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Contemporary Cardiology In Asymptomatic Atherosclerosis: Pathophysiology, Detection and Treatment, Preventive Cardiology: The SHAPE of the Future.
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Showing Rating details. More filters. Sort order. FAQ Policy. About this book Despite recent advances in the diagnosis and treatment of symptomatic atherosclerosis, available traditional screening methods for early detection and treatment of asymptomatic coronary artery disease are grossly insufficient and fail to identify the majority of victims prior to the onset of a life-threatening event. Show all. Pages Rauoof et al. Feldman, Charles L. Raggi, Paolo et al. Show next xx. Recommended for you.

Adiponectin is thought to be also involved in the regulation of necrotic core development. In patients with stable CAD and in acute coronary syndrome, a decrease in plasma adiponectin values has been found to be associated with an increase in necrotic core in both culprit and non-culprit lesions assessed by intravascular ultrasounds, suggesting that in this clinical setting lower adiponectin levels reflect plaque vulnerability Otake et al.


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Accordingly, the association of decreased plasma adiponectin level and increased necrotic core ratio has not been demonstrated in patients with stable CAD Sawada et al. Adiponectin is thought to decrease atherosclerosis progression through inhibition of both neointimal thickening and SMC proliferation and migration into the intima. As recently suggested by Barseghian et al. Barseghian et al. On this line, a meta-analysis of 19 studies confirmed an increase of endogenous adiponectin levels with thiazolidinediones use. Accordingly, pioglitazone exhibited the potential of coronary plaque stabilization in patients with type 2 diabetes by increasing adiponectin levels and reducing the necrotic-core component Ogasawara et al.

The stroke represents the second leading cause of death and is a major contributor to health-care cost.

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Asymptomatic Atherosclerosis: Pathophysiology, Detection And Treatment by Morteza Naghavi

As recently reviewed by Endres et al Endres et al. Moreover, it has been indicated Pischon et al. In that review Endres et al. In several studies a close relationship between cholesterol plasma levels and stroke has not been found and hypercholesterolemia is thought to have major responsibility in atherothrombotic stroke only Endres et al. Although it is still unsettled whether statin use is useful in primary prevention of atherothrombotic stroke in subjects with mild hypercholesterolemia, evidence exists on the other side Naghavi et al,.

Several cancer subtypes gastrointestinal, hematological, female-specific, urologic and lung cancer have been observed to be associated with low LDL-cholesterol levels and the mechanisms by which preclinical cancer might induce low LDL-cholesterol plasma levels are largely unknown. The issue of a potential increased risk of cancer in patients treated with hypolipidemic drugs has been already faced in previous pages see section 3. The problem of an increased risk of cancer by hypolipidemic drugs has been raised since the late seventhies by the Clofibrate trial, a WHO Cooperative Trial on primary prevention of ischemic heart disease using clofibrate Oliver et al.

Recent meta-analyses Benn et al. This study has left unsettled the issue of the potential cause-effect relationship between LDL-cholesterol lowering by statin use and cancer. However, a recent metaanalysis of data on cancer from , paricipants in 25 randomized trials, it has been concluded that, at least in the five years treatment period no evidence emerged of any effect of statin therapy on cancer incidence or mortality at any particular site Emerson et al. Has the story come to an end?

Why Don't We Know Who Should Take an Aspirin to Prevent Cardiovascular Disease?

Atherosclerosis has been generally viewed as a chronic and inevitably progressive disease characterized by continuous accumulation of atheromatous plaque within the arterial wall. In the last 25 years an important step-up progression occurred with the introduction of a variety of anti-atherosclerotic therapies, the most important of which are the so called statins, which rank among the most extensively studied therapies in contemporary medicine, opening the door to an effective anti-atherosclerotic treatment in addition to standard non pharmacologic measures. Almost simultaneously, invasive and non-invasive imaging techniques of atherosclerosis have been attempted in the course of years and an extraordinary development in non-invasive assessment has been realized during the last two decades.

X-ray angiography is still considered the gold standard imaging technique for vessel patency studies but it does not usually allow obtaining information on plaque structure as well as differentiating stable from unstable plaques and the risk of rupture. This technique typically suffers from these limitations and even to day many cardiologists unfortunately still behave as if the absence of angiographic abnormalities indicates the normality of coronary artery anatomy and absence of atherosclerosis Davis et al.

All these methods are used in clinical setting and the type of investigation closely dependent on the clinical problem the individual patient has and on which techniques are locally available.

Asymptomatic Atherosclerosis Pathophysiology, Detection and Treatment Contemporary Cardiology

As it has already been discussed in previous pages high-quality studies have demonstrated that a correlation exits between the severity of atherosclerosis in one arterial territory and involvement of other arteries and that these tests can predict the risk of future CAD events Fowkes et al. Accordingly, noninvasive atherosclerosis imaging has evolved into a central method in clinical cardiology and both CCS and B-mode ultrasonography have recently become the most used techniques as first line approach for atherosclerosis detection in primary prevention setting Greenland et al.

Expert recommendations have endorsed the use of these imaging modalities in primary prevention Stein et al. According to Canadian Lipid Guidelines Genest et al. These guidelines Genest et al. In the following pages in addition to a brief review on the usefulness of noninvasive techniques the attention will be focused on noninvasive plaque imaging by ultrasound which is available in every clinical setting enabling first line study of plaque burden and structure with assessment of potential regression during statin treatment.

Due to inability of surface ultrasound to imaging coronary artery circulation, attention has focused on other techniques such as CT and MRI Kim et al. As far as MRI is concerned, appropriate sequences are needed for plaque imaging and the contrast-enhanced MRI used for clinical purposes is inadequate to this end Fig. Contrast-Enhanced MRI left panel and B-mode ultrasonography right panel of the left crotid artery in a patient with carotid atherosclerosis. In this case the MRI exam has been perfomed for the clinical purpose of a better assessment of vessel stenosis.

Plaque imaging would have required a different exam with T1-T2 weighted sequences. Due to its non-invasiveness carotid MRI has been recently proposed as tool for monitoring individual response to cardiovascular therapy Yuan, High-resolution MRI has been recently used for the noninvasive evaluation of carotid plaques showing that is possible to analyze the structure and molecules inside the plaque and to distinguish symptomatic from asymptomatic plaques and patients with low versus high risk through identification of iron deposition Raman et al.

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Moreover, discrimination between lipid core, fibrous cap, intraplaque haemorrhage and calcification as well as distinguishing macrophage-rich from macrophage—poor lesions is possible Kooi et al. From these studies emerged the finding that patients with a lipid-rich necrotic core with or without intraplaque haemorrhage represent the desired phenotype for monitoring treatment effects.

It has been recently also suggested Underhill et al.


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But new evidence that even low-dose ionizing radiation from cardiac imagingand therapeutic procedures is associated with an increased risk of cancer Eisenberg et al. During the last 25 years, after the seminal papers by Pignoli and his coworkers Pignoli, ; Poli et al. But at present, after dozens of published studies, the evidence to quantitatively support the use of a CIMT measurement to help in risk stratification on top of a risk function is limited Platinga et al.

The advent of modern CT and high resolution MRI, ranked these techniques at the first approach in the assessment of preclinical atherosclerosis by the American Heart Association guidelines Greenland et al. Quantification of coronary artery calcium, the so called coronary calcium score CCS , as an estimate of atherosclerotic plaque burden has become the current major application of non-contrast CT. It has been generally suggested that a zero CCS might exclude the need for coronary angiography among asymptomatic patients.

However, it has been also shown in studies that increasing the cut-point for calcification markedly improved the specificity but decreased the sensitivity. But a number of recent studieschallenged this statement. The first study Lester et al. The second from Mohlenkamp et al.

Mohlenkamp et al. Moreover, and in contrast with the published recommendations on the subject, a third new study from Gottlieb et al. Gottlieb et al. The finding of very low or even absent coronary calcium by CT in patients with documented carotid and femoral atherosclerosis has been found in a preliminary study from our group Fig.

Asymptomatic Atherosclerosis

As far as the effect on CCS by statin treatment is concerned, initial retrospective studies and observational data suggested that statin treatment resulted in reduction of coronary calcium but a recent exam of five randomized controlled trials proved that statin treatment does not reduce CCS values, with similar progression in either the treated and placebo group Gill Jr, The amount of carotid atherosclerosis has been arbitrarily graded into 6 grades from low to severe according to the amount of plaques in both arteries IMT value has not been taken into account.

CCS has been graded according to Agatstone score units. Close relationship exists on the presence and the amount of atherosclerosis between the two methods, with ultrasound findings being more sensitive than CCS in identifying subjects with atherosclerosis. These findings have been confirmed in studies and support the view that ultrasounds should be considered the first line approach in the screening for atherosclerosis in apparently healthy people with CV risk factors. Of note, other clinical circumstances have been suggested to take advantage from use of CCS measurement, these include: 1 distinguishing ischemic from non-ischemic etiology of dilated cardiomyopathy, 2 identifying patients in emergency department with chest pain and nonspecific ECG, 3 predicting very low subsequent event rates in patients with acute MI and negative CCS test.

However, and differently from asymptomatic patients setting, prognostic studies in symptomatic patients are lacking probably because a very large number of patients is needed in this setting to obtain the evidence. In any case, according to guidelines Greenland et al. Finally, as far as the role of the race is concerned, despite a generally higher prevalence of cardiovascular risk factors also included a broad trait of endothelial dysfunction in this population group Friedewald et al. Overall, as reported in recent guidelines, despite a higher prevalence of cardiovascular risk factors in blacks, the majority of studies demonstrated a lower prevalence and amount of coronary calcification compared to whites.

The recently published MESA study Multi-Ethnic Study of Atherosclerosis showed that traditional CV-risk-factor-based prediction models, such as the Framingham score, are improved by the addition of CCS especially in patients at intermediate risk for future coronary artery disease, ultimately suggesting the superiority of CCS and CIMT vs the Framingham risk score for risk prediction. The CCS resulted in a high reclassification rate in the intermediate-risk cohort, demonstrating the benefit of imaging of subclinical coronary atherosclerosis in carefully selected individuals with intermediate risk Erbel R, et al.

As far as the CIMT is concerned, a recent reclassification analysis of the ten-year follow-up of the Carotid Atherosclerosis Progression Study CAPS has challenged its value as a marker of future CV events rate and did not support its clinical usefulness for risk stratification in primary prevention setting Lorentz et al, But evidence has been provided that when associated with risk factor assessment the CIMT may still be a valid tool in risk prediction in dyslipidemic patients Baldassarre et al, The bottom line was that we have clear evidence that these two noninvasive methods of risk assessment are superior to Framingham risk score alone, and we think that the time has come to incorporate into new guidelines the cheaper, and completely safe, B-Mode ultrasound technique in primary prevention setting mainly focused on plaque detection.

The new high-resolution imaging technologies have enhanced our understanding of the atherosclerotic disease process and recently a new modified American Heart Association classification scheme system based on morphological plaque features and the propensity of plaque for thrombosis has been suggested for use Donnelly et al. Based on lipid deposition, fibrous cap thickening, lipid pool transition into necrotic core, calcium deposition, plaque disruption, haemorrhage and thrombosis, a number of categories of coronary atherosclerotic lesions have been identified and reported in Table 1 Stary et al.

Present status of CT technology clearly indicate that its diagnostic accuracy for the detection of the presence of atherosclerosis is superior over the detection of significant stenosis ultimately suggesting a progressive shift of this technique in the future towards the study of the atherosclerotic process per se rather than to simply assess the stenosis severity Van Velzen et al. As atherosclerosis begins early in life and then remains clinically silent for decades, a distinct opportunity for early intervention comes from the identification of subclinical stages of the disease.

Accordingly, the concept that atherosclerosis must be viewed as a preventable disease, which should be approached not only in terms of risk-factor control but also in terms of early disease detection, plaque prevention and plaque stabilization, has rapidly gained acceptance Naghavi et al. But even plaque regression the holy grail for therapeutic interventions appears possible and has become a new target in our clinical practice during the last ten years.

Together with a proposal for a strategy for primary CV disease prevention this evidence will be accordingly presented in the following pages. Coronary atherosclerosis starts early in the life and it is progressive in nature and when angiografically identified as minimal vessel stenosis its burden is already diffuse. By the time a patient has developed minor obstructive disease on angiography, an extensive systemic atheroma is already present. This finding underscores the importance of an aggressive risk factor modification and statin use since early stages of atherosclerosis in asymptomatic subjects Lavoie et al.

In recent years several studies addressed the prognostic implications of detecting asymptomatic atherosclerosis in the general apparently healthy population. Pathological, epidemiological and clinical studies indicate tha atherosclerosis is a systemic disease which develops with a variable extension and severity in all conduit arteries. In particular, an almost constant association exists between carotid, femoral, and coronary artery disease, with first clinical manifestation usually due to a CAD.

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Similarly, the presence of peripheral occlusive or sub-occlusive artery disease independently predicted myocardial infarction and death in 1, individuals with either carotid or femoral plaques by ultrasound Lamina et al. And early atherosclerosis increased IMT in femoral arteries predicted single-vessel CAD whereas advanced atherosclerotic plaques was usually associated with more severe CAD Sosnowski et al. Evidence of the systemic nature of the atherosclerotic process comes also fromseveral studies of prevalence of occult CAD in patients with peripheral artery disease or stroke. In a recent study in patients with cerebral infarction without history of CAD Amarenco et al.

Evidence of high prevalence of subclinical atherosclerosis in the general population comes also from another recent study on a randomly selectedsample of subjects mean age Also on this line are the results from the mass screening recently introduced in United Kingdom where an ultrasound scan of the abdomen is offered to all men over 64 years for the screening of abdominal aorta aneurysm by ultrasonography. In a large randomized trial in 67, men, age 65 to 74 years, it has been shown that in the group invited for screening the mortality was halved because of elective surgery : an approach that additionally proved to be highly cost-effective Kim et al.

As far as the role of carotid IMT as a predictor of future events is concerned, in a recent meta-anlaysis of 41 randomized trials it has been shown Costanzo et al. Similarly, a recent review including The American Society of Echocardiography consensus document Stein et al. Neither those persons with a past history of intensive professional sport activity appear protected by the atherosclerotic assault of modern life as demonstrated by a recent paper in which former professional football players, despite their elite athletic histories, have a similar prevalence of advanced subclinical atherosclerosis as a clinically referred population of overweight and obese men Hurst et al.

In response to the wall lipid infiltration and plaque formation the arterial wall changes its structure according to two types of anatomical remodelling, positive and negative. Positive remodelling is characterized by outward expansion and negative remodelling by vessel shrinkage. Paradoxically the apparent beneficial and more frequent phenomenon of outward wall expansion is associated with the feature of unstable lesions fig.

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These important morphological features have been studied in coronary vessels by intravascular ultrasound IVUS and angioscopy, but optical coherence tomography with its unique ability of identifying lipid content, fibrous cap thickness and its macrophage density, is the method of choice Yabushita et al. Recently, a first report on virtual histology-IVUS assessment of natural history 1 year follow-up with repeated examinations of coronary artery lesions morphology has been published Kubo et al.

In this study it has been demonstrated that most thin capped fibroatheroma had plaque progression most stabilized or healed but new developed whereas fibrotic and fibrocalcific plaque did not demonstrate any geometric changes during the follow-up and no spontaneous plaque regression has been observed, as usual. AS highlighted in previous pages an ischemic event is usually associated with an advanced atherosclerotic lesion.

And since early regression studies Blankenhorn et al. According to this line of conduct we have had evidence in the last 10 years on the possibility to induce plaque regression even up to complete disappearance: moreover we have realized how B-mode ultrasound imaging can help us and motivate patients in many ways in primary prevention setting. As it will be suggested in the next pages, our experience has confirmed the hypothesis that lipid lowering therapy selectively depletes the atherosclerotic plaques lipid content and prevents plaque disruption.