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New concepts and paradigms in cardiovascular medicine: the noninvasive management of coronary artery disease

K. Lance Gould, MD

Weatherhead PET Imaging Center for Preventing or Reversing Atherosclerosis
University of Texas Medical School
Houston, Texas

Summary
Introduction
Pathophysiology of coronary events
Endothelial dyfunction
 Cholesterol- lowering trials for stabilizing or
reversing coromary atherosclerosis
Role of low-fat food
How low should cholesterol be? can it be too low
Is the term "Reversal Treatment" apropriate ?
 Limitations of coronary arteriography
and invasive procedurew
New concepts in perfusion imaging
Mortality and myocardial infarction after
revasculariza revascularization procedures
Noninvasive management of coronary
artery disease
Conclusion
References

 Coronary atherosclerosis is a diffuse heterogeneous process that occurs throughout the length of epicardíal coronary arteries. Myocardial infarction and unstable coronary syndromes are caused most commonly by plaque rupture of lipid rich, less severe coronary artery stenoses. Vigorous cholesterol lowering by low fat food and lipid active drugs, control of hypertension, and smoking abstinence stabilize plaque and markedly reduce coronary events and angina pectoris with greater improvement in survival than reported for elective invasive revascularization procedures. The term "regression" or "reversal" of coronary artery disease (CAD) as used clinically incorporates the spectrum of beneficial changes in plaque composition and pathology, modest improvement in anatomic severity, endothelial healing, increased coronary flow and flow capacity, decreased symptoms, and improved survival. Standard coronary arteriography and standard noninvasive diagnostic tests (as commonly used) are inadequate for identifying or assessing severity of diffuse CAD. Newer technology or approaches using noninvasive positron emission tomography (PET), invasive intravascular ultrasound or pressure or flow velocity guide wires provide important new insights into the presence and severity of both segmental and diffuse CAD. Revascularization procedures may be beneficial in selected, restricted circumstances, primarily for 3-vessel disease and reduced left ventricular function and for "hibernating" or "stunned" myocardium. However, the benefits of revascularization procedures on survival in patients with good left ventricular function have not been convincingly documented, with substantive evidence that adverse outcomes outweigh the potential benefits. This collective new knowledge provides the basis for a shift in the management of CAD from an invasive, procedure-oriented viewpoint currently dominant in cardiology toward a noninvasive orientation that views the problem as a graded, continuous, heterogeneously diffuse disease process for which reversal treatment is optimal. Noninvasive management of CAD based on reversal treatment is a valid, safe, effective primary step, but it requires patient and physician knowledge. CAD should be treated immediately at the time of a firm diagnosis by simultaneous, vigorous risk factor management, low fat diet and a station class drug. For control of high-density lipoprotein and triglycerides, other lipid active drugs should be added or substituted for statins if side effects prevent their use. Low fat food and weight control by appropriate caloric carbohydrate restriction are essential for reducing the highly atherogenic postprandial lipid surge that is not affected by statins. This vigorous reversal treatment, with aggressive antianginal and anti-platelet management as needed, should be used in every patient with diagnosed CAD before elective revascularization procedures are considered. In the author's experience, the majority of patients will pursue an effective reversal regimen when it is presented and managed appropriately with strong support by a knowledgeable participating physician providing sustained, intense guidance and pharmacology control. For the minority of patients not responding to vigorous medical treatment or demonstrating progression, coronary arteriography and revascularization procedures are then appropriate.

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Currently the diagnosis and management of coronary artery disease (CAD) focuses on electrocardiographic (ECG) exercise testing, stress perfusion imaging, stress echocardiography or gated blood pool imaging, coronary arteriography, balloon angioplasty, and coronary artery bypass grafting (CABG). Inherent in this approach is a fundamental thinking process that is binary, i.e., an orientation toward "yes or no" decisions as to whether or not the patient has significant disease. This thought process is surgical, growing from the development of CABG, propagated back through the diagnostic evaluation, and reinforced by widespread use of percutaneous transluminal coronary angioplasty (PTCA).

Reflecting this binary mindset, the accuracy of a noninvasive diagnostic test is traditionally describes in terms of sensitivity and specificity in comparison with coronary arteriography. This approach requires a dichotomous classification of patients based on a decision to perform arteriography or not. This binary viewpoint carries over into the interpretation of the arteriogram as having a significant segmental stenosis or not, the cut off commonly being visually estimated = 50% diameter narrowing. Binary thinking then carries over to a traditional choice of invasive therapeutic procedure: PTCA or CABG, or neither. For a paradigm of cardiovascular medicine in which definitive diagnosis and management are primarily based en binary decisions for or against an invasive or surgical procedure, this dichotomous classification of noninvasive test results is appropriate.

However, since 1990, new knowledge about the pathophysiology of coronary atherosclerosis, coronary events, and treatment provides the basis for an entirely different paradigm for cardiovascular medicine1-2; it is based on the following observations, reviewed in detail and referenced subsequently: (1) 85% of myocardial infarctions (Mls) develop at relatively less severely narrowed sites in coronary arteries where lipid~rich plaques rupture, leading to thrombosis and spasm; (2) coronary atherosclerosis is diffuse, and plaque rupture can occur throughout the length of any epicardial coronary artery; (3) coronary atherosclerosis alters endothelial and vasomotor function of the microvasculature, causing altered patterns of perfusion on rest/stress perfusion images as a sign of early coronary atherosclerosis; (4) the diagnostic accuracy of coronary arteriography for diffuse coronary atherosclerosis is poor, as low as 10% compared to intracoronary ultrasound, thereby making arteriography substandard for identifying and quantifying the diffuse disease underlying most clinical events; (5) vigorous cholesterol lowering markedly reduces cardiac events and mortality more than invasive procedures, which do not alter long-term survival or cardiovascular events; and (6) new techniques for interpreting positron emission tomography (PET) perfusion images and absolute flow measurements reflect the presence of diffuse coronary atherosclerosis, endothelial dysfunction, and their changes with vigorous cholesterol lowering-more than is revealed by coronary arteriography.

These observations and associated therapeutic options are no longer compatible with binary, procedure-based decision-making. Coronary atherosclerosis is diffuse, not discrete. Its progression and outcomes arise from diffuse, continuous processes throughout the coronary tree. Quantifying its severity requires graded, Multifaceted, continuous measurements of severity. Its treatment requires graded, multifaceted, therapeutic steps. In this context, the traditional binary thinking process for diagnosis and treatment, focused en segmental stenoses and localized mechanical procedures, is inappropriate. This new knowledge should be the basis for a shift in the clinical thinking process for diagnosis and treatment, from a dichotomous, segmental, mechanical, invasive viewpoint to a noninvasive one oriented toward a graded, continuous, diffuse disease process that is optimally treated medically.

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Pathophysiology of coronary events

The explanation for sudden death, MI, or unstable coronary syndromes following a prolonged silent phase of coronary atherosclerosis is most commonly rupture of an atherosclerotic plaque associated with localized coronary thrombosis and/or spasm (Figure l).3-17 The major determinants of plaque rupture are a relatively large lipid core, a thin cap, and an accumulated macrophage content. None of these pathologic characteristics are related to each other or to severity of luminal stenosis.17

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Fig.1: Schematic of plaque rupture underlying acute
coronary syndromes. (Reproduced with permission from Gould.1)

A large body of evidence has shown that plaque rupture typically occurs at milder stenoses, those of 40%-60% diameter narrowing or less. 3-17 Such mild stenoses typically do not cause symptoms or ischemia on treadmill testing, which, therefore, may not correlate well with future coronary events in the general population of patients with coronary atherosclerosis. 18-24 The younger, lipidrich, less severe plaques with little luminal narrowing are more prone to rupture than older, more scarred, more severe stenoses. Consequently, 65% of stenoses associated with subsequent MI exhibit <50% luminal diameter narrowing, and 85% exhibit <70% diameter narrowing (Figure 2). 3,6,25

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Fig. 2: Severity of coronary artery stenosis at sites of plaque rupture
causing acute myocardial infarction in patients with coronary
arteriogram before and at the time of infartion.
(Reproduced with permission from Circulation25

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,26,27 and these are subject to plaque rupture. Quantitation of focal stenoses en coronary arteriograms does not correlate with risk of plaque rupture or with the cumulative effects of diffuse coronary atherosclerosis, multiple stenoses, or endothelial dysfunction in the context of the maximum perfusion capacity of the integrated arterial/arteriolar vascular system.

Intracoronary ultrasound also demonstrates in vivo the presence of diffuse, extensive coronary atherosclerosis in the absence of segmental stenoses by arteriography.28-38 Thus, either with or without significant or symptomatic segmental coronary artery stenoses, coronary atherosclerosis is a diffuse process of the entire epicardial coronary artery tree subject throughout to the risk of plaque rupture and associated coronary events in the absence of vigorous risk factor management.

Endothelial dyfunction

Functional vasomotor abnormalities of the coronary arteries are observed with either early or advanced coronary atherosclerosis, either with or without hemodynamically significant segmental coronary narrowing.39-66 Risk factors such as smoking, diabetes, hypertension, hypercholesterolemia, hypertriglyceridemia, and coronary atherosclerosis impair epicardial coronary arteries and distal arteriolar vasodilation mediated by endothelium at resting and stress conditions.39-66 This endothelial dysfunction is regionally heterogeneous among different coronary arteries, along the lengths of coronary arteries, and within the microcirculation.45-50. Atherosclerosis of proximal conduit, epicardial, and coronary arteries, even without significant stenosis, is associated with impaired endothelially mediated vasodilation of the distal microcirculation. 42,51-56,62 Thus, the functional, endothelially mediated vasomotor abnormalities of epicardial coronary arteries are also seen in the coronary microcirculation, despite the absence of anatomic atherosclerosis distally in small vessels.

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Cholesterol- lowering trials for stabilizing or reversing coromary atherosclerosis

In recent randomized trials 67-117 listed in Table 1, vigorous cholesterol lowering by a moderate low-fat diet and cholesterol-lowering drugs or intensive lífestyle change stopped progression or caused partial regression of CAD in up to 85% of treated subjects. The anatomic regression in these recent trials was only modest, 3-10% diameter stenosis units, depending on stenosis severity at baseline, but this regression was consistently observed and statistically significant. There was a proportionately larger, major decrease in clinical events-MI, death, CABG, or PTCA-in 30%-85% of the various treatment groups undergoing vigorous cholesterol lowering compared with control groups.

Table 1

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For example, the first of the major statin trials, the Familial Atherosclerosis Treatment Study (FATS), showed a 73% decrease in coronary events over the 2-year treatment period and an 85% decrease in coronary events 6,67,86,93 after the first 6 months.6,67,86,93 FATS utilized double drug therapy, in contrast to monotherapy in most other trials. Furthermore, the combination drugs used in the 2 arms of FATS have recently been shown to decrease the postprandial lipid surge. The size of the postprandial lipid response correlates with progression of disease more than low-density lipoprotein (LDL) cholesterol levels. Monotherapy with a statin, as used in other trials, does not alter the postprandial lipid surge, with a corresponding less dramatic decrease in coronary events.

Other larger trials of statin monotherapy have confirmed substantial decreases in cardiovascular events. The Scandinavian Simvastatin Survival Study (4S) demonstrated a 42% decrease in coronary deaths and a 37% 82,98,111 decrease in cerebrovascular events.82,98,111 In 4S, both men and women, younger and older persons benefited comparably, although other studies have suggested that women respond better than men to lipid lowering.69,82,89,90,112 The pooled pravastatin trials showed a 62% reduction in MI and strokes.95,97,101,110, The West of Scotland Coronary Prevention Study (WOSCOPS)88 showed significant reduction of coronary events in people with elevated cholesterol without known CAD. In all of these studies, PTCA and CABG were also markedly reduced.

The reason for proportionately greater clinical benefit than extent of anatomic regression appears due to plaque stabilization and reduction in the risk of plaque rupture that causes acute unstable coronary syndromes, particularly at sites of relatively mild narrowing in diffusely atheromatous coronary arteries.3-17 FATS showed that twothirds of the occlusions and coronary events occurred at sites of <70% diameter stenosis,6 consistent with the high proportion of coronary events arising from milder stenoses.3-17 More severe stenoses may have caused occlusion but were not associated with MI or death.

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Role of low-fat food

Several methods for lowering cholesterol demonstrate clinical benefits, including very low-fat, low cholesterol diet alone (<10% of calories as fat), moderate low-fat diet combined with one or more cholesterol-lowering drugs, and ileal bypass surgery. Those studies with more vigorous cholesterol lowering of = 35%, double-drug therapy, or very low-fat diets tend to show greater benefit on regression and prevention of events than studies with less vigorous intervention. In recent randomized trials, control groups following a less rigorous American Heart Association diet with 20% of calories as fat showed overall progression of CAD and continuing coronary events.

There is substantial evidence that dietary fat contributes substantially to cardiovascular risk, independent of and in addition to fasting lipid levels. The mechanism of increased risk due to fatty food separate from fasting cholesterol levels appears due to the postprandial lipid surge in ver-y-low-density lipoprotein (VLDL), chylomicron remnants, and triglycerides.118 An abnormally high postprandial triglyceride response predicts the presence of CAD as well as any other lipid fraction, whereas fasting triglycerides are less predictive but remain an important risk factor.118

After a fatty meal, the VLDL, triglycerides, and triglyceride-HDL components immediately rise while HDL falls over a period of 8 hours.119 These elevated lipid fractions are associated with a procoagulatory change in Factor VII:C. Both the postprandial lipid surge and the procoagulatory changes are eliminated by a low-fat meal. The size of the postprandial lipid curve-particularly the small chylomicron remnants and VLDL-and apolipoproteins B-48 and B- 1 00 levels are directly and closely related to arteriographic progression of coronary artery stenoses.120 Young adult sons without manifest heart disease who have fathers with CAD have abnormal postprandial triglyceride responses associated with familiar risk of CAD, independent of other lipid fractions.121

Increased triglyceride levels are also related to increased cardiovascular risk, independently of HDL 118-125 although high triglyceride levels are substantially more predictive of risk in conjunction with low HDL levels, 126-132 particularly in older persons.128,132 Drugs that principally lower triglycerides, such as the fibrates or niacin, slow progression of coronary artery stenoses, reduce coronary events, lower fibrinogen levels, 67,113,114,133,134,135 and improve coronary artery vasomotor response to exercise. 136

Statins alone do not reduce the postprandial surge in triglycerides, VLDL, and chylomicron remnant particles. However, the combination of statins plus niacin135 or statins plus fibrates134 reduces or eliminates the postprandial lipid surge. Current trials of statin monotherapy with <20% calories as dietary fat demonstrate significant, ~50% reduction in cardiovascular risk. However, substantial cardiovascular risk remains due to the postprandial lipid surge, which exposes the coronary arteries to atherogenic material for 8 hours after each meal containing substantial amounts of fat and which persists, unaffected by statins.

A low-fat diet is associated with stabilization or regression of stenoses and with lowering of cardiovascular risk to approximately the same extent as with statins. 68,70 73,75,78,83,85,137-142 However, as with statins, there is substancial remaining risk since fasting lipid levels are not as low as achievable after statins. Therefore, either statin monotherapy or very low-fat diet alone is associated with 50% to 60% remaining cardiovascular risk due to suboptimal lowering of lipids throughout every 24 hours of exposure of the coronary arteries to atherogenic material.
However, double drug therapy-such as niacin plus a statin, fibrates plus a statin, or the combination of a very low-fat diet plus a statin-reduces or eliminates the atherogenic postprandial lipid surge and optimally reduces cholesterol levels throughout every 24 hour period.67,71,113,114,133,134,136 In the author's experience, very low-fat food and statins in combination reduce cardiovascular events by >90%, consistent with the results of FATS with double drug therapy (which also eliminated the postprandial surge). This effect of double drug therapy en the postprandial lipid response was not known at the time of FATS but now explains its remarkable benefit. (Figure 3) summarizes this concept of combining very low fat food with a statin for optimal reduction in cardiovascular events.1

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Fig.3: Schematic showing effects of statins on fasting cholesterol levels
but not on the postprandial lipid surge consisting of very low-density
lipoprotein cholesterol, triglycerides, and chylomicron remnants that are
highly atherogenic. (Reproduced with permission from Gould.1)

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How low should cholesterol be? can it be too low

In the correlation between cardiovascular deaths and cholesterol levels in the 10-year follow-up of 361,662 men screened for the Multiple Risk Factor Intervention Trial (MRFIT) program, mortality decreased continuously and directly related to decreasing cholesterol down to levels of 140 mg/dL79. Meta-analysis of 2 recent trials 143 indicates that 5-year cardiovascular events decrease linearly with decreasing cholesterol levels, without a plateau or loss of benefit at very low cholesterol levels (Figure 4).

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Fig. 4: Relation between cholesterol levels and cardiovascular (CV) events
benefit at the lowest cholesterol levels based on meta-analysis of the
cholesterol and Recurrent Events (CARE) and Post Coronary Artery Bypass
Graft (Post-CABG) studies. (Reproduced with permission from Circulation 143).

In patients with CAD and relatively normal or mildly to moderately elevated cholesterol levels, further cholesterol lowering confers substantial benefit compared with controls.6,67,78-82,86,89,98,104,117,143 In FATS, people with lower LDL had greater regression than those with higher LDL.86 In 4S, the group with lower LDL levels treated with simvastatin had reduced cardiovascular events comparable to those with higher LDL levels.82,98 In LCAS patients with normal or minimally elevated cholesterol, further cholesterol lowering was beneficial, independent of baseline cholesterol levels. 117

Very low cholesterol levels and very low-fat diets do not cause excess moncardiovascular deaths or psychological problems. 144-150 The purported association between low cholesterol and traumatic death or cancer has been shown to be due to pre-existing medical conditions that cause excess deaths and also lower cholesterol, such as depression, alcoholism, gastrointestinal disease, and cancer.144,145,148-150 When these pre-existing conditions are accounted for or removed from the analysis, low cholesterol is not associated with excess noncardiovascular deaths. In the recent large randomized trials, statin treatment did not cause excess noncardiovascular deaths. The risk of significant side effects requiring stopping of treatment was the same for the statins and placebo. 82 Low-fat food is associated with less depression and decreased hostility compared with higher-fat food.146 Very low calorie diets are not associated with adverse psychological reactions. 147
Thus, in patients with CAD and relatively normal cholesterol levels, lowering cholesterol to well below normal ranges has substancial benefits with little risk. The essential major advance derived from these multiple cholesterol-lowering trials is the demonstration of partial regression or no progression by vigorous cholesterol lowering with an associated major decrease in clinical events proportionately larger than might be expected on the basis of the modest anatomic regression observed. Based on these reports and the author's personal experience, achieving lean body mass and a total cholesterol of<140 mg/dL, an LDL of <90 mg/dL, with an HDL of >45 mg/dL by using a very low-fat diet and lipid altering drugs increases to >90% the probability of partial regression or no progression of disease and absence of clinical events. As such, this treatment paradigm might be called a "reversal treatment" for coronary atherosclerosis in that it markedly decreases symptoms and the probability of MI, death, PTCA, or CABG, and is a relatively low-cost alternative to traditional invasive approaches.

Is the term "Reversal Treatment" apropriate ?

In view of the modest changes in anatomic severity of coronary artery stenoses after lipid lowering, the commonly used term "regression" or "reversal" might be questioned. Atherosclerosis in the coronary arterial wall consists of a complex mix of cholesterol deposition, cellular proliferation, inflammation, calcification, functional abnormalities of vasomotion, and platelet interactions. With vigorous cholesterol lowering, lipid content and inflammatory cells in the wall decrease and functional abnormalities improve but cellular and fibrotic elements remain with calcification.13,56,60,151,152

Endothelially mediated vasomotor function is adversely affected within hours after a fatty meal,153,154 associated with the postprandial surge in VLDL, chylomicron remnants, and triglycerides.66,118-125 Abrupt lowering of cholesterol by LDL apheresis improves endothelial function immediately. 155,156 As shown by PET imaging, both resting perfusion defects81 and stress perfusion defects are improved within 6 weeks to 3 months after a successful regimen of cholesterol lowering.81,157

Exercise capacity, perfusion defects, and coronary flow reserve are improved, with decreased angina, within weeks to months after cholesterol lowering, consistent with improved endothelial mediated vasomotor function. 81,104,116,135,153-160 The arterial lumen becomes somewhat larger due in part to functional vasodilation, to diminution of lipids and inflammation, and in part due to structural remodeling of the artery, 36,38,152,161 which, although improved, remains scarred and smaller than normal 56. However, with diminution of lipids and inflammation, plaque stabilization occurs, with a decrease in unstable coronary syndromes and coronary events. These pathologic correlates of coronary events, or lack of events, parallel the clinical observation that progression of stenosis severity on arteriograms is associated with subsequent coronary events, whereas stabilization or partial regression by arteriography is associated with low risk of coronary events.

Thus, the term reversal or regression as used clinically incorporates the spectrum of beneficial changes in plaque composition and pathology, compensatory arterial structural changes, arteriographic severity, vasomotor function, flow capacity, symptoms, and prognosis. Certainly, regression back to normal in all of these processes does not occur. However, the term regression or reversal appropriately characterizes the cumulative benefits seen clinically, i.e., a symptom-free individual at low risk of coronary events with continuing lifelong risk factor modification.

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 Limitations of coronary arteriography and invasive procedurew

The errors in visually interpreted coronary arteriograms are well documented.162,163 Experienced arteriographers characteristically overestimate percent diameter narrowing by 30% to 60%. 162 Even when objectively measured, percent diameter narrowing fails to account for the integrated hemodynamic effects of other stenosis dimensions, multiple stenoses in series, diffuse atherosclerotic narrowing, and endothelially mediated vasomotor dysfunction-all of which have major effects en myocardial perfusion. l

The problem of diffuse CAD is particularly important since it is commonly present but unrecognized. Compared with intravascular ultrasound, the diagnostic sensitivity of visually interpreted coronary arteriograms for identifying diffuse coronary atherosclerosis ranges from as low as 7%34 to 43%, 164-166 with a specificity of 95%. Thus, visual interpretations of coronary arteriograms severely underestimate mild or diffuse coronary atherosclerosis and overestimate severity of >50% diameter narrowing stenosis.

Therefore, standard coronary arteriography, as now visually interpreted in terms of localized percent stenosis, is a poor standard for assessing coronary atherosclerosis and inferior to functional measures of severity that reflect the effects of diffuse disease, multiple stenosis, and endothelially mediated vasomotor function.1 However, coronary arteriography is an important, ingrained part of cardiovascular evaluation that will remain widely used. Since most coronary events arise from early, lipid-rich plaques or diffuse disease without an abnormal lumenogram or hemodynamically significant narrowing, a way of analyzing coronary arteriograms to identify and quantify the extent or severity of diffuse coronary atherosclerosis would be useful. Determining the relative contribution of diffuse and segmental narrowing by coronary arteriography could potentially provide the optimal basis for making decisions about revascularization procedures. In the absence of significant segmental stenoses, mild or diffuse disease identified by coronary arteriography would also provide a definitive diagnosis as the basis for lifelong cholesterol-lowering drugs and risk factor modification, even for patients with normal cholesterol levels.

This diffuse coronary disease without segmental narrowing not only carries a high risk of plaque rupture, it may also have profound hemodynamic effects and cause ischemia. For example, fluid dynamic analysis shows that 3 discrete 30% to 35% diameter stenoses in series have little effect on maximum coronary flow capacity or coronary flow reserve, which is normally about 4 times baseline resting flow. However, a diffuse 30% to 35% narrowing along the length of a coronary artery reduces its flow reserve from a normal of 4 times baseline to only 1.5 to 2 times baseline flow.1

This effect of diffuse disease may be particularly important in determining whether PTCA improves arterial coronary flow capacity or not. For example, a segmental stenosis of 68% diameter stenosis combined with diffuse 35% diameter narrowing completely eliminates coronary flow reserve, or the capacity to increase coronary flow. The coronary flow reserve, or ratio of maximum flow to resting baseline flow, is therefore 1.0. Anatomically successful PTCA of the 68% stenosis in this circumstance will improve flow reserve to only 1.6, still severely reduced, due to the residual effects of the diffuse disease remaining after PTCA. However, regression diffusely along the entire length of the artery and only modest regression of the segmental stenoses, as expected after vigorous cholesterol lowering, will increase flow capacity substantially more than by PTCA1 as well as reducing the risk of plaque rupture and coronary events.

To identify and quantify diffuse coronary artery narrowing more precisely en arteriograms, we have developed a quantitative analysis methodology of the entire coronary arterial tree en calibrated arteriograms that provides complete geometric measurements of all lumen sizes, arterial lengths, localized stenoses, and diffuse narrowing of the coronary arteries.1,26,27 The expected normal size of the coronary arterial lumens for the size of its regional vascular bed in the absence of atherosclerosis is also precisely determined from the tree analysis of the arteriogram. This expected normal lumen size at each point along the length of the artery is then compared to the observed size reduced by diffuse disease. We have shown that in patients with even mild segmental stenoses, the lumen diameters of coronary arteries are diffusely 30% to 50% smaller than what they normally should be for the regional mass served. 26

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New concepts in perfusion imaging

In the context of new knowledge about coronary atherosclerosis, noninvasive testing assumes a pivotal role. Noninvasive diagnostic assessment and follow-up of CAD needs to provide definitive, stand-alone certainty, without attenuation and technical deficiencies, that reflects the continuum of coronary atherosclerosis now shown to be treated best by noninvasive management. The approach here focuses en noninvasive diagnosis and management of CAD based en reversal treatment. From this perspective, the optimal diagnostic test should fulfill the following criteria: (1) be noninvasive, other than an intravenous injection; (2) have high diagnostic accuracy that is definitive and comparable to or better than coronary arteriography for deciding whether or not to embark on lifelong reversal treatment; the test must have accuracy in identifying early or advanced atherosclerosis (sensitivity) and accuracy in identifying normals (specificity) for ruling out significant segmental coronary artery stenoses; (3) have proven ability to show progression or regression of CAD as well as or better than coronary arteriography; (4) have the capacity for quantifying coronary artery function, particularly maximum blood flow capacity in the heart muscle that may be impaired before significant segmental stenoses, ischemia, symptoms, or contractile dysfunction develop; (5) detect early atherosclerosis or dysfunctional coronary arteries due to abnormal endothelial function associated with diffuse atherosclerosis even before coronary flow reserve is impaired; (6) quantify absolute myocardial perfusion and perfusion reserve in mL/min per gram to identify balanced or diffuse 3-vessel disease.

Several new concepts in perfusion imaging provide clinical insights into the pathophysiology of CAD. Our laboratory has developed new ways of using PET scanning to evaluate myocardial perfusion to reflect the recently recognized importance of diffuse atherosclerosis, endothelial dysfunction and stabilization-reversal treatment of CAD.1 The information provided for individual patients from these new approaches to PET perfusion imaging substantially enhances the comprehensive, noninvasive management of coronary disease not possible by any other technology. With current knowledge of coronary pathophysiology and its treatment, the reported calculations of the sensitivity and specificity of PET perfusion imaging compared with coronary arteriography have little meaning or value if the PET perfusion images are interpreted and quantified properly.1

The first of these new concepts in perfusion imaging is that diffuse coronary atherosclerosis causes a graded base to apex, longitudinal perfusion gradient. 1,167 Relative perfusion is best at the base of the heart, lower in mid sections, and lowest at the apex in a continuous graded change. This pattern of abnormal perfusion contrasts with the circumscribed, localized perfusion defects characterizing segmental coronary artery stenoses. The fluid dynamic basis explaining this graded, longitudinal, base to apex perfusion gradient is branch steal, in which relatively less stenotic or nonstenotic coronary arterial branches shunt off flow from the diffusely narrowed major coronary arteries after dipyridamole or adenosine stress.

The second of these new concepts in perfusion imaging is that the endothelial dysfunction of the coronary microcirculation due to atherosclerosis causes abnormal, inhomogeneous resting perfusion that improves after dipyridamole or adenosine stress1 Endothelium produces a variety of vasoactive substances, particularly nitric oxide, that are important for maintaining resting vasomotor tone and resting coronary blood flow. Many vascular insults impair endothelial function including smoking, hypercholesterolemia, hypertension, low HDL, and coronary atherosclerosis. The endothelial dysfunction causes heterogeneous, altered vasomotor tone at resting conditions due to altered nitric oxide production with increased vasoconstriction at rest as well as vasoconstrictive responses to a variety of stimuli that normally cause vasodilation, such as acetylcholine and exercise.

Endothelial dysfunction manifests en PET perfusion imaging as heterogeneously decreased perfusion en the resting image, with a "moth-eaten" appearance or discrete resting perfusion defects that improve, resulting in more homogeneous perfusion, after dipyridamole or adenosine stress. In addition to resting perfusion heterogeneity, severe endothelial dysfunction may reduce coronary flow reserve after adenosine or dipyridamole because the component of increased flow due to flow-sensitive, endothelially mediated vasodilation is lost or reduced1 Endothelial dysfunction associated with atherosclerosis improves with vigorous risk factor management, preceding subsequent anatomic regression.1,168 After beginning vigorous lipid treatment, endothelial healing begins within weeks to months, followed by improved vasomotor tone and improved coronary flow reserve. The resting PET perfusion abnormalities improve, reflecting improved endothelial function, separate from improved stress perfusion defects, reflecting anatomic regression of stenoses.

The third new concept in perfusion imaging is that PET perfusion imaging is as good or better than quantitative coronary arteriography for following progression or regression of CAD. 1,83 Changes in coronary flow are a function of the lumen radius raised to the fourth power (Poiseuille's Law). Therefore, small changes in radii of severe stenoses that are difficult to measure accurately en an arteriogram cause definite, readily apparent effects by perfusion imaging. Perfusion imaging also documents changes in multiple stenoses and changes in lumen size along the length of the artery.

Finally, perfusion depends en endothelially mediated vasomotor function of both epicardial arteries and the microcirculation. Thus, the cumulative anatomic and functional changes associated with progression/regression of the entire coronary vasculature are reflected in the perfusion image. Perfusion imaging by PET, therefore, better recognizes the cumulative anatomic and functional changes occurring with progression/regression, in contrast to the limited information derived from the change recorded as the anatomic luminal narrowing of 1 small segment measured on the arteriogram. The improvernent in perfusion abnormalities en PET images after vigorous cholesterol lowering demonstrates the functional changes in the atherosclerotic coronary arterial tree associated with the modest extent of anatomic regression by arteriography.

In clinical practice and in cholesterol-lowering trials, CAD documented by quantitative coronary arteriography has been the basis for both definitive diagnosis and follow-up of changes in severity of disease. However, reliance on an invasive diagnostic test for noninvasive reversal treatment precludes consideration of a principally noninvasive alternative approach to managing CAD.

For noninvasive diagnosis, cardiac PET accurately detects localized and diffuse CAD and assesses its severity, thereby providing a reliable basis for lifelong reversal treatment. PET identifies which coronary arteries are involved and the quantitative severity of disease, and is accurate in asymptomatic and in symptomatic subjects. For following changes in disease severity, either progression or regression, PET is as good or better than coronary arteriography.1,83 Therefore, noninvasive diagnostic PET imaging has advanced to the accuracy and clinical utility of standard coronary arteriography for the principally noninvasive management of CAD.

However, PET is not widely accessible and is commonly considered to be too expensive. In fact, the total charges for PET studies, which cover costs of establishing and running current PET centers using the rubidium-82 generator for cardiac studies, are comparable to the total charges for single-photon emission computed tomography (SPECT), using thallium or sestimibi. The overall costs of cardiac care are reduced by the use of PET due to fewer coronary arteriograms and revascularization procedures with lower event rates1,169,170

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Mortality and myocardial infarction after revasculariza revascularization procedures

Long-term follow-up in randomized trials of coronary bypass surgery show either limited or no decrease in deaths and Mls.171-179 lnsubsetsofpatientswithreduced left ventricular ejection fraction171-178 and underperfused viable myocardium, revascularization improves survival,1,171,172 but not in patients with normal ejection fractions.173-178 A meta-analysis179 of all trials of bypass surgery found a survival benefit of 17% over controls. The improved survival compared with controls in cholesterol-lowering trials is substantially greater, in the range of 30% to 75%.

In the randomized trial of PTCA, Randomized Intervention Treatment of Angina (RITA 2), deaths and Mls were twice as great in the group undergoing PTCA as in those medically treated.180 In the Duke data base report, PTCA conferred no improvement on survival or decrease in Mls compared with controls.181 In the Asymptomatic Cardiac Ischemia Pilot (ACIP) study, CABG confirmed significant survival benefit, but PTCA did not, in comparison with controls.182 However, in the ACIP study, the medically treated subjects were admittedly undertreated, without either cholesterol-lowering treatment or optimal anti-anginal treatment.182

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Noninvasive management of coronary artery disease

New knowledge about mechanisms and treatment of atherosclerosis interacts with and requires revisions in our use of invasive procedures. From one viewpoint, the current, primarily invasive approach based on coronary arteriography and revascularization procedures is outmoded and inadequate in the face of new clinical algorithms utilizing vigorous lipid and risk factor control as an alternative to invasive procedures for the primary treatment of CAD. As the author of the only textbook en quantifying coronary artery stenosis, my point of view is not intended to negate invasive procedures but to update their application and integrate them into a different, more appropriate role in our evolving concepts of cardiovascular medicine.1

The fundamental issue is the role of invasive arteriographic lumenology and PTCA or CABG of localized segmental stenoses in the management of the diffuse atherosclerotic process in the walls of the coronary arteries.

Conclusion

The principally noninvasive management of CAD based en reversal treatment is not antithetical to invasive procedures. Rather, noninvasive management based en reversal treatment is a valid, safe, effective alternative that requires patient and physician knowledge. Based en automated, objective, quantitative analysis of PET images, before and after vigorous cholesterol lowering, the size and severity of myocardial perfusion abnormalities after dipyridamole stress decrease or improve in patients undergoing intense lifestyle changes and/or treated with cholesterol-lowering drugs-and this compares favorably with an increase or worsening in patients treated with standard anti-anginal therapy alone (Figure 5).

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Fig. 5: Myocardial perfusion by positron emission tomography over a 5-year
period showing progression (upper panel and regression (lower Panel)
(Reprinted with permission from Gould 183)

As summarized in this article, objective data indicate that CAD should be treated immediately at the time of a firm diagnosis by simultaneous, vigorous risk factor management, low-fat food, and a statin class drug. Other lipid-active drugs should be added to control HDL and triglycerides or substituted for statins if side effects prevent their use. Every patient with diagnosed CAD should undergo such vigorous treatment, with aggressive anti-anginal management as needed, before elective revascularization procedures are considered. In the author's experience, even progressive unstable angina frequently responds to the noninvasive approach without ever needing a revascularization procedure with comparable or lower risk of mortality or MI.

In my experience, the majority of patients will pursue an effective reversal regimen when it is presents and managed appropriately with strong support by a knowledgeable participating physician. However, a minority of patients do not respond to vigorous medical treatment or will not alter risk factors, despite predictable future morbidity and mortality. For such patients, coronary arteriography and revascularization procedures may be appropriate, with reversal treatment playing a secondary role. The invasive procedures that are essential should be done with thorough understanding of diffuse discase using quantitative analysis of the entire coronary arteriographic tree integrated with intravascular echocardiography, assessment of flow velocity, and/or pressure measurements that clearly define physiologic severity of segmentar coronary artery stenoses versus diffuse disease as the basis for revascularization procedures in the minority of patients who need them. The majority of patients, however, respond to vigorous risk factor management.

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(Am J Med. 1998; 1 04(6A):2S-1 7S. C 1998 by Excerpta Medica, Inc., with permission)

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