Persons with diabetic retinopathy (DR) have an increased risk of clinical cardiovascular events. Our study aimed to determine whether DR is associated with a range of measures of subclinical cardiovascular disease (CVD) in persons without clinical CVD.
Population-based, cross-sectional epidemiologic study
Nine hundred and twenty seven persons with diabetes without clinical CVD in the Multi-Ethnic Study of Atherosclerosis.
DR was ascertained from retinal photographs according to modification of the Airlie House Classification system. Vision threatening DR (VTDR) was defined as severe non-proliferative DR, proliferative DR or clinically significant macular edema. Subclinical CVD measures were assessed and defined as follows: high coronary artery calcium (CAC) score, defined as CAC score≥400; low ankle-brachial index (ABI), defined as ABI<0.9; high ABI, defined as ABI≥1.4; high carotid intima-media thickness (IMT), defined as highest 25% of IMT; and carotid stenosis, defined as >25% stenosis or presence of carotid plaque.
MAIN OUTCOME MEASURES
Associations between DR and subclinical CVD measures.
The prevalence of DR and VTDR in this sample was 30.0% and 7.2%, respectively. VTDR was associated with a high CAC score (odds ratio [OR] 2.33, 95% condifence interval [CI] 1.15–4.73), low ABI (OR 2.54; 95%CI, 1.08–5.99) and high ABI (OR 12.6, 95% CI, 1.14, 140.6), after adjusting for risk factors including hemoglobin A1c level and duration of diabetes. The association between VTDR and high CAC score remained significant after further adjustment for hypoglycemic, anti-hypertensive and cholesterol-lowering medications. DR was not significantly associated with measures of carotid artery disease.
In persons with diabetes without a history of clinical CVD, the presence of advanced stage of DR is associated with subclinical coronary artery disease. These findings emphasize the need to be careful about the use of anti-vascular endothelial growth factor for the treatment of DR.
While there is no doubt that high risk patients (those with >20% ten year risk of future cardiovascular event) need more aggressive preventive therapy, a majority of cardiovascular events occur in individuals at intermediate risk (10%–20% ten year risk). Accurate risk assessment may be helpful in decreasing cardiovascular events through more appropriate targeting of preventive measures. It has been suggested that traditional risk assessment may be refined with the selective use of coronary artery calcium (CAC) or other methods of subclinical atherosclerosis measurement. Coronary calcification is a marker of atherosclerosis that can be quantified with the use of cardiac CT and it is proportional to the extent and severity of atherosclerotic disease. The published studies demonstrate a high sensitivity of CAC for the presence of coronary artery disease but a lower specificity for obstructive CAD depending on the magnitude of the CAC. Several large clinical trials found clear, incremental predictive value of CAC over the Framingham risk score when used in asymptomatic patients. Based on multiple observational studies, patients with increased plaque burdens (increased CAC) are approximately ten times more likely to suffer a cardiac event over the next 3–5 years. Coronary calcium scores have outperformed conventional risk factors, highly sensitive C-reactive protein (CRP) and carotid intima media thickness (IMT) as a predictor of cardiovascular events. The relevant prognostic information obtained may be useful to initiate or intensify appropriate treatment strategies to slow the progression of atherosclerotic vascular disease. Current data suggests intermediate risk patients may benefit most from further risk stratification with cardiac CT, as CAC testing is effective at identifying increased risk and in motivating effective behavioral changes. This article reviews information pertaining to the clinical use of CAC for assessing coronary atherosclerosis as a useful predictor of coronary artery disease (CAD) in certain population of patients.
computed tomography; electron beam; prognosis; review; coronary artery calcification; calcium score; atherosclerosis; multi-detector computed tomography
Peripheral arterial disease (PAD) increases with age and ankle-brachial index (ABI) ≤ 0.9 is a noninvasive marker of PAD. The purpose of this study was to identify risk factors related to a low ABI in the elderly using two different methods of ABI calculation (traditional and modified definition using lower instead of higher ankle pressure). A cross-sectional study was carried out with 65 hypertensive patients aged 65 years or older. PAD was present in 18% of individuals by current ABI definition and in 32% by modified method. Diabetes, cardiovascular diseases, metabolic syndrome, higher levels of systolic blood pressure and pulse pressure, elevated risk by Framingham Risk Score (FRS), and a higher number of total and antihypertensive drugs in use were associated with low ABI by both definitions. Smoking and LDL-cholesterol were associated with low ABI only by the modified definition. Low ABI by the modified definition detected 9 new cases of PAD but cardiovascular risk had not been considered high in 3 patients when calculated by FRS. In conclusion, given that a simple modification of ABI calculation would be able to identify more patients at high risk, it should be considered for cardiovascular risk prediction in all elderly hypertensive outpatients.
Arterial stiffness leads to left ventricular (LV) mass through non-atherosclerotic pathways in mice. In humans, a high ankle brachial index (ABI) indicates stiff peripheral arteries, and is associated with cardiovascular disease (CVD) events. Whether high ABI is associated with LV mass in humans, and whether this may reflect consequences of arterial stiffness, atherosclerosis, or both is unknown.
Among 4,972 MESA participants without clinical CVD, we used linear regression to evaluate the association of low (< 0.90) and high (>1.40 or incompressible) ABI with LV mass by cardiac magnetic resonance imaging (MRI). Intermediate ABIs served as the reference category. To determine the effect of subclinical atherosclerosis, models were adjusted for common and internal carotid intima media thickness (cIMT) and log-transformed coronary artery calcification (Ln[CAC+1]).
Compared to subjects with intermediate ABI, LV mass was higher with either low (2.70g/m2 higher, 95% CI 0.65–4.75) or high ABI (6.84 g/m2 higher, 95% CI 3.2–10.47) after adjustment for traditional CVD risk factors, kidney function, and CRP. However, further adjustment for cIMT and CAC substantially attenuated the association of low ABI with LVMI (1.24 g/m2 higher, 95% CI −0.84–3.33), whereas the association of high ABI was minimally altered (6.01 g/m2 higher, 95% CI 2.36–9.67).
High ABI is associated with greater LV mass; an association that is not attenuated with adjustment for subclinical atherosclerosis in non-peripheral arterial beds. High ABI may lead to greater LV mass through non-atherosclerotic pathways.
vascular stiffness; medial arterial calcification; left ventricular mass; heart failure; cardiovascular disease
Studies have shown that rheumatoid arthritis (RA) patients are two to five times more likely to develop premature cardiovascular disease, thus shortening their life expectancy by five to 10 years. This risk has risen to approximately 12.6% in the urban population and 7.4% in the rural population of India. The Framingham risk score (FRS) identifies patients at increased cardiovascular risk and helps determine the need for preventive interventions. An investigation of the patients’ coronary arteries and coronary artery calcification (CAC) – a measure of atherosclerotic plaque – has been found to be a strong predictor of cardiovascular disease.
To identify important biological markers for easy and non-invasive identification of cardiovascular disease in RA patients, and to investigate whether there is a relationship between the FRS and coronary artery atherosclerosis in RA patients.
The present study included 43 established RA patients and 50 healthy individuals (controls). Traditional and nontraditional risk factors were studied and compared with the control group. Insulin resistance was assessed using the homeostasis model of assessment of insulin resistance (HOMA-IR) and the homeostasis model of assessment of beta cell function. The FRS and the 10-year cardiovascular risk were compared between RA patients and controls. The presence of CAC was determined using electron-beam computed tomography, and the association between the FRS and CAC was examined.
Significant differences in body mass index, waist circumference, rheumatoid factors (immunoglobulin [Ig]G, IgM and IgA) and inflammatory markers – C-reactive protein and erythrocyte sedimentation rate – were noted. There was significant correlation between HOMA-IR and body mass index, hypertension and C-reactive protein, but no correlation was seen with the homeostasis model of assessment of beta cell function. Significant differences were observed in the nontraditional biomarkers in RA patients, thus supporting their importance. Calcium deposition was observed in only seven RA patients.
RA patients with increased C-reactive protein levels and erythrocyte sedimentation rates showed an increase in serum insulin levels and significant differences in HOMA-IR, thus indicating insulin resistance, which could lead to underlying progression of artherosclerosis. Significant differences were observed in the nontraditional risk factors, which could be chosen as biomarkers for endothelial dysfunction. There was a significant correlation between calcium score and the FRS in seven patients, suggestive of an underlying risk of atherosclerosis.
Atherosclerosis; ELISA; HOMA-B; HOMA-IR; Inflammation; Insulin resistance; Rheumatoid arthritis
Cardiovascular risk functions fail to identify more than 50% of patients who develop cardiovascular disease. This is especially evident in the intermediate-risk patients in which clinical management becomes difficult. Our purpose is to analyze if ankle-brachial index (ABI), measures of arterial stiffness, postprandial glucose, glycosylated hemoglobin, self-measured blood pressure and presence of comorbidity are independently associated to incidence of vascular events and whether they can improve the predictive capacity of current risk equations in the intermediate-risk population.
This project involves 3 groups belonging to REDIAPP (RETICS RD06/0018) from 3 Spanish regions. We will recruit a multicenter cohort of 2688 patients at intermediate risk (coronary risk between 5 and 15% or vascular death risk between 3-5% over 10 years) and no history of atherosclerotic disease, selected at random. We will record socio-demographic data, information on diet, physical activity, comorbidity and intermittent claudication. We will measure ABI, pulse wave velocity and cardio ankle vascular index at rest and after a light intensity exercise. Blood pressure and anthropometric data will be also recorded. We will also quantify lipids, glucose and glycosylated hemoglobin in a fasting blood sample and postprandial capillary glucose. Eighteen months after the recruitment, patients will be followed up to determine the incidence of vascular events (later follow-ups are planned at 5 and 10 years). We will analyze whether the new proposed risk factors contribute to improve the risk functions based on classic risk factors.
Primary prevention of cardiovascular diseases is a priority in public health policy of developed and developing countries. The fundamental strategy consists in identifying people in a high risk situation in which preventive measures are effective and efficient. Improvement of these predictions in our country will have an immediate, clinical and welfare impact and a short term public health effect.
Clinical Trials.gov Identifier: NCT01428934
Risk assessment; cardiovascular diseases; primary prevention; primary health care.
It has been proposed that coronary artery calcium (CAC) can be used to estimate an arterial age in adults. Supporting this concept is that chronologic age, as used in cardiovascular risk assessment, is a surrogate for atherosclerotic burden. This measure can provide the patient with a more understandable version of their CAC score (e.g. you are 55 years old, but your arteries are more consistent with an arterial age of 65). We describe a method of estimating arterial age by equating estimated coronary heart disease (CHD) risk for observed age and coronary artery calcium (CAC). Arterial age is then the risk-equivalent of coronary artery calcium. We use data from the Multi-Ethnic Study of Atherosclerosis (MESA), a cohort study of 6814 participants free of clinical cardiovascular disease, followed for an average of 4 years. Estimated arterial age is obtained as a simple linear function of log-transformed CAC. In a model for incident CHD risk controlling for both age and arterial age, only arterial age was significant, indicating that observed age does not provide additional information after controlling for arterial age. Framingham risk calculated using this arterial age is more predictive of short-term incident coronary events than Framingham risk based on observed age (area under the ROC curve 0.75 for Framingham risk based on observed age, 0.79 using arterial age, p=0.006). In conclusion, arterial age provides a convenient transformation of CAC from Agatston units to a scale more easily appreciated by both patients and treating physicians.
Coronary artery calcium (CAC) is an integral part of atherosclerotic coronary heart disease (CHD). CHD is the leading cause of death in industrialized nations and there is a constant effort to develop preventative strategies. The emphasis is on risk stratification and primary risk prevention in asymptomatic patients to decrease cardiovascular mortality and morbidity. The Framingham Risk Score predicts CHD events only moderately well where family history is not included as a risk factor. There has been an exploration for new tests for better risk stratification and risk factor modification. While the Framingham Risk Score, European Systematic Coronary Risk Evaluation Project, and European Prospective Cardiovascular Munster study remain excellent tools for risk factor modification, the CAC score may have additional benefit in risk assessment. There have been several studies supporting the role of CAC score for prediction of myocardial infarction and cardiovascular mortality. It has been shown to have great scope in risk stratification of asymptomatic patients in the emergency room. Additionally, it may help in assessment of progression or regression of coronary artery disease. Furthermore, the CAC score may help differentiate ischemic from nonischemic cardiomyopathy.
coronary calcium scoring; coronary artery disease; CAC; cardiomyopathy; angiography; chest pain; Framingham; risk stratification; risk factors
Recent studies indicate that subclavian stenosis (SS), diagnosed by a large systolic blood pressure difference (SBPD) between the right and left brachial arteries, is associated with cardiovascular disease (CVD) risk factors and outcomes. We sought to describe the epidemiology of SS and determine its association with markers of subclinical CVD in the baseline cohort of the Multi-Ethnic Study of Atherosclerosis.
We defined SS by an absolute SBPD ≥15 mmHg. Peripheral artery disease (PAD) was defined by an ankle-brachial index ≤0.90. The coronary artery calcium score (CAC) and the common-carotid artery intima-media thickness (CCA-IMT) were measured by computed tomography and B-mode ultrasound, respectively. Odds ratios for the associations of SS with risk factors and subclinical disease were estimated using logistic regression.
Of 6,743 subjects studied, 307 participants (4.6%) had SS, with a higher prevalence in women (5.1%) than men (3.9%), and in African-Americans (7.4%) and non-Hispanic whites (5.1%) than Hispanic (1.9%) or Chinese (1.0%) participants (p<0.01). In a model including age, gender, ethnicity, traditional and novel CVD risk factors, significant associations with SS were observed for C-reactive protein (highest vs. three lower quartiles: OR=1.41; 95%CI: 1.06-1.87) and brachial artery pulse pressure (OR=1.12 /10 mmHg; 95%CI: 1.03-1.21). Adjusted for age, gender, ethnicity, traditional and novel CVD risk factors, SS was significantly associated with PAD (OR=2.35; 1.55-3.56), with CCA-IMT (highest vs. the lower three quartiles: OR=1.32; 1.00-1.75), and high CAC (score >100 vs. score=0; OR=1.43; 1.03-2.01).
The subclavian stenosis is positively associated with other markers of subclinical atherosclerosis.
subclavian artery; blood pressure; atherosclerosis; epidemiology
To compare the predictability of the Framingham Risk Score (FRS), United Kingdom Prospective Diabetes Study (UKPDS) risk engine, and the Systematic Coronary Risk Evaluation (SCORE) for carotid atherosclerosis and peripheral arterial disease in Korean type 2 diabetic patients.
Among 1,275 registered type 2 diabetes patients in the health center, 621 subjects with type 2 diabetes participated in the study. Well-trained examiners measured the carotid intima-media thickness (IMT), carotid plaque, and ankle brachial index (ABI). The subject's 10-year risk of coronary heart disease was calculated according to the FRS, UKPDS, and SCORE risk scores. These three risk scores were compared to the areas under the curve (AUC).
The odds ratios (ORs) of all risk scores increased as the quartiles increased for plaque, IMT, and ABI. For plaque and IMT, the UKPDS risk score provided the highest OR (95% confidence interval) at 3.82 (2.36, 6.17) and at 6.21 (3.37, 11.45). For ABI, the SCORE risk estimation provided the highest OR at 7.41 (3.20, 17.18). However, no significant difference was detected for plaque, IMT, or ABI (P = 0.839, 0.313, and 0.113, respectively) when the AUCs of the three risk scores were compared. When we graphed the Kernel density distribution of these three risk scores, UKPDS had a higher distribution than FRS and SCORE.
No significant difference was observed when comparing the predictability of the FRS, UKPDS risk engine, and SCORE risk estimation for carotid atherosclerosis and peripheral arterial disease in Korean type 2 diabetic patients.
Risk Assessment; Peripheral Arterial Disease; Carotid Artery Thrombosis; Diabetes Mellitus, Type 2
Atherosclerosis is the leading cause of cardiovascular disease (CVD). Traditional risk factors can be used to identify individuals at high risk for developing CVD and are generally associated with the extent of atherosclerosis; however, substantial numbers of individuals at low or intermediate risk still develop atherosclerosis.
A case-control study was performed using microarray gene expression profiling of peripheral blood from 119 healthy women in the Multi-Ethnic Study of Atherosclerosis cohort aged 50 or above. All participants had low (<10%) to intermediate (10% to 20%) predicted Framingham risk; cases (N = 48) had coronary artery calcium (CAC) score >100 and carotid intima-media thickness (IMT) >1.0 mm, whereas controls (N = 71) had CAC<10 and IMT <0.65 mm. We identified two major expression profiles significantly associated with significant atherosclerosis (odds ratio 4.85; P<0.001); among those with Framingham risk score <10%, the odds ratio was 5.30 (P<0.001). Ontology analysis of the gene signature reveals activation of a major innate immune pathway, toll-like receptors and IL-1R signaling, in individuals with significant atherosclerosis.
Gene expression profiles of peripheral blood may be a useful tool to identify individuals with significant burden of atherosclerosis, even among those with low predicted risk by clinical factors. Furthermore, our data suggest an intimate connection between atherosclerosis and the innate immune system and inflammation via TLR signaling in lower risk individuals.
Cardiovascular disease (CVD), associated with vascular atherosclerosis, is the major cause of death in Western societies. Current risk estimation tools, such as Framingham Risk Score (FRS), based on evaluation of multiple standard risk factors, are limited in assessment of individual risk. The majority (about 70%) of the general population is classified as low FRS where the individual risk for CVD is often underestimated but, on the other hand, cholesterol lowering with statin is often excessively administered. Adverse effects of statin therapy, such as muscle pain, affect a large proportion of the treated patients and have a significant influence on their quality of life.
Coronary artery calcification (CAC), as assessed by computed tomography, carotid artery intima-media thickness (CIMT), and especially presence of plaques as assessed by B-mode ultrasound are directly correlated with increased risk for cardiovascular events and provide accurate and relevant information for individual risk assessment. Absence of vascular pathology as assessed by these imaging methods has a very high negative predictive value and therefore could be used as a method to reduce significantly the number of subjects who, in our opinion, would not benefit from statins and only suffer from their side-effects.
In summary, we suggest that in very-low-risk subjects, with the exception of subjects with low FRS with a family history of coronary artery disease (CAD) at young age, if vascular imaging shows no CAC or normal CIMT without plaques, statin treatment need not be administered.
Framingham Risk Score; cardiovascular disease; coronary artery calcification; carotid artery intima-media thickness; statin; atherosclerosis
Peripheral artery tonometry (PAT) is a novel method for assessing arterial stiffness of small digital arteries. Pulse pressure can be regarded as a surrogate of large artery stiffness. When ankle-brachial index (ABI) is calculated using the higher of the two ankle systolic pressures as denominator (ABI-higher), leg perfusion can be reliably estimated. However, using the lower of the ankle pressures to calculate ABI (ABI-lower) identifies more patients with isolated peripheral arterial disease (PAD) in ankle arteries. We aimed to compare the ability of PAT, pulse pressure, and different calculations of ABI to detect atherosclerotic disease in lower extremities. We examined PAT, pulse pressure, and ABI in 66 cardiovascular risk subjects in whom borderline PAD (ABI 0.91 to 1.00) was diagnosed 4 years earlier. Using ABI-lower to diagnose PAD yielded 2-fold higher prevalence of PAD than using ABI-higher. Endothelial dysfunction was diagnosed in 15/66 subjects (23%). In a bivariate correlation analysis, pulse pressure was negatively correlated with ABI-higher (r = −0.347, p = 0.004) and with ABI-lower (r = −0.424, p < 0.001). PAT hyperemic response was not significantly correlated with either ABI-higher (r = −0.148, p = 0.24) or with ABI-lower (r = −0.208, p = 0.095). Measurement of ABI using the lower of the two ankle pressures is an efficient method to identify patients with clinical or subclinical atherosclerosis and worth performing on subjects with pulse pressure above 65 mm Hg. The usefulness of PAT measurement in detecting PAD is vague.
Ankle-brachial index; peripheral arterial disease; hypertension
Lower extremity peripheral arterial disease (PAD) is a marker of widespread atherosclerosis. Individuals with PAD, most of whom do not show typical PAD symptoms ('asymptomatic' patients), are at increased risk of cardiovascular ischaemic events. American College of Cardiology/American Heart Association guidelines recommend that individuals with asymptomatic lower extremity PAD should be identified by measurement of ankle-brachial index (ABI). However, despite its associated risk, PAD remains under-recognised by clinicians and the general population and office-based ABI detection is still poorly-known and under-used in clinical practice. The Prevalence of peripheral Arterial disease in patients with a non-high cardiovascular disease risk, with No overt vascular Diseases nOR diAbetes mellitus (PANDORA) study has a primary aim of assessing the prevalence of lower extremity PAD through ABI measurement, in patients at non-high cardiovascular risk, with no overt cardiovascular diseases (including symptomatic PAD), or diabetes mellitus. Secondary objectives include documenting the prevalence and treatment of cardiovascular risk factors and the characteristics of both patients and physicians as possible determinants for PAD under-diagnosis.
PANDORA is a non-interventional, cross-sectional, pan-European study. It includes approximately 1,000 primary care participating sites, across six European countries (Belgium, France, Greece, Italy, The Netherlands, Switzerland). Investigator and patient questionnaires will be used to collect both right and left ABI values at rest, presence of cardiovascular disease risk factors, current pharmacological treatment, and determinants for PAD under-diagnosis.
The PANDORA study will provide important data to estimate the prevalence of asymptomatic PAD in a population otherwise classified at low or intermediate risk on the basis of current risk scores in a primary care setting.
Trial registration number
Clinical Trials.gov Identifier: NCT00689377.
Prediction models to identify healthy individuals at high risk of cardiovascular disease have limited accuracy. A low ankle brachial index is an indicator of atherosclerosis and has the potential to improve prediction.
To determine if the ankle brachial index provides information on the risk of cardiovascular events and mortality independently of the Framingham Risk Score and can improve risk prediction.
Relevant studies were identified by collaborators. A search of MEDLINE (1950 to February 2008) and EMBASE (1980 to February 2008), was conducted using common text words for the term ‘ABI’ combined with text words and Medical Subject Headings to capture prospective cohort designs. Review of reference lists and conference proceedings, and correspondence with experts was conducted to identify additional published and unpublished studies.
Studies were included if (1) participants were derived from a general population (2) ankle brachial index was measured at baseline and (3) subjects were followed up to detect total and cardiovascular mortality.
Pre-specified data on subjects in each selected study were extracted into a combined dataset and an individual participant data meta-analysis conducted on subjects who had no previous history of coronary heart disease.
Sixteen population cohort studies fulfilling the inclusion criteria were included. During 480,325 person years of follow up of 24,955 men and 23,339 women, the risk of death by ankle brachial index had a reverse J shaped distribution with a normal (low risk) ankle brachial index of 1.11 to 1.40. The 10-year cardiovascular mortality (95% CI) in men with a low ankle brachial index (≤ 0.90) was 18.7% (13.3% to 24.1%) and with normal ankle brachial index (1.11 to 1.40) was 4.4% (3.2% to 5.7%), hazard ratio (95% CI) 4.2 (3.5 to 5.4). Corresponding mortalities in women were 12.6% (6.2% to 19.0%) and 4.1% (2.2% to 6.1%), hazard ratio 3.5 (2.4 to 5.1). The hazard ratios remained elevated on adjusting for Framingham Risk Score, 2.9 (2.3 to 3.7) for men and 3.0 (2.0 to 4.4) for women. A low ankle brachial index (≤0.90) was associated with approximately twice the 10-year total mortality, cardiovascular mortality and major coronary event rate compared with the overall rate in each Framingham category. Inclusion of the ankle brachial index in cardiovascular risk stratification using the Framingham Risk Score would result in reclassification of the risk category and modification of treatment recommendations in approximately 19% of men and 36% of women.
Measurement of the ankle brachial index may improve the accuracy of cardiovascular risk prediction beyond the Framingham Risk Score. Development and validation of a new risk equation incorporating the ankle brachial index is warranted.
The absence of coronary artery calcium (CAC) is a marker of very low cardiovascular risk. Endothelial cells may have an effect on the initiation and propagation of arterial calcification. We aimed to identify the relationship between the absence of CAC and endothelial function in individuals without cardiovascular disease and diabetes.
Methods and Results
CAC was assessed using electron-beam computed tomography and the calcium score was then computed. Endothelial function was measured by assessing reactive hyperemia-induced vasodilation and expressed by the reactive hyperemia index (RHI). Of 82 patients, 39 had non-detectable calcium (CAC score=0) and 43 had a CAC score >0. In the CAC score=0 group, the prevalence of normal endothelial function was 84.6%, compared to 48.8% in the CAC score >0 group, P=0.001. The absence of CAC was highly correlated with normal endothelial function (γ=0.704, P<0.001). On average, endothelial function was significantly better in the CAC score=0 group than in the CAC score >0 group (RHI 2.2±0.6 vs. 1.8±0.5, P=0.002). In a multivariate logistic regression model, only normal endothelial function (odds ratio [OR] 5.03, 95% confidence interval [CI] 1.55–16.27, P=0.007) and age (years) (OR 0.91, 95% CI 0.86–0.96, P=0.002) were independently associated with the absence of CAC.
Normal functional status of the vasculature may be important for the prevention of coronary calcification and may partly account for the low cardiovascular risk of absent CAC. (Circ J 2012; 76: 2705 – 2710)
Atherosclerosis; Coronary artery calcium; Electron-beam computed tomography; Endothelial function
Carotid intima-media thickness (CIMT) can be reliably determined in vivo by carotidian ultrasound and is an accessible and reliable method to assess subclinical atherosclerosis. Available epidemiological data showed that CIMT is significantly correlated with future cardiovascular events. However it has limited value to help risk stratification on top of standard risk-derived functions such as Framingham risk score. It is particularly useful in individuals classified as being at intermediate or high risk by the presence of multiple conventional risk factors.
CIMT has a class IIa (LOE: B) reccommendation for cardiovascular risk assessment according to the practice guidelines published in 2010, emphasizing the presence of high risk if the common carotid artery intima–media thickness is above the 75th percentile. There is no indication to measure IMT in patients with full-blown atherosclerotic carotid disease, although carotidian ultrasound still remains a very useful tool to assess the severity of disease even in these subjects.
Progression of CIMT (also associated with increasing age) can be delayed by some drugs (statins, colestipol and niacin) and by risk factors modification. However, there is no consistent data demonstrating a link between progression of CIMT and coronary and cerebral events. Subsequently, studies using CIMT progression as primary outcome to indicate the influence of a certain therapy on cardiovascular risk are inherently misleading as suggested in the recently published ACC/AHA Guidelines.
rheumatoid arthritis; inflammation; metabolic syndrome; accelerated atherosclerosis
While the Framingham Risk Score provides a reasonable estimation of risk in certain subgroups, the majority of MIs occur in individuals classified as low or moderate risk. Coronary Artery Calcium (CAC) testing provides an individualized measure of atherosclerotic burden that integrates an individual’s cumulative lifetime risk factor exposure that cannot be obtained from serum markers.
Methods and Results
We briefly summarize the existing evidence for the use of CAC scanning in primary prevention and performed a meta-analysis of the existing randomized controlled data investigating the impact of CAC screening on lifestyle modification, risk factors, and downstream testing. We identified four trials published between 2003 and 2011 with a total of 2,490 participants, >75% of whom came from the Early Identification of Subclinical Atherosclerosis by Noninvasive Imaging Research (EISNER) trial. Three of the trials reported a non-significant increase in smoking cessation in the scan versus no-scan group with a pooled mean of 1.15 (95% CI 0.77 – 1.71). A significant reduction in SBP and LDL was noted in the EISNER trial, but the pooled estimates were 0.23mmHg (95% CI −2.25 – 2.71) and 0.23mg/dL (95% CI −5.96 – 6.42), respectively. Only the EISNER trial reported medication usage according to CAC score. They found a higher CAC score associated with an increased prescription of lipid lowering medications (p=<0.001) and a CAC=0 associated with fewer prescriptions for lipid lowering medications (p=0.02).
Our meta-analysis highlights the paucity of randomized evidence linking CAC scanning to improved intermediate and hard outcomes in primary prevention. Future trials are urgently needed to determine the impact of CAC screening on lifestyle modification, risk factor modification, and downstream testing.
coronary artery disease; risk factors; primary prevention; imaging
Various measures of arterial stiffness and wave reflection have been proposed as cardiovascular risk markers. Prior studies have not assessed relations of a comprehensive panel of stiffness measures to prognosis in the community.
Methods and Results
We used proportional hazards models to analyze first-onset major cardiovascular disease (CVD) events (myocardial infarction, unstable angina, heart failure or stroke) in relation to arterial stiffness (pulse wave velocity, PWV), wave reflection (augmentation index, carotid-brachial pressure amplification) and central pulse pressure in 2232 participants (mean age 63 years, 58% women) in the Framingham Heart Study. During median follow-up of 7.8 (range 0.2 to 8.9) years, 151 of 2232 participants (6.8%) had an event. In multivariable models adjusting for age, sex, systolic blood pressure, use of antihypertensive therapy, total and HDL cholesterol concentrations, smoking and presence of diabetes, higher aortic PWV was associated with a 48% increase in CVD risk (95% CI, 1.16 to 1.91 per SD, P=0.002). After adding PWV to a standard risk factor model, integrated discrimination improvement was 0.7% (95% CI, 0.05 to 1.3%, P<0.05). In contrast, augmentation index, central pulse pressure and pulse pressure amplification were not related to CVD outcomes in multivariable models.
Higher aortic stiffness assessed by PWV is associated with increased risk for a first cardiovascular event. Aortic PWV improves risk prediction when added to standard risk factors and may represent a valuable biomarker of CVD risk in the community.
aorta; arterial stiffness; pulse wave velocity; cardiovascular disease; prognosis
Even among asymptomatic people at low risk (<10%) by Framingham Risk Score (FRS), high coronary artery calcium (CAC) scores signify higher predicted risk of coronary heart disease (CHD) events. We sought to determine non-invasive factors (without radiation exposure) significantly associated with CAC in low-risk, asymptomatic persons. In a cross-sectional analysis, we studied 3046 participants from MESA at low 10-year predicted risk (FRS <10%) for CHD events. Multivariable logistic regression was used to assess the association of novel markers with presence of any CAC (CAC >0) and advanced CAC (CAC ≥ 300). CAC >0 and CAC ≥ 300 were present in 30% and 3.5% of participants, respectively. Factor VIIIc, fibrinogen and sICAM were each associated with CAC presence (P ≤ 0.02); and C-reactive protein, D-dimer and carotid intima-media thickness (CIMT) with advanced CAC (P ≤ 0.03). The base model combining traditional risk factors had excellent discrimination for advanced CAC (C-statistic, 0.808). Addition of the 2 best-fit models combining biomarkers plus/minus CIMT improved the c-statistics to 0.822 and 0.820, respectively. All 3 models calibrated well, but were similar in estimating individual risk probabilities for advanced CAC (prevalence = 9.97%, 10.63% and 10.10% in the highest quartiles of predicted probabilities versus 0.26%, 0.26% and 0.26% in the lowest quartiles, respectively). In conclusion, in low risk individuals, traditional risk factors alone predicted advanced CAC with high discrimination and calibration. Biomarker combinations +/− CIMT were also significantly associated with advanced CAC, but improvement in prediction and estimation of clinical risk were modest compared to traditional risk factors alone.
coronary calcium; biomarkers; novel markers; low-risk; risk factors
The aim of this study was to investigate the relationship between obesity, insulin resistance and atherosclerosis in type 2 diabetes mellitus (T2DM) patients. Total 530 patients with T2DM were included. To evaluate the severity of atherosclerosis, we measured the coronary artery calcification (CAC) score, intima-media thickness (IMT) of the common carotid artery, and the ankle-brachial pressure index (ABPI). Subjects were classified according to body mass index (BMI), a marker of general obesity, and waist-to-hip ratio (WHR), a marker of regional obesity. The insulin sensitivity index (ISI) was measured by the short insulin tolerance test. All subjects were classified into four groups, according to BMI: the under-weight group, the normal-weight (NW) group, the over-weight (OW) group, and the obese (OB) group. WHR and systolic blood pressure, triglycerides (TG), HDL-cholesterol (HDL-C), free fatty acids (FFA), fibrinogen, and fasting c-peptide levels were significantly different between BMI groups. TG, HDL-C, FFA, fibrinogen and ISI were significantly different between patients with and without abdominal obesity. In the OW group as well as in the NW group, carotid IMT, ABPI and CAC score were significantly different between patients with and without abdominal obesity. This study indicates that abdominal obesity was associated with atherosclerosis in T2DM patients.
Obesity; Insulin Resistance; Diabetes Mellitus Type 2; Atherosclerosis
The Framingham risk score (FRS) is widely used in clinical practice to identify subjects at high risk for developing coronary heart disease (CHD). However, FRS may not accurately identify subjects at risk. We measured subclinical atherosclerosis in the coronary arteries and aorta with the presence of calcium (CAC and AC, respectively) and in the common carotid artery by intima-media thickness (CIMT) in 498 healthy subjects. The distribution of these subclinical atherosclerosis measures was evaluated across 3 strata of the FRS. CAC, AC and CIMT were significantly independently associated with FRS. The FRS increased with the number of arterial sites with atherosclerosis. Sixty-nine percent of the subjects categorized in the low risk group (FRS<10%), 95% of the intermediate risk group (FRS 10–20%), and 100% of the high risk group (FRS>20%) had 1 or more vascular imaging studies demonstrating subclinical atherosclerosis. Among the low risk group, subjects with atherosclerosis had a longer history of lifetime smoking compared to those without atherosclerosis. In conclusion, subclinical atherosclerosis is prominent across the spectrum of FRS. Evaluation of subclinical atherosclerosis in different arterial sites in addition to FRS may be useful in targeting subjects for lifestyle and other interventions.
Subclinical atherosclerosis; Framingham risk score; Carotid IMT; Coronary artery calcium; Aortic calcium
While asymptomatic patients should have a lower risk of cardiac events compared to symptomatic patients referred for cardiac stress testing, comparable event rates have been noted in some prior prognostic studies. To test if a high burden of undetected atherosclerosis among asymptomatic patients helps explain such findings, we compared atherosclerotic burden, as measured by coronary artery calcium (CAC) scanning, in propensity-matched groups of volunteers and asymptomatic patients.
CAC scans were performed on a research basis in 136 asymptomatic patients referred for exercise myocardial perfusion SPECT and in 1,398 volunteers. We performed matching by propensity scores to compare volunteers with the same CAD risk factor profile as our asymptomatic patients.
Among our matched groups, asymptomatic patients had significantly greater mean CAC scores than volunteers (394 ± 805 vs 151 ± 349, P = .001), primarily due to a higher frequency of CAC scores >1,000 (15.4% vs 2.5%, P < .001). Inducible myocardial ischemia by SPECT was present in 7% of patients, but was selectively concentrated among those with CAC scores >1,000, occurring in 27.0% of such patients vs only 1.9% among patients with CAC scores <1,000 (P < .0001).
In contrast to asymptomatic volunteers, asymptomatic patients referred for cardiac stress testing possess more extensive atherosclerosis as measured by CAC. Among asymptomatic patients with high CAC scores, the frequency of concomitant inducible myocardial ischemia is high. These results help explain prior prognostic studies concerning asymptomatic patients and indicate the importance of making a clinical distinction between healthy subjects and asymptomatic patients with respect to atherosclerotic risk.
Coronary calcification; ischemia; atherosclerosis; coronary artery disease
Peripheral arterial disease (PAD), along with coronary artery disease and cerebrovascular disease, is a manifestation of systemic atherosclerosis. These cardiovascular diseases (CVDs) are the leading cause of death in the world, representing 30% of all global deaths. Although population-based studies indicate that PAD has a relatively benign course in the legs, patients with PAD show more cardiovascular comorbidity and have at least twofold risk of fatal coronary artery disease and cerebrovascular accidents compared with the general population. These studies suggest that noninvasive testing using the ankle-brachial index (ABI) is also an accurate marker of subclinical CVD and thus may hold promise for early identification of individuals at the greatest risk for major CVD events.
The Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II) defines a cutoff ABI value of 0.90 or less for diagnosing PAD at rest. This threshold value has been reported to be 95% sensitive in detecting angiogram-positive PAD and almost 100% specific in identifying apparently healthy individuals. In persons without PAD, arterial pressures increase with greater distance from the heart, resulting in higher systolic blood pressures at the ankle than at the the brachial arteries. Thus, persons without atherosclerosis typically have an ABI greater than 1.00. But what is the significance of ABI values between 0.91 to 1.00, which are conventionally regarded as ‘no disease’? The present article gives an overview of current knowledge of borderline PAD (ie, an ABI of 0.91 to 1.00).
Ankle-brachial index; Borderline peripheral arterial disease; Cardiovascular disease; Cardiovascular risk; Peripheral arterial disease
OBJECTIVE: To determine the ability of carotid intima-media thickness (CIMT) and coronary artery calcium score (CACS) to detect subclinical atherosclerosis in a young to middle-aged, low-risk, primary-prevention population.
PATIENTS AND METHODS: Patients aged 36 to 59 years who underwent determination of CIMT and CACS at our institution between May 1, 2004, and April 1, 2008, were included in the study. Those with diabetes mellitus or a history of coronary, peripheral, or cerebral vascular disease were excluded. Other information, such as Framingham risk score (FRS), was obtained by a review of clinical and laboratory data.
RESULTS: Of 118 patients, 89 (75%) had a CACS of zero and 94 (80%) were men; mean ± SD age was 48.9±5.7 years. The mean FRS of this group was 4.0; 86 patients (97%) were considered at low risk (<1% annualized rate) of cardiovascular events. Evidence of carotid atherosclerosis was found in 42 (47%; 95% confidence interval, 37%-58%) of these 89 patients; carotid plaque was found in 30 (34%); and CIMT above the 75th percentile was found in 12 (13%) of age-, sex-, and race-matched control patients. Of the 40 patients with low-risk CIMT (below the 50th percentile), 4 (10%) had a CACS at or above the 50th percentile.
CONCLUSION: Subclinical vascular disease can be detected by CIMT evaluation in young to middle-aged patients with a low FRS and a CACS of zero. These findings have important implications for vascular disease screening and the implementation of primary-prevention strategies.
Subclinical vascular disease can be detected by carotid intima-media thickness evaluation in young to middle-aged patients with a low Framingham risk score and a coronary artery calcium score of zero; these findings have important implications for vascular disease screening and the implementation of primary-prevention strategies.