As life expectancy doubled between 1800 and 2000, atherosclerosis replaced infectious diseases as the main cause of death in the developed world. But is atherosclerosis a purely modern phenomenon, precipitated by lifestyle changes and an ageing population, or was it common in ancient societies too?

Thompson et al. performed whole-body CT scans on 137 mummies from four different geographical areas to look for calcification and therefore atherosclerosis. Atherosclerosis was present in the aorta in 28 (20%) mummies, iliac or femoral arteries in 25 (18%), popliteal or tibial arteries in 25 (18%), carotid arteries in 17 (12%), and coronary arteries in six (4%). Of the five vascular beds examined, atherosclerosis was present in one to two beds in 34 (25%) mummies, in three to four beds in 11 (8%), and in all five vascular beds in two (1%). Of note the age at the time of death was positively correlated with atherosclerosis (mean age at death 43 years for mummies with atherosclerosis vs 32 years for those without; p<0·0001) and with the number of arterial beds involved (p<0·0001).

Conclusions:

This unique study performed CT imaging of mummies from different geographical regions and found that atherosclerosis was common in four ancient populations, and therefore challenges the assumption that it is a largely modern disease.

• Thompson RC, Allam AH, Lombardi GP et al. Atherosclerosis across 4000 years of human history: the Horus study of four ancient populations. Lancet 2013; published online March 10, 2013. http://dx.doi.org/10.1016/ S0140-6736(13)60598-X

Unrecognised myocardial infarction (UMI) may be more prevalent than previously suspected.  Although several population studies have described the prevalence of UMI based on ECG findings, this method has limited sensitivity.  Cardiac magnetic resonance (CMR) imaging with late gadolinium enhancement has been extensively validated for the detection of myocardial infarction.  The aim of this study was to determine the prevalence and prognosis of recognised and unrecognised MI diagnosed with CMR in a elderly population, and to compare these findings with the use of ECG.

Data from 936 individuals (aged 67 to 93 years) from a community-dwelling cohort of older individuals in Iceland were analysed; 670 were randomly selected, and 266 had diabetes.  The main outcome measures were the prevalence and mortality of MI up until September 2011.

91 of the 936 (9.7%) participants where known to have had an MI (recognised MI (RMI)).  157 patients had UMI detected by CMR (17%), which was more prevalent than the 46 UMI detected by ECG (5%; P<.001).  Amongst those with diabetes (n=337), UMI was more commonly detected by CMR than ECG (21% vs. 4%; P<.001).  Over a median of 6.4 years, 33% of participants with recognised MI died, and 28% with unrecognised MI died; both of these were higher than the 17% of patients with no MI who died.  Unrecognised MI by CMR improved risk stratification for mortality over RMI, and after adjusting for age, sex, and a history of MI, UMI by CMR remained associated with mortality and significantly improved risk stratification for mortality, however UMI as detected by ECG did not.

Conclusions:

In this community study of older individuals, the prevalence of unrecognised MI on cardiac MRI was higher than the prevalence of recognised MI and was associated with increased mortality risk.

• Schelbert EB, Cao JJ, Sigurdsson S et al.  Prevalence and Prognosis of Unrecognized Myocardial Infarction Determined by Cardiac Magnetic Resonance in Older Adults.  JAMA 2012;308:890-897.

In recent years invasive coronary angiography (ICA) has been supplemented by the measurement of fractional flow reserve (FFR) to determine whether a coronary stenosis impairs delivery of oxygen to the heart. However this technique has not previously been available through non-invasive methods. While the use of coronary computed tomography (CT) calcium scoring and angiography has been increasing, it remains a limitation of the technique that the haemodynamic significance of any lesions seen cannot be assessed.

The DeFACTO (Determination of Fractional Flow Reserve by Anatomic Computed Tomographic Angiography) study determined whether a noninvasive calculation of FFR derived from computational fluid dynamics (FFRCT) could diagnose haemodynamically significant coronary artery disease, using invasive FFR as the reference standard.

The study involved 252 stable patients with known or suspected coronary disease from 17 centers in 5 countries, all of whom under went CT, coronary angiography with FFR measurement, and FFRCT. The accuracy of FFRCT and CT for the diagnosis of ischaemia was compared to invasive FFR as the reference standard. The main outcome measure was whether FFRCT plus CT could improve the per-patient diagnostic accuracy.

137 participants in the study (54.4%) had an abnormal FFR. Although the study did not achieve its prespecified primary outcome goal, compared with obstructive coronary disease diagnosed by CT alone, FFRCT was associated with improved discrimination (P<.001).

Conclusions:

The use of noninvasive FFRCT plus CT was associated with improved diagnostic accuracy vs CT alone for the diagnosis of haemodynamically significant coronary artery disease.

• Min JK, Leipsic J, Pencina MJ et al. Diagnostic Accuracy of Fractional Flow Reserve From Anatomic CT Angiography. JAMA 2012;308:doi:10.1001/2012.jama.11274.

The primary prevention of cardiovascular disease involves classifying individuals according to their global cardiovascular risk. However, those at intermediate risk represent a particular challenge; while some may require aggressive treatment, others may be best managed by lifestyle measures alone. Biomarkers that have shown promise in improving risk discrimination include carotid intima-media thickness (CIMT), coronary artery calcium (CAC) scoring, brachial flow-mediated dilation (FMD), ankle-brachial index (ABI), high-sensitivity C-reactive protein (CRP) and, in addition, having a family history of coronary heart disease (CHD). Determining whether – and by how much – risk prediction can be improved by various markers could help to determine the most efficient strategy for the use of primary prevention drugs.

1330 intermediate risk participants (Framingham risk score of >5% and <20% for a coronary event within the next ten years) in the Multi-Ethnic Study of Atherosclerosis (MESA) were followed up for a mean of 7.6 years. The area under the receiver operator characteristic curve (AUC) and net relassification improvement were used to compare the incremental contributions of each marker when added to Framingham risk score, plus race/ethnicity.

94 coronary heart disease (CHD) and 123 cardiovascular (CVD) events occurred overall. Coronary artery calcium, ankle-brachial index, high-sensitivity CRP, and family history were independently associated with incident CHD in multivariable analysis, but carotid intima-media thickness and brachial flow-mediated dilation were not. Although addition of each of the markers individually to the Framingham risk score improved the AUC, coronary artery calcium afforded the highest increment, and brachial flow-mediated dilation the least. Similarly, the net reclassification improvement for incident CHD was highest for coronary artery calcium. Similar results were obtained for incident CVD.

Conclusions:

In this study of patients at intermediate risk for cardiovascular disease, coronary artery calcium provided superior discrimination and risk reclassification when compared to other novel risk markers.

• Yeboah J, McClelland RL, Polonsky TS et al. Comparison of Novel Risk Markers for Improvement in Cardiovascular Risk Assessment in Intermediate-Risk Individuals. JAMA 2012;308:788-795.

Although current cardiovascular risk equations perform reasonably well in predicting disease, improvement is still needed.  One way to do this would be to include a measure of preclinical atherosclerosis in risk prediction algorithms.  Measurement of common carotid initima-media thickness (CIMT) could be of use in this regard, but evidence that it can aid existing risk scores in prediction of the absolute risk of cardiovascular events has been inconsistent.

In this meta-analysis, the authors’ aim was to determine whether common CIMT could improve the 10-year risk prediction of first-time myocardial infarction and stroke above that of the Framingham risk score.  Relevant studies performed between 1950 and 2012 were selected, where patients had had a baseline CIMT performed and were then followed up for a first cardiovascular event.  Individual data were combined into one data set and an individual participant data meta-analysis was performed on individuals without existing cardiovascular disease.

14 population-based cohorts were analysed, contributing data for 45,828 individuals.  Over a median follow-up of 11 years, 4007 first-time myocardial infarctions or strokes occurred.  The authors looked at the accuracy of the Framingham risk score with and without the incorporation of CIMT.  The C statistic of both models was similar, and the net reclassification improvement with the addition of common CIMT was small (0.8%). Looking specifically at those at intermediate risk, the net reclassification improvement was 3.6% in all individuals, with no differences noted between men and women.

Conclusion:

Adding common CIMT measurements to the Framingham Risk Score was associated with a small improvement in 10-year risk prediction of first-time myocardial infarction or stroke.  However, it is unlikely that such a small improvement will be of clinical importance.

•   Den Ruijter HM, Peters SAE, Anderson TJ et al.  Common Carotid Intima-Media Thickness Measurements in Cardiovascular Risk Prediction.  A Meta-analysis.  JAMA 2012;308:796-803.

Patients with Human Immunodeficiency Virus (HIV) demonstrate a high prevalence of noncalcified coronary atherosclerotic lesions.  However, the specific mechanisms that lead to this remain unknown.  In this study Subramanian et al. used ¹⁸fluorine-2-deoxy-D-glucose positron emission tomography (¹⁸F-FDG-PET) to assess arterial wall inflammation in patients with HIV, and compared this to traditional and nontraditional risk makers.

A group of 27 HIV patients without known cardiac disease underwent ¹⁸F-FDG-PET and coronary computed tomography for coronary artery calcium scanning also.  Two separate non-HIV control groups were used; one was matched to the HIV group for age, sex, and Framingham risk score (FRS) and also had no known atherosclerotic disease, the other was matched on sex and selected based on the presence of known atherosclerotic disease.   The main outcome measure the ratio of FDG uptake in the arterial wall of the ascending aorta to venous background (target-to-background ratio, TBR).

All HIV patients were receiving antiretroviral therapy and had good CD4 counts.  Arterial inflammation in the aorta (aortic TBR) was higher in the HIV patients when compared to the non-HIV patients matched for FRS (P<.001), even after adjustment for traditional risk factors (P=.002).  However, aortic inflammation was similar in the HIV group compared to the non-HIV atherosclerotic control group.  Among patients with HIV, aortic TBR was associated with sCD163 levels (a circulating marker of monocyte and macrophage activation), but not with C-reactive protein or D-dimer.

Conclusions:

Using FDG-PET, this study found that patients with HIV had increased arterial inflammation when compared to noninfected control participants with similar cardiovascular risk factors.

• Subramanian S, Tawakol A, Burdo TH et al.  Arterial Inflammation in Patients with HIV.  JAMA 2012;308:379-386.

Carotid intima-media thickness (cIMT) is an ultrasound marker of early atherosclerosis.  Increasing cIMT thickness has been shown to correlate with an increased risk of subsequent cardiovascular events in general populations, independent of other major risk factors.  However, whether a change in cIMT thickness over time affects the risk of cardiovascular events has not been systematically investigated.  The first stage of the PROG-IMT project (individual progression of carotid intima media thickness as a surrogate of vascular risk) analysed the association of cIMT progression with the risk of cardiovascular events on a large dataset derived from general populations.

For this meta-analysis, the authors initially identified general population studies that assessed cIMT at least twice and followed up participants for myocardial infarction (MI), stroke, or death; patients with a previous history of MI or stroke were excluded.  36,984 participants from 16 eligible studies were included.  Over a mean follow-up of 7.0 years, 1519 MIs, 1339 strokes, and 2028 combined endpoints (MI, stroke, or vascular death) occurred.  When adjusted for vascular risk factors, mean common carotid IMT progression was associated with a hazard ratio (HR) of 0.98 (0.95-1.01) for the combined endpoint.  However, the mean cIMT was found to associate with cardiovascular risk (HR 1.16).

Conclusions:

This study found no association between cIMT progression and cardiovascular risk, therefore questioning the use of this technique for cardiovascular screening or as a biomarker in clinical trials.

• Lorenz MW, Polak JF, Kavousi M et al.  Carotid intima-media thickness progression to predict cardiovascular events in the general population (the PROG-IMT collaborative project): a meta-analysis of individual participant data.  Lancet 2012;379:2053-62

Recently evidence has emerged suggesting the prognostic value of CT coronary angiography (CTCA), however whether it can provide extra information over and above routine clinical workup – including exercise treadmill testing – remains uncertain.  Dedic et al. determined to answer this question in patients with stable chest pain and suspected coronary artery disease (CAD).

The study enrolled 471 patients who underwent exercise ECG testing and CTCA, with exercise ECG tests being classified as either normal, ischaemic, or non diagnostic.  The primary outcome measure was a major adverse cardiac event (MACE), defined either as cardiac death, nonfatal myocardial infarction, or unstable angina requiring hospitalization and revascularization (beyond 6 months). Univariable and multivariable Cox regression analysis was used to determine the prognostic values, while clinical impact was assessed with the net reclassification improvement metric.

Over a mean follow-up of 2.6 years 44 MACEs occurred in 30 patients.  The presence of coronary calcification (hazard ratio [HR], 8.22 ), obstructive CAD (HR, 6.22), and nondiagnostic stress test results (HR, 3.00) were univariable predictors of MACEs. In the multivariable model, CT angiography findings (HR, 5.0) and nondiagnostic exercise ECG results (HR, 2.9) remained independent pre-dictors of MACEs. CT angiography findings showed incremental value beyond clinical predictors and stress testing (P <.001), whereas coronary calcium scores did not have further incremental value (P = .40).

Conclusions:

This study shows again that CT angiography findings are a strong predictor of future adverse events, in this study showing incremental value over clinical predictors, stress testing, and coronary calcium scores.

• Dedic A, Genders TSS, Ferket BS et al.  Stable Angina Pectoris: Head-to- Head Comparison of Prognostic Value of Cardiac CT and Exercise Testing.  Radiology 2011;261:428-436.

In recent years it has become clear that treatment of coronary artery disease – and in particular percutaneous coronary intervention (PCI) – must be guided by imaging techniques that give some information on the extent of myocardial ischaemia.  While nuclear medicine techniques such as SPECT (single-photon emission computed tomography) have become widespread, and have a high negative predictive value, they still expose patients to ionising radiation.  Furthermore, the sensitivity of SPECT has been noted to vary.  Cardiac Magnetic Resonance Imaging (MRI), is a potential alternative that uses no ionising radiation, provides high-resolution images, and is capable of assessing various cardiac parameters in one comprehensive examination.

The CE-MARC study (Clinical Evaluation of MAgnetic Resonance imaging in Coronary heart disease) was designed to provide a real-world comparison of stress perfusion MRI and SPECT, using coronary angiography as the gold standard.  752 patients with stable angina (not including those who had had previous bypass surgery) were recruited over a three year period.  Of these, 378 were assigned to CMR then SPECT, while 374 were assigned to SPECT then CMR.  Overall 39% of patients had significant coronary disease as detected by X-ray angiography.  For multiparametric CMR the sensitivity was 86·5% (95% CI 81·8—90·1), and specificity 83·4% (79·5—86·7), compared to the sensitivity of SPECT which was 66·5% (95% CI 60·4—72·1), and specificity 82·6% (78·5—86·1).  The sensitivity and negative predictive value of CMR and SPECT differed significantly (p<0·0001 for both) but specificity and positive predictive value did not (p=0·916 and p=0·061, respectively).

Conclusions:

This large, prospective trial of stress perfusion MRI shows its high diagnostic accuracy and superiority over SPECT imaging.  As such CE-MARC is a landmark trial that is likely to challenge the current dominance of nuclear imaging for the assessment of myocardial perfusion.

• Greenwood JP, Maredia N, Younger JF et al.  Cardiovascular magnetic resonance and single-photon emission computed tomography for diagnosis of coronary heart disease (CE-MARC): a prospective trial.  Lancet 2011;379:453-460

Hypoperfusion of the anterior wall and septum seen on MRI (left) and SPECT (centre). Angiography demonstrates this to be due to LAD and diagonal disease.

In the JUPITER study, patients with low cholesterol levels but raised high-sensitivity C-reactive protein (hsCRP) levels were seen to benefit from treatment with rosuvastatin, although overall cardiovascular events were low.  In this study, the authors investigated whether the use of coronary artery calcium (CAC) scoring could further stratify risk in a population of patients from the Multi-Ethnic Study of Atherosclerosis (MESA) who all met criteria for entry into the JUPITER study.

950 participants were selected, and the burden of coronary artery calcium was scored as either 0, 1-100, or >100.  Coronary heart disease and cardiovascular disease event rates and multivariable-adjusted hazard ratios were compared after stratifying amongst the three CAC groups.  The 5-year number needed to treat was calculated by applying the benefit recorded in JUPITER to the event rates within each CAC strata.

The median follow-up was 5.8 years.  444 (47%) in the MESA JUPITER population had CAC scores of 0 and in this group very low rates of coronary heart disease events were seen: 0.8 per 1000 person-years.  74% of all coronary events were in the 239 (25%) of participants with CAC scores of more than 100: 20.2 per 100 person-years.  For cardiovascular disease, therefore, the number needed to treat was 124 for patients with a CAC of 0, 54 for those with a score of 0-100, and 19 for those with a score of over 100.  Of note, hsCRP was not associated with either coronary heart or cardiovascular disease after multivariable adjustment.

Conclusions:

CAC can be used to further risk stratify patients who meet the criteria for entry into the JUPITER trial, and could be used to target those patients who are likely to benefit the most (and the least) from statin therapy.

• Blaha MJ, Budoff MJ, DeFilippis AP et al.  Associations between C-reactive protein, coronary artery calcium, and cardiovascular events: implications for the JUPITER population from MESA, a population-based cohort study.  Lancet 2011; 378:684-692.