With this conference, I would like to introduce Cyberounds^® members to my colleague and friend, Dr. Lance Gould. With a background in physics, Dr. Gould did the original work defining what a significant coronary obstruction is, first in animals and then in humans. His research not only established criteria for the angiographic assessment of coronary stenoses but also laid the foundation for modern stress myocardial perfusion imaging which is the diagnostic cornerstone of non-invasive coronary artery disease today. Subsequently, he and others have demonstrated the benefits of cholesterol reduction on the presence and severity o f coronary disease. In this issue of Cyberounds^®, he discusses his most recent findings in this very important area.

- Richard W. Smalling, M.D., Ph.D., Cardiovascular Moderator

Overview

This review presents the scientific basis for the comprehensive, non-invasive management of coronary artery disease using definitive, non-invasive, perfusion imaging and vigorous risk factor treatment. Such treatments are designed to stop the progression and/or cause regression of coronary atherosclerosis and stabilize plaque to prevent the clinical events of myocardial infarction, sudden death and unstable coronary syndromes requiring Percutaneous Transluminal Coronary Angioplasty (PTCA) or bypass surgery.

Conservative current estimates suggest that 20% to 40% of middle aged individuals in the United States have coronary heart disease. Most of it is asymptomatic with up to 60% of heart attacks or sudden death occurring without prior warning symptoms sufficient to incur medical evaluation or treatment. Sixty-five percent of myocardial infarctions are caused by stenoses of less than 50% diameter narrowing and 86% of myocardial infarctions occur with stenoses of less than 70% diameter narrowing by preinfarction arteriography.(1),(2) The mechanism of cardiovascular events without prior symptoms is plaque rupture and thrombosis of lipid rich plaque that caused no significant coronary artery narrowing before the acute plaque rupture.(3),(4)

The major determinants of plaque rupture are

1. a large lipid core in the arterial wall
2. a thin, easily-ruptured endothelial lining of the arterial lumen capping the lipid pool and
3. the extent of macrophages in the region of the atheromatous plaque secreting lytic enzymes that foster plaque rupture.

None of these pathologic characteristics are related to each other or to severity of luminal stenosis.(5)

Plaque rupture typically occurs at milder stenoses of 40% to 60% diameter narrowing or less.(1),(2),(3),(4),(5) Such mild stenoses typically do not cause symptoms or ischemia on treadmill testing which, therefore, do not predict future coronary events in the general population of patients with coronary atherosclerosis.(6) The younger, lipid rich, less severe plaques with little lumen narrowing are more prone to rupture than older, more scarred, more severe stenoses.

Quantitative coronary arteriography of the entire coronary vascular tree indicates that patients with segmental coronary artery narrowing, even mild narrowing, have coronary artery lumen diameters that are diffusely 30% to 50% smaller than normals for the size of the regional distal myocardial mass(7) and subject to plaque rupture. Quantification of focal stenoses on coronary arteriograms does not account for the cumulative effects of diffuse coronary atherosclerosis, multiple stenoses, or endothelial dysfunction on the maximum perfusion capacity of the integrated arterial/arteriolar vascular system or for future risk of plaque rupture.

Functional vasomotor abnormalities of the coronary arteries appear with early or advanced coronary atherosclerosis and with or without hemodynamically significant segmental coronary narrowing.(8) Atherosclerosis of proximal, conduit, epicardial, coronary arteries even without significant stenosis is associated with impaired endothelial mediated vasodilation of the distal micro circulation. Thus, the functional, endothelial mediated, vasomotor abnormalities of epicardial coronary arteries are also seen in the coronary micro circulation despite absence of anatomic atherosclerosis distally in small vessels.

In the absence of significant flow-limiting stenoses, endothelial dysfunction is a marker for atherosclerosis that is early, reflecting lipid rich plaques subject to plaque rupture. Consequently, identifying even mild myocardial perfusion defects due to mild stenoses or identifying endothelial dysfunction non-invasively by positron emission tomography (PET) are grounds for reversal treatment. Cholesterol-lowering improves the endothelial mediated dilatory capacity of both coronary arteries and distal arterioles as well as markedly reducing risk of cardiovascular events.

Cholesterol Lowering Drugs For Stabilizing or Reversing Coronary Atherosclerosis

In recent randomized trials,(16),(17),(18),(19),(20),(21),(22),(23),(24),(25) vigorous cholesterol- lowering by moderate low fat diet and cholesterol-lowering drugs (such as the statins, gemfibrozil or niacin), or adopting a very low- fat diet resulted in stopping progression or partial regression of coronary artery disease in up to 85% of treated subjects. The anatomic regression in these recent trials was only modest, 3% to 10% diameter stenosis units depending on stenosis severity at baseline, but was consistently observed and statistically significant. There was a proportionately larger, major decrease in clinical events of myocardial infarction, death, and the need for bypass surgery or balloon angioplasty in 30% to 85% of the treatment groups undergoing vigorous cholesterol lowering compared to control groups.

The first of the major "statin" trials, the Familial Atherosclerosis Treatment Study (FATS) trial,(3),(16) for example, showed a 73% decrease in coronary events over two years treatment and an 85% decrease in coronary events after the first six months. The FATS trial utilized double drug therapy in contrast to monotherapy in most other trials. Combination meds have recently been shown to decrease the post-prandial lipid surge. The size of the post-prandial lipid response correlates with progression of disease more than LDL cholesterol levels. Monotherapy with a statin as used in other trials does not alter the post-prandial lipid surge with a corresponding less dramatic decrease in coronary events.

Other larger trials of monotherapy with a statin have confirmed a substantial decrease in cardiovascular events. The Scandinavian Simvastatin Survival Study(4S) trial using simvastatin showed a 42% decrease in coronary deaths and a 37% decrease in cerebrovascular accidents.(19),(23),(25) Men and women, younger and older persons benefited comparably, confirmed by other studies. The improved survival in 4S was significant after one year of treatment, increasing to 50% reduction in the fifth year. There was a 62% reduction in myocardial infarction and strokes in the pooled Pravastatin Trials.(24) The West of Scotland Coronary Prevention Study (WESCOPS) trial demonstrated reduction of coronary events in people with elevated cholesterol without known coronary heart disease.(21) In all of these studies PTCA and bypass surgery were also markedly reduced.

In these recent randomized trials, control groups following an American Heart Association diet with 20% of calories as fat showed overall progression of coronary artery disease and continuing coronary events. In contrast, patients on diets of less than 10% of calories as fat showed regression or no progression. Dietary fat contributes substantially to cardiovascular risk independent of and in addition to fasting lipid levels. The increased risk from fatty food, separate from fasting cholesterol levels, is correlated with the post-prandial triglyceride and VLDL lipid surge.(26),(27),(28) An abnormally high post-prandial triglyceride and VLDL response predicts the presence of coronary artery disease as well as or better than any other lipid fraction.(28)

After a fatty meal, the triglycerides and VLDL components rise while HDL falls over a period of eight hours.(26),(27),(28) These elevated lipid fractions are associated with pro-coagulation changes. Both the post-prandial lipid surge and the procoagulatory changes are eliminated by a low fat meal. The size of the post-prandial lipid curve, particularly the small chylomicron remnants and VLDL are directly and closely related to arteriographic progression of coronary artery stenoses.(28)

Statins alone do not reduce the post-prandial surge in triglycerides, VLDL and remnant particles. However, the combination of statins plus niacin or statins plus fibrates reduce or eliminate the post- prandial lipid surge.(29) Current trials of statin monotherapy with 20% or higher calories as dietary fat demonstrate significant reduction in cardiovascular risk. However, substantial cardiovascular risk remains because the post-prandial lipid surge, unaffected by statins, persists. Despite statin treatment, a large post-prandial lipid surge exposes the coronary arteries to atherogenic material for eight hours after each meal containing even modest amounts of fat. Therefore, either statin monotherapy or very low fat diet alone is associated with 50-60% remaining cardiovascular risk, as sub-optimal lowering of lipids throughout every 24 hours exposes coronary arteries to atherogenic material.

Double drug therapies such as niacin plus a statin, fibrates plus a statin or the combination of a very low fat diet (10% of calories as fat) plus a statin also reduce or eliminate the atherogenic post- prandial lipid surge and optimally reduce cholesterol throughout the 24-hour period. In the author's experience very low fat food and statins or multiple lipid drugs in combination reduce cardiovascular events by 90% or more, consistent with results of the FATS trial with double drug therapy that eliminates the post-prandial surge. This effect of double drug therapy on the post-prandial lipid response was not known at the time of the FATS trial but now explains its remarkable benefit. Very low cholesterol levels and very low fat diets do not cause excess non-cardiovascular deaths. In fact the opposite occurs--in patients with coronary artery disease and relatively normal cholesterol, lowering cholesterol to well below normal ranges has substantial benefit.(30)

Changes in Myocardial Perfusion and Endothelial Function During Regression/Progression

Lipid-lowering trials that measured arteriographic percent diameter narrowing or absolute minimum diameter for following progression or regression of disease shared several common limitations as follows:

• The degree of regression was anatomically modest, being 5%- 10% diameter stenosis units.
  
  Percent diameter stenosis is poorly related to flow capacity of coronary arteries or coronary flow reserve.
• Progression or regression of coronary artery stenoses may be associated with complex shape changes or remolding in which the integrated hemodynamic effects of percent narrowing, absolute arterial lumen area and length are not accounted for by any single geometric dimension such as percent stenosis.
• Quantifying single focal stenoses on coronary arteriograms does not account for multiple stenoses, diffuse atherosclerosis or the associated dynamic vasomotor abnormalities which are frequently present. Therefore it does not reflect the perfusion capacity of the entire integrated coronary arterial tree affected by atherosclerosis. However, coronary flow reserve and maximal myocardial perfusion reflects all the integrated consequences of these changes.

We have demonstrated that vigorous cholesterol lowering by dietary fat restriction or cholesterol lowering drugs over a relatively short time of 90 days improves myocardial perfusion in patients with coronary artery disease before anatomic regression occurs.(18) These observations suggest that lowering cholesterol improves endothelial mediated vasomotor function. The improvement in myocardial perfusion is sustained and marked at five-year follow-up.(20)

Figure 1 shows an example of PET after dipyridamole at baseline (upper row) and after five years as a control (lower row) in right (septal), anterior, left lateral and inferior views. Relative radionuclide uptake is shown in a graded-color scale ranging from maximum activity (100%) in white downward in 5% increments corresponding to the stepped color scale through red, yellow, green, blue and black as minimum activity, shown in the color bars. The final study (lower row) compared to baseline (upper row) shows definite worsening throughout the heart, particularly inferiorly corresponding to progression of three vessel disease by quantitative coronary arteriography.

Thus, progression or regression of coronary artery disease can be followed non-invasively by objective quantification or by qualitative visual interpretation of perfusion abnormalities by rest-dipyridamole PET perfusion imaging. PET reflects the integrated flow capacity of the entire coronary arterial/arteriolar tree affected by single or multiple localized segmental stenoses, diffuse atherosclerosis and associated abnormal vasomotor function. Changes in size and severity of perfusion abnormalities observed by PET are comparable or greater than changes in stenosis severity by coronary arteriography in the same patients.(20)

Figure 2 shows an example of PET after dipyridamole at baseline (upper row) and after five years of lifestyle change (lower row) with the same views and color scale. The inferior perfusion defect becomes visibly less severe with better, more uniform perfusion in the defect and in the rest of the heart corresponding to regression of three vessel disease by quantitative coronary arteriography.

Outcomes of Bypass Surgery and Balloon Dilation Compared to Outcomes After Lipid Lowering

Revascularization procedures are commonly done as the primary therapy for coronary heart disease either with or without symptoms or medical treatment. Long-term follow-up in randomized trials of coronary bypass surgery shows either limited or no decrease in overall risk of myocardial infarction or mortality in patients randomized to initial bypass surgery compared to medical treatment which, in general, did not include vigorous cholesterol lowering.(31) For patients with unstable angina and normal ejection fraction, survival after coronary bypass surgery is significantly worse than for medical management.(32) In a direct randomized trial of bypass surgery, PTCA and medical management of Left Anterior Descending (LAD) stenoses of 80% stenosis or greater, at a three year follow-up there was no difference in myocardial infarction, death or level of angina in the three treatment groups(34) where medical treatment did not include cholesterol lowering. Moreover, in bypass trials, the medically-treated groups did not include systematic cholesterol lowering with its now documented improved survival.

In a meta-analysis of major coronary bypass trials, overall mortality was decreased by 17% in the surgical group compared to the medical group treated largely with anti-anginal drugs without systematic vigorous lowering of cholesterol.(33) By comparison, in the 4S trial of cholesterol lowering, the overall mortality was reduced by 30%.(19),(23) Cardiovascular events were reduced by 42% in the 4S Trial,(19),(23) by 62% in the pooled Pravastatin trials,(24) and by 73% to 85% in the FATS Trial.(16) Therefore, in the large number of patients with coronary heart disease and normal ventricular function, the current predilection for revascularization procedures as primary treatment does not improve and may adversely affect survival whereas cholesterol lowering dramatically reduces infarction and mortality.

In contrast to 25 or more randomized trials of cholesterol lowering, there are no randomized trials of PTCA versus medical management. Outcomes after PTCA compared to medical management in non-randomized patients show no statistically significant differences in mortality even for severe three vessel disease with severe proximal LAD narrowing.(35)

The reason for lack of improved survival after revascularization procedures in patients with abnormal ventricular function is that these procedures do not alter the basic atherosclerotic process occurring throughout the coronary artery. Plaque rupture and coronary events therefore continue in the absence of a vigorous reversal program. Since revascularization procedures do not reduce risk of myocardial infarction or mortality in patients with normal ventricular function, the argument frequently given for a revascularization procedure "to prevent a heart attack or dying" is fundamentally incorrect. The literature indicates that the best treatment for preventing heart attack and death due to coronary artery disease is reversal treatment with vigorous cholesterol lowering.

For patients with normal ejection fraction, severe three-vessel coronary artery disease is not associated with any worse outcome than mild three-vessel disease. Severe stenoses that progress to occlusion commonly cause no cardiac event because slow closure allows enough time for collateral development to occur, as shown by the FATS Trial. Most coronary events, 85%, arise from milder lipid rich plaque that are not flow limiting and cause no symptoms or ischemia.(1),(2) The major factors causing plaque rupture - size of lipid core, cap thickness and macrophage content are unrelated to each other or to severity of stenosis.(1),(2),(3),(4),(5)

Conclusion

The comprehensive non-invasive management of coronary artery disease is a valid, effective alternative to revascularization procedures in most patients. In this non-invasive approach, non- invasive PET replaces standard stress testing and coronary arteriography, while vigorous risk factor treatment replaces PTCA and bypass surgery. This synthesis of current medical literature into the comprehensive, principally non-invasive management of vascular and coronary heart disease is scientifically well-grounded and clinically applicable, as demonstrated by the author's personal clinical practice as example beyond academic conjecture. This approach is as rational, clinically feasible and better validated than current more invasive practice paradigms and, in an age of economic concern, reduces costs of cardiovascular care by over 35%.(25)