction, fatal CHD, or cardiac procedure. The new measure was compared with the Framingham Risk Score (FRS) and European Systematic Coronary Risk Evaluation (SCORE). The Personal HEART score for men included age, diabetes, hypertension, hypercholesterolemia, smoking, physical activity, and family history. In men, the area under the receiver-operator characteristic curve for predicting 10-year CHD for the Personal HEART score (0.65) was significantly different from that for the FRS (0.69, p = 0.03), but not for the European SCORE (0.62, p = 0.12). The Personal HEART score for women included age, diabetes, hypertension, hypercholesterolemia, smoking, and body mass index. The area under the curve for the Personal HEART score (0.79) for women was not significantly different from that for the FRS (0.81, p = 0.42) and performed better than the European SCORE (0.69, p = 0.01). In conclusion, the Personal HEART score identifies 10-year risk for CHD based on self-report data, is similar in predictive ability to the FRS and European SCORE, and has the potential for easy self-assessment.     

A comparison of the PROCAM and Framingham point-scoring systems for estimation of individual risk of coronary heart disease in the Second Northwick Park Heart Study

We have compared the predictive value of the PROCAM and Framingham risk algorithms in healthy UK men from the Second Northwick Park Heart Study (NPHS-II) (50-64 years at entry), followed for a median of 10.8 years for coronary heart disease (CHD) events. For PROCAM, the area under the receiver operating characteristic (ROC) curve was 0.63 (95% CI, 0.59-0.67), and not significantly different (p = 0.46) from the Framingham score, 0.62 (0.58-0.66). Sensitivities for a 5% false-positive rate (DR(5)) were 13.8 and 12.4%, respectively. Calibration analysis for PROCAM gave a ratio of observed to expected events of 0.46 (Hosmer-Lemeshow test, p < 0.0001) and 0.47 for Framingham (p < 0.0001). Using measures taken at 5 years of high-density lipoprotein cholesterol and (estimated) low-density lipoprotein cholesterol levels increased the ROC by only 1%. An NPHS-II risk algorithm, developed using a 50% random subset, and including age, triglyceride, total cholesterol, smoking status, and systolic blood pressure at recruitment, gave an ROC of 0.64 (0.58-0.70) with a DR(5) of 10.7% when applied to the second half of the data. Adding family history and diabetes increased the DR(5) to 18.4% (p = 0.28). Adding lipoprotein(a) >26.3 mg/dL (relative risk 1.6, 1.1-2.4) gave a DR(5) of 15.5% (p = 0.55), while adding fibrinogen levels (relative risk for 1S.D. increase = 1.5, 1.1-2.0) had essentially no additional impact (DR(5) = 16.9%, p = 0.95). Thus, the PROCAM algorithm is marginally better as a risk predictor in UK men than the Framingham score, but both significantly overestimate risk in UK men. The algorithm based on NPHS-II data performs similarly to those for PROCAM and Framingham with respect to discrimination, but gave an improved ratio of observed to expected events of 0.80 (p = 0.01), although no score had a high sensitivity. Any novel factors added to these algorithms will need to have a major impact on risk to increase sensitivity above that given by classical risk factors.     

Risk prediction of coronary heart disease based on retinal vascular caliber (from the Atherosclerosis Risk In Communities [ARIC] Study)

Recent studies showed that such retinal vascular signs as quantitative retinal vascular caliber were associated with increased risk of incident coronary heart disease (CHD), but whether these retinal vascular signs add to the prediction of CHD over and above traditional CHD risk factors was not addressed. Whether these signs add to the prediction of CHD over and above the Framingham risk score in people (n = 9,155) without diabetes selected from the ARIC Study was investigated. Incident CHD was ascertained using standardized methods, and retinal vascular caliber and other retinal signs were measured from retinal photographs. After a mean of 8.8 years of follow-up, there were 700 incident CHD events. Women with wider retinal venular caliber (hazard ratio 1.27/1-SD increase, 95% confidence interval 1.08 to 1.50) and narrower retinal arteriolar caliber (hazard ratio 1.31/1-SD decrease, 95% confidence interval 1.10 to 1.56) had a higher risk of incident CHD after adjusting for Framingham risk score variables. Area under the receiver operator characteristic curve increased from 0.695 to 0.706 (1.7% increase) with the addition of retinal vascular caliber to the Framingham risk model. Risk prediction models with and without retinal vascular caliber both fitted the data and were well calibrated for women. In men, retinal vascular caliber was not associated with CHD risk after adjustment. Other retinal vascular signs were not associated with 10-year incident CHD in men or women. In conclusion, although retinal vascular caliber independently predicted CHD risk in women, the incremental predictive ability over that of the Framingham model was modest and unlikely to translate meaningfully into clinical practice.     

Association of fibrinogen and lipoprotein(a) as a coronary heart disease risk factor in men (The Quebec Cardiovascular Study)

Fibrinogen has been prospectively found to correlate with coronary heart disease (CHD) but a similar association has not been well established for lipoprotein (a) (Lp(a)). Plasma lipids, Lp(a), and fibrinogen levels were measured in 2,125 men (aged 47 to 76 years) who were free of clinical CHD. During a 5-year follow-up period, 116 first CHD events were documented. Men with CHD were older, smoked more, had a higher prevalence of diabetes, and higher levels of systolic blood pressure, cholesterol, low-density lipoprotein cholesterol, Lp(a), and fibrinogen, and lower plasma high-density lipoprotein cholesterol levels. Only fibrinogen levels in the upper tertile of the distribution compared with the lower tertiles were associated with a significant risk of CHD (adjusted risk ratio 2.5; 95% confidence interval [CI] 1.4 to 4.2; p = 0.0010). Such an association was not observed with Lp(a). To assess a possible relation between fibrinogen and Lp(a) to the risk of CHD events, men were assigned to 1 of 4 groups according to fibrinogen median levels and a Lp(a) cut-off level of 300 mg/L: group 1: fibrinogen < 4.05 g/L and Lp(a) < 300 mg/L; group 2: fibrinogen < 4.05 g/L and Lp(a) > or =300 mg/L; group 3: fibrinogen > or =4.05 g/L and Lp(a) < 300 mg/L; and group 4: fibrinogen > or =4.05 g/L and Lp(a) > or =300 mg/L. Using group 1 as a reference, a significant risk ratio was only documented in group 4 (2.5; 95% CI 1.2 to 5.1; p = 0.0132). In this population, high fibrinogen levels associated with high Lp(a) levels significantly increased the risk of CHD.     

Comparative value of coronary artery calcium and multiple blood biomarkers for prognostication of cardiovascular events

The value of coronary artery calcium (CAC) scoring versus multiple biomarkers in increasing risk prediction for cardiovascular disease (CVD) remains unknown. The study group consisted of 1,286 asymptomatic participants (mean ± SD 59 ± 8 years old) with no known coronary heart disease. Mean follow-up time was 4.1 ± 0.4 years with the primary outcome of combined CVD (cardiac death, myocardial infarction, stroke, and late target vessel revascularization). CAC was calculated by the method of Agatston. Biomarkers measured were C-reactive protein, interleukin-6, myeloperoxidase, B-type natriuretic peptide, and plasminogen activator-1. During follow-up 35 participants developed CVD events including cardiac deaths (6%), myocardial infarction (23%), strokes (17%), and late revascularizations (54%). In Cox proportional-hazards models adjusted for Framingham Risk Score (FRS), presence of log CAC beyond FRS was associated with increased hazards for CVD events (hazard ratio 1.7, 95% confidence interval [CI] 1.4 to 2.0, p <0.001). Multiple biomarkers score was also associated with increased risk beyond FRS (hazard ratio 2.1, p = 0.02) per 1-U increase in score; however, the c-statistic did not increase significantly (0.75, 95% CI 0.68 to 0.84, p = 0.32). The c-statistic increased when log CAC was incorporated into FRS without or with multiple biomarkers score (c-statistic 0.84, p = 0.003 and p = 0.008 respectively). Addition of CAC to risk factors showed significant reclassification (net reclassification improvement 0.35 (95% CI 0.11 to 0.58, p = 0.007; integrated discrimination index 0.076, p = 0.0001), whereas addition of multiple biomarkers score did not show significant reclassification. In conclusion, in this study of asymptomatic subjects without known CVD, addition of CAC but not biomarkers substantially improved risk reclassification for future CVD events beyond traditional risk factors.     

Framingham risk equation underestimates subclinical atherosclerosis risk in asymptomatic women

BACKGROUND: Coronary heart disease (CHD) is the leading cause of death among American women. Currently, global risk assessment derived by Framingham risk equation (FRE) is used to identify women at increased risk for CHD. Electron-beam computed tomography (EBCT) derived coronary artery calcium (CAC) scores are validated markers for future CHD events among asymptomatic individuals. However, the adequacy of FRE for identifying asymptomatic women with CAC is unknown. METHODS AND RESULTS: We studied 2447 consecutive non-diabetic asymptomatic females (55 +/- 10 years). Based upon FRE, 90% were classified as low-risk (FRE < or = 9% 10-year risk of hard CHD events), 10% intermediate-risk (10-20%), and none were considered as high-risk (> 20%). Coronary artery calcium was present in 33%, whereas CAC > or = 100 and CAC > or = 400 were seen in 10 and 3% of women, respectively. Overall, 20% of women had age-gender derived > or = 75th percentile CAC. According to FRE, the majority (84%) of women with significant CAC > or = 75th percentile were classified as low-risk. Approximately half (45%) of low-risk women with > or = 2 CHD risk factors and a family history of premature CHD had significant CAC. CONCLUSION: Framingham risk equation frequently classifies women as being low-risk, even in the presence of significant CAC. Determination of CAC may provide incremental value to FRE in identifying asymptomatic women who will benefit from targeted preventative measures.     

The Framingham prediction rule is not valid in a European population of treated hypertensive patients

BACKGROUND: Stratification of population groups according to cardiovascular risk level is recommended for primary prevention. OBJECTIVE: To assess whether the Framingham models could accurately predict the absolute risk of coronary heart disease (CHD) and stroke in a large cohort of middle-aged European patients with hypertension, and rank individual patients according to actual risk. DESIGN: A prospective cohort study comparing the actual risk with that predicted by either the Framingham equations or models derived from the INSIGHT study. PATIENTS AND SETTING: From the INSIGHT prospective trial, conducted in eight countries of Western Europe and Israel, we selected 4407 European patients younger than 75 years without previous cardiovascular events. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Major cardiovascular events. RESULTS: In this population (45% men, mean age 64.1 years), 124 (2.8%) patients had CHD and 96 (2.2%) had strokes after a median follow-up of 3.7 years. Overestimation of absolute CHD risk by the Framingham equation was observed in all countries (from 2% in the UK to 7% in France), whereas predicted risk of stroke was close to the actual risk. However, patients in the highest risk quintile within each country had a threefold greater risk of a cardiovascular event than those in the lowest quintile. CONCLUSIONS: The Framingham models should not be used to predict absolute CHD risk in the European population as a whole. However, these models may be used within each country, provided that cut-off points defining high-risk patients have been determined within each country.     

A clinical risk score for atrial fibrillation in a biracial prospective cohort (from the Atherosclerosis Risk in Communities [ARIC] study)

A risk score for atrial fibrillation (AF) has been developed by the Framingham Heart Study; however, the applicability of this risk score, derived using data from white patients, to predict new-onset AF in nonwhites is uncertain. Therefore, we developed a 10-year risk score for new-onset AF from risk factors commonly measured in clinical practice using 14,546 subjects from the Atherosclerosis Risk In Communities (ARIC) study, a prospective community-based cohort of blacks and whites in the United States. During 10 years of follow-up, 515 incident AF events occurred. The following variables were included in the AF risk score: age, race, height, smoking status, systolic blood pressure, hypertension medication use, precordial murmur, left ventricular hypertrophy, left atrial enlargement, diabetes, coronary heart disease, and heart failure. The area under the receiver operating characteristics curve (AUC) of a Cox regression model that included the previous variables was 0.78, suggesting moderately good discrimination. The point-based score developed from the coefficients in the Cox model had an AUC of 0.76. This clinical risk score for AF in the Atherosclerosis Risk In Communities cohort compared favorably with the Framingham Heart Study's AF (AUC 0.68), coronary heart disease (CHD) (AUC 0.63), and hard CHD (AUC 0.59) risk scores and the Atherosclerosis Risk In Communities CHD risk score (AUC 0.58). In conclusion, we have developed a risk score for AF and have shown that the different pathophysiologies of AF and CHD limit the usefulness of a CHD risk score in identifying subjects at greater risk of AF.     

Comparison of current guidelines for primary prevention of coronary heart disease

OBJECTIVE: In primary prevention of atherosclerotic disease, it is difficult to decide when medical treatment should be initiated. The main goal of the study was to compare different guidelines for coronary heart disease (CHD) risk assessment and initiation of lipid-lowering therapy. DESIGN: Cross-sectional evaluation. SETTING: An outpatient lipid and diabetes clinic in a university hospital. PARTICIPANTS/METHODS: Risk factor data obtained on 100 consecutive patients (58 men and 42 women) without clinical evidence of cardiovascular disease were used to compare the Framingham risk equation, the U.S. National Cholesterol Education Program (Adult Treatment Panel III) (NCEP ATP III) guidelines, the joint European Societies guidelines, the joint British guidelines, the revised Sheffield table, and the Munster Heart Study calculator (PROCAM) CHD risk assessment and lipid-lowering therapy. RESULTS: Guidelines could be applied to different subsets of the cohort, ranging from 22% (PROCAM) to 95% of the cohort (revised Sheffield table). All guidelines (except PROCAM) could be applied to a total of 62 patients. Guidelines predicted > or =20% risk for developing CHD over 10 years in 53% (NCEP ATP III), 26% (European) and 32% (British), while Framingham predicted this risk level in 34%. CHD risk was estimated to be > or =3%/year in 5% according to Sheffield, while Framingham predicted this risk in 13%. Lipid-lowering drug therapy is recommended in 52% by NCEP ATP III, while European, British, and Sheffield guidelines recommend this in 26%, 35%, and 5%, respectively. CONCLUSIONS: Guidelines for assessing CHD risk and lipid-lowering therapy differ greatly. Therefore, these algorithms must be used with caution.     

Effectiveness of aggressive management of dyslipidemia in a collaborative-care practice model

The Cardiovascular Risk Identification and Treatment Center was established in 1997, adopting a collaborative-care clinic model for the purpose of improving the management of high-risk patients with dyslipidemia. This was a retrospective analysis of 417 high-risk patients with ≥1 year of follow-up laboratory data. Analysis included changes in total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), non-HDL, triglycerides, and total cholesterol to HDL ratio; lipoprotein goal achievement; Framingham risk score; liver function; and cardiovascular events. At baseline, 66% of patients had coronary heart disease (CHD) or equivalent risk, 45% were not receiving dyslipidemia therapy, and 29% were on statin monotherapy. After 3 years in the program, 56% were receiving combination therapy, 41% were on monotherapy, and 2% were not on therapy. The 3 most common treatment regimens were statin plus niacin (36%), statin alone (22%), and niacin alone (14%). All lipoproteins improved from baseline (p <0.001). Overall, 62% to 74% of patients reached singular lipid goals and 35% achieved combined lipid goals. Patients with Framingham 10-year CHD risk of >20% were reduced from 6% to <1%. Only 29 patients (7.0%) had a cardiovascular event, including 5 (1.0%) who experienced a myocardial infarction. Aspartate aminotransferase/alanine transferase elevation >3 times normal occurred in 1% of patients. In conclusion, a collaborative-care practice model adopting individualized, aggressive pharmacologic and nonpharmacologic treatment strategies is highly effective in achieving lipid goals, is sustainable, and is safe. Furthermore, this approach yields reduced projected 10-year CHD risk. A low rate of cardiovascular events was observed.     

Distribution of lifestyle and emerging risk factors by 10-year risk for coronary heart disease.

BACKGROUND: The Framingham risk score has been used for coronary heart disease (CHD) risk assessment. Recently, additional risk factors not included in the Framingham algorithm have received much attention and may help improve risk assessment. We examined the distributions of lifestyle and emerging risk factors by 10-year risk of CHD. METHODS: We calculated 10-year CHD risk (<10%, 10-20%, and >20%) for 8355 participants in the National Health and Nutrition Examination Survey (NHANES) 1999-2002 using the Framingham risk score as modified by the National Cholesterol Education Program Adult Treatment Panel III guidelines. We examined the prevalence of lifestyle risk factors [body mass index (BMI) and waist circumference] and various emerging risk factors [C-reactive protein (CRP), white blood cell count, fibrinogen, homocysteine, glycosylated hemoglobin, and albuminuria] as well as prevalence of high CHD risk by levels of these risk factors. RESULTS: All examined CHD risk factors were significantly associated with increasing 10-year CHD risk among men and women. Odds of being in the highest CHD risk group were greater at higher levels of examined risk factors. Means for most risk factors were slightly higher for women than the means for men. Sizeable proportions of participants with lower 10-year CHD risk had high levels of lifestyle and emerging risk factors: 60.8% were overweight, 33.8% had high CRP concentrations, 24.1% had serum fibrinogen >400 mg/dl and 6% had an albumin/creatinine ratio >/=30. CONCLUSIONS: Lifestyle and emerging risk factors, in addition to those included in the Framingham risk score, may be important in CHD risk assessment.     

Prediction of intermittent claudication, ischemic stroke, and other cardiovascular disease by detection of abdominal aortic calcific deposits by plain lumbar radiographs

There has been little attention to vascular calcium testing for generalized assessment of cardiovascular disease (CVD) outcomes, such as intermittent claudication (IC) and ischemic stroke (IS). We hypothesize that aortic calcium is an important predictor of CVD outcomes. Lumbar x-rays were obtained in 848 men and 1,301 women (mean ages 59.7 and 60.1 years, respectively) from the original cohort of the Framingham Heart Study. Abdominal aortic calcium (AAC) deposits were graded using a previously validated scale. Participants were categorized according to a 10-year Framingham coronary heart disease (CHD) risk score. Multivariable Cox proportional hazards analyses were performed to relate AAC to CVD outcomes. There were 199 IC events, 201 IS events, 702 CHD events, and 1,121 CVD events during 32 years of follow-up. Multivariable adjusted hazard ratios for the third versus first AAC tertile in the combined cohort were 1.68 (95% confidence interval [CI] 1.12 to 2.50) for IC, 1.73 (95% CI 1.12 to 2.65) for IS, 1.59 (95% CI 1.26 to 2.00) for CHD, and 1.64 (95% CI 1.37 to 1.97) for CVD. Hazard ratios for IC and IS were similar in magnitude to those for CHD and CVD. A high AAC score was associated with significantly higher incidence of events in subjects at intermediate Framingham CHD risk for all end points. Risk prediction based on cardiovascular risk factors improved for most outcomes when AAC was added. In conclusion, there was a graded, increasing, and independent association of AAC with incident IC and IS, similar in magnitude to risks predicted for CHD and CVD. AAC appears to be useful for risk stratification in patients at intermediate CHD risk.     

Racial differences in the significance of coronary calcium in asymptomatic black and white subjects with coronary risk factors.

OBJECTIVES: To compare the significance of a specific feature of coronary atherosclerosis--coronary calcium--in asymptomatic black and white subjects with coronary risk factors. BACKGROUND: The natural history and clinical evolution of coronary atherosclerosis differs between blacks and whites. Differences in the underlying pathobiology of atherosclerosis may be one determinant of the ethnic variability in the clinical manifestation of coronary atherosclerosis. METHODS: In 1,375 high-risk but asymptomatic subjects (93 blacks [6.8%] and 1,282 whites [93.2%]) with at least one risk factor but no prior evidence of coronary disease, we assessed coronary risk factors, calculated Framingham risk of a coronary event and evaluated coronary calcium with digital subtraction fluoroscopy. We then followed these subjects clinically for 70 +/- 13 months, noting the occurrence of the following coronary events: death due to coronary heart disease (CHD); myocardial infarction (MI); angina pectoris; and performance of coronary bypass or angioplasty. RESULTS: Risk factor profiles were similar in black and white subjects (6-year Framingham risk 15 +/- 7% in blacks, 14 +/- 8% in whites [NS]). Coronary calcium was present in 59.9% of white subjects but only 35.5% of black subjects (p = 0.0001). Nevertheless, after 70 months of follow-up, more blacks than whites (22 blacks [23.7%] vs. 190 whites [14.8%]; p = 0.04) suffered one of the following end points: CHD death, MI, angina or revascularization. The age, gender and coronary risk-adjusted odds ratio of black race for at least one event was 2.16 (95% CI 1.34 to 3.48). CONCLUSIONS: Despite having a lowered prevalence of coronary calcium than high risk whites, high risk blacks suffer more CHD events. Coronary calcium therefore does not carry the same pathobiologic significance in blacks that it does in whites, consistent with the concept that there are specific racial differences in the natural history of CHD and its evolution into clinically manifest events.     

A genetic risk score based on direct associations with coronary heart disease improves coronary heart disease risk prediction in the Atherosclerosis Risk in Communities (ARIC), but not in the Rotterdam and Framingham Offspring, Studies

ObjectiveMultiple studies have identified single-nucleotide polymorphisms (SNPs) that are associated with coronary heart disease (CHD). We examined whether SNPs selected based on predefined criteria will improve CHD risk prediction when added to traditional risk factors (TRFs).MethodsSNPs were selected from the literature based on association with CHD, lack of association with a known CHD risk factor, and successful replication. A genetic risk score (GRS) was constructed based on these SNPs. Cox proportional hazards model was used to calculate CHD risk based on the Atherosclerosis Risk in Communities (ARIC) and Framingham CHD risk scores with and without the GRS.ResultsThe GRS was associated with risk for CHD (hazard ratio [HR] = 1.10; 95% confidence interval [CI]: 1.07–1.13). Addition of the GRS to the ARIC risk score significantly improved discrimination, reclassification, and calibration beyond that afforded by TRFs alone in non-Hispanic whites in the ARIC study. The area under the receiver operating characteristic curve (AUC) increased from 0.742 to 0.749 (Δ = 0.007; 95% CI, 0.004–0.013), and the net reclassification index (NRI) was 6.3%. Although the risk estimates for CHD in the Framingham Offspring (HR = 1.12; 95% CI: 1.10–1.14) and Rotterdam (HR = 1.08; 95% CI: 1.02–1.14) Studies were significantly improved by adding the GRS to TRFs, improvements in AUC and NRI were modest.ConclusionAddition of a GRS based on direct associations with CHD to TRFs significantly improved discrimination and reclassification in white participants of the ARIC Study, with no significant improvement in the Rotterdam and Framingham Offspring Studies.     

Sex-specific threshold levels of plasma B-type natriuretic peptide for prediction of cardiovascular event risk in a Japanese population initially free of cardiovascular disease

Elevated plasma B-type natriuretic peptide (BNP) levels have been reported to be related to a high risk for cardiovascular (CV) disease in the general population. However, there has been no accurate determination of the threshold levels of plasma BNP that indicate an increased potential for the development of general CV events (i.e., heart failure, stroke, and myocardial infarction) and the validity of these levels for predicting CV events compared to classic risk markers. To establish gender-specific thresholds of plasma BNP levels associated with increased risk for CV disease in the general population, baseline BNP levels were determined in community-dwelling adults (n = 13,209, mean age 62 ± 10 years,) and CV events in the cohort were captured prospectively. The cohort was divided by deciles of plasma BNP level in each gender. A Cox proportional-hazards model was used to determine the relative hazard ratios among the deciles. In addition, to compare the utility of plasma BNP to the Framingham 10-year risk score for predicting general CV events, receiver-operating characteristic analysis was performed. During follow-up, CV events were identified in 429 patients in the cohort. Compared to the reference decile level (first to fourth), the hazard ratio was significantly increased from the ninth decile in men (greater than approximately 37 pg/ml) and the highest decile in women (greater than approximately 55 pg/ml). The area under the curve generated on receiver-operating characteristic analysis of plasma BNP testing was comparable to that for the Framingham risk scoring system (0.67 vs 0.68 in men, 0.63 vs 0.68 in women; p = NS for both). In conclusion, within a community-based general population with no CV history, plasma BNP levels higher than defined thresholds show increased risk for general CV events, and the predictive ability for CV events occurring within several years may be comparable to that of an established long-standing risk score.     

Impact of impaired fasting glucose on cardiovascular disease: the Framingham Heart Study.

OBJECTIVES: We sought to determine whether impaired fasting glucose (IFG) predicts cardiovascular disease (CVD) events. BACKGROUND: It is unclear which glucose threshold should define prediabetes. We compared the 1997 and 2003 American Diabetes Association (ADA) definitions of IFG to predict CVD. METHODS: Framingham offspring participants free of CVD, categorized by the 1997 ADA IFG definition (fasting plasma glucose 110 to 125 mg/dl; 6.1 to 6.9 mmol/l) or the 2003 definition (100 to 125 mg/dl; 5.6 to 6.9 mmol/l), were followed from 1983 to 2004. Pooled logistic regression was used to calculate multivariable-adjusted odds ratios (ORs) for incident coronary heart disease (CHD; 291 events) or CVD (423 events). RESULTS: Four-year CHD event rates among women were 1.3% (100 to 109 mg/dl), 2.3% (110 to 125 mg/dl), and 2.9% (diabetes); whereas corresponding rates in men were 2.9%, 3.0%, and 8.7%. For the 2003 IFG definition, the OR for CHD among women was 1.7 (95% confidence interval [CI] 1.0 to 3.0, p = 0.048), whereas for the 1997 IFG definition, the OR for CHD in women was 2.2 (95% CI 1.1 to 4.4, p = 0.02), which was almost as high as for women with diabetes (OR 2.5, 95% CI 1.2 to 5.2, p = 0.01). For CVD, only the 1997 IFG definition yielded significantly greater odds of CVD in women (OR 2.1, 95% CI 1.2 to 3.6, p = 0.01). Men were not at increased odds of developing CVD or CHD by either definition. CONCLUSIONS: In women, both IFG definitions were associated with increased CHD risk, whereas neither IFG definition identified men at increased short-term risk for CHD or CVD. The finding that women with FPG 110 to 125 mg/dl had similar CHD risk compared with women with diabetes suggests that CHD risk in women may be elevated at a lower glucose level than for men.