Incremental predictive value of vascular assessments combined with the Framingham Risk Score for prediction of coronary events in subjects of low-intermediate risk

Background: In patients with low-intermediate risk, the use of the Framingham Risk Score (FRS) may not allow accurate prediction of the occurrence of coronary events. Objective: To determine whether non-invasive vascular sonographic assessments add value to the FRS for prediction of coronary events. Methods: Brachial artery flow-mediated dilatation (FMD), carotid intima-media thickness (IMT) and the presence of carotid plaque in 70 male subjects (mean (SD) age 62 (9) years) with a low-intermediate FRS who presented with a recent coronary event were evaluated and compared with those in 35 male controls matched for age (mean age 60 (9) years). Results: Patients with a recent coronary event had a significantly higher FRS than controls. They had a significantly lower FMD (3.56 (2.41)% vs 5.18 (2.69)%, p = 0.003) and significantly higher prevalence of carotid plaque (67% vs 40%, p = 0.008), but there was no significant difference in mean maximum IMT between the two groups (1.01 (0.28) vs 0.96 (0.14) mm, p = 0.32). Multivariate analysis revealed that FMD ≤ 4.75% was an independent predictor of an acute coronary event. Of the three vascular markers, FMD ≤ 4.75% and presence of carotid plaque provided the best diagnostic accuracy for a coronary event, with area under the curve (AUC) of 0.70 and 0.64 (p = 0.001 and p = 0.033), respectively, based on receiver operating characteristic curve analysis. Furthermore, incorporating carotid plaque or FMD ≤ 4.75% into the FRS (AUC = 0.72 and AUC = 0.78) provided incremental benefit in risk stratification over FRS alone (AUC = 0.66) (p = 0.008 and p = 0.007, for comparison of difference in two receiver operating characteristic curves). Conclusions: Incorporating a measure of FMD or carotid plaque burden with FRS significantly increases the accuracy of predicting coronary events in subjects of low-intermediate risk and hence should be considered as additional investigations to improve coronary risk assessment.published_or_final_versio

Molecular imaging in atherosclerosis

Atherosclerosis is the major cause of cardiovascular disease, which still has the leading position in morbidity and mortality in the Western world. Many risk factors and pathobiological processes are acting together in the development of atherosclerosis. This leads to different remodelling stages (positive and negative) which are both associated with plaque physiology and clinical presentation. The different remodelling stages of atherosclerosis are explained with their clinical relevance. Recent advances in basic science have established that atherosclerosis is not only a lipid storage disease, but that also inflammation has a fundamental role in all stages of the disease. The molecular events leading to atherosclerosis will be extensively reviewed and described. Further on in this review different modalities and their role in the different stages of atherosclerosis will be discussed. Non-nuclear invasive imaging techniques (intravascular ultrasound, intravascular MRI, intracoronary angioscopy and intravascular optical coherence tomography) and non-nuclear non-invasive imaging techniques (ultrasound with Doppler flow, electron-bean computed tomography, coronary computed tomography angiography, MRI and coronary artery MR angiography) will be reviewed. After that we focus on nuclear imaging techniques for detecting atherosclerotic plaques, divided into three groups: atherosclerotic lesion components, inflammation and thrombosis. This emerging area of nuclear imaging techniques can provide measures of biological activity of atherosclerotic plaques, thereby improving the prediction of clinical events. As we will see in the future perspectives, at present, there is no special tracer that can be called the diagnostic tool to diagnose prospective stroke or infarction in patients. Nevertheless, we expect such a tracer to be developed in the next few years and maybe, theoretically, it could even be used for targeted therapy (in the form of a beta-emitter) to combat cardiovascular disease

Role of computed tomography and magnetic resonance imaging in patients with cardiovascular disease

Background: Although there have been recent advances, cardiovascular disease remains the commonest cause of premature death in the United Kingdom. There is a need to develop safe non-invasive techniques to aid the diagnosis and treatment of patients with cardiovascular disease.Objectives: The aims of this thesis are: (i) to establish whether coronary artery calcification can be measured reproducibly by helical computed tomography; (ii) to establish the effect of lipid lowering therapy on the progression of coronary calcification; (iii) to determine whether multidetector computed tomography can predict graft patency in patients who have undergone coronary artery bypass grafting; and (iv), to investigate the role of magnetic resonance imaging to assess plaque characteristics following acute carotid plaque rupture.Methods: In 16 patients, coronary artery calcification was assessed twice within 4 weeks by helical computed tomography. As part of a randomised controlled trial, patients received atorvastatin 80 mg daily or matching placebo, and had coronary calcification assessed annually. Fifty patients with previous coronary artery bypass surgery who were listed for diagnostic coronary angiography underwent contrast enhanced computed tomography angiography using a 16-slice multidetector computed tomography scanner. Finally, 15 patients with recent symptoms and signs of an acute transient ischaemic attack, amaurosis fugax or stroke underwent magnetic resonance angiography of the carotid arteries using dedicated surface coils. Plaque volume, regional plaque densities and neovascularisation were determined before and after gadolinium enhancement.Results: Quantification of coronary artery calcification demonstrated good reproducibility in patients with scores > 100 AU. Despite reducing systemic inflammation and halving serum low-density lipoprotein cholesterol concentrations, atorvastatin therapy did not affect the rate of progression of coronary artery calcification. Computed tomography angiography was found to be highly specific for the detection of graft patency. Assessment of plaque characteristics by magnetic resonance scanning in patients with recent acute carotid plaque was feasible and reproducible.Conclusions: Coronary artery calcium scores can be determined in a reproducible manner. Although they correlate well with the presence of atherosclerosis and predict future coronary risk. there is little role for monitoring progression of coronary artery calcification in order to assess the response to lipid lowering therapy. Computed tomography can be used reliably to predict graft patency in patients who have undergone coronary artery bypass grafting, and is an acceptable non-invasive alternative to invasive coronary angiography. Magnetic resonance imaging techniques ' can be employed in a feasible, timely and reproducible manner to detect plaque characteristics associated with acute atherothrombotic disease

Inflammation and characteristics of atherosclerotic plaque

Atherosclerosis, or the accumulation of lipids within the arterial wall, is the underlying process responsible for the majority of cardiovascular disease (CVD). Inflammation is one of the essential forces driving the development and progression of atherosclerosis. Several cells, chemokines, and co-stimulatory molecules of the innate and adaptive immune response have been associated with atherosclerosis and cardiovascular risk. Another important risk factor associated with atherosclerotic CVD risk is psychosocial stress, and it has been widely hypothesized psychosocial stress influences CVD through increased inflammation. Within atherosclerotic plaque, greater inflammatory content is associated with plaque instability and greater likelihood of plaque to result in a cardiovascular event via erosion or rupture. B-mode ultrasound is an imaging technique that allows for the measurement and characterization of atherosclerotic plaque in the superficial arteries such as the carotid and femoral arteries. The measurement and characterization of plaque in subclinical stages affords us the opportunity to better understand the processes contributing to the development of atherosclerosis and for the identification of individuals who may be at risk of having a cardiovascular event. In this dissertation, the associations between the circulating burden of inflammation and coagulation with measures of plaque presence, burden, and characteristics in the carotid and femoral arteries are evaluated with the intention of better understanding the inflammatory mechanisms contributing to plaque instability. Additionally, we assessed inflammatory burden as a potential mediator of the relationship between perceived everyday discrimination, a measure of psychosocial stress, with carotid plaque characteristics. Overall, we did not find any independent associations between inflammatory and coagulation burden with measures of femoral plaque presence, burden, and characteristics among healthy older adults. However we did find several associations between inflammatory and coagulation burden with various measures of carotid plaque burden and characteristics independent of traditional CVD risk factors among women in midlife. We also identified inflammatory burden as a partial mediator of the relationship between everyday discrimination and carotid plaque height. The findings presented in the following chapters have public health significance because they highlight important associations between circulating inflammatory and coagulation burden with measures of carotid plaque burden and characteristics among women, and suggest that increased inflammatory and coagulation burden may serve as mechanisms contributing to the progression and complication of atherosclerotic plaque among women at midlife. Furthermore, our results suggest that increased inflammatory burden and greater atherosclerotic plaque height may be mechanisms through which experiences of discrimination increase cardiovascular risk among midlife women

A genetic association study of carotid intima-media thickness (CIMT) and plaque in Mexican Americans and European Americans with rheumatoid arthritis

Background and aims: Little is known about specific genetic determinants of carotid-intima-media thickness (CIMT) and carotid plaque in subjects with rheumatoid arthritis (RA). We have used the Metabochip array to fine map and replicate loci that influence variation in these phenotypes in Mexican Americans (MAs) and European Americans (EAs). Methods: CIMT and plaque were measured using ultrasound from 700 MA and 415 EA patients with RA and we conducted association analyses with the Metabochip single nucleotide polymorphism (SNP) data using PLINK. Results: In MAs, 12 SNPs from 11 chromosomes and 6 SNPs from 6 chromosomes showed suggestive associations (p \u3c 1 × 10-4) with CIMT and plaque, respectively. The strongest association was observed between CIMT and rs17526722 (SLC17A2 gene) (β ± SE = -0.84 ± 0.18, p = 3.80 × 10-6). In EAs, 9 SNPs from 7 chromosomes and 7 SNPs from 7 chromosomes showed suggestive associations with CIMT and plaque, respectively. The top association for CIMT was observed with rs1867148 (PPCDC gene, β ± SE = -0.28 ± 0.06, p = 5.11 × 10-6). We also observed strong association between plaque and two novel loci: rs496916 from COL4A1 gene (OR = 0.51, p = 3.15 × 10-6) in MAs and rs515291 from SLCA13 gene (OR = 0.50, p = 3.09 × 10-5) in EAs. Conclusions: We identified novel associations between CIMT and variants in SLC17A2 and PPCDC genes, and between plaque and variants from COL4A1 and SLCA13 that may pinpoint new candidate risk loci for subclinical atherosclerosis associated with RA

Coronary Angiography

In the intervening 10 years tremendous advances in the field of cardiac computed tomography have occurred. We now can legitimately claim that computed tomography angiography (CTA) of the coronary arteries is available. In the evaluation of patients with suspected coronary artery disease (CAD), many guidelines today consider CTA an alternative to stress testing. The use of CTA in primary prevention patients is more controversial in considering diagnostic test interpretation in populations with a low prevalence to disease. However the nuclear technique most frequently used by cardiologists is myocardial perfusion imaging (MPI). The combination of a nuclear camera with CTA allows for the attainment of coronary anatomic, cardiac function and MPI from one piece of equipment. PET/SPECT cameras can now assess perfusion, function, and metabolism. Assessing cardiac viability is now fairly routine with these enhancements to cardiac imaging. This issue is full of important information that every cardiologist needs to now

The determinants of intra-plaque neovascularisation: a study by contrast-enhanced carotid ultrasonography

Atherosclerosis is a chronic inflammatory disorder, initiated by arterial wall injury, mediated by well-recognised cardiovascular risk factors and culminating in formation of plaques, the patho-biological substrate that precedes events such as stroke and myocardial infarction. Intraplaque neovascularisation (IPN) is one of several defence mechanisms in response to atherosclerosis. With development of an atherosclerotic plaque within the intima, the distance between the deeper intimal layers and the luminal surface increases, producing hypoxia within the arterial wall. This stimulates release of pro-angiogenic factors that induces neoangiogenesis in an attempt to normalise oxygen tension. However, these neo-vessels are fragile, immature and leaky and thought to be the primary cause of intraplaque haemorrhage, now appreciated to be a key risk factor for plaque rupture. Therefore, the presence of IPN is now widely recognised as a precursor of the “vulnerable plaque”. Contrast-enhanced ultrasound (CEUS) is a non-invasive method of imaging carotid plaques and, as contrast bubbles travel wherever erythrocytes travel, they permit visualization of IPN. Prior research studies have demonstrated that CEUS can detect IPN with a high degree of accuracy (on comparison with histological plaque specimens) and have shown a relationship between extent of plaque neovessels and plaque echogenicity and between plaque neovascularization and prior cardiovascular events. However, CEUS is a relatively recently described imaging technique and there were a number of unanswered questions in this field, some of which formed the basis for study in this research Thesis. In this Thesis, research studies were conducted on human subjects using CEUS imaging to identify IPN and its determinants. The incidence and determinants of IPN in healthy asymptomatic individuals was unknown and was studied in subjects from the London Life Sciences Population (LOLIPOP) study, a large study exploring mechanisms for differences in cardiovascular disease (CVD) between South Asian and European White individuals. The study found that approximately half of all plaques contain IPN. The only variable associated with IPN presence in an adjusted analysis was Asian ethnicity. This finding potentially has significant implications as it may help explain, in part, the greater CVD burden observed in Asian populations. A study comparing visualization of the carotid tree during B-mode and CEUS imaging was also conducted. Both IMT visualization and plaque detection were significantly improved by CEUS, implying that CEUS is superior to B-mode imaging for detection of sub-clinical atherosclerosis. Radiotherapy (RT) damages arterial walls and promotes atherosclerosis. The carotid arteries frequently receive significant incidental doses of radiation during RT treatment of head and neck cancers. The effect of RT on plaque composition – specifically IPN – had not been studied and thus a collaborative cardio-oncological study was conducted to assess the effects of RT upon IPN in cancer survivors who had previously received RT. A significant association between RT and IPN was found which may provide insights into the mechanisms underlying the increased stroke risk amongst cancer survivors treated by RT. Finally, a collaboration with biophysicists was formed to develop and validate a novel algorithm for quantitative analysis of IPN. Patients clinically scheduled to undergo carotid endarterectomy were recruited and underwent CEUS imaging prior to surgery. This study did not achieve its principal aims due to challenges with patient recruitment, challenges in image quality and with the quantification software also. Future directions of study in this promising field have been addressed in the thesis summary.Open Acces

High resolution ultrasound and arterial wall changes in early atherosclerosis

Non-invasive vascular testing evolved initially to meet the needs of the surgeon to identify haemodynamically significant lesions. However, with refinement of techniques and the development of high resolution ultrasound, it has become possible to detect early lesions and to measure the thickness of die arterial wall with an accuracy of 0.2mm. Such measurements have epidemiological and prognostic potential. They may allow the study of progression (or regression) of atherosclerotic disease before symptoms develop. The aim of this thesis was to assess the value of arterial wall measurements of intima-media thickness and compliance of the common carotid artery in the prediction of early atherosclerotic disease. Four different anatomical patterns of carotid bulb morphology have been identified, according to the position of the bulb origin in relation to the flow divider. It has been demonstrated that bulb morphology influences the site of early plaque formation. The presence of plaque at the carotid and femoral bifurcations was found to be associated with increased intima-media thickening of the common carotid artery. Histological analysis of common carotid arteries taken at post-mortem showed that this diffuse intima-media thickening is the result of deposition of cholesterol crystals, medial atrophy, fatty and fibrous change, and accumulation of necrotic debris, the features characteristic of plaques, even though discrete plaques rarely occur at this site. Subsequently, a number of clinical studies were undertaken which demonstrated that the intima-media thickness is increased in diabetics, hypopituitary patients and claudicants as compared to controls. It was found that the intima-media thickness of the common carotid artery could be used to predict the presence of bifurcation plaques and macrovascular disease. The work of this thesis has demonstrated that high resolution ultrasound is a powerful technique for die study of the arterial wall and should be tested in prospective studies for its suitability as an epidemiological tool

Non-invasive imaging of diabetic vascular disease

A high proportion of diabetic subjects are referred with atherosclerotic disease and higher risk for cardiovascular events. Rapid expansion of the use of non-invasive coronary and peripheral arteries imaging, facilitated by technological advances, have found diagnostic and prognostic roles in this population. This review, which includes important and actual works, guidelines, and algorithms on cardiovascular disease in the diabetic population, indicates mandatory screening for arterial disease in these patients in light of their appropriate management. Nuclear Med Rev 2010; 13, 1: 39–4