A Thrombus in the Wall
Vela Menon, MD
Splendid heart that ne'er missed a beat,
For three score years and eight,
That served all vessels large and small,
Lies betrayed today, By a thrombus in the wall.
The smooth flow of blood through arteries and veins depends to a large extent on an intact and normally functioning vascular endothelium. The endothelium is not a mere passive lining of the vessel’s interior but an active participant in the proper functioning of blood vessels. Cytokines from endothelial cells can constrict or dilate vessels and permit or prevent entry of inflammatory cells into vessel walls. Damaged or dysfunctional endothelial cells allow lipids to enter vessel walls and begin the process of atherosclerosis.
A normally functioning endothelium is the best protection a vessel has against atherosclerosis.
Atherosclerosis is a slow and insidious process that ultimately compromises blood flow in affected vessels. Fatty streaks in the intima of blood vessels are the earliest microscopically visible manifestation of a process that can lead to atherosclerosis. Inflammation around these fatty streaks produces cytokines that cause hypertrophy and hyperplasia of smooth muscle cells and facilitate lipid accumulation. And as lipids accumulate, the localised atherosclerotic plaque expands. Soon fibroblasts come into the picture and encase the lipid core and inflammatory cells around it in a fibrous cap. As the plaque grows further in size, the arterial lumen is narrowed and clinical symptoms can occur.
Inflammation plays a major role in the pathogenesis of atherosclerosis. Inflammation can also change a stable plaque into an unstable one. An unstable plaque is one that has a surface on which platelet thrombi and blood clots can adhere to. These clots dramatically narrow the lumen of affected blood vessels and cause acute ischemic syndromes.
The key to preventing atherosclerosis probably lies in maintaining normal endothelial function. Good control of diabetes, hypertension and lipids are part of this strategy. Reducing vascular inflammation will also reduce endothelial dysfunction.
THE SIGNIFICANCE OF ELEVATED BLOOD CHOLESTEROL
The relationship between elevated blood cholesterol and atherosclerotic vascular disease was evident from the 1930s. Doctors recognised that young people with hereditary xanthomatosis had an increased prevalence of coronary heart disease and myocardial infarctions.
In 1971, epidemiological data from more than 5000 people followed up for fourteen years in the Framingham Heart Study, showed a direct correlation between total cholesterol levels in the blood and the development of ischemic heart disease.
In 1986 the Multiple Risk Factor Intervention Trial (MRFIT) again demonstrated this relationship between increased cholesterol levels and cardiovascular mortality. This trial was published in the Lancet and it showed that increased cardiovascular risk began with total cholesterol levels of 4.68mmol/L (181mg per dL) and above.
LOWERING TOTAL CHOLESTEROL AND LDL CHOLESTEROL
Among the first of the trials to show the benefit of lowering cholesterol levels was the Lipid Research Clinics Primary Prevention Trial published in the Journal of the American Medical Association (JAMA) in 1984. This trial studied 3800 men who had elevated cholesterol levels and other risk factors for coronary artery disease. The study group was given Cholestyramine and diet modification advice. The control group was given placebo and diet modification advice. After 7 years of follow up the results showed that those who took cholestyramine had a reduced risk of cardiovascular disease.
Another study, the Helsinki Heart Study, published in the New England Journal of Medicine (NEJM) in 1987, treated dyslipidemic patients with Gemfibrosil and demonstrated that treated patients had a lowered cardiovascular risk.
In 1995 the results of the West of Scotland Coronary Prevention Study (WOSCOPS) was published in the NEJM. This was a large primary prevention study involving over 6500 men who had elevated LDL cholesterol levels. The study group was given Pravastatin while the control group received placebo. After five years of follow-up the results showed that those who took Pravastatin had a significantly reduced cardiovascular risk.
The Lipid Research Clinic trial, the Helsinki Heart Study and WOSCOPS were primary prevention trials in which the people who were studied did not yet have any clinical evidence of vascular disease. These trials demonstrated that it was possible to delay or prevent atherosclerosis-induced cardiovascular disease by correcting abnormal cholesterol levels.
A publication in 1994 in the Medical Clinics of North America, after a meta-analysis of four large primary prevention trials, suggested that a 24 percent reduction in non-fatal myocardial infarction and a 14 percent reduction in fatal myocardial infarction could be expected because of cholesterol lowering therapy.
A large volume of evidence has also accumulated showing the value of lowering elevated cholesterol levels in those who already have clinically established cardiovascular disease due to atherosclerosis. The Stockholm Ischemic Heart Disease Prevention Trial (1988) showed that the combination of clofibrate and niacin to reduce cholesterol levels was beneficial for those who had already suffered a myocardial infarction.
A large study called the Scandinavian Simvastatin Survival Study, or the 4S study, published in the Lancet in 1994, told us that correcting lipid abnormalities with simvastatin produced a significant reduction in cardiovascular events in those with coronary heart disease.
The Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) studied patients above 70 years of age who had either existing cardiovascular disease or was at increased risk for the same. This study, published in the Lancet 2002, showed that reducing LDL cholesterol in the elderly was useful in protecting against heart attacks.
The Heart Protection Study (Lancet, 2002) treated people having atherosclerotic vascular disease with simvastatin and showed that all such people benefited from cholesterol lowering, irrespective of their baseline cholesterol levels. This study also clearly demonstrated the benefit of lowering cholesterol in those with diabetes, strokes and peripheral arterial disease.
The Anglo Scandinavian Cardiac Outcomes Trial (ASCOT) Lipid Lowering Arm published in the Lancet 2003 showed the value of lowering cholesterol in patients who had hypertension. Here 10mg of Atorvastatin was given to hypertensive patients with elevated total cholesterol. The trial was stopped early because of a significant reduction in cardiovascular risk among those who took atorvastatin.
The Collaborative Atorvastatin Diabetes Study (CARDS) published in the Lancet 2004, looked at the value of lowering LDL cholesterol in diabetic patients with a low dose of atorvastatin, irrespective of their baseline cholesterol levels (the average LDL cholesterol at baseline was around 3mmol/L). The results of the study suggest that LDL lowering with atorvastatin is beneficial for primary prevention of cardiovascular disease in diabetic patients.
Many other studies have used angiograms and vascular ultrasound examinations to show that atherosclerotic plaques inside coronary arteries either reverse in size or slow down their progress when serum LDL cholesterol is lowered. Some of these trials are the Familial Atherosclerosis Treatment Study (FATS) in 1990, the St. Thomas Atherosclerosis Regression Study (STARS) in 1992, the Canadian Coronary Atherosclerosis Intervention Trial in 1994 and the Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) in 2005.
Reducing lipid levels without medication - through ileal bypass surgery - has also been shown to have cardiovascular benefits (Program on Surgical Control of Hyperlipidemia published in the New England Journal of Medicine in 1990). However there is now statistical data to suggest that lowering lipid levels with statins provide a better degree of cardiovascular protection when compared to lowering cholesterol by other means (a report from the American College of Cardiology, 2006)
HOW LOW SHOULD LDL CHOLESTEROL BE?
How low should LDL cholesterol be in order to get the maximum cardiovascular benefit? The National Cholesterol Education Program (third report of the Adult Treatment Panel) in 2001 had given guidelines for the target levels of LDL cholesterol in different groups of patients. The guidelines categorized patients into three broad groups:
a. High risk
b. Moderate risk and
c. Low risk
High risk patients are those with coronary heart disease or coronary equivalents. (Coronary equivalents refer to cerebrovascular disease, peripheral arterial disease or diabetes mellitus). Their LDL cholesterol target is below 2.6mmol/L (100mg/dL).
Moderate risk patients are those with 2 or more cardiovascular risk factors and a ten-year Framingham risk score between 10 and 20 percent. Their LDL cholesterol target is below 3.4mmol (130mg).
Low risk patients are those with no risk factors or who have only one risk factor. Low risk people have a risk score of less than 10 percent on the Framingham scale. For them the LDL cholesterol level target is below 4.1mmol (160mg).
After the publication of these guidelines there were a few large trials that experimented with lowering LDL cholesterol much below the recommended target values.
The Heart Protection Study (HPS) in 2002 showed that reducing LDL cholesterol to as low as 1.7mmol (65mg) with simvastatin 40mg daily was associated with significant cardiovascular benefits. The Pravastatin or Atorvastatin Evaluation and Infection Trial (PROVE-IT) showed us that lowering LDL cholesterol to 1.6mmol/L (62mg) was good. A third trial called Treating to New Targets (TNT) found that reducing LDL cholesterol to 2mmol/L (77mg) was better than keeping it at 2.6mmol (100mg).
From the impressive results of these trials, the NCEP added a modification to their third report of the Adult Treatment Panel. The recommendations now state that in very high risk patients, the target for LDL cholesterol can be an optional 1.8mmol/L (70mg). The guidelines do not give this as a definite recommendation but consider it as an optional goal.
REDUCING TRIGLYCERIDES AND NON-HDL CHOLESTEROL
The euphoria over the ability to reduce cardiovascular mortality through cholesterol reduction was soon dampened by the realisation that reducing LDL cholesterol did not completely reduce cardiovascular mortality. Most trials of cholesterol lowering gave only a thirty to forty percent reduction in cardiovascular mortality.
An analysis of trials where lipid-lowering drugs caused significant triglyceride reduction in addition to LDL cholesterol lowering showed that cardiovascular mortality could be further reduced by lowering triglycerides.
Non-HDL cholesterol includes LDL cholesterol and triglyceride-rich lipoprotein particles like VLDL (Very Low Density Lipoprotein).
Trials like the Helsinki Heart Study (1987), the Bezafibrate Infarction Prevention Study (2000) and the Greek Atorvastatin Coronary Heart Disease Evaluation Study (2002) have all demonstrated the added benefit of lowering triglycerides in addition to LDL-cholesterol.
Guidelines for cardiovascular risk reduction from the National Cholesterol Education Program (NCEP) Adult Treatment Panel 3, recommend that LDL cholesterol reduction be a primary target of therapy while non-HDL cholesterol reduction be considered a secondary target of therapy. Doctors are advised to achieve LDL cholesterol goals first and non-HDL cholesterol goals after that. The target for non-HDL cholesterol is defined as 30mg plus the LDL cholesterol target value. The recommended target level for triglycerides is 150mg (1.7mmol).
INCREASING HDL CHOLESTEROL
HDL cholesterol is a scavenger of excess cholesterol and takes away unwanted cholesterol from muscle, fat, heart and blood vessels. It also mops up the excess cholesterol from other lipoprotein particles like LDL and VLDL. High density lipoprotein cholesterol is part of what is called the reverse cholesterol transport system because its main role is in transporting cholesterol from the periphery to the liver.
The association between cardiovascular disease and low HDL cholesterol was shown in a paper in the American Journal of Medicine (1977) which analysed the epidemiological data from the Framingham Heart Study. Then studies like the Veterans Affairs HDL Intervention Trial in 1999 (VA HIT), the HDL Atherosclerosis Treatment Study in 2001 (HATS) as well as the Helsinki Heart Study in 1987 have all shown that increasing HDL cholesterol levels by medication reduces cardiovascular risk.
With the recognition of a constellation of abnormalities called the Metabolic Syndrome, it is now increasingly clear that low HDL cholesterol is associated with increased cardiovascular risk.
The National Cholesterol Education Program (2001) guidelines recommend that HDL cholesterol for men be above 40mg/dL (1.04mmol/L) and above 50mg/dL (1.3mmol/L) for women. Pharmacological strategies for increasing high density lipoprotein particles include the use of Fibrates, Niacin and inhibitors of the enzyme Cholesterol Ester Transfer Protein (CETP).
Statins generally increase HDL cholesterol modestly by five to ten percent only.
A mention is needed about using CETP inhibitors to raise HDL cholesterol. Torcetrapib is a CETP inhibitor and has been shown to raise HDL cholesterol by 60 percent. However a trial called the ILLUMINATE trial involving this drug was stopped prematurely in 2007 because of an increase in deaths and cardiac events in those who took Torcetrapib.
ARE VERY LOW LEVELS OF CHOLESTEROL SAFE?
There has always been concern about the safety of reducing cholesterol levels in the blood. Articles that appeared before 1994 had suggested that the cardiovascular benefits of lowering cholesterol came at the price of increased non-cardiovascular mortality. It was felt that lowering cholesterol led to increased suicides, violent deaths and cancers.
Studies like PROSPER (2002) and TNT (2005) have shown an increase in non-cardiovascular deaths, mainly due to cancers, in their study patients in whom LDL cholesterol has been reduced. However the authors of these trials believe that these are not significant and are not related to cholesterol lowering. The 4S study, the WOSCOPS trial, and the HPS – all large trials – did not show any significant harm by lowering cholesterol. A meta-analysis of five trials that used statins versus placebo for cholesterol lowering was published in the American Journal of Medicine (June 2001) under the heading “Do statins cause cancer?” The result of the analysis was that there was no increased risk of cancer because of statin use.
CORONARY NARROWING, THE ENDOTHELIUM AND CLINICAL EVENTS
As evidence for the benefits of cholesterol reduction increased, two observations were made that needed explanation. The first was that the severity of coronary luminal narrowing due to atherosclerosis was not always directly related to ischemic cardiac events. There are people with 75 percent coronary narrowing who only have effort angina while there are others who develop a myocardial infarction with coronary narrowing much less than that.
The second puzzling observation was that while lowering cholesterol led to a significant decrease in cardiovascular events, there was no proportionate increase in the affected arterial lumen diameters. Trials have demonstrated a trifling 1 to 2 percent increase in coronary lumen diameter with cholesterol lowering while showing a 30 to 40 percent reduction in cardiac events.
Cholesterol reduction therefore appears to reduce cardiovascular risk in ways that go beyond the size of the atheroma in the vessels.
We now know that correction of lipid abnormalities has a beneficial effect on the vascular endothelium and that this endothelial effect is largely responsible for the reduced cardiovascular risk.
A paper in the American Heart Journal in 1977 had described autopsy findings in the hearts of 17 patients who died of myocardial infarction. The autopsies were done within 48 hours of death. In all of them there were thrombi in the infarct-related vessel lumen. Some of the thrombi were completely occlusive while the others were only partially occlusive. In 16 out of those 17 hearts, there was also evidence of ulceration of the underlying vessel endothelium. Similar findings with thrombi and rupture of atherosclerotic plaques have been reported from other studies too.
The evidence now points to the fact that most myocardial infarctions occur because of atherosclerotic plaque rupture and thrombus formation. This is referred to as atherothrombosis. It is not the size of the atherosclerosis plaque alone that matters. What is probably more important than plaque size is the stability of the plaque and the degree of endothelial dysfunction associated with it.
The normal vascular endothelium does not allow thrombi to form on its surface. Its endothelial cells secrete cytokines like nitric oxide (NO), tissue plasminogen activator (tPA) and plasminogen activator inhibitor (PAI-1). These cytokines are important in maintaining normal endothelial function. Normal endothelium also inhibits the migration of inflammatory cells into the vessel wall by regulating the expression of proteins called adhesion molecules.
Endothelial function has been studied by the intracoronary infusion of acetylcholine. These experimental studies have shown that normal coronary arteries dilate on acetylcholine infusion whereas atherosclerotic segments of coronary arteries constrict.
Dysfunctional vascular endothelium has less nitric oxide, more inhibitor of plasminogen (PAI-1) and increased expression of adhesion molecules. This results in less vasodilatation, increased tendency for thrombi formation and increased likelihood of inflammatory cells entering the vessel wall when compared to normal endothelium.
Elevated cholesterol levels, diabetes mellitus, hypertension, and smoking can all cause endothelial dysfunction and predispose to atherosclerosis. Correcting these risk factors improves endothelial function and thereby reduces the risk of plaque rupture and thrombosis.
ATHEROSCLEROSIS AS AN INFLAMMATORY DISORDER
That atherosclerosis might be a chronic inflammatory disorder is a concept that is finding acceptance. For many years scientists have noted elevated levels of C-reactive protein (CRP) in the blood of patients who have coronary artery disease. CRP is a sensitive and reliable marker of systemic inflammation. Experimental data has shown that elevated CRP is associated with impaired endothelial nitric acid production.
In the Physicians Health Study over 20000 healthy physicians above the age of 40 years were followed up for 14 years. For the first six years, half of them were given low dose aspirin prophylaxis. The group that received aspirin showed a highly significant 40 percent reduction in myocardial infarctions. A small group (about 1000) among these physicians had their baseline CRP estimated and a retrospective analysis was done to see if their baseline CRP had any influence on subsequent cardiovascular events. In an article in the NEJM (April 1997), it was shown that those physicians who had higher CRP levels suffered more myocardial infarctions and strokes. The benefit of aspirin was greater in those who had higher CRP levels in the blood.
The data from the Physicians Health Study therefore suggested that the beneficial effect of aspirin was related not only to its anti-platelet effect but also to its anti-inflammatory effect.
Scientists have long searched for the cause of this inflammation. The presence of microorganisms like Chlamydia pneumoniae and Herpes viruses in atherosclerotic lesions have led to the theory that atherosclerosis is due to chronic infection. The sera of patients with coronary heart disease often have antibodies to Chlamydia pneumoniae or other types of Chlamydia species. Observational studies on animals have shown that infection can be a stimulus to thrombosis on an atherosclerotic plaque. A report in the New England Journal of Medicine (2004) showed an infection-related increase in the risk of myocardial infarction and stroke.
Trials have tested the hypothesis that Chlamydial infection is responsible for atherosclerosis. An editorial in the NEJM in April 2005 informs us that from 2000 to 2005 there have been at least eight published trials testing the efficacy of antibiotics in coronary heart disease.
The results of two such trials were published in the New England Journal of Medicine in 2005 and these give us information about the role of antibiotics in coronary heart disease.
The Pravastatin or Atorvastatin Evaluation and Infection Trial (PROVE-IT) which was primarily a study of cholesterol-lowering therapy in patients with acute coronary syndromes, also looked at the benefit of treating such patients with the antibiotic Gatifloxacin. The study patients were given Gatifloxacin for ten days every month for about two years. The results showed no cardiovascular benefit with Gatifloxacin treatment.
Another trial called The Azithromycin and Coronary Events Study (ACES) treated patients with stable coronary artery disease using 600mg Azithromycin/week for one year and compared the results with placebo treatment. The results showed that there was no reduction in cardiovascular events because of treatment with Azithromycin.
These two trials – PROVE IT and ACES – showed convincingly that antibiotic treatment does not help reduce cardiovascular events. The failure of antibiotics to reduce CV risk suggests that the clinical consequences of atherosclerosis are not due to active bacterial infection. However it does not exclude the possibility that infection may still have a role in initiating atherosclerosis just as the Epstein Barr virus has a role only in initiating certain kinds of cancers and not in the consequences of those cancers.
What then is the clinical significance of the epidemiological evidence for persistent inflammation? The slowly emerging answer to this question is that vascular inflammation is the result of damage to the structure or function of the endothelium. And this endothelial dysfunction and damage is promoted by the hyperglycemia of diabetes, by the elevated blood pressure of hypertension, by dyslipidemia and by the destructive free radicals caused by tobacco smoking.
Aspirin has an anti-inflammatory effect and has been shown to be useful in those with an elevated CRP level (Physicians Health Study). Recent evidence shows that statins too have a beneficial effect by reducing inflammation.
In the PROVE-IT study (mentioned earlier), it was found that whenever statins reduced CRP levels below 2mg per litre, cardiovascular risk was lowered. In the Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) study, a group of people with documented coronary artery narrowing due to atherosclerosis was treated with either Pravastatin or Atorvastatin for 18 months. The results also showed that lowering CRP levels with statins was associated with a decrease in the rate of progression of coronary atheromas.
The PROVE-IT and REVERSAL data emphatically show us that reducing vascular inflammation by the use of statins decreases cardiovascular events and slows the progression of atherosclerosis. This beneficial effect is likely to be related to normalisation of endothelial dysfunction.