Concept One

The media and the adventitia are significantly affected by atherosclerosis, although traditionally it has been primarily thought of as a disease of the intima that may lead to rupture of a plaque that is not very stenotic on angiography. Plaque rupture is likely preceded by rupture of the internal elastic lamina that separates the intima and the media. The joint impact of disease in the intima (high cholesterol) and disease in the media (inflammation) causes rupture that may decompress the intima and may be a predisposing factor to plaque rupture.

Inflammation of the media occurs as the artery expands in the very early stages of atherosclerosis. Factors likely important in plaque rupture, which begin as the disease begins to expand eccentrically, were identified by Fuster and colleagues in research in more than 500 aortic specimens obtained at autopsy. At the site of plaque rupture (American Heart Association Type 6), rupture of the internal elastic lamina very close to the intimal rupture into the lumen and significant inflammation of the media, atrophy and fibrosis were found.

Surprisingly, in plaques that rupture, a large number of new vessels (vasavasorum) were found in the intima, media and adventitia. Fuster thinks the vasavasorum in the inflammation likely comes from the adventitia, and is a reaction to the activity in the intima when it begins to rupture cholesterol. The artery wall reacts from the adventitia as a defense mechanism. Studies by other investigators contend the vasavasorum may originate from the lumen of the artery.

Concept Two

In contrast to the traditional view of the causes of MI and the lipid-rich, vulnerable plaque, Fuster and colleagues found that the numbers of vasavasorum and the rupture of internal elastic lamina, followed by the classic process of plaque rupture were the most important risk factors for plaque rupture. Importantly, the reaction of the adventitia and the media to the deposition of cholesterol in the intima probably has significant implications in terms of the final outcome of an artery leading to an acute coronary syndrome (ACS).

The plaques that lead to a stroke are not vulnerable in the strict definition. In fact, they are very stenotic and fibrotic. MRI data show that the stenotic lesion in the carotid arteries has rather extensive deposition of fat in the blood. The coronary plaque that leads to an infarction is soft and, in contrast, the plaque in the carotid artery that leads to a stroke is very stenotic and fibrotic. The high resistance in systole causes the stenotic plaque in the carotid artery to rupture close to the adventitia, where carotid arteries are very rich in vasavasorum. In fact, it is an intramural hematoma. The coronary plaques that rupture tend to be soft and early stage plaques, because there is insufficient energy to break up plaque that is fibrotic and stenotic, due to the primarily diastolic flow in coronary arteries.

Lipid-rich plaque in the thoracic aorta is the cause of about one-half of cryptogenic strokes, according to MRI studies. Vulnerable plaques with a very high lipid pool are present in coronary arteries, but are too numerous and extensive to be searched for prospectively. In contrast, there are regions like the carotid artery where the at-risk plaque is not vulnerable and does not have much fat. Thus, today the term high-risk plaque is preferred, rather than the vulnerable plaque, depending on the region of interest.

In an attempt to modify plaques with a high lipid content in carotid arteries, Fuster and colleagues treated patients with hypercholesterolemia with two different doses of simvastatin. Strikingly, at 24 months in 17 patients who had an MRI every six months, the stenotic lesion in the carotid artery changed little, but the thickness of the plaque began to decrease after six months, due to fat decreasing near the adventitia and substituted by connective tissue. Interestingly, the fat goes away through the vasavasorum of the adventitia. The vasavasorum is a reaction to the problem and probably takes care of the excess of cholesterol. The stenotic lesion remains the same. So, plaques grow eccentrically and regress eccentrically, while the stenotic lesion remains the same. The decrease in the number of myocardial infarctions in studies of statins probably relates to the change in the composition of the plaque; fat is replaced by connective tissue and becomes more solid.

Concept Three

A high level of tissue factor activity was identified in the lipid-rich pool of so-called vulnerable plaques by Fuster and colleagues in the 1990s. This tissue factor, the first element of the clotting system, was in the same area the macrophages accumulated. Investigators in Germany showed in patients with ACS that many macrophages in the plaque underwent apoptotis. Fuster and colleagues then developed the hypothesis that the macrophage goes into the artery, like the vasavasorum, to remove excess oxidized LDL. But, the macrophage undergoes apoptosis when it becomes overloaded with fat and can no longer function. Fuster and colleagues demonstrated that macrophages, apoptosis and tissue factor are co-localized. In an animal model, they have explored the concept that tissue factor is released during apoptosis.

HDL helps the macrophage release excessive oxidized LDL. Work in a rat model under high cholesterol showed that macrophages invade the thoracic aorta and that a process called reverse cholesterol transport functions to remove the excessive oxidized LDL. Further work showed that when the distal aorta from an animal with low HDL is transplanted into an animal with high HDL, the macrophages go away and the atherosclerotic process regresses. Simultaneously, connective tissue synthesis occurs. This is similar to the situation with statins, which help the artery remove excess oxidized LDL and the process stops when connective tissue synthesis occurs. Tissue factor activity and metalloproteinases completely disappear.

In the rabbit model with atherosclerotic disease in the aorta, the combination of a PPAR agonist and a statin caused complete regression of the atherosclerotic plaque. PPAR has many roles including the activation of HDL through the ABC-1 transporter.

Further study is continuing with PPAR agonists to enhance the HDL phenomenon in humans in plaques of the aorta and carotid arteries.

Concept Four

[Karl Note:  I view high levels of C-reactive protein as a symptom of a problem, not a cause.  In any event, as many drugs and even alternative therapies aim at symptoms, rather than causes, Dr. Gordon suggests that C-Reactive Protein levels can be reduced by at least 50% by using a refined version of the herb, Cat's Claw. This has the commercial name of FYI or For Your Inflammation.  Click here for more.]

Thirty percent of MIs occur in arteries that are very fibrotic with no plaque rupture and no endothelium, because it is torn off by the blood traveling at a high velocity due to the Venturi effect. The concept that a clot occurs because the blood is hyper-coaguable in the presence of diabetes, high cholesterol and cigarette smoking was developed by Fuster and colleagues.

[Karl Note:  Dr. Gordon indicates that "hyper-coaguability" is a serious and real problem -- a large factor in heart disease.  However, he also indicates that the usual "blood thinning" drugs, such as aspirin, Vioxx and Celebrex all cause harmful side-effects, while the oral chelation, with EDTA, reduces blood clotting safely and well.  (Lecture Notes #15)

A significant hyper-coaguable state with thrombus in the chamber is seen in patients with high LDL and high cholesterol. Studies show that either simvastatin or pravastatin significantly decreases thrombogenicity within four weeks. Interestingly, this occurs before cholesterol is reduced in the circulation.

Significant thrombogenicity due to blood exposure to collagen is seen in patients with severe diabetes. Aggressive treatment of the diabetes for one month is associated with increasing thrombogenicity. A linear relation between an increase in thrombogenicity as the blood goes through the chamber and the presence of high tissue factor in the blood was shown using a new assay that simultaneously measures thrombogenicity and tissue factor activity in cigarette smokers and diabetics with hypercholesterolemia. As the thrombogenicity drops, tissue factor activity also drops. The high level of tissue factor activity returned to normal when the risk factors were modified in patients with diabetes, hyperlipidemia, and who were smokers.

Fuster and colleagues believe that vesicles found by electro-microscopy are pieces of monocytes in the circulating blood that have been activated and are apoptotic, and that they release tissue factor.

Monocytes isolated from humans with the risk factors of hyperlipidemia, diabetes or smoking, are significantly enhanced and become apoptotic in the presence of agonists, like tissue necrotic factor. Vesicles that link the monocytes with the platelet are released. Tissue factor activates the clotting system in the platelet membrane. Then, hypothetically, a clot occurs because of the hyper-coaguable state in an area without endothelium.

These observations led to the development of the concept that in acute coronary syndromes many of the clots occur because of apoptotic phenomena of the vessel wall, leading to tissue factor activity. When the plaque ruptures, it encounters tissue factor. It may be that the process is reversible by enhancing the HDL pathway. It may be that the hyper-coaguable state is the precipitating factor in some settings and in others it is the vessel wall.

C-reactive protein has been a marker of significant cardiovascular events and has been predictive in clinical trials. Fuster thinks that C-reactive protein is a marker of inflammation in the blood; monocytes in the blood and white cells are activated by the risk factors of hyperlipidemia, diabetes and cigarette smoking. They might release interleukins that go into the liver, and there might be C-reactive protein that activates the monocytes in the circulation. The concentrations of C-reactive protein that may cause significant problems are too high to be generated by pockets of macrophages in the vessel wall. This has led to the hypothesis by Fuster that tissue factor activity increases in the blood in the presence of a hyper-coaguable state, with a simultaneous, parallel high level of C-reactive protein. Research is underway to test this hypothesis.

Concept Five

Angiographic studies from Japan have shown that the plaques that grow do so rapidly. It is likely that the clot organized by connective tissue begins as a silent clot, and the sudden awareness of exertional angina is probably due to plaque rupture or a clot on top of connective tissue. The clot is very active in some areas and inactive in others, because a clot attracts monocytes from the circulation and releases tissue factor. This is why atherothrombosis is so common after a first thrombus. Sequential studies showed that clot organization requires 8 weeks, after which time it can be quantified by MRI. Thereafter, the presence of connective tissue makes it impossible to determine whether or not there had been a clot.

Tissue factor pathway inhibitor sufficient to block the entire hyper-coaguable state given over 15 days prevented clotting or lumen narrowing in a pig model after angioplasty of the left anterior descending coronary artery.

Concept Six

The role of rapamycin was elucidated in Fuster's laboratories. It was learned that the genetic alteration of P-27, P-53, and P-57 could lead to cancer of the colon or the breast. They developed a program to find drugs that enhance P-27, an inhibitor of the cell cycle. They found that smooth muscle cells in vitro did not proliferate or migrate under rapamycin, an element in the cyclosporin family. Another experiment in the setting of angioplasty showed that in the coronary arteries of pigs there was a significant clot and proliferation of smooth muscle cells. When rapamycin was given to the pigs, there was no proliferation and the clot dissolved through the native fibrinolytic system. Presently, worldwide about 250 patients have received rapamycin-coated stents, with a restenosis rate of zero. This is an interesting example of moving from the bench to the clinical site in just five years, with a spectacular breakthrough in the process of the restenosis phenomenon.

Summary