Plaque rupture flow chart reading

I am having a bit of trouble interpreting flow charts given in my biology question sets.

Given the following stimulus

The Question is :

In which of the following options does each substance play two different roles in the series of events from plaque ruprture to MI?

  1. ADP and collagen
  2. Collagen and Fibrinogen
  3. Antithrombin III and collagen
  4. Fibrinogen and antithrombin III

The answer is:

"Fibrinogen binds to the glycoprotein (GO) IIb/IIIa leading to the cross-linking of platelets. It is also converted into fibrin which stabilises these cross-links and leads to aggregation. Antithrombin III inhibits the activation of the coagulation cascade and also inhibits the production of thrombin. The answer is D.

My issue is:

This answer doesn't make sense to me.

The fibrinogen square connects to the "Cross links-platelets via GPIIb/III receptor" square, which THEN connects to the "Platelet cross-links stablised" square (i.e. "Fibrinogen" doesn't directly connected to "Platelet cross-links stablised").

Why does this count as "two different roles" yet e.g. "Exposure of collagen" connecting to "platelets adhere to collagen" which connects to "Platelet activation release of TXA2 and ADP" not count as "two different roles".

The Vulnerable Atherosclerotic Plaque: Strategies for Diagnosis and Management

Careful editing allows the authors to avoid repetition and provide comprehensive coverage of pathology, detection, and management. This thorough and authoritative reference will change the way interventionists look at the disease.

Meds Target, Tame Vulnerable Plaque

While prospectively detecting and treating vulnerable plaque remains a challenge, some medications, current and emerging, can help stabilize plaque for secondary prevention, according to a European Society of Cardiology (ESC) position paper.

The ESC Working Group of Atherosclerosis and Vascular Biology noted in the paper that strong clinical evidence has shown the ability of statins to stabilize plaque, along with positive results for aspirin and other antiplatelet agents, beta-blockers, and renin-angiotensin-aldosterone system inhibitors.

Researchers also noted the existence of some evidence showing plaque stabilization abilities for peroxisome proliferator activated receptor (PPAR) agonists, niacin, omega-3 fatty acids, and some HDL-raising therapies, according to the paper published online in Thrombosis and Haemostasis.

Vulnerable Plaques

Led by Seppo Ylä-Herttuala, MD, chairman of the ESC position paper task force, researchers noted that at least 75% of symptomatic coronary thrombi are caused by plaque rupture.

They described vulnerable plaques as those with thin fibrous caps, large lipid cores, and outward, or positive, remodeling.

A further categorization divides vulnerable plaque into two major types: rupture-prone and erosion-prone.

Rupture-prone plaques are homogenous, characterized by large and soft lipid-rich necrotic cores, with thin and inflamed fibrous caps. They have neovascularization properties and spotty calcification.

Erosion-prone plaques are heterogeneous, with no known distinct morphological features. However, they are rarely associated with expansive remodeling and only sparsely inflamed.

"So, irrespective of the plaque type, it is a misconception that vulnerable plaques are globally inflamed," researchers wrote.

The fibrous caps of vulnerable plaques contain abundant blood-derived leukocytes, including monocytes, macrophages, and T-lymphocytes.

Preclinical evidence suggests that some T-cells promote atherosclerosis, while others reduce atherosclerosis. "Thus, immunomodulation, which aims to change the T-helper cell milieu and promote Tregs [regulatory T-cells], seems an attractive possibility," the authors wrote.

Since T-cells promote plaque vulnerability locally through their effects on macrophages, research has focused on PPAR agonists and liver X receptor agonists, which have been shown in preclinical studies to positively affect macrophage inflammatory response.

An atheroprogressive immune response can also be counterbalanced by atheroprotective cytokines. For example, inhibiting transforming growth factor-&beta accelerated atherosclerosis and induced a vulnerable plaque phenotype in mice. Drugs that favor the expression of cytokines might help stabilize vulnerable plaque.

Chemokines, a large family of small, related cytokines that regulate cell trafficking of leukocytes to areas of injury, also have been shown to be integral players in the pro-inflammatory response. Inhibiting certain chemokines could help transform vulnerable to stable plaques.

Extracellular proteases including matrix metalloproteinases and cathepsins from macrophages promote many of the adverse structural changes associated with plaque vulnerability. "Inhibiting proteases directly or preventing their secretion into the plaque extracellular matrix appear attractive pathways to new plaque stabilizing treatments," Ylä-Herttuala and colleagues suggested.

Endothelial dysfunction is linked to activation of oxidative stress pathways, which aggravate atherosclerotic plaque formation. In preclinical models, it's been shown that up-regulating the nitric oxide pathway attenuates the atherosclerosis process. New drugs could potentially target this pathway, thus limiting endothelial dysfunction, which is "as an independent predictor of major adverse cardiac events."

Plaque Stability

The authors noted the difficulty of establishing dietary factors related to plaque stabilization. However, the effect of the Mediterranean diet, which has been shown to significantly reduce cardiovascular mortality by 9%, "seems to be related to increased consumption of nutrients, such as folates, omega-3 acids, polyphenols and vitamin D."

They pointed to only one study with direct evidence of nutrients on plaque stability (Lancet 2003 361: 477&ndash485). The study of 162 patients awaiting endarterectomy found that the inclusion of fish oil in the diet reduced the content of macrophages in the excised carotid arteries.

The ESC position paper noted the use of biomarkers, particularly high-sensitivity C-reactive protein, a marker of inflammation, to gauge one's risk of adverse cardiovascular events.

It also pointed to other "promising" biomarker targets such as chemokines and cytokines, tissue metalloproteinases, hemostatic factors, and myeloperoxidase. But all of these potential biomarker targets need validation and confirmation, the authors stated.

"A good biomarker needs to be specific for disease development or progression, to have a high predictive value for events and, if possible, should reflect successful treatment," the authors wrote, adding that there is a "pressing need for more specific and prognostic biomarkers to be added to the established risk factors to optimize risk prediction."

Genetic research has identified certain genes associated with cardiovascular disease. However, no data yet point to a specific genetic signature of the vulnerable plaque. "Although a specific (single) genetic test to identify a patient who carries rupture prone plaques is the ultimate goal, this seems currently unlikely," researchers wrote.

Catheter-based imaging modalities such as intravascular ultrasound (IVUS), virtual histology (VH)-IVUS, and optical coherence tomography (OCT), have added to the understanding of vulnerable plaque.

IVUS has validated that positive remodeling is associated with ruptured plaques. VH-IVUS, which characterizes plaque composition, has linked positive remodeling with a necrotic core.

OCT, which has higher resolution than IVUS, has added to the understanding of the thin fibrous cap on vulnerable plaques. OCT may one day be used to assess the effect of statins in plaque stabilization, Ylä-Herttuala and colleagues posited.

"Techniques emerging for future use include coronary CT, MRI and imaging techniques using markers of metabolic activity of certain cell types (e.g., macrophages) such as 18-FDG-PET," they wrote.

Studies of statins or statins plus other drugs (such as niacin) have demonstrated reductions in cardiovascular events, suggesting the hypothesis that these strategies lead to plaque stabilization. "However, current knowledge is still limited," the authors said.

They noted two statin studies that showed an effect on inflammation and plaque stability.

Crisby et al. showed that lesions from patients receiving pravastatin had significantly higher collagen content and less inflammatory cells, "suggesting that these plaques were more stable than plaques from untreated patients" (Circulation 2001 103: 926&ndash933).

Cortellaro et al. demonstrated that lesions from patients given atorvastatin exhibited fewer macrophages and inflammatory cells (Thromb Haemost 2002 88: 41&ndash47).

"Plaque rupture and subsequent thrombotic occlusion of the coronary artery account for as many as three quarters of myocardial infarctions," Ylä-Herttuala and colleagues wrote.

While the concept of plaque stabilization is two decades old, more recent research has lead to a better understanding of the pathophysiology of vulnerable plaque. Ultimately, this knowledge will help in the development of drugs to target specific atheroprogressive pathways.

New Method Effective In Detecting Dangerous Coronary Plaque

A significant number of patients who suffer a heart attack never have any warning signs. For many of these individuals, the source of the problem is noncalcified plaque, a buildup of soft deposits embedded deep within the walls of the heart's arteries, undetectable by angiography or cardiac stress tests -- and prone to rupture without warning.

Now a new noninvasive method has shown success in detecting and measuring noncalcified plaque. In a pilot clinical study led by investigators at Beth Israel Deaconess Medical Center (BIDMC), the technique -- voxel analysis used in conjunction with MDCTA (multi-detector computed tomography angiography) -- was shown to be equally as effective as catheter coronary angiography in identifying patients at risk for heart disease. Reported in the June 2008 issue of the American Journal of Roentgenology (AJR), the new findings may help doctors monitor the effects of medical treatment to reduce patients' risk of atherosclerosis and heart disease.

"The importance of quantifying plaque is critical because total plaque burden is considered the most important predictor of coronary events," explains the study's senior author Melvin Clouse, MD, PhD, Emeritus Chairman of the Department of Radiology and Director of Radiology Research at BIDMC and Deaconess Professor of Radiology at Harvard Medical School. "Furthermore, the rupture of soft noncalcified plaque has been implicated as the cause of heart attack."

Exercise stress testing and coronary angiography, the standard methods for diagnosing atherosclerosis and heart attack risk, both work by visualizing the lumen, the channel through which blood flows.

However, because the lumen also increases in size as plaque progresses, coronary artery disease may go undetected until late in the disease process. And, adds Clouse, "Because soft plaque buildup may not significantly narrow the lumen, conventional angiography and stress tests fail to provide a complete picture of plaque accumulation."

The investigators set out to evaluate a new method of plaque assessment using multidetector computed tomography angiography (MDCTA). Unlike coronary angiography, in which a catheter is threaded through the femoral artery and up into the heart, MDCTA is not invasive. The CT scanning method, comprised of 64 separate scans, provides a detailed cross-sectional view of the blood vessel wall based on the amount and volume of blockage present. Its ability to differentiate plaque density makes it particularly useful in distinguishing between stable plaque and unstable plaque.

"The latest MDCT scanners have made it possible to detect noncalcified plaque," explains Clouse. "However, due to a number of technical and physiologic factors, accurate and reproducible measurements of this plaque was difficult and time-consuming. We, therefore, developed a new technique that would overcome these obstacles."

The researchers analyzed 41 normal and eight abnormal arterial cross sections with noncalcified plaque selected from 10 patients undergoing MDCTA for percentage of stenosis and plaque volume using a voxel analysis technique, in which density values are measured to identify the boundaries between epicardial fat and the outer arterial wall and between the inner wall and the lumen.

"Voxel analysis estimates the volume of plaque in a blood vessel based on a range of volumetric densities," explains Clouse. Within the selected volume, the number of voxels having a density within the range of plaque is established, from which the volume of plaque is then estimated. (In CT scans, voxel values are Hounsfield units, which give the opacity of material to X-rays.) The detailed measurements -- nearly 2,300 in total -- provided physicians with a detailed picture of the coronary arteries and surrounding areas.

"By plotting a voxel histogram across the arterial wall, we were able to measure the amount of plaque, as well as the narrowing of the artery," explains Clouse. Importantly, he notes, the technique additionally defines the outer boundary of the adventitia, the connective tissue surrounding the artery. Though considered extraneous to the artery, the adventitia appears to play a critical role in the disease process.

"Using this new method, we hope to be able to be able to better assess the effects of medication treatment and lifestyle interventions in treating atherosclerosis," says Clouse, who as a member of a team of clinical investigators will study the effects of lifestyle intervention (diet, exercise and omega-3 fatty acid supplement) or salsalate medication compared to placebo on coronary artery calcification as assessed by MDCTA. (See description below.)

Coauthors of the AJR report include Vassilios Raptopoulos, Adeel Sabir, Norihiko Yoshimura, and Shezhang Lin of BIDMC's Department of Radiology Francine Welty and Pedro Martinez-Clark of BIDMC's Department of Cardiology and Jacqueline Buros of the PERFUSE Core Laboratory and Data Coordinating Center, Harvard Medical School.

Funded by the National Heart, Lung and Blood Institute (NHLB), the trial will be conducted at Beth Israel Deaconess Medical Center, Joslin Diabetes Center and Tufts New England Medical Center. Leading the TINSAL-CVD study are Allison Goldfine, MD, Director of Clinical Research at Joslin Diabetes Center Steven Shoelson, MD, PhD, of Joslin Diabetes Center Ernest Schaefer, MD, of The Jean Mayer USDA Human Nutrition Center on Aging at Tufts University BIDMC cardiologist Francine Welty, MD, PhD, and BIDMC Director of Radiology Research Melvin Clouse, MD.

Story Source:

Materials provided by Beth Israel Deaconess Medical Center. Note: Content may be edited for style and length.

Pathophysiology of coronary artery disease

During the past decade, our understanding of the pathophysiology of coronary artery disease (CAD) has undergone a remarkable evolution. We review here how these advances have altered our concepts of and clinical approaches to both the chronic and acute phases of CAD. Previously considered a cholesterol storage disease, we currently view atherosclerosis as an inflammatory disorder. The appreciation of arterial remodeling (compensatory enlargement) has expanded attention beyond stenoses evident by angiography to encompass the biology of nonstenotic plaques. Revascularization effectively relieves ischemia, but we now recognize the need to attend to nonobstructive lesions as well. Aggressive management of modifiable risk factors reduces cardiovascular events and should accompany appropriate revascularization. We now recognize that disruption of plaques that may not produce critical stenoses causes many acute coronary syndromes (ACS). The disrupted plaque represents a "solid-state" stimulus to thrombosis. Alterations in circulating prothrombotic or antifibrinolytic mediators in the "fluid phase" of the blood can also predispose toward ACS. Recent results have established the multiplicity of "high-risk" plaques and the widespread nature of inflammation in patients prone to develop ACS. These findings challenge our traditional view of coronary atherosclerosis as a segmental or localized disease. Thus, treatment of ACS should involve 2 overlapping phases: first, addressing the culprit lesion, and second, aiming at rapid "stabilization" of other plaques that may produce recurrent events. The concept of "interventional cardiology" must expand beyond mechanical revascularization to embrace preventive interventions that forestall future events.


Growing genetic lineage mapping experiments have definitively shown a wide-ranging plasticity of vascular smooth muscle cells (VSMCs) in atherosclerotic plaque and suggested that VSMCs can modulate their phenotypes in response to plaque microenvironment. Here, a multiscale hybrid discrete–continuous (HDC) modeling system is established to investigate the complex role of VSMC phenotypic switching within atherosclerotic lesions. The cellular behaviors of VSMCs and macrophages, including proliferation, migration, phenotypic transformation and necrosis, are determined by cellular automata (CA) rules in discrete model. While the dynamics of plaque microenvironmental factors, such as lipid, extracellular matrix (ECM) and chemokines, are described by continuous reaction–diffusion equations in macroscopy. The simulation results demonstrate how the VSMC activities change the extracellular microenvironment and consequently affect the plaque morphology and stability. The regulation of VSMC phenotypes can affect not only the plaque morphology (necrotic core size and fibrous cap thickness) but also the deposition and distribution of microenvironmental factors (lipoprotein, ECM, and chemokines). In addition, it is found that plaque vulnerability can be inhibited by blocking VSMC transdifferentiation to a macrophage-like state and promoting it to a myofibroblastic phenotype, which suggests that targeting VSMC phenotypic switching could be a potential and promising therapeutic strategy for atherosclerosis.

ESC calls for research into vulnerable plaques

Sophia Antipolis, France: Tuesday 14 June : The European Society of Cardiology (ESC) Working Group of Atherosclerosis and Vascular Biology has published a position paper to raise the profile of vulnerable plaques and the need for greater use of therapies to promote plaque stabilisation. The position paper, published online today in Thrombosis and Haemostasis, is also calling for more research into the causes of plaque rupture, and for the development of better diagnostics and treatments.

“We want more medical professionals to understand the concept that stabilising vulnerable plaques offers a fundamental approach to preventing cardiovascular events,” said Seppo Ylä-Herttuala, chairman of the position paper task force.
Indeed, he added, several statin trials for secondary prevention have reported a reduction in cardiovascular events, and furthermore ant platelet therapies have been shown to have a beneficial effect.

“Introducing stabilisation of vulnerable plaques as part of secondary prevention would offer the opportunity to wipe out half of coronary events,” said Ylä-Herttuala, from University of Eastern Finland (Kuopio, Finland).

“Wide spread stabilization of vulnerable plaques would also have important socio economic implications dramatically reducing the need for invasive treatments,” said Christian Weber, also a member of the working group.

The idea of vulnerable plaques is that not all plaques (the fatty deposits in arterial walls) are equal and that some are particularly prone to rupture and causing cardiovascular events . These plaques are not necessarily the same as those that cause symptoms such as angina. Explaining the concept of vulnerable plaques, Weber, from Ludwig-Maximilians-University (Munich, Germany) said that it is thought that inflammatory cells resulting from ongoing inflammation destabilise the structure of the plaque. “It is believed that they degrade the fibres that make the plaque stable, leading to a greater potential for the plaque to rupture,” he said.

The concept of plaque stabilisation was introduced to explain how acute coronary events could be reduced by lipid lowering therapy without accompanying regression of coronary atherosclerosis seen on angiography.

Part of the motivation for producing the working paper, said Ylä-Herttuala, was to provide general clinicians with greater guidance. “The whole field can be really confusing. After patients have been treated with statins for two or three years family doctors can be really concerned that they see no changes on angiograms. In such cases there’s a danger that they may decide to stop life saving treatment.”

The position paper reviewed the current state of knowledge around unstable plaques exploring the role of inflammation, chemokines, growth factors, platelets, angiogenesis and smoking. Evidence for therapies such as statins, antiplatelet therapies, and antihypertensive treatments were outlined, in addition to reviewing new approaches ,such as the development of drugs targeting the fibrous cap. Detection of unstable plaques through genetic testing, biomarkers and imaging was also explored.

“The single most important advance that would help us to tackle vulnerable plaques would be to have a non invasive imaging tool that would allow us to identify at risk patients before they suffer an event,” said Ylä-Herttuala.

The position paper is also calling for more translational research into imaging, biomarkers and the development of new treatments. “There is a real need to develop treatments specifically for the purpose of stabilising vulnerable plaques. At the moment we only have treatments that were discovered to have a beneficial effect through serendipity,” said Weber.

Thwarting deadly heart blockages with organic nanoparticles

Cardiovascular disease, which kills one Australian every 12 minutes, is caused by a hardening of the arteries due to abnormal deposits of fat and cholesterol (known as plaque) in the inner lining of the artery a process known as atherosclerosis. When plaque deposits rupture, this can cause heart attacks and stroke. But what if the plaque could be prevented from rupturing using microscopic nanoparticles?

That's the potential of exciting new organic nanoparticles first developed in Canada for cancer diagnosis and treatment. Now, researchers at the Centre for Nanoscale BioPhotonics (CNBP) are exploring how these nanoparticles could be used to identify and disarm unstable plaque deposits.

"These particles have been used in detecting and treating tumors, but we suspect they can be used for vascular health, for detection and treatment of atherosclerosis," said Victoria Nankivell, a Ph.D. student at the CNBP partner organization, the South Australian Health and Medical Research Institute, in Adelaide. "There are some unique characteristics of this nanoparticle that make it suitable for targeting key cells in atherosclerosis, such as macrophages, a key cell type found in atherosclerotic plaque."

Macrophages are a type of white blood cell of the immune system that engulfs and digests cellular debris and foreign material, such as microbes. Macrophages, in particular, produce small proteins, known as cytokines, that encourage inflammatory immune responses, enlarging the plaque and making it more likely to rupture.

Once the plaque has ruptured, this leads to blockages in the blood vessels that feed the heart, causing a heart attack or vessels that feed the brain, causing a stroke.

The new nanoparticles, known as porphysomes, are organic nanoparticles invented by Prof Gang Zheng, a partner investigator of the CNBP based at University of Toronto's University Health Network. Used to detect and accurately map cancer tumors, they can also be easily tracked with low-light fluorescence and have large cores which can be loaded with drugs and other agents.

Porphysomes are based on a protein that's found in high density lipoproteins, or HDLs, known as "good cholesterol." HDLs are known to limit the inflammatory processes that underlie atherosclerosis by interrupting plaque creation at several key stages.

Dr. Christina Bursill, CNBP's chief investigator of vascular health based at the University of Adelaide node, and Nankivell's supervisor, had a hunch porphysomes might also have anti-inflammatory effects in atherosclerosis. She started a collaboration with Prof Zheng's group to test out the idea. And she was right.

"We've now shown in culture that porphysomes do have anti-inflammatory effects in atherosclerotic plaques," said Nankivell. "When we stimulate macrophages with an inflammatory stimulus, these particles reduce the inflammatory response in those macrophages.

"We've also shown that the particles can increase the removal of cholesterol from macrophages—that's something that HDL also does," she added. "We don't quite know what it is about the porphysomes that are making it anti-inflammatory, so we want to investigate that further."

Porphysomes can also carry short-lived radioactive nuclides for extremely accurate tracking. Hence, Bursill's team plans use them to detect and track the progression of atherosclerosis in mice, to understand how the nanoparticles have their effect. For this, they are collaborating with the Baker Heart and Diabetes Institute in Melbourne, which has bred experimental mice that can be induced to develop atherosclerosis that closely resembles the plaque instability that leads to plaque rupture in humans.

Plaque presents a double threat

Plaque itself can pose a risk. A piece of plaque can break off and be carried by the bloodstream until it gets stuck. And plaque that narrows an artery may lead to a blood clot (thrombus) that sticks to the blood vessel&rsquos inner wall.

In either case, the artery can be blocked, cutting off blood flow.

If the blocked artery supplies the heart or brain, a heart attack or stroke occurs. If an artery supplying oxygen to the extremities (often the legs) is blocked, gangrene, or tissue death, can result.

Pathogenesis of Atherosclerosis A Review

Copyright: ©2016 Aziz M, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


In this review, we would discuss the chief pathways involved in the pathophysiology of atherosclerosis. We would also highlight the end terminal events of this sequel with due consideration to risk factors, clinical features, diagnosis and treatment. The aim of the review is to get into the fine details of all possible causes and pathophysiologic mechanisms responsible for atherosclerosis so that new treatment modalities can emerge and reduce the morbidity and mortality associated with atherosclerosis.


Atherosclerosis has been derived from a Greek word, Athero meaning gruel [1]. Marchand introduced the term &ldquoatherosclerosis&rdquo describing the assosciation of fatty degeneration and vessel stiffening [2]. It&rsquos the patchy intramural thickening of the subintima. The earliest lesion is the fatty streak. Fatty streak evolve to fibrous plaque and unstable plaque are responsible for clinical events.

Atherosclerosis is marked by atheromas, patchy intimal plaques. Most common location is lumen of medium sized and large arteries. The plaque has cellular component -namely of inflammatory cells, smooth muscle cells, a fibrous component of &ndashconnective tissue and a fat component of lipids. Prominent risk factors of consideration are Hypertension, Diabetes, Dyslipidemia, obesity, sedentary life style, Family history, smoking. Intraplaque rupture, bleeding, thrombosis and stenosis cause symptoms. Diagnosis is clinical and definitive diagnosis is made through Imaging tests. Management plan includes behavior modifications (Physical activity with low caloric diet, rich in fiber component) and main class of drugs used in treatment are antiplatelet drugs and antiatherogenic drugs.

It is the leading cause of morbidity and mortality in the US and western world. In the current era cardiovascular disease (CVD) remains the MCC of death all over the world. In 2008, 17 million deaths were recorded from CVD. More than 3 million of these deaths occurred in people below the age of 60 and could have largely been prevented [3]. There are growing inequalities in the occurrence and outcome of CVD between countries and social classes.


We would discuss the chief pathways involved in the pathophysiology of atherosclerosis. We would also highlight the end terminal events of this sequel with due consideration to risk factors, clinical features, diagnosis and treatment.


Atherosclerosis is a chronic inflammatory disease. Atherosclerosis begins with fatty streak which is a accumulation of lipid laden foam cells in the intimal layer of the artery [4]. Lipid retention is the first step in the pathogenesis of atherosclerosis which is followed by chronic inflammation at susceptible sites in the walls of the major arteries lead to fatty streaks, which then progress to fibroatheromas which are fibrous in nature (Table 1) [5,6].

Description Thrombosis
Nonatherosclerotic intimal lesions
Intimal thickening Normal accumulation of smooth muscle cells (SMCs) in the intima in the absence of lipid or macrophage foam cells. Absent
Intimal xanthoma Superficial accumulation of foam cells without a necrotic core or fibrous cap based on animal and human data, such lesions usually regress. Absent
Progressive atherosclerotic lesions
Pathologic intimal thickening SMC-rich plaque with proteoglycan matrix and focal accumulation of extracellular lipid Absent
Fibrous cap atheroma Early necrosis: focal macrophage infiltration into areas of lipid pools with an overlying fibrous capLate necrosis: loss of matrix and extensive cellular debris with an overlying fibrous cap. Absent
Thin cap fibroatheroma A thin, fibrous cap (< 65 µm) infiltrated by macrophages and lymphocytes with rare or absence of SMCs and a relatively large underlying necrotic core intraplaque hemorrhage/fibrin may be present. Absent
Lesions with acute thrombi
Plaque rupture Fibroatheroma with fibrous cap disruption the luminal thrombus communicates with the underlying necrotic core Occlusive or nonocclusive
Plaque erosion Plaque composition, as above no communication of the thrombus with the necrotic core can occur on a plaque substrate of pathologic intimal thickening or fibroatheroma Usually nonocclusive
Calcified nodule Eruptive (shedding) of calcified nodules with an underlying fibrocalcific plaque with minimal or absence of necrosis Usually nonocclusive
Lesions with healed thrombi
Fibrotic (without calcification) Fibrocalcific (+/- necrotic core) Collagen-rich plaque with significant luminal stenosis lesions may contain large areas of calcification with few inflammatory cells and minimal or absence of necrosis these lesions may represent healed erosions or ruptures Absent

Table 1: Stages of Atherosclerosis: Modified AHA consensus classification based on morphologic descriptions.

Atherosclerosis is a continuous progressive development. Fatty streak develop at 11-12 years and fibrous plaques at 15-30 years (Figure 1, depicts the conversion of Fatty Streak to Fibrous Plaques) [7] and they develop at the same anatomic sites as the fatty streaks making it more evident that fibrous plaques arise from fatty streak. Pathologic intimal thickening leads to fatty streak, leads to fibrous cap atheromas, lead to plaques, finally leading to sudden cardiac death [8,9].

Figure 1: Conversion of fatty streak to Fibrous plaques.

Fatty streaks evolve to atherosclerotic plaques which is composed of three components namely of inflammatory cells, smooth muscle cells, a fibrous component of&ndashconnective tissue and a Fat component of lipids [10].

Endothelial Injury plays the inciting role. Turbulent blood flow leads to endothelial dysfunction, it inhibits production of NO, a potent vasodilator and stimulates production of adhesion molecules which attract inflammatory cells. Other risk factors also contribute to this step. The net result is Monocytes and T cells bind to the endothelial cells and migrate to the subendothelial space. Lipids in the blood, LDL, VLDL bind to endothelial cells and oxidize in the subendothelial space. Monocytes in subendothelial space engulf oxidized LDL and transform to foam cells. This mark the first stage i.e., fatty streak. Macrophages further elaborate proinflammatory cytokines which recruit smooth muscle cells. There is smooth muscle cell replication and increase in dense extracellular matrix. End result lesion is a subendothelial fibrous plaque composed of lipid core surrounded by smooth muscle cells and connective tissue fibers (Figures 2 and 3) [11].

Figure 2: Stages of Atherosclerosis.

Figure 3: Pathway of Atherosclerosis.

There is sequential involvement of arterial layers, intima, then media and finally adventitia. Arterial wall lesions have a central cholesterol rich lipid core surrounded by inflammatory response. Every lesion has lipid accumulation and inflammation. Plaque distorts media/adventitia, increases caliber of arterial lumen and decreases its size simultaneously. New Vasa Vasorum invade diseased intima, cause hemorrhage within arterial wall, leading to intramural hemorrhage and increased fibrous tissue. Rupture of thin fibrous caps leads to thrombosis and healing. Cyclic healing of clinically silent ruptures leads to multiple layer of healed tissue and the end result is sudden cardiac death. Calcium deposits as small aggregates convert later to large nodules in the wall. Erosion of endothelium leads to thrombosis. Increase plaque mass causes stenosis and finally leading to lethal ischemia [12].

There are two types of plaques stable and unstable [13]. Stable plaques regress or are static or they grow slowly. Unstables plaques are complicated by erosion, fissure, rupture and cause stenosis, thrombosis, infarction. Most clinical events result from complications of unstable plaque, hence plaque stabilization can reduce morbidity and mortality associated with atherosclerosis.

Plaque is ruptured by enzymes secreted by activated macrophages in the plaque. Once plaque ruptures, plaque contents get exposed to circulating blood and the end result is thrombosis [14]. The resultant thrombosis may change plaque shape, occlude lumen of blood vessel, may embolise or the plaque contents may embolise. Low risk plaques are more fibrous in content and have low lipids and do not cause 100% blockade while unstable plaques have thick lipid core and thin fibrous cap narrow lumen <50% and tend to rupture unpredictably [15].

The end result of the stenosis caused by the plaques are the Terminal Events-Acute Coronary Syndrome, Myocardial Infarction, Fatal Arrhythmias, Sudden Cardiac death (Figures 4 and 5 depict the terminal events that arise due to stenosis due to plaques) [16].

Figure 4: Steps in terminal events.

Figure 5: Terminal events that arise due to stenosis due to Plaques.

Risk factors

Age, Family history, Male sex, smoking, Diabetes mellitus, hypertension, alcohol, Chlamydia infection, Hyper homocysteinemia, Obesity, Sedentary lifestyle [17].


Elastic and muscular arteries. MC arteries affected are aorta, carotid, coronary and ileofemoral arteries. MC artery to be involved is Aorta. Branch points are the common sites. Proximal coronary arteries are more susceptible [18].

Clinical features

Atherosclerosis is initially asymptomatic [19]. Symptoms develop when lesions impede blood flow. When plaques grow, arterial lumen is reduced causing transient ischemic symptoms, stable exertional angina, intermittent claudication, unstable angina, infarction, ischemic stroke, rest pain in the limbs, aneurysm, arterial dissection, sudden death [20].


Patients with signs and symptoms of ischemia should be evaluated using history, physical examination, fasting lipid profile, plasma glucose and HbA1c. Patients with documented disease at one site should be evaluated at other sites.

CT Angiography, is often used as an initial screening test [21]. Other diagnostic procedures used are catheter based tests-intravascular ultrasonography, angioscopy, plaque thermography, elastography, immunoscintigraphy. Certain serum inflammatory markers CRP, LP associated phospholipase A2 predict cardiovascular events. Other Imaging studies that detect plaque are&ndashAngiography, USG, CIMT, MRI.


Behavior Modifications include a diet rich in fruits, vegetables, fibers with regular physical activity and smoking cessation could help in getting a favourable lipid profile. Drugs to treat Dyslipidemia, hypertension and diabetes are often required. These help in improving endothelial function, reducing inflammation and give a favourable clinical outcome. Additional drugs used are statins, antiplatelet drugs (aspirin, clopidogrel), ACE inhibitors and Beta Blockers. Aspirin is indicated for prevention of coronary atherosclerosis in high risk patients. Clopidogrel is used for patients who are intolerant to aspirin and also for treating ST segment and non ST segment elevation MI. Statins, ACE inhibitors, ARB reduce risk of atherosclerosis with their anti-inflammatory properties. Statins by stabilizing the plaques, play vital role in management of atherosclerosis.

Statins induce changes in plaque tissues, hence are important in causing regression in atherosclerosis (Table 2 discusses the Statins induced changes in plaque tissues) [4,11,18].

1. Alter Plaque Size
2. Alter Cellular Composition/Chemical Composition.
3. Alter Arterial Lesions.
4. Reduce Clinical Consequences/Events.
5. Alter Plaque Chemical Composition.
6. Alter Plaque biological activities centered on inflammation + Cholesterol
7. Decrease risk of clinical events.
8. &darr LDL &&Yuml HDL
9. &darr CVS morbidity/Mortality
10. Retard development of atherosclerotic plaque & cause plaque stabilization.
11. &darr Rate of Plaque development
12. &darr Coronary plaque progression.
13. &darr atheroma volume.
14. &darr Macrophage in Plaque
&darr Lymphocyte in Plaque
&darr Lipid content
&darr Collagen content
&darr Inflammation
&darr Oxidation
&darr Enzyme Proteolytic activity
(&darr MMP-2/MMP-9/COX-2)
&darr Rupture
15. &darr Development of atherosclerotic plaques.
16. Clinical events delayed.
17. Favorable Alteration in composition of advanced plaque.
18. &darr Plaque size.
19. &darr CVD events/&darr Clinical Consequences.
20. Alter Arterial Lesion.

Table 2: Statins induced changes in Plaque tissues.

Fish oil supplements-Omega 3 fatty acids play vital role in creating favourable lipid profile. Vitamins&ndashFolate, vitamin B6 and B 12 treat hyper homocysteinemia which is an important cause of Dyslipidemia.


Atherosclerosis is the leading cause of death in the developed countries. Deep understanding of the causes and underlying mechanism of pathogenesis will help to delineate causes and will help to plan out innovative management. As our knowledge about the pathogenesis of atherosclerosis improves more treatment options will emerge.